dosage form final

lect. 14

Challenges to Oral Absorption: The GI Route Factors to Consider: • Acid stability - Enteric coating • Solubility* - Enhance active's solubilization • Permeability* - Use of permeation enhancers • Gut and 1st Pass enzyme stability - Modified release dosage forms - Adjuvants (enzyme inhibitors) The SDF (solid dosage form) addresses all factors of the GI system: • gastric emptying • pH, enzymes, bile, etc. • motility • physiology (S, D, J, I, C) • regional absorption • surface area • digestion • lymphatics ...as well as dietary and other considerations: • dietary factors • pathologies • concurrent medications Essentially, only dissolved drugs are absorbed Dissolution may be rate limiting to absorption - The basis of IVIVC per USP and FDA guidelines Circumstances may require specific release rates (Kd) - Overcome (saturate) local or 1st pass enzymes - regional absorption Variety of controlled release: Immediate, Delayed, Sustained, Pulsatile... ...Releasing Capsules - Hard Gelatin Capsules; Soft Gels - Liquid filled Hard Gels; Enrobed tablets • Tablets - Coated (sugar; film; enteric; compression coated) - Molded tablets (e.g., cylindrical triturates) - Fast dissolve (lyophile discs) - Effervescent based tablets • Others: - Sachets... powders within a paper pouch (peds= put powder in applesauce) - Wafer bars... similar to a breakfast / sports bar - Pellets... small round or cylindrical beads - Pills... small round SDF - Troches... drug in a lozenge history: Gelatin capsule invented in 1834 - Masked unpleasant taste and odors - Individually dropper (liquid) filled; sealed with gelatin solution drop • Hard gelatin capsule patented in 1846 • Use of capsules / encapsulation increased in early 1900's - Extemporaneous compounding (manual filling) of powders into capsules - First appeared in USP XII, in 1942 • Manual filling relatively uncommon now but still performed - Discontinuation of products by manufacturers - Ease of capsule swallowing vs. that of tablets - Improved compliance by combining meds - Participation in clinical trial protocols [speed to clinic and for blinding] Hard Gelatin Capsules Description • Composition - Main component is gelatin from hydrolyzed collagen • Type A, B gelatin: A = acid hydrolyzed; B = base hydrolyzed • Gelatin is sourced from animals (hides/bones/skin) so consider: - Raw animal source must be BSE/TSE free - Strict vegans - Ethnic/religious groups with dietary laws - Other components: opacifying agents (TiO2), colorants (dyes), plasticizers (glycerin, sorbital), preservatives (SO2, parabens) • Terminology - Capsule "Body" is initially filled with powder - Capsule "Cap" closes over and locks onto body - Capsule band seals closure to prevent tampering / adulteration • Size Nomenclature - Size 5 is smallest capsule: 130µL ~ 100mg fill wt - Size 000 is largest capsule: 1.4mL ~ 1gram fill wt - Sizes 1 and 0 more common Most capsules are at intermediate sizes: • Avoids difficulty swallowing horse pills • Avoids difficulty of handling very small capsules Hard Gelatin Capsules Capsule Anatomy 1. Tapered rim prevents faulty joining 2. Indentation for pre-closed position prior to filling 3. Major groove locks cap to body after filling and closure Hard Gelatin Capsules Advantages • Patient compliance / acceptability - Ease of swallowing - Masking of unpleasant taste, odors • Reproducibility - During manufacturing and in disintegration performance • Formulation flexibility... diverse fill materials - Powders, granule, beads, pellets, small tablets - Semisolids, molten components, liquids - Simple formulation, with fewer components than tablets • Useful for clinical trials - Rapid path to the clinic from point of drug discovery - Ease of blinding in Placebo or Active control trials (e.g., overencapsulation of tablets) Hard Gelatin Capsules Disadvantages • Manufacturing - Slow production speed at ~ 140k/hr - Limited number of capsule (raw material) suppliers - Generally requires individual blister packaging • Formulation Issues - QC on fill weights is difficult if powder has poor flow properties - Segregation of active in powder blends possible: variable assay - Stability issues with moisture (e.g., moisture uptake/loss between gelatin capsule and contents) • Occasional difficulty swallowing in the elderly - Capsules may stick to the esophagus after swallowing - Soluble / salt drugs are very irritating when opened on esophagus - Advise patient to swallow with half cup of water while standing Powder Flow =critical Five factors affect powder flow • Particle size - Optimal size ~ 100 micron - Homogeneity is good but dusty "fines" can aid as a glidant • Particle density - Dense powder particles have better flow • Moisture content - Moist powder leads to cohesion and poor flow - Dry powder may lead to static charge and irregular flow - Environmental/climate humidity may affect moisture content • Particle shape - Round is optimal - Elongated, rod shaped or flat particles tend to pack • Particle surface roughness - Rough surfaces... impair flow - Glidant excipients (including dusty 'fines') fill in rough edges Measuring Powder Flow • Angle of repose - Steep angles represent poor flow > 40 degrees very poor flow < 25 degrees excellent flow • Tap Density for Compressibility Index From Bulk & Tap densities: [(T-B)/T]x100% The more compressible, the poorer the flow: [(0.6 -0.3)/0.3]x100% = 50% compressible [(0.6-0.59)/0.6]x100% = 2% compressible • Orifice "Flodex" device (pictured) - Increase hole size until flow occurs The smaller hole = better flow Rathole Index proportional to poor flow Capsule Formulations and Manufacturing • Formulations: - Adequate flow properties of powder blend - Low segregation potential - Cohesiveness of tamped plug - Low adhesion to equipment (tamping pins) - Good chemical and physical stability - Good disintegration and subsequent dissolution - Accommodate ease of dosing; identification; brand loyalty • Manufacturing - Hand-filling capsules (~100/hr) - Manual filling with a device (~1000/hr) - Small scale filling machine (~25,000/hr) - Production scale filling machine (> 100,000/hr) • GMP Considerations (21CFR211) - Assure: safety, identity, strength-potency, purity and quality... Required for all pharmaceuticals Categories of Capsule Excipients • Fillers (diluents) - Function: bulk up fill; impart cohesiveness*; enhance flow - Examples: starch, lactose, dicalcium phosphate - Composition: 25 - 75% of fill wt. • Disintegrants - Function: swelling action to enhance disintegration - Examples: sodium starch glycolate (SSG), crospovidone (XPVP) - Composition: 4 - 8 % • Glidants and Lubricants - Function: increase powder fluidity and reduces adhesion* - Examples: colloidal silica dioxide, magnesium stearate - Composition: 0.25 - 1 % • Capsule and external components - Capsule source (animal†, vegetable, polymer, etc) and colorants - Polish aids (carnauba wax, EtOH), inks (multiple ingredients) • Composition: << 0.1% *Cohesion = material sticks better to itself (tamped plug) Adhesion = material sticks better to other materials (to tamping pins) †Avoid BSE / TSE contamination (source herd certified BSE free) Take Home Points • Understand Capsule nomenclature / size info - Capsule body, cap, band - Sizes: 000, 00, 0, 1... 5 (large to small) • Basic Composition - Main component is animal derived gelatin • Potential BSE/TSE risk • Consider: Strict Vegans; Ethnic/religious diet restrictions • Be ready and capable to manually fill - Address compliance in elderly or peds... - Clinical studies, other reasons - Consider powder segregation during encapsulation • Stability concerns - Moisture uptake/loss: brittle capsules - Ensure proper packaging / storage conditions -identity (make sure right API in there) is likely a critical attribute in release testing of a new batch of capsules vs not for stability testing -powder particle size and flow is NOT likely a critical attribute in release testing of a new batch of capsules b/c won't need to open back up appearance is likely a critical attribute in release testing of a new batch of capsules tamper resistance is NOT likely a critical attribute in release testing of a new batch of capsules= we're not doing tamper resistance bc it doesn't affect purity, etc. assay is likely a critical attribute in release testing of a new batch of capsules (ex: if say have 100mg, make sure 100mg in there) one year stability results is NOT likely a critical attribute in release testing of a new batch of capsules release Testing tests materials for identity, potency, impurities, physical properties and safety under cGMP compliance.

Lect. 5

Common Routes of Drug Administration • Oral • Buccal and sublingual • Subcutaneous • Intramuscular • Intravenous • Topical • Transdermal • Ocular • Otic • Vaginal • Rectal • Respiratory or inhalation • Nasal • Intrathecal NOTE: Most of these routes of administration can be used for both local and systemic delivery. Choosing a Route of Administration • Some drugs must be delivered by particular routes. • Route fundamentally affects onset and duration of drug activity. • Often many forms of a drug are produced, that are suitable for different routes of administration • Ultimate choice of route of administration depends on: - Desired onset and duration of drug effect. - Patient's compliance and discomfort, etc. - Disease state. Invasive routes of administration physically compromise a barrier. - IV, SC, IM= NOT anal • Non-invasive routes of administration require the drug molecule to cross at least one cellular barrier. - Oral - Nasal - Pulmonary - Transdermal - Etc. Broad classification of routes of administration: - TOPICAL: For local effect, drug applied at desired site of action. ex: steroid injection into knee counts too here - ENTERAL: For systemic effect, drug given via digestive tract. • Includes oral, buccal and rectal. - PARENTERAL: For systemic delivery, drug given through routes other than GI tract. • Commonly refers to injections (IV, IM, SC). • Includes inhalation. • FDA recognizes 112 routes of administration Ultimate Goal: To have the drug reach the site of action in a concentration which produces a pharmacological effect. • No matter how the drug is given (other than IV) it must pass through at least one biological membrane before it reaches the site of action. • Most dosage forms are solid or semisolid, and the drug must first be released before it can be absorbed. - In many cases, disintegration or deagreggation will facilitate drug going into solution. Advantages of the Oral Route • CONVENIENT - Portable, no pain, easy to take. • CHEAP - No need to sterilize (but must be hygienic of course), compact, multi-dose bottles, automated machines produce tablets in large quantities. • VARIETY - Fast release tablets, capsules, enteric coated, layered tablets, slow release, suspensions, mixtures. Disadvantages of the Oral Route • SOMETIMES INEFFICIENT - High dose or low solubility drugs may suffer poor availability. • UNSUITABLE DRUG - Proteins and macromolecules are either too big, highly charged, or degraded by the environment in the GI tract. • FIRST-PASS EFFECT - Drugs absorbed orally are transported to the general circulation via the liver. Thus drugs which are extensively metabolized will be metabolized in the liver during absorption. FOOD - Food and GI motility can effect drug absorption. Often patient instructions include a direction to take with food or take on an empty stomach. • LOCAL EFFECT - Antibiotics may kill normal gut flora and allow overgrowth of fungal varieties. Thus, antifungal agent may be included with an antibiotic. • UNCONSCIOUS PATIENT - Patient must be able to swallow solid dosage forms. Liquids may be given by tube. Oral Administration of Proteins and Polypeptides • Shortcomings DO NOT negate popularity. - The non-ideal route, is favored because it is preferred by patient compliance. • Most proteins are lost due to pre-systemic metabolism or in the "First Pass Effect." • GI absorption of macromolecules is minimal due to solubility and permeability hurdles (molecular size). • Facilitated absorption design cultivates some risks at mucosal and vascular surfaces. Alternate Routes to Oral Administration for Proteins and Macromolecules: Route Dissolution Solubility Permeability Rectal Marginal Amphiphilic Excellent Topical Poor Lipophilic Limited Parenteral Excellent Hydrophilic Excellent Respiratory Good Hydrophilic Good Nasal Good Amphiphilic Excellent Ophthalmic/ Otic Transient Hydrophilic Good Parenteral Routes • Includes: - intravenous (IV) - subcutaneous (SC) - intramuscular (IM) • Drugs may be given into a peripheral vein over 1 to 2 minutes or longer by infusion. • Rapid injections are used to treat epileptic seizures, acute asthma, or cardiac arrhythmias. Intravenous Route (IV) • Advantages: - Rapid - A quick response is possible. - Total dose - The whole dose is delivered to the blood stream. Large doses can be given. - Veins are relatively insensitive to irritation by irritant drugs at higher concentration. • Disadvantages: - Suitable vein may be difficult to find. - Because of the rapid response, toxicity can be a problem. - Requires trained personnel. - Expensive - Sterility, pyrogen testing and larger volume of solvent means greater cost. Subcutaneous Route (SC) • Advantages: - Can be given by patient, e.g. insulin. - Absorption slow but usually complete, and improved by massage or heat. • Disadvantages: - Can be painful. - Irritant drugs can cause local tissue damage. - Maximum of 2 mL injection thus often small doses limit use. Intramuscular Route (IM) • Advantages: - Larger volume can be given by IM than SC. - A depot or sustained release effect is possible with IM injections. • Disadvantages: - Trained personnel required for injections. The site of injection will influence the absorption, generally the deltoid muscle is the best site. - Absorption is sometimes erratic, especially for poorly soluble drugs. The solvent maybe absorbed faster than the drug causing precipitation of the drug at the site of injection.

Lect. 9

Invasive versus non-invasive delivery • What do we mean by invasive delivery? - Injection with a needle - Breaking / penetrating the skin - Mechanical disruption of the skin • Can you define non-invasive delivery? - Oral is most common - 90% of pharmaceutical products present as tablets, capsules, gelatin capsules - Nasal, pulmonary absorption, transdermal - Common to all - passing across a mucosal or cellular barrier Invasive delivery systems are used for both local delivery and systemic delivery • Systemic delivery systems - When systemic circulation of the drug can be used to efficiently access receptor systems / organs / sites of interest • Localized delivery systems - Targeted delivery of drugs to a particular site within the body - Maximizing concentration of drug at the site of interest and minimizing systemic exposure to the drug - Usually due to systemic toxicity of the drug or poor availability of drug at the site when delivery systemically Invasive delivery systems are used for both immediate release and extended release • Immediate release delivery systems - Injection of a solution formulation designed to release drug immediately - Rapid peak blood level (Cmax) is obtained followed by elimination of drug • Extended release delivery systems - Device or formulation designed to slowly release drug into the blood stream - Therapeutic level of drug is maintained for an extended period of time Invasive delivery systems designed to meet different delivery paradigms • Injectable solutions (IV, SC, IM) - Drug property controlled drug absorption and elimination - Ex: Daily or multi-daily injectable products • Infused solutions (SC, IV) - Pump infusion rate governs injection site input rate (to achieve steady state exposure) - Ex: Most are hospital use products • Complex formulations / depots (SC, IM) - Formulation controls injection site input rate to achieve longer term exposure - Ex: Designed for daily to weekly products Delivery Device and Aids Overview • Pre-filled syringes • Needle Stick Prevention Devices • Reconsitution aids for lyophilized products • Auto-injectors • Needle-free devices • Pens • Pumps • IV devices Auto-Injectors • Definition - PFS based systems that usually are utilized for single, fixed dose therapies (EPO and TNF) • Reusable • Disposable Pens • Definition- Cartridge based systems that usually are utilized for adjustable and multiple dose therapies. (Insulin and Growth Hormone) • Reusable • Disposable Needle Free Injectors • Definition- High pressure systems that utilize very small orifices that produce a fine stream from the formulation which penetrates the skin without use of a needle. Used in both chronic and single dose therapies (Insulin, Growth Hormone, others) • Reusable • Disposable Alternative Devices • Pumps • Micro Needle Arrays • Iontophoresis Devices Injectable systems are more complex and costly than most oral products: What should you be thinking about? What does your patient need to know? • Device considerations - What kind of device? Reusable, disposable - What disposables are required? Needles, catheters - Conditions for handling and storage? • Formulation considerations - Shelf-life stability (expiration date) - In-use stability and handling What do you need to know? • Drug safety - Side effects (injection site reactions), warnings, etc... • Pharmacokinetics - Route of administration (IV, SC, IM) - Pharmacokinetics (how often is injection required?) • Reimbursement - Insurance coverage - Cost of device to patient (disposable or reusable) - Cost of disposables to patient (needles, catheters, sharps container) Devices for immediate release injectables are typically designed to be patient friendly • Vial and syringe is simplest example and sometimes the first presentation to the market / sometimes the only one if a hospital setting is the primary use - Example: Many insulin products, hospital based anesthetic and pain products • Pen injectors are very common for chronically injected products - Examples: insulin, human growth hormone, parathyroid hormone • Needle-free injection systems are in development Pen injection device for immediate release Formulation considerations •Stability at room temperature for 1 month is required •Typically aqueous solution fomulations Device considerations •Disposable or reusable (replacable cartridge)? •Dose titration (dial a dose) •Needle replacement / supply •Possible needle shield. Needle-free injection devices for immediate release products are meant to replicate pen injections and designed to eliminate "injection pain" Formulation considerations •Stability at room temperature for 1 month is required •Typically aqueous solution fomulations Device considerations •Devices sometimes have a loud thump at startup •Dose titration (dial a dose) Devices can also be used to obtain extended release delivery profiles • External pumps - Simplest examples are pumps in hospital settings delivering aqueous solutions via existing IV lines - A patient friendly example for chronic insulin use: MiniMed or Disetronic subcutaneous insulin infusion • Implantable pumps - Example: Viadur, one year Duros (Alza) osmotic pump (leuprolide for prostate cancer) - Example: Synchromed (Medtronic) implantable pump for chronic pain Implanted devices for long term localized drug therapy: Intrathecal administration • Pump is used to obtain high CSF concentrations while maintaining 100-fold lower systemic concentration - Example: Intrathecal Baclofen therapy (Medtronic) using Synchromed pump The most common localized drug injection: Lidocaine in the dentist's office • Local injections used to numb local nerves for minor surgical procedures • The most common anesthetic in use today MiniMed-Medtronic insulin infusion pump delivers basal and bolus insulin in diabetic patients requiring tighter glucose control Formulation considerations -Devices are designed for standard fast-acting insulin formulations •Device considerations -Device is worn like a pager and has a plastic infusion set attached to a subcutaneous catheter -Catheter site is changed every three days -Insulin cartridge is replaced/refilled as needed daily or every few days Duros osmotic pump for delivery up to 12 months [viadur leuprolide acetate implant] •Formulation considerations -Internal volume ~150 µL -Highly concentrated drug solution in DMSO solvent -Pump rate is on the order of microliters per day so DMSO exposure is below ICH guideline daily limit -Stability at 37C for months is required •Device considerations -Titanium tube administered by a trochar / minor surgery - remove through minor incision Complex formulation solutions provide options for extended release products • Intravenous injection of liposomes for targeted delivery to organs / minimizing side effects - Example: Ambisome (Gilead) • Targeted local injection for sustained local action - Example: Lipid systems injected locally for post-surgical pain (DepoDur, Pacira) • SC or IM injection of polymer/liposome/gel systems for systemic delivery of drugs The type of delivery system is governed by 1) duration of action, 2) site of action/medical need, and 3) formulation constraints •Zn Insulin suspension for daily administration •Biodegradable polymers for local administration and systemic delivery= weeks/months •Implantable systems for systemic delivery >3 months Liposomes have been used for targeted delivery of cancer agents to tumors and for minimizing side effects due to systemic toxicity Liposomes are also used to sustain release systemically or at a local injection site • Example: DepoDur is indicated for up to 48 hours sustained pain relief by epidural injection Liposomes are also used to sustain release systemically or at a local injection site • Example: DepoDur is indicated for up to 48 hours sustained pain relief by epidural injection Biodegradable polymer systems have been developed for injection to release drug over weeks to months •PLGA polymer system is commonly used and has been in many medical products for many years •Sutures, devices, now injection formulations •Degradation of the polymer produces lactic acid and glycolic acid which are cleared naturally Chemical structure of PLG copolymer where x represents lactide and y represents glycolide Ratio of hydrophobic to hydrophilic residues (x,y) controls the rate of degradation and release Biodegradable polymer systems are usually presented as microspheres for injection, can be used in gel-forming systems, are also used in implantable polymer systems •PLGA microsphere is produced by an emulsion formation process which incorporates drug •PLGA implant is produced by an extrusion (melting process) •PLGA polymer systems are designed to degrade chemically in the body at 37C •Storage of PLGA systems is typically as a lyophilized formulation which is stored at 2-8C Biodegradable polymer injection system for sustained delivery can increase compliance in a needy population (schizophrenia) Complex formulation solutions also mean an increased complexity for the patient / physician / pharmacist prior to administration •Formulation stability constraints dictate preadministration mixing Collectively the formulation, the manufacturing process, and the container closure system with quality controls is the drug product

Lect. 17

Outer Ear: Auricle (Pinna) • Collects sound • Helps in sound localization • Most efficient in directing high frequency sounds to the eardrum Outer Ear: Auditory Canal • Approximately 1¼ inch in length • "S" shaped • Increases sound pressure at the tympanic membrane by as much as 5-6 dB due to acoustic resonance • Outer 1/3rd cartilage; inner 2/3rds mastoid bone • Lined with cerumen (aka earwax) glands • Cerumen plays important role in protecting eardrum by trapping dust particles, hair and debris Tympanic Membrane • Thin membrane • Vibrates in response to sound • Changes acoustic energy into mechanical energy • Boundary between outer and middle ear • First major barrier to fluid flow Middle Ear: The Ossicular Chain A: Malleus (latin: hammer) B: Incus (latin: anvil) C: Stapes (latin: stirrup) • Ossicles are smallest bones in the body • Act as a lever system, mechanically amplifying the energy • Footplate of stapes enters oval window of the cochlea Middle Ear: Eustachian Tube • Connects the middle ear to the back of the throat (nasopharynx) • Equalizes air pressure, which helps the eardrum to function optimally • Normally closed except during yawning or swallowing • Lined with mucous membrane Two major parts: - Cochlea: • Responsible for hearing • Small, complex spiral organ - Vestibular system: • Responsible for postural balance • 3 semi circular canals and 2 otolithic organs Structures of the Inner Ear: Cochlea • Snail-shaped organ with a fluid-filled channel • Converts mechanical energy into electrical signal Incoming signal vibrates the basilar membrane, which is sensed by hair cells Structures of the Inner Ear: Vestibular System • Three semi-circular canals and two otolithic organs • Canals: Cover all three dimensions; Head rotation moves fluid in a canal, which pushes on a structure called the cupula, which contains hair cells that sense the movement • Otolithic organs: Contain crystals that move during linear head movement; hair cells sense that crystal movement; Most signals from utricle stabilize vision, most signals from saccule control posture Common Ear Diseases: Outer Ear • Otitis externa (aka swimmer's ear) - Inflammation of the pinna and/or ear canal - Can be acute or chronic - Pain (ear is unusually sensitive), hearing reduction - Most often due to a bacterial or fungal infection • Risk of infection increases with prolonged water in the ear or damage to the skin of the ear canal - Inflammation can be a result of only dermatitis or eczema with no microbial infection Treatment for otitis externa - Clean outer ear, dry outer ear, pain management - Antibiotics are effective in combination with cleaning, drying outer ear - Can treat with topical steroid to manage inflammation for dermatitis/eczema (although long-term chronic use can lead to problems) Otitis media (~7M in USA per year) - Inflammation of the middle ear - Fluid buildup is a hallmark - Pain, hearing loss (sometimes permanent) - Often due to infection in the middle ear (but not always) - Often results from a separate infection •For example, a common cold infects the nasopharynx. Eustachian tube swells up and no drainage from middle ear is possible. Bacteria in the middle ear that would usually be drained through the Eustachian tube stay in the middle ear and proliferate. Otitis media - Children are highly prone because of shorter Eustachian tubes that are more horizontal than adults' (adults' slope down ~45 degrees) - Acute or chronic Due to pressure buildup in the middle ear, the eardrum can rupture. In some chronic cases, the rupture doesn't heal and constant discharge out of the ear is seen. Treatment for acute otitis media - Acute otitis media often resolves itself in 2-6 weeks • Infected fluid builds up, eardrum ruptures, drainage, healing - Difficulties with antibiotics • Systemic administration has poor penetration to middle ear • In children, intratympanic injection requires general anesthesia/sedation - Recent recommendations to *not* prescribe systemic antibiotics, just manage pain Treatment for chronic otitis media - Must be diagnosed with eardrum perforation and effusion for at least two weeks - Can install tympanostomy tube • Chronic otitis media with persistent effusion for 6 months (one ear) or 3 months (both ears) • Recurrent acute otitis media: 3 ear infections in 6 months or 4 infections in a year • Persistent Eustachian tube dysfunction • Barotrauma: Especially for prevention of recurrent episodes (e.g., after air travel, hypobaric chamber treatment) - The insertion of tympanostomy tubes is one of the most common surgical procedures performed on children. In the USA, it is the most common reason for a child to undergo a general anesthetic. Accompanied by antibiotic drops for 7 days Common Ear Diseases: Inner Ear • Ménière's Disease/Ménière's Syndrome • Autoimmune Inner Ear Disease • Labyrinthitis • Tinnitus Typical feature: The inner ear is surrounded by bone (labyrinth). Inflammation causes pressure to build and causes an imbalance between endolymph and perilymph. The membrane separating them can rupture. Altered chemical composition and/or pressure can lead to hearing loss, ringing (tinnitus), "fullness" (sensitivity), and/or vertigo. Often crippling acute episodes. Treatment for inner ear disorders - Systemic anti-emetics for nausea, motion sickness drugs or "vestibular dampeners" (anticholinergics, antihistamines, and benzodiazepines - not for chronic use), diuretics for lower fluid retention - Dexamethasone injection into middle ear • Administered in a clinic, local anesthetic needed • Must diffuse through oval or round window into inner ear (poor transmission) • Most drains out immediately through Eustachian tube -Gentamicin (toxic) injection into middle ear • Damage the inner ear on one side on purpose, let the other ear accommodate (result: only half the disease intensity, but patient loses half their hearing) - Surgical ablation - Conditioning exercises • Train inner ear by physical movement exercise Otic Drug Delivery: •The ear is not an effective route for delivering drug to the entire body (limited surface area, limited permeability) •Otic medicine focuses on management of ear diseases •Medication of outer ear is easy (very accessible) •Medication of middle ear is difficult (cut tympanic membrane or dose systemically) •Medication of inner ear is extremely difficult (no practical physical route, practically no effect from systemic administration) Advantages: - Achieve local (ear) effects without systemic side effects - Avoid first-pass metabolism (common in oral) - Allow reasonable residence time for advanced dosage forms (long acting depots, etc.) • Disadvantages: - Have a very limited absorption area - Dose may interfere with hearing - Causes moderate discomfort - May be difficult to dose properly - Systemic absorption is possible (a problem if drug is toxic) otic dosage forms: Multiple simple systems (physical state) and devices, designed for unique physiological delivery: - Simple liquids: aqueous solutions, peroxides, lipophilic solutions, sprays - Emulsions, creams, ointments and other semi-solids (enhance residence time) - Solids and gels (enhance residence time) - Suspensions (enhance residence time) - Implants (enhance residence time) - Polymeric inserts (enhance residence time) - Devices (enhance residence time) The preparation and manufacture of solutions, suspensions and solids for otic (and also opthalmic) requires specific cGMP considerations for: - Sterility - Preservative - Isotonicity - Buffering - Viscosity - Packaging Sterility and Preservation - Otic • Consistent with other sterile products • Solutions and suspensions must be sterilized for safe patient use • Preferable to sterilize O/O (otic/opthalmic) products in their final containers by autoclaving at 121oC for 15 minutes - Sometimes precluded by the thermal instability of the formulation's components • As an alternative, bacterial filtration, ethylene oxide, or radiation sterilization may be used • Preservative is required for multi-dose units Osmolarity and Tonicity in Pharmaceutical Formulations • Osmolarity is a measure of solutes per volume, presented as Osm/L (or Osm/kg for osmolality) • Each ion contributes to total: 2 mol/L NaCl = 4 Osm/L ions • Osmolarity includes all solutes, regardless of permeability • Tonicity relates to the pressure exerted on a cell (semipermeable) membrane due to solutes that can't cross the membrane Tonicity in Pharmaceutical Formulations • Rough estimate of tonicity can be obtained from adding up all of the ions (Na+, Cl-, etc.), but it is possible uncharged molecules could contribute and some charged don't contribute • Isotonic is equal pressure with 0.9% NaCl; cells/body fluids are ~290 mOsm/kg • Dextrose and urea are the main noncontributing osmoles used in a hospital setting (do not contribute to tonicity) • Can have issues if a formulation is hyper- or hypotonic Tonicity in Otic Formulations • Important because osmosis controls the transfer through a semi-permeable membrane at the site of absorption • ALL of the O/O solution components, including the active and inactive ingredients contribute to the osmotic pressure of a solution • In practice, the tonicity values of O/O solutions may comfortably range between 0.6 and 2.0% sodium chloride - Hypertonicity (crenation) and hypotonicity (hemolysis) are most critical for red blood cells, not lacrimal or otic fluids Buffering - Otic • Adjusted to match otic fluids • The pH adjustment by buffering leads to greater dosage form controls: 1. Greater comfort 2. Render the formulation more stable 3. Enhance the aqueous solubility of the drug 4. Enhance the drug's bioavailability (by favoring non-ionized molecular species) 5. Maximize preservative efficacy Viscosity and Thickening Agents - Otic • Control the fluidity of the dosage forms • Instillation of a drop depends on flow from the dispensing tip • The influence of shear is critical to producing a consistent volume • Packaging design and the temperature management of the product and container will ensure a consistent flow and drop formation from a bulk dispenser • The volume of the otic drop is designed to flood the ear canal in an optimal fashion based on bioavailability Otic Delivery Considerations • External ear: Remove excess earwax, dry away water, medicine for external ear infections - Mostly drops in solutions or suspensions - Convenient and inexpensive, but low residence time; increase in viscosity helps • Middle ear: Not accessible for direct application; Injection through tympanic membrane in clinic - Viscosity decreases drainage through Eustachian tube • Inner ear: Drugs from middle ear diffuse in or can administer by dose-device pumps or catheter - Not accessible to systemically administered drugs - No capacity to metabolize drugs Novel Areas of Otic Drug Delivery Systems Research • Colloidal Systems: - In situ activated gel-forming systems are preferred as they can be delivered in drop form with sustained release properties - Colloidal systems including liposomes and nanoparticles have the convenience of a drop, which is able to maintain drug activity at its site of action and is suitable for poorly watersoluble drugs Combinations of Technologies • New research focuses on combining drug delivery technologies for otic drug delivery systems • Developing systems prolong the contact time of the vehicle within the otic canal and also slow down the elimination of the drug • Research in permeation enhancers combined with gel systems to treat middle ear infection without physically disrupting the tympanic membrane • Combination of drug delivery systems could open a new directive for improving results and the therapeutic response of non-efficacious systems

lect. 22 pediatrics

Drug disposition and response is different in children - Body size and expression of metabolizing enzymes/transporters are heterogeneous and dynamic in the pediatric population - Ontogeny of receptor expression and function - The largest deviation from adult pharmacokinetics is observed in the first 12 to 18 months - In older children and adolescents, pharmacokinetic parameters approach adult values and are thus easier to predict - Relevant diseases often differ from adults - Age-appropriate formulations are critical Developmental Changes That Influence Drug Disposition -Acquisition of renal function -Metabolic Capacity -Changes in Body Composition -Changes in Gastrointestinal Function Pediatric drug dosing - Usually weight-based (i.e. mg/kg) OR stratified according to weight bands or age groups - Parenteral dosage forms may require dilution prior to administration to avoid toxicity - Children are often unable to swallow pills or capsules - Palatability of oral liquids - Dosage forms with modified release are not engineered to take into account pediatric GI physiology (i.e. pH) Formulations for Pediatric Patients • Liquid preparations (suspensions, solutions, syrup, drops, powders for reconstitution) • Solid dosage forms (tablets, capsules, granules, sprinkles) • Parenteral (intravenous injections or infusions, subcutaneous injections, intramuscular injections) • Rectal (suppositories) • Transcutaneous delivery systems (transdermal patches) • Opened capsules or crushed tablets - May be mixed with water, juice, or food - Problematic if "homemade" Age, ability to swallow capsules/tablets, and the disease being treated influence formulation selection Age-appropriate pediatric formulations are key to : - Safe and accurate dose administration - Reducing the risk of medication errors - Enhancing medication adherence - Improving therapeutic outcomes in children • Use of inadequate drug formulations in children may lead to: - Difficulty in swallowing conventionally sized tablets - Safety issues with certain excipients that are acceptable to adults - Adherence problems with unpalatable medicines Child-friendly dosage forms need to have a pleasant taste, a convenient dosing schedule, and be easy for children to swallow Historically, most drugs were used off-label in pediatric patients Problems: (1) we don't know the correct dose (2) we don't know if safety profile differs (3) lack of appropriate formulations may deny access and expose children to "homemade" formulations In the past ~ 15 years, thinking and policy has evolved Previously: Children must be protected from clinical research Now: Children must be protected through clinical research Legislation in the U.S. to Stimulate or Require Drug Development* in Pediatric Patients • 2002 - Best Pharmaceuticals for Children Act (BPCA) • 2003 - Pediatric Research Equity Act (PREA) • 2007 - BPCA and PREA reauthorized under the FDA Amendments Act (FDAAA) • 2013 - BPCA and PREA became permanent under the FDA Safety and Innovation Act (FDASIA) * and consequently formulation development Legislation in the U.S. to Stimulate or Require Drug Development in Pediatric Patients -PREA: • Studies are mandatory • Required only for indication under review • Orphan indications exempt • Results must be in labeling BPCA • Studies are voluntary and offer 6 month patent extension • Studies may expand indications • Orphan indications possible • Results must be in labeling Ethical Framework for Studying Drugs in Children • Children should only be enrolled in a clinical trial if the scientific objectives cannot be met by enrolling subjects who can provide informed consent (i.e. adults) • Clinical trial must either (i) have prospect of direct therapeutic benefit to the child or (ii) involve "not greater than minimal risk" • Children should not be placed at a disadvantage after being enrolled in a clinical trial, either through exposure to excessive risks or by failing to get necessary health care Key issues in developing pediatric formulations • Bioavailability/bioequivalence (BA/BE) of the new formulation • Stability of formulation (temperature, reliable drug release) • Impact of crushed tablets/open capsules • Palatability • Ability to achieve target PK parameter associated with efficacy in adults • Convenience PK of altered adult formulations can vary significantly from intact form • Danger of causing toxicity • Possibility of under-dosing • Product quality issues - Stability Crushed tablets/opened capsules versus intact dosage form= dose dump, inc C max and AUC, might also see this with food Statement of the Pediatric Pharmacy Advocacy Group http://www.ppag.org/ For every new chemical entity and currently marketed drug still under patent, with or without safety and effectiveness data in children, where no oral liquid dosage form is available, the manufacturer should be required to provide a formulation that effectively converts an oral solid or intravenous dosage form to an oral solution or suspension dosage form. Ideal oral pediatric dosage form • Tasteless/taste-masked • Minimal excipients • Flexible dosage • Orally dissolvable or easy to swallow • Stable Challenges for Oral Solutions • Solubility • Stability • Taste masking • Selection of excipients Typical ingredients: solubilizers, stabilizers, viscosity builders, sweeteners, colorants, flavors -excipients can affect drug exposure and safety concerns American Academy of Pediatrics has reported problems with many excipients including sulfites, saccharin, benzyl alcohol, propylene glycol, and lactose - Largely based upon anecdotal evidence Propylene Glycol • A solvent and vehicle for IV and orally administered drugs that are insufficiently soluble in water - Oral example: amprenavir, lopinavir - IV example: phenytoin, lorazepam Toxicity • Cardiovascular - Hypotension, bradycardia, widening of the QRS interval • Central Nervous System - CNS depressant effects similar to ethanol - Associated with seizures • Acidosis - Lactic acidosis (metabolized to lactic acid by the liver) • Nephrotoxicity Desired attributes of pediatric formulations • Safe and effective dosage forms that facilitate maximum compliance - Easy to swallow • Children under 12 years of age often have difficulty swallowing capsules and/or chewing tablets - Easy to administer • Multiple daily doses are difficult to administer to school age children • Pediatric formulation can be messy and difficult to administer - Good taste • Bitter drugs are a major cause of difficulty in administering drugs to children - Dose titration • Pediatric drugs are sometimes dosed according to body weight Oral solutions and suspensions • Easy to swallow - Liquid dosage forms are easy for young children and infants to swallow • Easy to administer - Administration can be messy and inaccurate if patient "spits up" - Multiply daily doses may be required • Due to the difficulties of maintaining a polymer coat in a liquid; controlled release formulations are not usually available • Other - Syrups can contain ethanol - Physical and chemical stability can be problematic • The need for cold storage can be inconvenient • Preservatives may be required • Taste - Taste masking often difficult to achieve - Taste masking methods include; flavoring and/or sweetening agents, taste receptor masking methods, high viscosity materials and hyperosmolarity • Inadequate taste masking of very bitter molecules • Dose titration - Very effective for dose titration Chewable tablets • Easy to swallow - Dosage form is suitable for relatively young children - Dosage not suitable for infants • Easy to administer - Multiple daily doses may be required • Controlled release formulations are not commercially available, but theoretically possible • Chewing may diminish extended release properties • Taste - Adequate taste masking is possible - Taste masking may involve flavoring and/or sweetening agents as well as polymer coating and use of ion exchange resins and microcapsules - Chewing may diminish taste masking or extended release properties • Dose titration - Dose titration involving splitting tablet not accurate thin strips • Easy to swallow - Dosage form disintegration times vary from 5-30 seconds to minutes - Easy for young children and infants to swallow - Do not require liquids to administer • Easy to administer - Controlled release formulations not available • Taste - Taste masking may involve sweeteners, materials that coat taste buds (Cremophor RH 40), ion exchange resins and a taste masking polymer • Inadequate taste masking of very bitter molecules • Dose titration - Dose titration involving splitting film not accurate • Other considerations - Dose limitation, usually <25 mg Orally disintegrating tablets (ODTs) • Easy to swallow - Dosage forms disintegrate in oral cavity in 10-40 sec - Easy for young children and infants to swallow - Can be easily dispersed in liquid prior to administration, if desired • Easy to administer - Do not require liquids to administer - Once a day dosing possible • A wide range of release profiles, immediate release and extended release can be achieved • Good taste possible - Taste masking options include coating with polymers which sequester bitter API • Very bitter API can be taste masked - Flavoring can be added to enhance taste • Dose titration - Dose titration not easy, ODTs typically are not scored • Other considerations - Good physical stability, do not require preservatives Granules or powders • Easy to swallow - Granules can be taken as is or sprinkled on food or in drinks - Easy for young children and infants to swallow • Easy to administer - Packaged in single dose sachets - A wide range of release profiles, immediate release and extended release can be achieved • Good taste possible - Taste masking options include coating with polymers which sequester bitter API - Flavoring can be added to enhance taste • Dose titration - Dose titration may be possible • Other consideration - Good physical stability, does not require preservatives - High dose potential Regulatory Requirements • The US and the EU both implemented new pediatric regulations in 2007 • These regulations mandate increased efforts in the development of pediatric formulations and pediatric studies

Lect. 21 Generics

How Does FDA Regulate Drugs Statute - the laws passed by Congress Regulations - They implement the statutes • Often time represents FDA interpretation of the statute but may be challenged Guidance Documents (Draft and Final) • Not binding on the applicant or FDA but represent FDA's current thinking MaPPs - describe internal FDA policy and procedure How Does FDA Regulate Drugs NDA/BLA - For prescription/OTC drugs OTC Approvals • Require NDA approval then ANDAs accepted • Same approval process as a new drug but testing to determine if patients can self diagnose and understand appropriate use. OTC Monograph Process • No Approval needed • Comment and rule making process Some Abbreviations NDA - New drug application (brand) ANDA - Abbreviated new drug application (Generic) RLD - Reference listed drug (usually the NDA) Cmax - Maximum concentration (rate) AUC - Area under the curve (extent) PE - Pharmaceutical equivalence TE - Therapeutic equivalence BE - Bioequivalence cGMP - Current good manufacturing practices FDA Actions on Unapproved Drugs Still on the trail of unapproved prescription drug products • 19 different drug classes since 2006 • Represents well over 1750 products Specific Examples • Cough cold combination products • Colchicine Tablets • Quinine Capsules • Codeine Tablets • Otic Products (2015) Brief Legislative History Pure Food and Drug Act of 1906 Federal Food, Drug and Cosmetic Act 1938 Kefauver-Harris Amendments of 1962 Waxman-Hatch Act 1984 Pure Food And Drug Act 1906 1st general regulation by Federal Government Precipitating factors Federal Food, Drug And Cosmetic Act 1938 Introduced safety standards Required application submission Toughened criminal sanctions Regulations on enforcement, inspection and sample collection Permitted public releases Federal Food, Drug And Cosmetic Act 1938 Introduced safety standards Required application submission Toughened criminal sanctions Regulations on enforcement, inspection and sample collection Permitted public releases Drug Price Competition and Patent Term Restoration Act 1984 (Hatch-Waxman Act) Speed-up approval of Generic drugs Reduce associated healthcare costs Eliminate duplicative, unnecessary clinical testing Assure development of new drugs through special incentives Product Classification Pre-38 Marketed prior to FFDCA No FDA approval First approval must have NDA (safety) No ANDA Pre-62 Approved for safety Reviewed for efficacy (DESI) ANDAs OK Post-62 Approved for safety and efficacy ANDAs OK Legislation Spurred By: Health Concerns 1906 Act 1938 Act 1962 Amendments 2003 PREA Economic Concern 1984 Hatch-Waxman 1992 PDUFA 1997 FDAMA 2002 BPCA 2002 PHSBPRA 2003 MMA 2007 FDAAA 2008 Q1 (Antibiotic Exclusivity) 2012 FDASIA (GDUFA) Was Hatch-Waxman a Success? 1984 - 19% of all Rxs filled generically 2018 - 90% of all Rxs filled generically • But only 23% of drug costs 2017 savings from generics $265.1billion (>$4 billion every week) 10 year savings over $1.68 trillion Consumer confidence increased Savings can improve compliance as patients don't have to chose between medication, food, heat, electricity, etc. at the end of the month Prescription Drug Cost All Over The News • New incentives for expediting generic AP - Complex products - 1st generic approval for a product - Where there is less than one product on the market - Competitive Generic Therapies 180-day exclusivity • Generics are part of the solution not part of the problem - but politicians don't care NDA vs. ANDA NDA: • Chemistry • Manufacturing • Controls • Labeling • Testing • Bioequivalence (Bioavailability) • Animal Studies • Clinical Trials ANDA: • Chemistry • Manufacturing • Controls • Labeling • Testing • Bioequivalence (no animal studies/clinical trials needed) Bioavailability (BA) Rate and extent to which the active ingredient is absorbed from a drug product and becomes available at the site of action BA studies involve the determination of drug levels in blood, plasma or urine Measures the rate (how fast) and extent (how much) of the drug appears in the biological fluid after a specific dose is administered Bioequivalence (BE) A comparison of the bioavailability of two or more drug products Two drug products or formulations containing the same active ingredients are bioequivalent if their rate and extent of absorption are the same Types of Evidence to Establish Bioequivalence in Decreasing Order of Accuracy, Sensitivity and Reproducibility 21 CFR 320.23 • In vivo plasma pharmacokinetic study • In vitro test correlated with in vivo • In vivo in animals (not likely for ANDA) • In vivo urinary excretion study • In vivo pharmacodynamic study • Comparative clinical trial (BE study with clinical end points) In Vivo Bioequivalence Waivers 21 CFR 320.22 • Criteria for Waiver of In Vivo Study Requirements • BE is Self Evident Parenteral products (Solutions) AA drug products Oral solutions BCS Class I products (Requirement to generate application specific data) Ophthalmic products Q1 and Q2 requirement Therapeutic Equivalence -Pharmaceutical Equivalence Same active ingredient Same dosage form Same Strength Same route of administration -Bioequivalence For typical studies - AUC and Cmax (log transformed) 90% CI are within 80.00- 125.00% of RLD PD results meet CI Waiver of in vivo study Questions Regarding Approved Generics Should the current bioequivalence metrics apply to all drug products? • Extended-release • Antiepileptic drugs • Narrow therapeutic Index drugs • Special delivery devices (OROS system) Methylphenidate ER issue What is an ANDA? Application submitted under section 505(j) of the Act Relies on previous FDA findings of safety and effectiveness Must be the "same as" the NDA product it copies Must have the same labeling as the RLD it copies Must be bioequivalent to the RLD it cites as the basis for submission ANDA Eligibility Same active ingredient(s) Same route of administration Same dosage form Same strength Same conditions of use Tablet / capsule size issues - Swallow-ability (includes size and shape) - Medication errors? Tablets/capsules of different strengths all same size and color - Dispensing errors - Patient confusion • Taste differences (liquids, suspensions, FDDFs) Patient perception - Is this really the same drug? - Did the pharmacist make a mistake? - Concern re: larger tablet may actually have more drug - Can/will the patient take it (too big)? - Patch size and adhesion - Shape - Transit time FDA Looking at "Switchability" and Approval Issues TE means the generic is therapeutically equivalent to the RLD The question then is if multiple generics are approved - can they be substituted for each other? • A=B ; A=C : Does B=C? FDA had funded research to investigate NTI Drugs and AEDs and ER products Complex generic products (Lovenox, Copaxone) Patent and Exclusivity Mutually exclusive concepts NDA has patent filing and ANDA Patent certification requirements Exclusivity 5-Year, 3-Year and 7-Year Hatch-Waxman exclusivity (180-day) Pediatric exclusivity (180-day) CGT exclusivity (180-day) Don't Confuse Patent and Exclusivity Patents awarded by USPTO • NDA holders required to file patent information in timely manner • ANDA applicants required to certify to listed patents Exclusivity awarded by FDA • New Chemical Entity (NCE) exclusivity • Other exclusivity Both patent and exclusivity provisions afford a period of market protection Patents - 20 years from filing • Does not affect filing of ANDA (for generics) • Impacts when generic can be approved -Exclusivity: • Prohibition on ANDA receipt by FDA (NCE only) • Prohibition on approval (3-year, 7-year ODE, or Pediatric exclusivity) Exclusivity 5-Year NCE • First FDA approval of a New Chemical Entity (no salt or ester of which has been previously approved) • FDA prohibited from receiving ANDA or 505(b)(2) application for 5 years • May receive application after 4 years if listed patent and ANDA applicant makes Paragraph IV 3-Year Exclusivity • FDA can accept but can't approve • May or may not be blocking • New clinical studies in humans, essential for approval at the time of approval Orphan Drug Exclusivity 7-Year Protection Tied to indication only ANDA can be submitted ANDA can't be approved • Unless other non-protected indication approved A Word on Biosimilars (19 approved) Complex proteins, peptides (>40), recombinant products, monoclonal antibodies Will not be ANDAs or classic generics Review will be in the New Drugs Division not OGD Therapeutic equivalence path not clear Additional safety and or efficacy studies needed Immunogenicity concerns Naming convention critical -FDA is under dept of health and human services -all prescription drugs are NOT FDA approved (only after like 2000) but all prescription drugs are FDA regulated -Drugs on the market for a long time=preceded regulations for approval -90% drug products are dispensed generically in US -animal studies CANNOT be used to support bioequivalence of generic drugs -exclusivity is only awarded by the FDA Patents are granted by the patent and trademark office anywhere along the development lifeline of a drug and can encompass a wide range of claims. Exclusivity is exclusive marketing rights granted by the FDA upon approval of a drug and can run concurrently with a patent or not. Sink conditions allow dissolution to happen more rapidly. -particle size doesn't matter under sink conditions FIVE Ideal Properties of APIs Crystalline Non-solvated High-melting Non-hygroscopic Water soluble These properties usually afford an API to be: Chemically and physically stable for storage Made reproducibly on a large scale Successful in several common dosage forms -most stable polymorph= lowest solubility Excipients include: Diluents, → similar particle size distribution to granulation binders, → used in manufacture of granules that are blended w/ other components and compressed/encapsulated Disintegrants, → cause tablets to break apart; help with dissoln lubricants, → prevent sticking of blend to compression punches and dies/encapsulator fillers, CAN SLOW dissoln, reduce compressibility Glidants → improve flow by reducing inter-particulate friction; generally these materials have poor flow and compressibility by themselves solubilizing agents, colorants, (usually for prod identification) sweeteners, Flavors (target certain populations) Which of the following would be an appropriate polymer for the design of a continuous release product?=pH ind= So you have a consistent release of your drug everywhere no matter where it is (intestines, stomach) so you get the right amt of drug for a therapeutic effect. DIfferent organ at different times of the day→ majority of time in large intestines. There are different pH it needs to be dissolving at. Which route of administration would be appropriate if the injection volume needed is greater than 2 mL? Intramuscular (Larger volume IM than SC) Suppositories are the only dosage form available for rectal and vaginal delivery.= FALSE If you have a lipophilic drug and would like to design a suppository with a slow release rate, the base you should choose is: Hydrogenated vegetable oil base Release profile: Fatty/oleaginous base: lipophilic → SLOW release, hydrophilic → RAPID Ex. Cocoa butter Hydrogenated veggie oil base Water soluble base: hydrophilic = moderate release rate (PEG, glycerinated gelatin bases) Which of the following is NOT a disadvantage to rectal delivery? Susceptible to first pass metabolism Foams /enema can spread over WIDER area than suppository CQAs help ensure: Patient safety Efficacy of the drug product Quality of the drug product CQA = characteristic that impacts the quality/safety of the drug product, such as a chemical, physical or microbio attribute. Ensures pt safety (efficacy and safety of therapeutic prod is maintained over shelf life) Which is the most important stability category and determines the expiration period? Chemical → potency, purity, 5 yr max exp date Physical → prod spec, pass/fail Microbiological → preservative effectiveness, sterility testing =Each is equally important for determining expiration period Lyophilization = manufacturing process used to remove water from a soln product. The main objective is to obtain a prod. That has a longer shelf-life. AKA Freeze Drying; conduct @ low pressure; 3 stages: freezing, primary drying, secondary drying Surfactant = substance which stabilizes an emulsion Usually amphiphilic (both hydrophobic groups and hydrophilic groups) Soluble in both organic solvents and water 5 factors affecting powder flow Particle size Particle density Moisture content Particle shape Particle surface roughness Size 000 = LARGEST ~ 1 g, Size 5 = SMALLEST ~ 100 mg Size 1 and 0 are more common Must identify critical formulation attributes of the excipient. Concentration, compatibility to everything in the product, bioavailability, manufacturability, stability, and safety. Sterility is a likely critical attribute for release testing of a new batch of capsules.=no Dissolution like a critical attribute for release testing of a new batch of capsules True Taste is a likely critical attribute for release testing of a new batch of capsules.=no Powder particle size and flow are likely critical attributes for release of a new batch of "intact capsules" False (hard to test flow inside capsule) Tamper resistance is a likely critical attribute for release testing of a new batch of capsules. True Appearance is likely True One year stability results are a likely critical attribute for release testing of a new batch of capsules. False If a tablet is too soft, then to make harder tables: Increase compression force Slow down press Alter formulation Which of the following critical quality attributes should be included in stability testing to assure no change during the shelf life of the tablet? Weight variation and/or content uniformity Which of the following is NOT TRUE regarding otitis externa or "swimmer's ear?" Most often due to bacterial or fungal infection=yes Involves inflammation of the pinna or ear canal=yes Inflammation can result from dermatitis or eczema with no microbial infection=yes Cannot be treated with topical steroids= FALSE Effectively treated with a combination of antibiotics and cleaning/drying of outer ear=yes Which of the following is NOT an advantage of otic drug delivery? Can achieve local effects without systemic side effects Avoids first-pass metabolism Allows reasonable residence time for advanced dosage forms (i.e. long acting depots) Easy to dose properly =FALSE= (inner ear is extremely difficult, middle ear = difficult, outer = easy) Advantages: Achieve local ear effects w/o systemic SE Avoid 1st pass met. Allow reasonable residence time for advanced dosage forms Disadv. Have very limited absorption area Dose inferee w/ hearing Causes moderate discomfort May be difficult to dose properly Systemic absorption is possible ( problem if drug = toxic) Which of the following is NOT a challenge to nasal delivery? Advantages: Large nasal mucosal SA for dose absorption Rapid drug absorp via highly vascularized mucosa Rapid onset of action Ease of admin, noninvasive Avoids "fear of needles" Excellent for pediatric use Avoidaice of GI and 1st pass metabolism Circumvent BBB, allowing direct delivery of CNS drugs Improved bioavail. Lower dose/reduced SE Min. after taste Improved convenience and compliance Self admin Disadvan. Low residence time Small volume Reproducibility of dosing is a concern Deposition and distribution pattern often irregular Method of admin Condition of nasal passage Environmental conditions Sensitive nasal mucosa Difficult to deliver hydrophilic drugs Avoid nasal delivery in pts w/ : common cold, persistent sneezing, nasal congestion, nasal inflamm, allergic rhinitis Occular drug delivery (very smilar to otic) Advantages: Achieve local effects w/o systemic SE Avoid 1st pass metabolism Allow reasonable residence time for advanced dosage forms Disadv: Have very limited absorption area May interfere w/ vision Causes moderate discomfort May be difficult to dose properly Systemic absorp possible The preparation and manufacture of solutions, suspensions and solids for ophthalmic use requires special cGMP considerations for: Sterility Preservation Packaging Viscosity All of the above=this Transdermal delivery: Advatanges By pass 1st pass metab. Variation assoiated w/ oral therapy are avoided continuity/ability to terminate med Multiday therapy w/ single application Avoid risk/inconvenience of parenteral therapy Extends activity of drugs w/ short half lives May provide an alternative when oral route is unsuitable Better pt compliance Disadv. Molecular size limited by skin barriers Low delivery requires potent drugs Active immune system causes skin irritation CQA - transdermal delivery Chemical stability Drug release consistency/physical stability Dosage uniformity Microbial enumeration and identification Antimicrobial preservatives effectiveness The largest number of topical products are formulated as: creams What factors limit the effectiveness of transdermal delivery? Molecular size limited by skin barrier Calculations of Partition Coefficient (octanol represents cells) and Flux are only relevant for systemic delivery of drug and are not important for treating conditions affecting skin. False it is important b/c can partition into skin The Hatch-Waxman Act: Speed up approval of generic drugs Reduce associated health care cost Elim. duplicative, unnecessary clinical testing Assure development of new drugs thru special incentives Patents awarded by USPTO 20 yrs Exclusivity => FDA New chemical entity (NCE) exclusivity 3,7,5 yrs, or 180 d (hatch-waxman, pediatric, CGT) Orphan Drug Exclusivity is tied only to: The designated orphan indication FDA is precluded from ACCEPTING a generic drug application if the Reference Listed Drug it refers to as the basis of its submission is subject to: 3-year Hatch-Waxman exclusivity Is covered by a patent Is subject to orphan drug exclusivity Is subject to new chemical drug entity= this=NCE's are protected for 5 years of drug exclusivity (A, B, C =can still receive the app but cannot grant generic app until exclusivity is done) The scale for pulmonary devices= mg Children are often unable to swallow pills or capsules until age: 6-7 From a clinical pharmacology perspective, pediatric patients can be thought of as "small adults." False

Lect. 23

Liposome= cell membrane but smaller b/c hydrophilic heads and hydrophobic tails= tails on instead forming a sphere of bilayer membrane, trapping aq in center -micelles= greasy center, only hydrophobic tails inside=only 1 tail no bilayer Peg is a stealth polymer, but dep where peg conjugated=can hide stuff> keep peg away fom active sites=interferes with target binding -if bind PEG to a protein= inc half life b/c bigger size, reduce immunogenicity of protein, PEG may interfere with target binding What is alternate delivery? Changing a drug formulation or chemistry from the original version to give some advantage (i.e. drug depot, drug conjugate) This presentation focuses on injected/implanted systems • Oral tablet controlled release exists for small molecule drugs (Ambien® vs. Ambien CR®) • Pulmonary, transdermal, other systems exist • Examples will be presented Reasoning for alternate delivery forms 1. improve PK Advantages from a pharmaceutics/company viewpoint: • Drug is eliminated quickly from the body, but sustained drug levels are desired (sometimes necessary for effect) • Can avoid or diminish toxic drug effects • Can aid poor solubility of drug • Can target a cell type, organ, etc. • Drug "life cycle management" (market advantage after expiration of original drug patent) Advantages for patients: •Easier route of administration, easier frequency of administration, patient convenience • Improve patient compliance • Possible easier insurance reimbursement Some drug delivery technologies in products today • Biodegradable depots • Other depots • Liposome/lipid • Zinc complexes, salts • Conjugates Biodegradable depots from QLT, Inc. • Inject (mostly SC or IM) a mix of drug and matrix material • Matrix material dissolves or degrades, releasing trapped drug= think like insulin Matrix material: Poly(lactic-co-glycolic) acid (PLGA) The most widely-used injectable, biodegradable polymer in drug delivery, only a limited number of others approved Good safety profile • Used in sutures and grafts since the 1960's • Water degrades PLGA into natural products, no enzymes necessary • Low toxicity and immunogenicity •Some fibrotic tissue at injection site after depot is gone How is solid matrix material (PLGA) containing drug administered? Microspheres • Inject as a slurry of solid particles Gels • Dissolve PLGA, add drug, then inject as a viscous liquid Implants • Inject thin rod with local anesthetic or minor surgical implantation Water-oil-water double emulsion technique= literally water and oil (PLGA) emulified together, then add another water to that mix= emulsified again= harden, wash, freeze dry Diffusion followed by degradation drug release mechanisms from PLGA systems 1. Some drug has immediate access to body, diffuses out 2. Remaining drug is released when polymer degrades, breaks apart -no ideal drug delivery but good enough Solvent-diffusion PLGA gel - Dissolve PLGA in n-methylpyrolidone (NMP), suspend solid drug, inject; solvent diffuses leaving PLGA trapping drug • Eligard®, leuprolide for prostate cancer from QLT/SanofiAventis (1,3,4,6 month products) Thermal-response gels • Matrix material (PLGAPEG-PLGA) is a liquid at low temp. and gel at high temp. • Inject cold liquid and it transitions to gel in the (warm) body • Hydrogels - water makes gel swell, pores formed, drug elutes (has been more useful in topical delivery, gastric retention systems) • Others - SABER™ from DURECT is a biodegradable gel because of properties of matrix material, sucrose acetate isobutyrate PLGA implant 14G needle • Drug/PLGA solid mix is extruded into rod shape, injected • Zoladex® (goserelin in PLGA) from AstraZeneca o 1, 3, 4 month delivery Other implant technology • Viadur® (leuprolide) with DUROS™ technology from ALZA/DURECT • Non-biodegradable (titanium), but 12 month delivery -osmosis causes piston to move and push drug out Nanospheres • Sub-micron particles (10 - 1000 nm) • Less needle clogging, smaller needle possible • Higher surface area = shorter delivery duration • Can cross GI mucosa because of small size, although low efficiency - Oral protein/peptide therapy possible? (!) - Trans-cellular mechanism not entirely understood, no products yet Dendrimers=• Drug can be trapped in core or associated with surface end groups • Nano-scale -polymer micelles=Can use lipids instead • Often nano-scale Liposomal delivery Lipid microparticles Slow-dissolving forms • Slowly soluble salt form of drug • Administered as slurry of solid particles • Often requires certain charge on drug • Lispro (Lilly) and Aspart (Novo): mutations that favor monomer (rapid-acting) • Glargine (Aventis): mutations that reduce solubility at pH 7.4 (long-acting) • NPH (Neutral Protamine Hagedorn): protamine (basic) complexes with insulin (intermediate-acting) Conjugated forms: PEGylation chemical conjugation from Amgen website Other large molecules can also be conjugated (Fc, HSA) Conjugated forms: increased glycosylation Conjugated forms • Bigger size = slower clearance, longer circulation • PEGylated sometimes much lower activity than nonPEGylated • PEGylated often less immunogenic • Some evidence of kidney build-up of PEG after longterm dosing • New Chemical Entity (more strict FDA req's for approval than depots, for example)

Lect. 12

Liquid Dosage Forms • Solution: A homogeneous mixture composed of one or more substances, known as solutes, dissolved in another substance, known as a solvent. It will not separate over any period of time. • Suspension: A heterogeneous liquid preparation containing fine particles of solute uniformly distributed throughout a vehicle. • Emulsion: A dispersed system containing at least two immiscible liquid phases. Liquid Dosage Forms - Advantages • High degree of flexibility possible when fine dosage adjustments are needed. • Convenient for pediatric and geriatric patients who have trouble swallowing solids. • Can be easily colored of flavored to make them aesthetically appealing. Liquid Dosage Forms - Disadvantages • Hard to mask drug taste. • Cumbersome to transport and measure dose accurately. • Shelf life of many drugs shortened in aqueous medium. • Complex manufacturing. • Difficult packaging, shipping and handling. Liquid Dosage Forms - Ingredients • API • Buffers - resist changes in pH. - To maintain stability, improve dissolution or increase palatability. • Preservatives - control growth of microorganisms. • Sweeteners - enhance palatability. • Coloring Agents - enhance aesthetic appeal - Should be inert, water soluble, and stable at formulation pH. • Flavoring Agents - mask taste of the drug. Solutions • A drug must be in solution before it can be absorbed (solids need to disintegrate and dissolve). • A solution is a homogenous system and thus the drug will be uniformly distributed throughout the preparation. - Elixirs - Syrups - Oral Sprays - Infusions and Decoctions - Tinctures - Spirits - Mouthwashes and Gargles Dispersions of finely divided solid particles of a drug in a liquid medium in which the drug is not readily soluble. • Practical issues: 1) Settlement or sedimentation of drug particles. 2) Redispersibility of sedimented particles. • In an ideal suspension: 1) Suspended particles should remain segregated. 2) Suspension should have appropriate flow properties. Physical stability depends on particle size. • Suspending agents are often hydrophilic colloids (e.g. cellulose derivatives, acacia, or xantham gums) added to suspensions to increase viscosity, inhibit agglomeration and decrease sedimentation. - As viscosity increases, sedimentation decreases, but more difficult to pour and swallow. • Redispersibility aided by having flocculating particles. - Floccule = An aggregate of particles very loosely held together. - The formulation is aided by modifying pH, using certain electrolytes of surfactants. An emulsion is a mixture of two immiscible (unblendable) substances. - One substance (the dispersed or internal phase) is present in the form of small liquid globules distributed through a dispersion vehicle (the continuous or external phase). • Oral use is limited to liquid APIs with an objectionable taste. Emulsions tend to have a cloudy appearance. • Emulsions are unstable and do not form spontaneously. - Energy input through shaking, stirring, homogenizers, or spray processes is needed. - Over time, emulsions tend to revert to the stable state of oil separated from water. - Surfactants can increase the kinetic stability of emulsions greatly so that, once formed, the emulsion does not change significantly over years of storage. A surfactant (also known as an emulsifier or emulgent) is a substance which stabilizes an emulsion. • Should be effective at low concentrations, should increase viscosity, and should prevent aggregation of dispersed globules. • They are usually organic compounds that are amphiphilic. - They contain both hydrophobic groups (their "tails") and hydrophilic groups (their "heads"). • They are therefore soluble in both organic solvents and water Surfactant Micelles • The lipophilic ends of the surfactant molecules dissolve in the oil, while the hydrophilic charged ends remain outside, shielding the rest of the hydrophobic micelle. Emulsions have also been used as drug delivery systems. • An increasing number of drugs are surface-active or even hydrophobic, and can provide significant problems for conventional formulation techniques. • Emulsion delivery is increasingly used to permit absorption at the site. • Types of emulsions include: - Oil in Water (o/w) - Water in Oil (w/o) - Multiple (w/o/w or o/w/o) - Microemulsions Solid Oral Dosage Forms • Most popular and widely used dosage forms. • Represent over 90% of prescription and OTC drugs. • The three most common oral solid dosage forms are: - Soft Elastic Capsules, (also called Soft Gel Capsules or Soft Gelatin Capsules) - Hard Gelatin Capsules - Compressed Tablets (coated and uncoated) Choice of dosage form depends on the solubility of the active pharmaceutical ingredient (API), - More water soluble forms are formulated as tablets or hard capsules. - API with limited water solubility is dissolved in non-aqueous vehicles and formulated into Soft Gel Caps. Soft Gel Capsules • Solid capsule (outer shell) surrounding a liquid or semi-solid center (inner fill). • An active ingredient can be incorporated into the outer shell, the inner fill, or both Soft Gel Encapsulation - History • 1834, patent issued for method to produce single-piece gelatin capsule (Mothes and Dublanc). - Sealed with a drop of gelatin solution. - Used individual iron molds. - Capsules filled individually with a medicine dropper. • Later the plate method was developed. - Sets of plates with pockets used to form the capsules. - Some companies still use this method. - Equipment is not produced commercially any more. All modern soft-gel encapsulation uses variations of the rotary die method. • Developed by R.P. Scherer in 1933 (later Cardinal Health, now Catalent). • Innovation was to use a rotary die to produce the capsules, with the filling taking place by blow molding. - Reduced wastage. - First process to yield capsules with highly repeatable dosage. • In 1949, the Lederle Laboratories division of the American Cyanamid Co. developed the "Accogel" process, allowing powders to be accurately filled into soft gelatin capsules Advantages of Soft Gels • Ease of Use - Easy to swallow - No taste - Unit dose delivery - Tamper-proof • Versatile - Wide variety of colors, shapes, and sizes - Accommodates a wide variety of compounds filled as a semi-solid, liquid, gel or paste - Immediate or delayed drug delivery - Can be used to improve bioavailability by delivering drug in solution or other absorption enhancing media Disadvantages of Soft Gels • Special manufacturing equipment required • Stability concerns with highly water soluble compounds, and compounds susceptible to hydrolysis • Limited choices of excipients/carriers compatible with the gelatin Paint Balls Most popular and largest quantified manufactured Soft Gel Capsule Formulation of Soft Gel Caps • Gelatin - Most popular polymer wall material • Plasticizers - Used to soften the finished gelatin - Often glycerol, sorbitol or polypropylene glycol • -Water - To hydrate the gelatin and sometimes to help solubilize the API • Other Additives - Preservatives to prevent mold growth in the gelatin shell - Often potassium sorbate or propyl hydroxybenzoate - Colors, flavors Gelatin • Irreversibly hydrolyzed form of collagen created by prolonged boiling of connective tissue • Of bovine, porcine, or piscine (fish) origin. • Comes in a variety of bloom strengths, - The higher the bloom strength, the more resilient the gel. • The limitations of bovine (i.e. bovine-related diseases) and porcine (i.e. not kosher) gelatin may be overcome by piscine (fish) gelatin. Inner Fill • Three primary types: - Neat Substance • Especially oily liquids - Solution Fills • Active ingredient dissolved in a carrier - Suspension Fills • Active ingredient dispersed in a carrier • Manufacturing done primarily by Specialty CROs (contract research organizations) Features offered by a leading contract manufacturer in softgel capsules • Self-emulsifying/microemulsion vehicle systems • Liquid (solution or suspension) fills • Wide range of softgel compatible vehicles (hydrophilic/lipophilic) • Virtually unlimited selection of shapes, sizes and colors • Unique formulations leading to patentable line extensions • New technologies including innovative shell forms and manufacturing techniques Soft Gel Manufacturing Process - 5 Steps (1) Fill material preparation - Production of a uniform and stable drug solution or suspension that can then be consistently encapsulated. (2) Gel melt preparation: - Production of a gel melt (mixture of gelatin, water and plasticizers) that can then be used to form ribbons on the encapsulation machine. (3) Encapsulation - Production of capsules from gel ribbons and fill material, with uniform and accurate dose of fill material in each capsule. (4) Drying: - After encapsulation, softgels are first tumble-dried and then tray-dried in special ambient temperature drying tunnels to a specified drying end point. (5) Finishing (Inspection/Washing/Packaging): - Dried capsules are inspected, washed, and packaged into bulk containers. Non-Gelatin Soft Capsules • Of interest due to: - Concern over bovine products - Kosher - Vegetarians Soft Gel Advantages Over Other Oral Dosage Forms • One piece dosage • Sealed tightly in automatic manner • Easy to swallow • Allow product identification, using colors and shapes • Uniformity, precision and accuracy between dosages • Safe against adulteration • Better stability than other oral delivery systems • Good bioavailability and rapid absorption • Rely on preference of the consumer, due to their security, appearance and functionality • Offer protection against contamination, light and oxidation • Unpleasant flavors are avoided due to encapsulation • Can be used for rectal, vaginal or ophthalmic delivery • Filling reproducibility is 1 to 2.5% • Elegant and attractive as a finished product

Lect. 3

Solubility is important b/c it affects: -Dissolution rate -Maximum Absorbable Dose (MAD) -Biopharmaceutics Classification System (BCS) -Ionization and salt selection -Identification of the most stable crystal form/polymorph The solubility of a compound is the concentration that can be reached when it is saturated in a solvent at a given condition. Thermodynamically, saturation occurs when the solution phase solute reaches equilibrium with the solid phase solute Importance of Solubility: 1. Binding assays (drug discovery) 2. Drug product performance 3. Analytical method development 4. Chemical reactions 5. Salt screening 6. Polymorph screening 7. Process crystallization 8. Absorption modeling 9. Equipment cleaning Solubility is dependent on equilibration conditions: - Temperature - pH (for ionizable compounds) - State of the solid (amorphous, crystalline, polymorphs); relates to the crystal lattice energy - Composition of the solvent - Impurities What is preformulation? Characterization studies performed prior to and in support of formulation development; prioritizes drug molecule's liabilities in relation to a desired dosage form and leads to selection of an appropriate solid-st/ate form of the API, ex: a salt form w/ an improved solubility -Preformulation activities span the discovery and development stages and thus help to bridge gaps between discovery and development groups Measured Properties Associated with Preformulation 1. Solution-phase Properties: -pKa, log P, solution-state stability (forced degradation: heat, pH, oxidation, light) 2. Solid-state Properties: crystallinity/crystal form, solid-state physical and chemical stability, melting point, residual solvents/solvation, hygroscopicity, excipient compatibility 3. Bulk & Mechanical Properties: Particle morphology (crystal habit, aggregates, agglomerates), particle size distribution, surface area, bulk & tap density, flowability, compressibility 4. Biopharmaceutics Properties: Solubility, dissolution, permeability, preclinical PK (metabolism, clearance, ...) Permeable drugs dissolved in the GI tract are readily absorbed into the circulatory system - Creates a sink condition, no build up of dissolved drug in the GI tract • -In-vivo dissolution rate is proportional to equilibrium solubility for permeable drugs Noyes-Whitney equation for in-vitro dissolution -Dissolution Rate (dm/dt) = (D·A) /l · (C1- C2) D = diffusion coefficient (cm2/sec) A = surface area of solid (cm2) l = stagnant layer THICKNESS (cm) C1 = saturated solution conc. (solubility) C1> C2> bulk solution conc. during disso. Under sink conditions: - bulk sol'n conc. remains << C2 << C1 and thus, disso. rate simplifies Dissolution Rate = (D·A) /l * (solubility) -basically inc dissolution inc solubility= directly proportional to solubility Maximum Absorbable Dose (MAD) SIMPLE Gastro-Intestinal Absorption Prediction • Oral delivery - MAD = S(mg/mL) x Ka(min-1) x VSI(mL) x tSI(min) - S = solubility in simulated intestinal fluid at 37ºC - Ka = absorption rate constant - VSI = 250 mL (small intestine fluid volume) - tSI = 240 min (small intestine transit time) - Assumes absorption occurs in small intestine, requires NO particle size input, requires NO knowledge of dissolution - Conservative estimate of maximum dose that will be fully absorbed Biopharmaceutics Classification System (BCS) for Oral Immediate Release (IR) Dosage Forms Class IV Low Solubility Low Permeability Class III High Solubility Low Permeability Class II Low Solubility High Permeability Class I High Solubility High Permeability -BCS High Solubility ≡ maximum dose strength fully soluble in 250 mL water across gastrointestinal pH (1 to 6.8, stomach to small intestine) and 37ºC. -BCS High Permeability ≡ extent of absorption in humans is ≥85% of administered maximum dose strength -Originally intended to help generic drug makers avoid bioequivalence (clinical) studies for certain IR dosage forms and thus reduce costs Ionization of Acids and Bases • A compound that donates a proton (a hydrogen ion, H+) to another compound is an acid. • A compound that accepts a proton from another compound is a base. - Definition - Brönsted-Lowry acids and bases HA ⇆ H+ + A- where HA is an acid B + H+ ⇆ BH+ where B is a base -For the reverse reactions: A- is a conjugate base and BH+ is a conjugate acid. For a base (conjugate acid) BH+ ⇆ B + H+ • Ka = [B]*[H+]/[BH+] • pKa = -log(Ka) = -log([B]*[H+]/[BH+]) • Alternative Definition of pKa pKa = pH at which the equilibrium concentrations of the unionized and ionized species in solution are equal Mathematically, when [B] = [BH+], pKa = -log([H+]) ≡ pH pKa at S-curve inflection point (50% ionized) Measurement technique examples • Potentiometric titration, plot (pH, Vtitrant) • Capillary electrophoresis (CE), plot (pH, meff) -ionization increases aq solubility -for acid: inc pH= inc ionization, thereby inc solb -for base: dec pH: inc ionization, thereby inc solb HA ⇆ H+ + A- = inc pH= acids dissociates= inc ionization, think like begets like= hydrophillic to inc solubility B + H+ ⇆ BH+ = dec pH= base dissociates= inc ionization, inc solb= so bases are inc solb in gut where dec pH rather than stomach Selecting API: API Solid-state Forms - 2 general types • Free Form is the active molecule by itself - Non-ionizable: Free Form = "Free Form" - Ionizable acid: Free Form = "Free Acid" - Ionizable base: Free Form = "Free Base" • Salt Form is a combination of ionized free acid or free base with a ionized counter-ion (proton transfer) to crystallize it Ideal APIs (free form or salt form) should be: 1. Crystalline (test by PXRD) 2. non-solvated (exception for strong hydrates, test by TGA) 3. high melting (~125ºC or higher, test by DSC) 4. non-hygroscopic (does not absorb ambient moisture, common problem for salt forms, test by DMS) 5. water soluble (often a problem for free forms, test by gravimetry/TGA or HPLC for buffered media) These 5 properties usually afford an API to be: • chemically and physically stable for storage • made reproducibly on a large scale • successful in several common dosage forms -if not ideal, acids and bases are usually made into salts to overcome their poor aq solubility of free form: Salt Selection= Overcome Poor Free Form Properties, Often low aqueous solubility Salt screening and selection - preformulation activity initiated for ionizable drug candidates that have liabilities in their free forms; desirable salts have the 5 properties listed on the previous slide Salt Selection Salt Screening • Free acid is reacted with pharmaceutically acceptable bases. − e.g., R-COOH + NaOH → R-COO-Na+ + H2O • -Free base is reacted with pharmaceutically acceptable acids. − e.g., R-NH2 + HCl → R-NH3 +Cl Polymorphism - the ability of one compound to exist in more than one crystal phase • True polymorphs have the same molecular structure and formula • Hydrates and other solvates are considered pseudo-polymorphs of the corresponding anhydrous (molecular formulae differ) • If an API can exist as multiple crystal phases, each crystal phase is called a polymorph • Polymorphs usually have similar aqueous solubility, with the most stable polymorph having the lowest solubility -The thermodynamically most stable crystal phase is almost without exception the desired form of the API due to its superior physical stability. -Pharmaceuticals The vast majority of API are preferred to be in the stable crystal phase (form), because metastable forms have the liability of physical-form instability; change in crystal form = change in API physical properties. Stable-form Screen =A specific type of polymorph screen utilizing solutionmediated phase transformation (SMPT) to identify the most stable crystal form or polymorph of a molecule • Slurry API initial form(s) in various solvents Initial form has a fair chance to be the stable form/ only form! -High solubility of the API in the slurry solvent is the most IMPORTANT factor, to ensure identification of the stable form!= usually at least 8.8mM -remember: oswald's law that the least stable form forms first usually, so you use stable form screen= dissolve small amount each in a solvent slurry and wait a few days to see if stable form forms from instable form

Lect. 10

What is a Critical Quality Attribute (CQA)? • A characteristic that impacts the quality/safety of the drug product, such as: − A chemical, a physical, or a microbiological attribute • Critical Quality Attributes Help Ensure Patient safety - The efficacy and safety of the therapeutic product is maintained over its shelf-life Code of Federal Regulations Title 21 (FDA) • General requirements for control of the drug product are listed in CFR Title 21 (www.ecfr.gov/) - Relevant sections from Parts 210, 211, 600 and for drug/device 820 - CFR is the law and enforceable by the FDA • Identification of and control of CQAs are required and enforced by other regulatory agencies such as Health Canada and EMA Examples of Critical Quality Attributes (1 of 2) • Appearance - Visual description of the product - If labeled as prefilled syringe, should look like a prefilled syringe and not a PEN or vial (packaging mistakes happen) - If labeled as a clear, yellow solution is should be free from particulates and yellow in color • Assay - % Label Claim of the active pharmaceutical ingredient - 100 mg/mL solution: test result of 98 mg/mL= 98% Label Claim - Controlled w/ a two-sided limit (95% to 105% of Label Claim) • Impurity Profile - Inherent process impurities (some impurities simply can not be removed) - Degradation products due to instability of the active ingredient over its shelf-life - Limits- Each impurity has a maximum allowable limit that was qualified in toxicological studies (human & non-human studies) Volume of Injection in Container - To demonstrate labeled volume can be delivered to the patient - Due to dead space/hold-up units are filled with a slight overfill • For a vial it is possible to extract more than the intended dose volume • For a prefilled syringes does the Instructions-for-Use state to prime or inject with the "bubble" (can impacts hold-up volume) • Hold-up volume can vary from part number to part number Other CQA to be discussed in upcoming slides - Osmolality, pH, endotoxins, Sterility, Particulate Matter Solubility (aqueous) • Solubility (related to CQA assay): - Achieved when the final energy state of the API is lower in given solvent than as a solid (not to be confused with dissolution rate) - Influenced by temperature, pH, solvent type, and other factors - Preparation of an admixture can impact product's solubility • Intrinsic Solubility: - Solubility of an ionisable API as a free acid or a free base in water • Apparent Solubility (or "formulated" solubility): - Solubility observed under given test conditions - Equilibrium solubility • The API formulated at its saturation point for a given set of conditions; however, typically an API is formulated as an unsaturated solution to account for the product's exposure in the real world (temperature, shipping vibration, process capability, etc...) • Ionized (salt form, pH), surfactants, cosolvents, etc to increase solubility - Nonequilibrium solubility • The addition of energy or nucleation inhibitors to form a supersaturated solution • Inherently unstable, but may maintain solubility over a "short" shelf-life Acceptable pH Range for an Injectable Product: - pH 7.4 physiologically ideal, but not always feasible due stability and/or solubility limitations of the API - Under many conditions, injections can be dosed safely with pH as low as 4 or as high as 9 - Some key considerations for non-neutral pH formulations • Injection volume (smaller more tolerable) • Injection rate (slower more tolerable) • Route of delivery (IV more tolerable) • Buffer capacity (lower is more tolerable) - Non-neutral formulations have the potential to cause glass to delaminate Buffer Capacity: - Resistance of a buffered solution to change pH upon addition of a titrant - Approximate buffer capacity (β)= ΔB/ΔpH • ΔB= grams of strong acid/base to Δ pH of a solution • ΔpH= Δ in pH units from strong acid/base addition - Buffer capacity is dependent on pH • Maximal when pH = pKa of the buffer species • ~ One-third of maximal when pH = pKa ± 1.0 - Buffer capacity is dependent on the concentration of the buffer • Directly proportional for a given buffer system - 10 mM phosphate buffer has half the buffer capacity of 20 mM phosphate buffer (compared at same pH) -dec buffer capacity= quickly equilibriates in body vs inc buffer capacity= stays its own pH longer Self-Buffered Formulations: - Self-buffering means the API has sufficient buffer capacity for pH control • Additional buffer component, such as sodium phosphate buffer, not required for the formulation - Self-buffered formulations are possible when: • API has pKa value near formulated pH • API is sufficiently concentrated • Buffer capacity of the API is impact by the above - Such drug products are examples of a "keep it simple" approach to formulation development • Only add excipients as needed to correct quality/performance deficiencies of the API • Need to justify the presence of an excipient to regulatory agencies How to Determine a pH Range for a Product: - What is the pH solubility and stability profile for • The API • All excipients used in the formulation - What is the expected process variability for pH • Analytical instrumentation variability • Manufacturing variables • Do not set a pH control limit tighter than what the process is capable of (process capability) • If the API's formulated concentration is based on pH solubility profile, then the process capability for pH should be considered - Type of primary packaging • Glass/polymer vial; stopper composition - Overall the pH range is usually driven by the pH dependence of the API's solubility and degradation pathways Osmolality: - Measurement of osmotic pressure for a solution • Osmotic physiological compatibility of a formulation - Measured as milliosmoles per kilogram solvent (mOsm/kg) • It is a colligative property • Related to the total solute concentration • Isotonic: • Homeostasis osmolality of blood • ~290 mOsm/kg (~range 270 to 300 mOsm/kg) • 0.9% (w/v) NaCl, 5% (w/v) glucose, and 10% (w/v) sucrose are isotonic • Hypertonic: - Osmolality >300 mOsm/kg • Hypotonic: - Osmolality <270 mOsm/kg Affect of Ionization: - Ionic compounds dissolve & dissociate into constituent ions, each of which contribute to osmolality • 0.15 M NaCl has ~ 2x the osmolality of 0.15 M sucrose NaCl → Na+ + ClC12H22O11 → C12H22O11 • Affect of Molecular Weight: - Osmolality depends on the number of solutes, not their mass • Osmolality of 0.3 M lactose is approximately the same as that of 0.3 M sucrose • Osmolality of 5% (w/v) glucose is approximately the same as that of 10% (w/v) sucrose • Formulation Considerations: - Depending on the method & route of administration, a given drug product can be formulated as a hypertonic or hypotonic solution • Formulation diluted into normal saline as an admixture • Administered as a slow IV push • Intravitreal administrated formulations should be isotonic -hypertonic= water moves out of RBCs, too much and the RBC will shrivel up and die -hypotonic= water will move into RBC, too much and RBC will burst Manufacturing Related Critical Quality Attributes • Compounding • Filling • Microbial control • Particulate control -the process is defined and under control Sterile pdt manufacturing: Some Compounding Considerations: Goal: Ensure a homogeneous solution & minimize bioburden without impacting the stability of the drug product - API addition- optimal addition rate - Type of compounding equipment • Tank type- Autoclaveable, plastic, stainless steel, etc... • Impeller geometry- - Is the impeller diameter (D) to tank diameter (T) optimal such as a D/T = ~0.33 for a typical impeller - Do you have turbulent/chaotic flow based on the Reynolds Number for your system (typically Rne > 2,000) - Does the resulting shear rate from the impeller tip speed impact the stability of the drug product • Does the mixer motor have enough power & is the mixing shaft suitable for the process Some Filling Considerations: - Fill line speed ("X" vials/min) - Fill volume/weight control - Fill needle drips - Fill needle clogs - Stopper placement - Crimp sealing - Environmental control - Light control Some Labeling/Packaging/Shipping Considerations: - What type of label adhesive and ink - Where to place the label and how (automated, semi-automated, manual) - Need for serialization- each unit marked with a serial number - What type of primary carton - How the dosage form will be placed into the primary carton - How the primary carton will be bulk packaged and palletized - Shipping temperature/modes/lanes/export/import/depot location - Safe for patient to travel with dosage form (x-ray exposure, etc...) - Is sterility assurance maintained Bacterial Endotoxins (BET) (1 of 5) • Endotoxins: - A pyogenic substance (pyrogen): induces fever - Most common example is lipopolysaccharide (LPS) • Membrane structural components of gram negative bacteria that released upon cell lysis • LPS induces fever, so by definition LPS is a pyrogen - Injection of high-levels of endotoxins causes fever and in some instances death • Measured as Endotoxin Units: - EU ("Endotoxin unit") • 0.25 EU ~0.05 ng LPS* (USP WFI limit ≤ 0.25 EU/mL) • ~1,000 bacteria cells* (E. coli) Endotoxin Testing • Historically done by "Pyrogen Test" (USP <151>) - Measure temperature increase after injection in rabbits - Con: not a direct measure of endotoxin • Now more commonly done by "Bacterial Endotoxins Test" (USP <85>) - Directly measure LPS (based on coagulation of Horseshoe crab blood) - Con: non-LPS pyrogenic materials not detected • Endotoxins Testing via USP <85>: - Several test methods to directly measure LPS • Gel-clot method (based on LPS coagulation of Limulus Amebocyte Lysate) • Chromogenic method (based on LPS colorimetric reaction with Limulus Amebocyte Lysate) - These test methods provide a direct/quantifiable measure of LPS, which is the most common source of exogenous pyrogens in the manufacturing environment - These test methods do not detected the presence of non-LPS pyrogenic materials • The USP rabbit test can be used to detected the presence of other pyrogens but does not quantify the amount Endotoxins Limit Calculated per USP <85>: - Based on body weight & route of administration • 0.2 EU/kg body weight per hour (intrathecal) • 5 EU/kg body weight per hour (general parenteral) • Single-sided upper limit (no lower limit) - Equation is K/M = EU/mL (for the formulation) • K = limit EU/kg based on route of delivery • M = max dose per kg body weight per hour • Note: Oncology products could be dosed by body surface area rather than body weight - Example • 10 mg max dose, 10 mg/mL formulation, 70 kg person & bolus subQ injection Admixture BET Limit: - Each component must be controlled so the cumulative BET does not exceed the maximum limit Control Occurs Before the Mfg Process: - "Depyrogenation" of all solution contact surfaces=really hot heat for long time basically • Vials, beakers, spatulas, mixing shaft/impeller... • Typically via dry heat, 250°C for 3 hours ≈ 3 log reduction of BET • There are many methods for BET reduction (USP<1228>) • Sterile filtration & standard autoclaving DOES NOT remove/reduce BET - Compound with water-for-injection • Per USP, WFI has <0.25 EU/mL limit • May not be RNase/DNase/Protease free - BET and bioburden control limits for • Drug substance, excipients, bulk solution, etc... • Note that killed negative bacteria releases LPS into the environment Bioburden: Number of viable bacteria, yeast, and molds in a bulk product prior to sterilization (i.e. compounded solution) • Bioburden Units: Measured as the number of Colony Forming Units (CFU) • Bioburden Testing: - Per USP <61> test • Pre-use testing of active ingredients & excipients - Controlled with appropriate CFU limits • In-process testing of bulk drug solution - The regulatory limit is 10 CFU per 100 mL for sterile filtration process - No objectionable bacterium (such as E. coli, Salmonella sp., P. aeruginosa, S. aureus, C. albicans, & Clostridium sp) - Depyrogenation reduces bioburden, but most bioburden reduction steps do not reduce BET Sterility: Sterility= destructive test so can't check everything PNSU: "Probability of a Non-Sterile Unit" - Industry standard is to strive for PNSU ~ 10-6 • 1 in a million chance a unit in a batch is not sterile • Currently, absolute assurance of a non-sterile unit is not feasible • One reason is every unit would need to be tested, thus leaves no units for dosing... • Bioburden contamination can be heterogeneous in a batch of drug product • USP <1211> overview of sterility assurance • Ways to Increase Confidence that PNSU is Low: - Terminally sterilize, if feasible - Use advanced aseptic processing- manufacture in advanced RABs or Isolators • Human factors- Separates the operator from direct contact w/ the drug product - Religiously follow good aseptic processing guidelines (eliminate human error) Sterility Testing: - USP <71> test: • 14 day incubation of drug product under growthpromoting conditions - Generally 2 different types of media & temperatures » One for bacteria » One for yeast/molds • Must be no evidence of microbial growth- no CFU - Drug product must not be bacteriostatic or fungistatic for the given test conditions Sterility Testing: - Drug product tested at time of production & over its shelf-life • Small volume parenterals typically 20 units tested - Statistically does not provide assurance of sterility - The cumulative mfg process controls w/ sterility testing ensure a low PNSU or that a batch is "sterile" • The container closure system must maintain sterile integrity over the drug product's shelf-life - Includes intended storage, shipping, and end-user conditions - Container/closure has appropriate "fit" & residual seal force (i.e. vial/stopper) - Container closure integrity tested analytically (bacterial ingress, helium leak testing, high voltage, vacuum decay, others...) Terminal Sterilization (TS): Drug product is sterilized in the primary container - In other words, the units are sterilized AFTER filling and closure • Thus, the term "terminal" - Per FDA/EMA parenteral products must be terminally sterilized via overkill process unless data justifies it is not feasible • Many active ingredients have unacceptable degradation upon TS • Some critical excipient(s) required for the formulation have unacceptable degradation upon TS • Reduced "kill" rates can be used Main Types of Terminal Sterilization: - Listed in USP <1229> - TS applicable to solution drug products • Autoclaving - Typical overkill cycle of 121°C, 15 minutes at high pressure w/ "dry" steam - TS applicable to lyophilized/dry powder drug products • Dry heat - Typical overkill exposure of 160°C for 2 hours • Gamma radiation - Typical overkill dose of ≥ 25 kGy • All units must be exposed to TS conditions - Non-uniformity of conditions in the autoclave, dry heat over, etc... are mapped • Equipment design, loading pattern, partial/full loads • So each unit receives at least the minimal validated exposure & no unit receives more than the maximum validated exposure for TS If Terminal Sterilization is NOT Possible: - Aseptic processing which includes • Control of Bioburden during the drug product manufacturing process - Equipment and fluid paths are sterilized/depyrogenated prior to use • Redundant filtration with 0.22 µm pore size "sterilizing" grade filters just before filling - Filter pore size can be smaller such as 0.1µm, but cannot be larger. - Bubble point testing of the filters pre/post use ensure no larger pore sizes in the filters • Qualifying the process with growth promoting media fills • PNSU for aseptic process cannot be calculated mainly due to unexpected human error for a given batch but is generally recognized as ~ 10-3 • Religiously following good aseptic processing guidelines (human factors) What happens when process controls to ensure the safe manufacturing of a sterile product are not followed: - Patients are harmed - Warning Letter from the FDA • Inspections, Compliance, Enforcement, and Criminal Investigations branch of the FDA • Public information Visible Particles • Method for Testing: - Defined in USP <1> ("Injections"): • 100% visual inspection of drug product - Each unit inspected under bright light & against black/white background - Each unit with a visible particulate is rejected - 50-100 µm particles not observed consistently • Additional inspection during release testing & over the shelf-life of the product • From USP <1>: "The inspection process shall be designed and qualified to ensure that every lot of parenteral preparations is essentially free from visible particulates." • Similar to Sterility testing, absolute assurance of no visible particles is challenging • Some products such as biologics may have inherent particles (read packet insert) Methods for Testing: - Detection of subvisible particles • USP <788> ("Particulate Matter in Injections") - Like sterility testing only a small subset of the batch is tested - Tested via analytical equipment & results reported for: » Particles <10 μm (no more than 6,000) » Particles <25 μm (no more than 600) • Importance of test is ensuring low probability of embolism • Similar to sterility, absolute assurance a unit from a given batch has an acceptable number of subvisible particles is not possible with current technology Overall the manufacturing process is designed to control and minimized exposure of the product to subvisible and visible particles

Lect. 18 Nasal

Why Nasal Drug Delivery? • Locally: solutions, suspension, and sprays are used for topical mucosal membrane therapy. For example, allergic sinusitis and rhinitis treatment • To the brain: in order to avoid the blood-brain barrier (BBB). • Systemically: avoid GI tract and first pass liver metabolism • Needle-free: Vaccination Nasal Administration Dosage Forms Dry Powder Inhaler (includes delivery device) Nasal Spray or Drops (includes delivery device) Aerosol or Nebulizer or Metered Dose Inhaler (includes delivery device) Nasal Ointment or Cream Advantages of Nasal Administration for Systemic Drug Delivery • Large nasal mucosal surface area for dose absorption • Rapid drug absorption via highly-vascularized mucosa • Rapid onset of action • Ease of administration, non-invasive • Avoids "fear of needles" • Excellent for Pediatric use • Avoidance of the gastrointestinal tract and firstpass metabolism (good for peptides, proteins) Advantages of Nasal Administration for Systemic Drug Delivery • Circumvent Blood Brain Barrier (BBB), allowing direct delivery of CNS-active drugs • Improved bioavailability. • Lower dose/reduced side effects. • Minimal aftertaste. • Improved convenience and compliance. • Self-administration. • New patent coverage for drug formulations about to expire Paranasal sinuses and nasal conchae condition inhaled air through warming and moistening • Hair in nostrils prevent large particles from entering lungs • Sneezing expels unwanted particles that are irritating the mucosal lining • Speech function: nasal vowels and consonants, vocal resonator Primary purpose of the nose is to protect the delicate lungs from hazardous exposure!! Anatomy and Physiology of the Nose Represent an Accessible Organ Portal • The nasal vestibule runs for about 15 mm from the nostrils (nares) to the nasal valve. • Behind the nasal valve is the nasal cavity, with a length of about 60 mm and a volume of 20mL, and this passes into the nasopharynx. • The nasal cavity is divided vertically for most of its length by the nasal septum, and each wall of the cavity contains three folds of indentations known as the nasal turbinates (or conchae). • This folding means that the nasal cavity has a relatively large surface area for its volume, approx. 160 cm2. • The wall has both hair and cilia. Physiology of the Nasal Cavity Makes it One of the Fastest Transport Routes • Systemic absorption is promoted by the rich blood supply feeding the nasal lining. • Nasal cavity has a large surface area readily accessible for drug absorption because of the presence of nasal turbinates. • Low molecular weight lipophilic drugs are well absorbed across the nasal cavity. These drugs can reach widespread circulation within a few minutes after dosing, as the venous blood passes from the nose directly into the systemic circulation. - Plasma profiles and bioavailabilities often comparable to those obtained from an intravenous injection. • Many drugs administered intranasally are absorbed faster and more efficiently than by oral administration, often resulting in a faster onset of action. Protective Mechanisms of Nasal Cavity and Pharynx • Bio-filter and air modifier: Filtering, warming, and humidifying inhaled air. • Inhaled droplets or particles become trapped by hair in the nasal vestibule or by the mucus layer in the main cavity, which gradually carries them to the back of the throat and down the gastrointestinal tract. • Its surface is coated with a continuous layer of mucous produced by subepithelial mucous glands. • The ciliated epithelium of the nasal passage facilitates the movement of the mucous layer. The mucous contains lysozyme, glycoproteins and immunoglobulins which act against bacteria and protects against their entry into the lungs. • The ciliary action and the sneeze reflex add further defense against external entry. • In addition, the nasal mucosa has a metabolic capacity for converting endogenous materials into compounds that are more easily eliminated from the body. Mechanisms of Nasal Absorption • Transcellular route: - Across cell membranes - Lipophilic drugs - Facilitated by concentration gradient - Yields similar bioavailability to IV • Paracellular route: - Through tight junctions between cells - Small polar molecules (<1kd) - Low absorption due to low pore area (~low surface area) - Proteins and peptides Nasal Drug Delivery Must Overcome Tight Junction Barriers Tight junctions are the connections between epithelial and endothelial cells that comprise various tissues of the body. • They regulate the passage of molecules across these natural barriers. Large MW drugs need to pass through these tissue barriers in order to get to their sites of action. • As part of the body's normal activity, tight junctions selectively open and close in response to various signals both inside and outside of cells. This allows the passage of large molecules or even entire cells across the tight junction barrier. Further Considerations for Nasal Delivery • The pH at the surface of the normal nasal mucosal cells is 7.39. • The mucus layer is slightly acidic at pH 5.5-6.5 • The local pH can be modified by the nasal formulation. - Drugs are more absorbed by passive diffusion as they become less ionized. • Aqueous channels between the cells provide a relatively good route for water-soluble compounds, which are limited mostly by molecular size. • Absorption promoters can facilitate absorption, e.g. cyclodextrins, chitosans, salicylates, phospholipids, DEET, and alkyl glycosides. Chitosan as a Penetration Enhancer for Nasal Drug Delivery • Chitosan formulation development methods have been successful in clinical studies for the nasal delivery of the peptide drugs PYY for obesity, PTH (parathyroid hormone) for osteoporosis, and the protein ß-interferon for multiple sclerosis. • Chitosan as a pharmaceutical excipient has unique properties that facilitate mucosal absorption of difficult to absorb drug molecules via its mucoadhesive properties. Limitations of Nasal Drug Delivery • Low residence time • Small volume - Large volumes interfere with normal physiological functions of the nose • Reproducibility of dosing is a concern - Deposition and distribution patterns often irregular - Method of administration - Condition of nasal passage - Environmental conditions Nasal mucosa is sensitive - Can't delivery drugs that cause irritation, inflammation or toxicity • It is difficult to deliver hydrophilic drugs • Avoid nasal delivery in patients with: - Common cold - Persistent sneezing - Nasal congestion - Nasal inflammation - Allergic rhinitis Intranasal delivery can be used to deliver drugs to the CNS. - Bypasses the CNS. - Minimizes systemic exposure. • Takes advantage of pathways along the olfactory and trigeminal nerves. • Intranasal insulin being developed for systemic treatment of diabetes showed delivery to the CNS. - Delivery of insulin to the CNS is being pursued as an Alzheimer's treatment. Nasal Dosage Forms • Incorporated into traditional spray applicators and complex metered delivery devices. • Nasal preparations are usually solutions or suspensions administered by drops or as a fine mist from a nasal spray container. • Topical treatment of the nasal-pharyngeal cavity includes ointments, gels, glycerogelatins and soft inserts. • Drugs may be introduced into the nasal passage for localized effects on the mucous membranes and underlying tissues (e.g. nasal congestion) Nasal Sprays May Be Used For Systemic Drug Delivery Aerosols • Deliver to anterior portion of respiratory region. • Increases in residence time increase absorption. • Can get accurate and reproducible doses. • Small droplet size gives excellent deposition and distribution, and is less likely to irritate. • Droplet size crucial to drug deposition. - >10 µm goes to upper respiratory tract - <0.5 µm is exhaled - 5-7 µm optimal • Drops are convenient to administer. - Difficult to control dose and site of application. - Fall on posterior part of respiratory region. - Cleared rapidly by nasal secretions. • Powders have longer residence time. - Produce effects for longer than solutions. - May cause irritation. - Not commonly used. • Ointments - Irritation potential and discomfort to patient. - Not commonly used. Delivery to the Brain • Olfactory region at roof of nasal cavity has direct access to CSF. (only part of body where this occurs!) • Extremely useful for delivery of polar drugs which have poor permeability across BBB. • Transcellular and Paracellular pathways. - Lipophilic drugs better absorbed via trancellular pathway. • Nasal route should be used cautiously for systemic administration because absorption into CSF can be dangerous. Variability in Delivery to the CNS • Different groups delivering similar drugs have gotten very different results. - Indicates that formulation and experimental differences can play a large role in delivery efficiency. • The exact mechanisms of delivery are not understood. - Olfactory and trigeminal nerve pathways. - Vascular pathway - Pathways involving CSF and lymphatics. Techniques in Administration • Head position - Seven positions were studied - https://www.researchgate.net/publication/699261 3_The_'best_method'_of_topical_nasal_drug_deli very_Comparison_of_seven_techniques - May not be a single best technique: Individualized approach, taking anatomy and head position into account is most appropriate Head position (continued) - Affects patient compliance • Angle of spraying - Slight tendency toward 35 to 45° angle • Administration technique - Sprays, nose droppers, needle-less syringes • Volume and Frequency - No systemic studies have been published evaluating the effect of volume on delivery to CNS Formulation Considerations • Strategies to improve drug solubility. - Encapsulation, microemulsions, nanoparticles. • Strategies to improve membrane permeability. - Permeation enhancers • Osmolarity - Changes can cause cells to swell or shrink. • pH and ionization state - Positively charged drugs may form electrostatic interactions with negatively charged nasal epithelial cells Vaccination and Immunization • Nasal mucosa is first structure to come into contact with pathogens in inhaled air. • Nasal secretions have antimicrobial and immunologic activity. • Nasally administered vaccines generate: - Local immunity: • Stimulate production of secretory IgA. - Systemic immunity: • Stimulate production of circulating IgM and IgG. Advantages and Limitations of Nasal Vaccines • Induces both local and systemic immunity • Ease of administration • Low in cost • Painless • BUT: Low absorption of live or attenuated antigen - Must add adjuvants - Chitosan containing antigen formulations can produce a greater immune response - Powders produce higher antibody titers, but cause irritation. Nasal Delivery Challenges • Conventional polar drug molecules and hydrophilic biopharmaceuticals (e.g. peptides, proteins, carbohydrates, antisense agents, and genes) present special drug delivery challenges. • Most peptides and proteins have shown poor bioavailability (~<1%) when administered via the nasal route. • LIMITING factors of nasal absorption are the POLAR nature and the LARGER size of these molecules. The molecules may also be unstable and prone to modification or degradation due to changes in the pH of the local environment or the presence of enzymatic systems. - Minor structural changes can render some polypeptides biologically inactive. • The mucus layer lining the epithelium represents one barrier to absorption. • The mucociliary clearance mechanism leads to a short residence time at the site of absorption. Combination Products and Devices Dry Powder Inhaler Nasal Spray Aerosol or Nebulizer or Metered Dose Inhaler Unique to nasal dosage forms is the delivery device for inhalation and sprays • Regulated by FDA as combination product (drug + device) • Device performance to deliver medication into nose must be demonstrated and controlled • Multiple FDA Guidances for Nasal Sprays, Inhalation Solutions, Inhalers, manufacturing of devices, etc. • Lots of physics: ex. plume geometry, spray pattern, droplet size distribution USP <1664>: High degree of concern and high risk of packaging interaction is Inhalation Aerosols and Spray • Why? Devices are often plastic and delivery is to lung

Lect. 20

Pathways of Transdermal Permeation: 1. Intercellular Route=around cells 2. Transcellular route= through cells= larger SA for drug delivery 3. Transappendageal route= through hairs and stuff= i.e. don't put on hairy skin Lipophilic Drugs: predominantly intra(trans)cellular route=goes through Hydrophilic Drugs: predominantly intercellular route Drugs Applied to Skin • Topical Delivery for local effect - Creams, ointments etc. • Transdermal Delivery for systemic effect - Skin as a route of administration Local Treatment of Skin Conditions • Effects on epidermis & upper dermis - Inflammation is involved in many skin disorders What do you need to make a topical products? • Oil-Based Excipients - Oil Phase in creams & lotions - Carrier for oil soluble drugs - Emollient and Occlusive moisturizer • Water • Surfactants - Emulsification of creams and lotions - Increase drug absorption • Humectants & Emollients - Increase water retention or prevent water loss - Skin Moisturization - Glycerin, Glycols, Mineral Oil • Emulsion Stabilizers - Deposit at the interface to stabilize emulsions - Cellulose Polymers, Carbomer • Solubilizers - Increase solubility of drug or excipients - Propylene glycol, Cyclodextrin • Viscosity Builder - Used to increase viscosity for physical stability and usability - Cellulose-based and other polymers • Antimicrobial Preservatives and Antioxidants Dosage Forms for Local Delivery • Traditional Dosage Forms - Ointments - Lotions - Solutions - Tinctures - Liniments - Pastes - Topical Powders • Popular Dosage Forms - Creams (most popular - Gels - Sprays - Foams - Sponges/Towelettes Quality Attributes of Topical Products • Chemical Stability - Complex excipients derived from natural sources - May contain a large number of known and un-known impurities in solution form - Excipients compatibility of active and functional ingredients is critical during development phase - Assay for active and preservatives - Monitoring known degradation products through shelflife Drug Release - Although not required for routine testing, in-vitro release is often used to compare different lots and brands of products during post-approval changes or introduction of generic version of branded products. - Franz diffusion cell is the most commonly used method for release testing. Medium may be temperature controlled and stirred to provide sink condition Consistency/Physical Stability - Multi-phase systems can become unstable and cause formulation breakdown such as phase separation and sedimentation - Generally evaluated by visual examination and viscosity • Dosage Uniformity - Improper manufacturing can produce variability in dosage delivered as high viscosity materials and often difficult to mix - Assay for active taken from various part of the package and packages manufactured at various points in filing process provides dosage uniformity Microbial Enumeration and Identification - All raw materials and finished products are controlled for total microbial burden (generally <100 CFU/gm) and no E. coli or Salmonella species. • Antimicrobial Preservative Effectiveness - APE testing is required during development and throughout the self-life - APE is measured as the ability of the formulation to prevent growth of bacteria, yeast & mold. • E. coli, P. aeruginosa, S. aureus • C. albicans, A. niger Why use Transdermal drug delivery? • By-passes the first-pass metabolism • Variation associated with oral therapy are avoided • Continuity / ability to terminate medication • Multiday therapy with single application • Avoids risk & inconvenience of parenteral therapy • Extends activity of drugs with short half lives • May provide an alternative when oral route is unsuitable • Better patient compliance Transdermal delivery reality check.. • About 25 drugs make up the entire segment of transdermal market treating only a handful of conditions • Why? - Molecular size limited by skin barrier - Low delivery requires potent drugs - Active immune system causes skin irritation Factors Affecting Percutaneous Absorption • Drug concentration/solubility in vehicle • Partition coefficient • Surface Area • Skin Hydration & Temperature • The site of application • Penetration enhancers • Other - Age ? Race ? Chemical Penetration Enhancements= to inc penetration of drug • Very active field of research in transdermal delivery - Organic solvents • Ethanol, Isopropyl myristate, N-methylpyrrolidone, DMSO, Lemonene, - Fatty acids and alcohols • Oleic acid, Lauryl alcohol - Detergents and surfactants • Bile acid, Polysorbates - Proprietary chemical • Azone, CPE-215, NexAct, SEPA Mechanism of Chemical Penetration Enhancers • Extraction of intercellular lipids & dilation of extracellular space between cornified cells • Increase in partitioning into skin • Increase in the fluidity of stratum corneum lipids • Increase in thermodynamic activity in vehicles - Most enhancers work by multiple mechanisms - No universal enhancer for all types of molecules - No chemical enhancer for macromolecules (peptides) Types of Transdermal Systems: 1. Drug Reservoir Membrane-Modulated Systems (CAN'T CUT)=backing>drug reservoir> control membrane>adhesive layer>peel strip -Release membrane may be prepared from a copolymer of ethylene acetate with vinyl acetate 2. Drug-in-Adhesive Diffusion-Controlled Systems(CAN CUT)= backing> drug in adhesive> lining -Drug is typically contained in a pressure sensitive adhesive (PSA): polyisobutylene (PIB) or polysiloxane or acrylatebased; acrylic adhesives used in most products • Noven's DOT Matrix technology uses adhesive blend of silicone, acrylic, and drug • Release liner material depends on adhesive used; typically fluorocarbon-coated polymer films used to line silicone adhesives and silicone coated films used to line acrylate based adhesives 3. Matrix Dispersion-type Systems (CAN'T CUT)= drug impermeable plastic backing> absorptive pad> occlusive baseplate aluminum foil and adhesive rim on sides> drug reservoir (drug/polymer matrix) -Matrices are often prepared with polymer mixtures such as PVP and PVA with the drug dissolved or dispersed at high temperature and then polymer gels on cooling Patch placement • Abdomen, upper arm, back & thigh most common • Avoid hairy areas • Rotate sites Proper Usage & Handling of Transdermal Patches • Once lining is pulled off, do not touch the sticky surface of the patch • Do not apply to broken or irritated skin • When applying a new patch, remove the old one ! Do not apply two to compensate for a missed one. Wear only for the designated period of time • Do not cut the patch Adhesive Failure • FDA has received several reports of "adhesion lacking" in TDDS • Poor adhesion can lead to improper dosing of patients, in addition to increased costs & possible safety issues • Potential accidental dosing of children from fallen or transferred patches possible Other Safety Issues • Increased absorption due to heat • Dose dumping - Leakage of gel reservoir - Failure of Electronics • Accidental ingestion or transfer • Misuse of controlled substances • Skin Burns during MRI Scans Variation of Dosage Forms: Gels & Solutions • AndroGel - 1% & 1.67% - Shoulder & Upper arm • Testim - 1% Single-dose Gel - Shoulder & Upper arm • Axiron - 30 mg / 1.5 mL - Under-arm Variation of Dosage Forms: Metered-Dose Spray (onto skin) • EvaMist (Estadiol) • 90 mcL/1.53 mg per spray • Symptoms of menopause • 1.7% Estradiol in Ethanol and Octisalate • Sustained release film Transdermal Products: Tid-bits • Transderm-Scop the first transdermal product (Alza/Ciba, 1981) • Several nitroglycerin patches available on market from various manufacturers - low dose, short half life - rapidly metabolized by liver - nitroglycerin ointment also used • Catapres TTS (clonidine) provides 7 days of continuous antihypertensive therapy • Estraderm (17 ß-estradiol) used for treatment of symptoms associated with menopause while Testoderm (testosterone) used for hormone replacement therapy in men Transdermal Products: Nicotine • Several nicotine patches available on market from various manufacturers - Nicoderm, Habitrol, Prostep, Nicotrol - Aid to smoking cessation • Typically, 21 mg/day over 24 hrs for 4-8 wks followed by weaning doses of 14 mg/day for 2-4 wks and then 7 mg/day for another 2-4 wks Enhancement Technologies in Development: Skin Microporation • Microneedles • Laser Ablation • Thermal Ablation (Altea Therapeutics - ?) • Radiofrequency ablation Skin Microporation • Minimally invasive technique to create micron sized temporary transport pathways • Painless and with acceptable skin tolerability- - Thermal microporation - Mechanical microneedles • Overview/silicone & metal needles • Soluble/Maltose microneedles Minimally invasive Micron-sized needles which are sharp enough to penetrate the barrier, but are small enough such that they do not reach the nerve endings and hence are painless Enhancement Technologies in Development: Energy assisted • Iontophoresis - Alza, Iomed/Empi, Transport Pharm., Travanti, Isis Biopolymer, Nupathe • Electro-osmosis, Electroporation • Phonophoresis, Magnetophoresis • Powder injection (Powderject/Pfizer) • Controlled Heat (CHADD/Zars Pharma for Synera) • Photomechanical waves Iontophoresis is already used in physical therapy clinics for localized delivery of drugs • For use with drugs in solution such as Iontocain (Lidocain for Iontophoresis) - Fill negatively charged on negative electrode chamber and vice-versa - Apply current to initiate drug delivery Pre-Medicated Iontophoresis Patch • Ionsys - E-Trans Fentanyl - Approved in 2006 for short term pain management • Programmed and patient controlled delivery, comparable to IV infusion Ultrasound (Phonophoresis, Sonophoresis) • Ultrasound waves (frequency > 20 kHz) cause disruption of lipid layers and cavitation to transport drug through skin • Modes of ultrasound - Continuous - Pulse Asymmetric collapse of a bubble near a surface, producing a jet of liquid toward the surface. Working with skin biology to open channels: Skin Penetrating Peptides Future Directions • Combination Strategies • Delivery of Microspheres and other Particulates • Understanding pore closure kinetics • Fabrication of metal microneedles and coating technologies • Understanding pore formation via sonophoresis -the most common method of enhancing penetration of molecule through skin is sorption promoting solvents

Lect. 19 Ocular Delivery

The Eye • Anterior and Posterior segments • Ocular diseases - Caused by malfunctioning, degeneration, infection, or inflammation of one or more of the sensitive ocular structures • Cornea has five layers - Hydrophilic and lipophilic, presents a biphasic environment, so drugs need biphasic solubility characteristics to gain access to inner eye Some common diseases Description Age related macular degeneration (AMD) Damage of macula destroys sharp central vision Cataract Clouding of the lens Diabetic eye disease Damage of blood vessels inside the retina Glaucoma Damage of optic nerve Ocular Drug Delivery • Advantages: - Achieve local effects without systemic side effects. - Avoid first-pass metabolism. - Allow reasonable residence time for advanced dosage forms. • Disadvantages: - Have a very limited absorption area. - May interfere with vision. - Causes moderate discomfort. - May be difficult to dose properly. - Systemic absorption is possible Routes for Drug Administration • Locally - Eye drops - Ointments - Injections 1. Periocular injection (subconjunctival, subtenon, peribulbar or retrobulbar (into optic nerve pt)) 2. Intraocular injections (intracameral (into anterior chamber of eye) or intravitral) • Systemically (Oral or IV, less common) Ophthalmic Dosage Forms • Include multiple simple systems (physical state) and devices designed for unique physiological delivery: - Simple liquids: aqueous solutions, peroxides, lipophilic solutions, sprays - Emulsions, creams, ointments and other semi-solids - Solids and gels - Suspensions - Implants - Polymeric inserts (drug impregnated) - Devices The preparation and manufacture of solutions, suspensions and solids for ophthalmic use requires special cGMP considerations for: - Sterility - Preservation - Isotonicity - Buffering - Viscosity - Bioavailability - Packaging Sterility and Preservation • Consistent with other sterile products. • Solutions and suspensions must be sterilized for safe patient use. • Preferable to sterilize products in their final containers by autoclaving at 121oC for 15 minutes. - Sometimes precluded by the thermal instability of the formulation's components. • As an alternative, bacterial filtration or radiation sterilization (of creams and ointments) may be used. - Filtration also removes particulate matter. Isotonicity • Critical since osmosis controls the transfer through a semi-permeable membrane at the site of absorption. • Body fluids, including blood and lacrimal fluids have an osmotic pressure which is isoosmotic with 0.9% w/v sodium chloride solution. • ALL of the solution components, including the active and inactive ingredients contribute to the osmotic pressure of a solution. • In practice, the isotonicity values of ophthalmic solutions may comfortably range between 0.6 and 2.0% sodium chloride. - Hypertonicity (crenation) and hypotonicity (hemolysis) are "most" critical for red blood cells, not lacrimal fluids. Buffering • Adjusted to match the normal tears (pH 7.4). • The pH adjustment by buffering leads to greater dosage form controls: 1. Greater comfort for the eye. 2. Render the formulation more stable. 3. Enhance the aqueous solubility of the drug. 4. Enhance the drug's bioavailability (by favoring unionized molecular species). 5. Maximize preservative efficacy. Excipients=low amts • Many of the ocular excipients in and formulation processes are closely guarded trade secrets -just know important categories of excipients for eye: Viscogens, stabilizers and preservatives Viscosity and Thickening Agents • Control the fluidity of the dosage forms. • Instillation of the drop preparation depends on flow from the dispensing tip. • The influence of shear is critical to producing a consistent volume of deposition. • Packaging design and the temperature management of the product and container will ensure a consistent flow and drop formation from a bulk dispenser. • The volume of the ophthalmic drop is designed to flood the corneal plain in an optimal fashion based on bioavailability. Vehicle • Ophthalmic drop uses purified USP water as solvent • Guidelines for obtaining purified water by distillation, deionization or reverse osmosis • Oils have been used as a solvent for products sensitive to moisture -intravitreal injection= most common -systemic abs of drug in eye is possible b/c drug can be absorbed into blood stream through the many compartments of the eye and drug is mostly in tears, some of which can be reabsorbed -bioavailability affects dosage form and conc b/c most topical eye drops are lost to tears making abs component quite small (usually 1%) -drugs are NOT rapidly abs in eye tissue b/c eye is BIPHASIC= hard af for drugs to cross Ocular Delivery Techniques: 1. Intraocular implants= inc risk of retinal detachment and intravitreal hemorrhage, invasive 2. systemic admin= limited/variable penetration= potential for systemic toxicity= usually oral? 3. intravitreal injections= inc risk of retinal detachment, hemorrhage, endophthalmitis and catatracts -rapidly diluted -repeat procedures necessary 4. topical application= limited penetration (<5% -rapid tear washout -poor patient compliance Physiological Factors That Affect Ocular Absorption: • Blinking may rapidly remove drugs from absorption site • Tears function to prevent infection, remove cellular debris and provide moisture - 7 microliters is normal tear volume - 30 microliters is maximum tear volume= over that, washes out - inc Tear production with inc dilution of instilled drug (normal defense) • Proteins in tears bind drug =dec efficacy • Eye infection may change retention of dosage form, and sometimes even cornea permeability Ophthalmic Formulations • Eye-drops are the conventional dosage forms that account for 90% of currently accessible ophthalmic formulations • Excellent acceptance by patients, and easy to prepare, filter and sterilize • One of the major problems encountered is rapid precorneal drug loss • To improve ocular drug bioavailability, there is a significant effort directed towards new drug delivery systems for ophthalmic administration Ointments: Not popular due to greasiness and inconvenience caused by blurred vision - Recommended for nighttime administration. - Increase ocular contact time • Suspensions: Lipophilic drugs - Longer contact time because particles are retained in conjunctival cul-de-sac - May cause irritation depending on particle size (need <10µm) Contact Lenses and Lens Solution • Special case of ophthalmic drug delivery • Three special cases of contact lens design (some may have impregnated drug depot) include: - Hard contact lenses - Soft contact lenses - Disposable soft lenses • Functionality of Contact lens Solutions: - Cleaners (surfactants) - Soaking or storage solutions (0.01% w/v solutions of benzalkonium Cl or Na edetate) - Wetting solutions (polyvinyl alcohol, hydroxyethylcellulose) Ophthalmic Drug Delivery Inserts =Depend on Physico-Chemical Properties - Soluble - Insoluble • Diffusional • Osmotic • Contact Lens - Bioerodible Pharmacokinetics in the Eye • Vitreous - Large hydrophilic and charged molecules active transport mechanisms - Often slower elimination than systemic circulation • Peculiarities for Development - Cannot sample ocular tissues in humans, only plasma - Exposure response relationships and tissue distribution in animals critical - Plasma levels guide human studies based on models from animals PK of eye: Fig. 1. Schematic presentation of the ocular structure with the routes of drug kinetics illustrated. The numbers refer to following processes: 1) transcorneal permeation from the lacrimal fluid into the anterior chamber, 2) non-corneal drug permeation across the conjunctiva and sclera into the anterior uvea, 3) drug distribution from the blood stream via blood-aqueous barrier into the anterior chamber, 4) elimination of drug from the anterior chamber by the aqueous humor turnover to the trabecular meshwork and Sclemm's canal, 5) drug elimination from the aqueous humor into the systemic circulation across the blood-aqueous barrier, 6) drug distribution from the blood into the posterior eye across the blood-retina barrier, 7) intravitreal drug administration, 8) drug elimination from the vitreous via posterior route across the blood-retina barrier, and 9) drug elimination from the vitreous via anterior route to the posterior chamber Market Overview - All Ocular Indications -#1 sales= anti-VEGF (cancers and macular degreneration) -2nd= glaucoma -top ocular pdt= from regereon= Eylea • Iontophoresis to allow topical delivery to both anterior and posterior tissues of the eye Glaucoma Treatments (Front of the Eye) • Majority are topical drops • Treat symptomatic increase in intraocular pressure (aqueous humor) • Delivery Systems - Primary focus on moving multiple daily drops to once per day - Inserts in development for once per week administration • Unmet Need for Delivery Systems - Once every three months injection - Subconjunctival injection depot - Patients see the doctor once every three months Glaucoma Delivery System Opportunities • Sustained Release Depot System - PLGA or other polymer implant or microparticle - Primarily small molecules - Polymer inserts • Physician administered therapy - Glaucoma physicians not yet comfortable with injection - Must be a simple injection • Delivery Constraints - Injection site is conjunctiva - Safety first - must not cause inflammation or tolerability issues - Volume of injection is preferably 50 microliters - 100 to 200 microliters may be tolerated - 27 gauge needle or better Sustained Release Implant Back of the Eye Diseases Diseases of the Retina, Vitreous, and Macula Drug Delivery to Posterior Segment • Diseases include neovascularization, macular degeneration, diabetic retinopathy, and posterior vitreous detachment - Some if untreated may lead to blindness • Posterior not accessible to drugs applied anteriorly on corneal membrane of conjunctival cul-de-sac • Implants of biodegradable and non-biodegradable polymers used to deliver drugs • Minor surgery required • Matrix implants for acute disorders • Reservoir implants for long standing disorders • Vitreal and scleral injections: repeated injections risky and inconvenient Back of the Eye Diseases • Diseases of the Retina, Vitreous, and Macula - Age related macular degeneration - Retinitis pigmentosa - Diabetic retinopathies - Neural changes induced by glaucoma • Age-Related Macular Degeneration (AMD) - Leading cause of severe vision loss in people over 50 - Most people have dry form - no treatment available - Wet form is less common but treatment exists - Laser photocoagulation therapy - Pharmacotherapies Dry AMD •Cells of macula breakdown •Drusen deposits •Death of RPE and photoreceptor cells •Blurry or spotty loss of clear, straight ahead vision •90% of cases Wet AMD •Abnormal blood vessels grow - neovascularization •Leak fluid and blood scarring macula •Straight ahead vision can be distorted or lost in a short period of time •10% of cases •90% of legal blindness Opportunities for Ocular Delivery Systems • Increasing retention time of drugs applied topically to corneal membrane or conjunctival culde-sac • Delivering drugs to posterior segment via application to anterior segment • Reducing complications associated with administration to posterior segment • Extended release products that avoid repeat injections

Lect. 1 and 2

FDA: Foods are safe, wholesome and truthfully labeled. • Drugs for both humans and animals, and vaccines for humans are safe and effective. • Blood used for transfusions is safe and in adequate supply. • Medical devices, from scalpels to CT scanners, are safe and effective. • Transplanted tissues are safe and effective. • Equipment that uses radiant energy, such as X-ray machines and microwave ovens, is safe. • Cosmetics are safe and properly labeled. Responsible for evaluating and approving new products. 1) The Center for Drug Evaluation and Research (CDER) 2) The Center for Biologics Evaluation and Research (CBER) 3) The Center for Devices and Radiological Health (CDRH) 4) The Center for Food Safety and Applied Nutrition (CFSAN) 5) The Center for Veterinary Medicine (CVM) GMP - Good manufacturing practice - Drug products to be administered to humans • GLP - Good laboratory practice - For labs conducting non-clinical studies (toxicology and pharmacology studies in animals). • GCP - Good compounding practice - Compounding is different from manufacturing due to: • The existence of specific practitioner-patientpharmacist relationships. • The quantity of medication prepared. • The conditions of sale. Investigational New Drug • The way a pharmaceutical company gets permission to ship an experimental drug across state lines before a marketing application has been approved. • Required for clinical studies that are for: - A new indication. - A change in the approved route of administration or dosage level. - A change in the approved patient population. - A significant change in the promotion of an approved drug. • IND must cover three broad areas: - Animal Pharmacology and Toxicology Studies • Preclinical data that assesses safety - Chemistry and Manufacturing Information • Composition, Manufacturing Methods, Stability, Activity - Clinical Protocols and Investigator Information • Detailed protocols of proposed clinical studies, and qualifications of the clinical investigators. • Can be initiated either by an investigator (physician) or a sponsor (pharmaceutical company). New Drug Application • Formal proposal that the FDA approve a new pharmaceutical for sale and marketing. • Want to show FDA that: - The drug is safe and effective. • The benefits outweigh the risks. - The labeling / package insert is appropriate and contains adequate information. - GMP was used, and the drug's identity, strength, quality and purity were preserved during manufacturing. NDA documentation should include: - Ingredients of the drug. - How the drug is manufactured, processed and packaged. - Animal study results. - Clinical trial results. - Drug behavior in the body. • After NDA is approved, new drug can be legally marketed in the US starting that day. Abbreviated New Drug Application • Application for a generic drug for an existing approved drug. - Comparable in dosage form, strength, route of administration, quality, performance characteristics and intended use. • Animal and clinical trial data is not required. • Must demonstrate bioequivalence. - Generic drug must perform in the same way as the approved drug. International Harmonization of Approval Process (ICH) • The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (www.ich.org). • Collaboration of regulatory authorities and experts from the pharmaceutical industry of Europe, Japan and US. • The purpose is to achieve greater harmonisation in requirements for product registration in order to reduce duplication of R&D efforts for new medicines. • The objective is a more economical use of resources, and the elimination of unnecessary delay in the global development and availability of new medicines • U.S. Code Title 21 - Food, Drug and Cosmetic Act -APIs= under GMP • Nutritional supplements are regulated as foods, not as drugs. Lipitor® (atorvastatin calcium) Tablets for oral administraton Trade Name Copyrighted, -Trademarked, Country-Specific -Generic Name= INN (ex-US, International Non-Proprietary Name (WHO))* USAN (US, United States Adopted Name (AMA))** Others -Dosage Form Description -which is the US adopted drug name? = atorvastatin calcium Types and Sources of APIs Small Molecules : -Inorganic salts (potassium chloride) • Isolated from natural sources (morphine) or fermentation of naturally occurring microbes (penicillin, lovastatin) • Chemical modification of natural product (hydrocodone, simvastatin) • Chemical synthesis (acetaminophen, atorvastatin) -Macromolecules • Biotechnology - Microbial fermentation to produce recombinant proteins (insulin) • Animal culture (adalimumab, erythropoeitin) API Physical Forms • Crystalline solids - Potential for polymorphism, solvates, stability - X-ray powder diffraction, DSC, TGA • Amorphous solids - Amorphous forms of crystalline solids - can be unstable - Stable in absence of crystalline phase - peptides - Surface area, adsorption issues can be important to stability • Gases, liquids - Inhaled anaesthetics (Sevoflurane) - Oils (nitroglycerine) • Solutions - Most biotechnology products are frozen Purified Drug Concentrate (PDC), formulated and ready for lyophilization in some cases - Extracts, tinctures API Manufacturing Processes • Highly diverse in complexity, process and scale - from grams per year (monoclonal antibodies) to thousands of tons per year (aspirin, ibuprofen). • All API manufacturing processes are validated to control SISPQ (Safety-Integrity-Strength-Purity-Quality). • Process details are confidential. • Generic APIs are commodity chemicals, and comply with compendial requirements (USP, Ph. Eur., JP). • Process details and controls are filed with regulators, and manufacturing is subject to regular inspection by authorities. • Vehicle for regulatory filing is a New Drug Application (NDA) for proprietary new drugs, or a Drug Master File (DMF) for generics. • Impurity profiles and physical properties can differ among manufacturers of the same generic API API Purification Methods Small molecules • Distillation and sublimation can often be applied to small molecule purification. • Crystallization is the next-cheapest and most effective method when applicable. Small molecules and macromolecules • Chromatographic purification is applied when necessary - this is routine for peptides and proteins. • Many types of chromatography are useful. - Affinity (highly specific, useful for capturing product from crude mixtures) - Ion-exchange (high capacity, aqueous solvents) - Reversed-phase (medium capacity, high efficiency) API Storage and Stability • Stability studies are typically conducted according to ICH guidelines, and include stressful storage conditions (temperature, light, humidity) to identify conditions that will impact SISPQ and characterize degradation products. • Storage containers are impermeable, compatible, suitable for shipment, and offer light protection when warranted. • APIs are generally stored under conditions that do not result in significant degradation over time. • Rather than an expiration dating period as for drug products, a retest interval is established. • Regulatory limitations on repeated retesting for commercial products. -literally a retest interval to see if drug pdt still ok, vs biologics= use expiration date b/c want to be more conservative API Development and Quality Control • Considerable regulatory guidance for new drug development is available from ICH, FDA, and the EU, covering: - Process development and validation - Analytical methods development and validation - Stability study conduct and interpretation - Specifications development and justification - Change control procedures • Quality control information for proprietary drugs is generally not in the public domain. • Compendial monographs (USP, Ph. Eur, JP) are available for most generic drugs, and provide basic test method descriptions and specification limits for identity, strength, purity and quality. - Assay Range - Impurities - Physical Properties - Biological Limits and Assays API Impurities • This category includes: - synthetic impurities and by-products, such as enantiomeric impurities - process impurities (unreacted reagents, residual solvents, elemental impurities) - degradation products that might be produced during storage or handling. • Characterization (isolation and structure determination) and toxicological evaluation of impurities is required for registering a new drug. • Quality specifications or monographs impose limits on total impurity content and individual impurity levels. Some "ordinary impurities" are listed in USP. • Impurity profiles can differ among manufacturers of an API, especially if they use different synthetic methods. This is a regulatory and quality issue. Pharmaceutically Important API Physical/Chemical/Biological Properties • Particle size and surface area • Wettability, density, contact angle, Zeta potential • Water or solvent content • Counter-ion identity • Ionization constants • Vapor pressure • Solubility, aqueous (pH-dependent) and non-aqueous • Intrinsic dissolution rate • Permeability • Potency • Absorption/Distribution/Metabolism/Excretion (ADME) • Crystal form (solid-state properties) • Hygroscopicity possible successful combinations for thereapeutic usefulness: high solb, high perm= low-high required potency -low solubility, high perm= med-high req potency -high solb, low perm= med-high req potency -low solb, low perm= high potency required Particle Size and Surface Area • Solid APIs are usually defined as powders (<250 µm) for homogeneity, ease of handling. • Simple milling is usually used to produce uniform powders. • Useful methods include wet sieve, dry sieve, laser diffraction, optical techniques, gas adsorption, mercury intrusion. • Micronization (<10 µm) can improve dissolution rate, wettability, uniformity of suspension dosage forms. • Nanoparticle formation (<0.5 µm) can reduce crystallinity and improve dissolution rate, apparent solubility and oral bioavailability. • Small particle sizes can cause handling and safety issues, and can lead to excessive surface moisture adsorption and reduced stability. Crystal Form • Regulatory filings for new API will specify crystal form, but compendial monographs usually do not. • Polymorphism (the existence of more than one stable crystal packing arrangement) is common in crystalline APIs • Polymorphs can have different stability, solubility and other properties. - Polymorph interconversion can cause severe problems in manufacturing or stability of API or dosage form - The most stable polymorph is usually preferred for pharmaceutical use • Ostwald's Rule: The least stable polymorph crystallizes first

Lect. 4

Just understand diff types and categories of excipitents, final= not like the poll ev questions more like why would u use a disintegrant, don't memorize expients "Excipients are components of a finished drug product other than the active pharmaceutical ingredient (API) and are added during formulation for a specific purpose. Although listed as inactive ingredients by FDA, excipients generally have well-defined functions in a drug product." This may: • Facilitate preparation and commercial manufacturing • Improve performance (efficacy and safety) - Dissolution and Bioavailability • Improve shelf-life - Stabilize (chemical, physical and microbiological) • Improve patient compliance • Facilitate identification and marketing=color, form, print -ICH Q8 Guidance • Pharmaceutical Development Section - design a quality product and its manufacturing process to consistently deliver the intended performance of the product - knowledge that establishes that the type of dosage form selected and the formulation proposed are suitable for the intended use. - At a minimum, those aspects of drug substances, excipients, container closure systems, and manufacturing processes that are critical to product quality should be determined and control strategies justified. Critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product Excipients - Concentration - Compatibility in the formulation • API • with other excipients - Bioavailability - Manufacturability - Provide their intended functionality - Stability - Safety Excipient Selection • International or Domestic=diff grades • Kosher • Natural or Synthetic excipient• Lactose Intolerant • BSE/TSE (Bovine Spongiform Encephalopathy/Transmittable Spongiform Encephalopathy) =aka any animal pts? or • Maximum product usage to allowable daily intake, • Compendial • Intended Use Excipient Types: • Diluents • Binders • Disintegrants • Lubricants • Glidants • Solubilizing Agents • Colorants • Sweeteners • Flavors Diluents • Select the diluent to have a similar particle size distribution to the granulation or • Make the granulation to a similar size of the diluent selected • Should have good flow and binding properties Diluents (don't memorize) • Lactose - Spray Dried, Granulated, Anhydrous • Microcrystalline Cellulose (non-silicified, silicified) - Many particle size grades available • Calcium Phosphate - Dibasic anhydrous, Dibasic dihydrate, Tribasic • Calcium Carbonate • Compressible Sugar • Dextrates • Maltodextrins • Pregelatinized Starch • Mannitol, Sorbitol, Xylitol, Maltitol (chewable tablets) Binders • Binders are typically not used as an excipient in direct compression tablet formulations • Binders are used in the manufacture of granules that are blended with other components and compressed/encapsulated • May be used in solution, dry or a combination • Common Binders - Celluloses (hypromellose 2910, hydroxypropyl cellulose) - Polyvinylpyrrolidone - Starch - Pre-gelatinized Starch Disintegrants Disintegrants swell causing tablets to break apart. The ultimate goal of a disintegrant is to aid in dissolution of the active drug substance • Common Disintegrants - Sodium Starch Glycolate - Croscarmellose Sodium - Crospovidone - Starch, Pregelatinized Starch - Microcrystalline Cellulose - Materials that have swelling properties can be used as disintegrants Lubricants • Prevent sticking of the blend to the compression punches and dies/encapsulator fillers • Aid in ejection of the tablet from the die • Can slow dissolution (magnesium stearate) • Reduce compressibility • Common Lubricants - Magnesium Stearate - Calcium Stearate - Stearic Acid - Sodium Stearyl Fumarate - Talc - Hydrogenated Vegetable Oil - Sodium Benzoate - Polyethylene Glycol (high molecular weights) Glidants • Improve flow by reducing inter-particulate friction • Generally these materials have poor flow and compressibility by themselves • Common Glidants - Silicon Dioxide - Colloidal Silicon Dioxide - Talc Solubilizing Agents • Used to improve solubility/bioavailability of an API • Common solubilizing agents - Cyclodextrins - Glyceryl Monostearate - Poloxamer - Sodium carboxymethylcellulose - Sodium lauryl sulfate - Polyoxyethylene esters, sorbitans and stearates Color Additives • Used in low concentrations for product identification • Colorants are approved per country - FDA, http://www.fda.gov/ForIndustry/ColorAdditives/ColorAdditiv esinSpecificProducts/InDrugs/ucm121166.htm - 21Code of Federal Regulations (CFR) section is linked for each color listed - Vendor info • http://www.colorcon.com/regulatory- compliance/documents - Select Color Additives have daily intake limitations (e.g. combined total of D&C Red No. 6 and D&C Red No. 7 does not exceed 5 milligrams per daily dose of the drug) Sweeteners • Aspartame - Must report phenylalanine amount in formulation • Acesulfame K • Sucralose - Heat stable • Sodium Saccharin - Safety concerns • Sodium Cyclamate - Safety concerns Flavors • Citric, malic, fumaric acid • Flavors (e.g. mint, grape, cherry) • For taste-masking • Flavor selected based on drug taste and target population • Used in low concentrations • Flavors composed of many chemicals - May impact stability Controlled/Extended/Delayed Release Polymers • Celluloses - Hypromellose (HPMC)/Hydroxypropyl Cellulose (HPC) (controlled/extended release) • Hydroxypropyl acetate succinate (enteric) • Methacrylic acid copolymers (Eudragit®) - pH dependent/pH independent (controlled/extended/enteric release) • Polyethene oxides - (controlled/extended release) • Polyethlene Glycol (solutions/suspensions) • Glyceryl monostearate Additional Agents • Thickening/Suspending Agents - Cellulose • HPMC/hyroxyethyl cellulose (HEC)/carboxy methyl cellulose (CMC) - Tragacanth - Xanthan Gum - Guar Gum - Povidone - Sodium Alginate • Preservatives (mainly found in liquid products) - Methylparaben - Propylparaben - Sodium Benzoate • Antoixidants/Chelating Agent (mainly found in liquid products) - Ascorbic, fumaric, malic, citric acid - EDTA (Edetic acid; Ethylenediaminetetraacetic acid), NaEDTA Solvents/Diluents • Used as a diluent/solubilizer/sweetner or as a process aide which is removed on drying (granulation binder or film coating solution) • Water • Non-aqueous (isopropyl, methanol, acetone) • Propylene glycol • Glycerin • Polyethylene glycol • High fructose corn syrup Types of water • Purified (solvent/oral formulations) • Sterile - Sterile water for injection - Sterile water for inhalation - Sterile water for irrigation • Bacteriostatic water for injection (contains antimicrobial agents) • Water for injection • Carbon dioxide free water • De-aerated water • Hard (contains calcium carbonate) • Soft (contains calcium carbonate) Excipient Safety Regulations • Current FDA Guidance for a New Excipient (Ref. 2) - Pivotal toxicology studies (assess pharmacological activity) - Vary based on duration of use (<14 days, 14 d-3 mo., >3 months) - Additional requirements for pulmonary, injectable and topical - Photosafety - Exceptions - lifesaving therapies, pediatric use Safety - BSE/TSE • Commercial protein derived from the native protein collagen • Raw Materials - Pig-skin - Cattle hide - Bone - Other (Fish skins and poultry bone) • BSE = Bovine Spongiform Encephalopathy - Bovine bone and hides are non-infectious - CNS is the carrier - Contamination (of bones) is issue

Lect. 16

Ideal Therapeutic Aerosols -Contain a safe and efficacious drug in a user friendly device! - Contains minimal quantities of inert excipients - Monodisperse, small particle size - Low velocity after generation - High concentration and rate of generation - Highly reproducible characteristics - Low bioburden (solids) or sterile (liquids) - Delivers the drug to the target site Formulation Challenges Particle Engineering • Insoluble drugs • Shear sensitive • Thermolabile • Excipients • Conformational changes • Instability (Chemical & Physical) Particle "Engineering" Different approaches • Microspheres • Liposomes • Porous particles • PEGylated particles PulmoSphere® Manufacturing =lots of holes Fluorocarbon -in-water Emulsion + Active and wall-forming materials in water> both into Spray Dryer Comparison of Dry Powder Formulations: Micronized drug particles (2-3µm) attached to lactose carrier particle = giant, uneven powder dispersion plume Drug incorporated into PulmoSphere® particles (2-3µm)= lots of tiny ones, not blended with lactose= even powder dispersion plume= Bigger aerosilation diameter b/c flies more slowly b/c more holes Pulmonary Delivery Systems Metered Dosed Inhalation pMDI Soft Mist Inhalation (Single breath & breath actuated) Dry Powder Inhalation DPI (Passive & Active) Continuos nebulizers (Jet & Ultrasonic) -portability is preferred Metered Dose Inhalers (MDI) • Mature Technology / Established Vendors • Non-aqueous suspensions or solutions • Pressurized Metered Dose Inhalers (pMDIs) • Portable • Apparently Easy to Use • Remaining Product Is Uncontaminated • Tamper-proof • Protects Drug from: Light, O2 and H2O • Multiple Dose • Accurate Dose Metering • High Respirable Fraction • Inexpensive Contemporary Issues with pMDI • Only 5-10% drug deposition in the lung • Patients do not use their inhalers optimally • Hydrofluoroalkane (HFA) Proof of concept for protein and peptide delivery still needed, due to excipient and compatibility. • Used to be the first choice of Big Pharma since delivery platform was well accepted and established jet Nebulizers (Characteristics) Compressed Air •Solution cools during use (~ 10°C) • Solution concentrates during use •Some fragile molecules are degraded (specially high MW biomolecules) •Repeated nozzle shearing •Nebulization time of minutes •Not considered portable -the solution cools in a jet nebulizer b/c of evaporation Ultrasonic Nebulizers (Characteristics) • Droplets size depends on device design and solution properties: - Surface tension - Density • Auxiliary fan entrains small droplets • Larger droplets recirculate • Solution warms up to +15°C • Biomolecules can be degraded • Power consumption limits portability • Nebulization time in minutes Mist Inhalers • Drug delivered in a single inhalation and or breath actuated • Single dose or multiple doses in a handheld unit • Less contamination problems than conventional nebulizers • Drug solution specific to device Dry Powder Inhalers • Dry powders • Automatic coordination between dose delivery and inhalation • No propellants • Potential drug stability advantages • High dose carrying capacity • Product differentiation & patent protection • Most devices are patented (more than 40 in development) -deaggregation=aerosol plume Active Dry Powder Inhalers • A micronized or spray-dried powder is: - Inhaled - Deaggregated - Entrained - Metered • Using energy from the device and patient Passive Dry Powder Inhalers • A micronized or spray-Dried powder is: - Inhaled - Deaggregated - Entrained - Metered • Using energy from only the patients inhalation Efficiency of Systems • in-vitro and in-vivo Characterization In Vitro Particle Sizing For Product Design & Stability Particle Size Measurement •Cascade impactors & impingers •Time of flight • laser diffraction & scattering Andersen Cascade Impactor Simulation of the Human Respiratory System: stage #: -1, 0, 1, etc.. to 7 where -1 to 1= throat, 2-4= brochial airway, 5 to 7=alveoli Aerodynamic Size Measurement • FPF= Fine particle fraction - % particles that have the ideal aerodynamic size (less than 5µm) • FPD= Fine Particle Dose (lung deposition) - Mass of particles that have the ideal aerodynamic size (less than 5µm) after dosing • Inhalable dose - Particles of unknown size that can be inhaled (typically less than 10µm) • OPD= Oropharingeal Deposition - Typically particles larger than 5µm • MMAD= Medium Mass Aerodynamic Diameter- how far/fast it flies • GSD= Geometric Standard Deviation= uniform -increase FPF %= better efficacy In Vivo Measurements For the Visualization of Drug Delivery/ Deposition to the Targeted Site. Gamma Scintigraphy (comparison of two different inhalers)= radioactive, see what's in lungs 3D SINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY (SPECT)= like MRI machine for lungs Challenges in pulmonary delivery: Factors Affecting Lung Deposition -To obtain a desirable deposition, pharmacists must advise the patient about the correct use of the delivery system. Patient • Breathing Pattern • Technique • Disease State • Lung Anatomy • Inhaled Particle Size • Aerosol Generation Device (Principle and Design) • Shape, Density, Charge, • Hygroscopicity Lung Defense Mechanisms. • Physical ( Airways) Particle Size. - Upper Air Ways (Impaction) >10µ (specially nose) - Reflexes • Sneezing (URT) (Impaction/ Coughing (LRT) Sedimentation) 5-10µ - Muco-ciliary escalator - Immunological Clearance by phagocytes Systemic Delivery of lungs= possible • Insulin/diabetes was main driver. - Exubera® from Nektar (discontinued) - Air ®, from Alkermes (discontinued) - Afrezza TM, from Mannkind (approved June, 2014) - AERx®, from Aradigm (discontinued) - Promaxx, from Baxter (discontinued) • Inbrija inhaled levodopa, Acorda Therapeutics (Dec 2018) • Most of the research is focused on local therapy. - Inhaled antibiotics, Olodaterol (COPD), antivirals, Flu vaccines, antifungals (e.g., tobramycin-Novartis, GLP1, amphoterecin B) -in general a harder tablet WON'T: -have a shorter disintegration time -dissolve faster -same bioavailability or Cmax as tablet w/ lower hardness -be more difficult to swallow -to make a tablet harder: -inc compression force -alter formulation to be more compressable -inc compression dwell time by slowing down the process -engage pre compression roller to double up on compressions per unit

Lect. 7

Pdts that should be compounded: Narrow-therapeutic index drugs • Toxic drugs • Modified release preparations -not all pdts should be compounded Extemporaneous Compounding is Justified to Meet Individual Patient Needs. ...The drugs that pharmacists compound are not FDA-approved and lack an FDA finding of safety and efficacy. However, FDA has long recognized the important public health function served by traditional pharmacy compounding. FDA regards traditional compounding as the extemporaneous combining, mixing, or altering of ingredients by a pharmacist in response to a physician's prescription to create a medication tailored to the specialized needs of an individual patient. See Thompson v. Western States Medical Center, 535 U.S. 357, 360-61 (2002). Traditional compounding typically is used to prepare medications that are not available commercially, such as a drug for a patient who is allergic to an ingredient in a mass-produced product, or diluted dosages for children. Through the exercise of enforcement discretion, FDA historically has not taken enforcement actions against pharmacies engaged in traditional pharmacy compounding. Rather, FDA has directed its enforcement resources against establishments whose activities raise the kinds of concerns normally associated with a drug manufacturer and whose compounding practices result in significant violations of the new drug, adulteration, or misbranding provisions of the FDCA. If You Must Compound for the Masses • Must Comply with cGMP requirements • Will be Inspected by FDA according to a risk-based schedule • Must Meet Certain Other Conditions, Such as Reporting Adverse Events and Providing FDA with Certain Information on the Products Compounded Compounding Guidance • <795> Pharmaceutical Compounding - Non-sterile Preparations • <797> Pharmaceutical Compounding - Sterile Preparations • <800> Pharmaceutical Compounding - Hazardous Substance • <823> Radiopharmaceuticals - Compounding • <1075> Good Compounding Practices • <1160> Pharmaceutical Calculations in Prescription Compounding • <1191> Stability Considerations in Dispensing Practice • FDA CPG 460.100 Hospital Pharmacies Status as Drug Manufacturer • FDA CPG 460.200 Pharmacy Compounding Materials that may be used as ingredient sources for compounded products. • Ingredients - Substances with USP/NF monographs - Substances in FDA approved by Section 503 • USP or NF grade material is preferred • ACS or FCC may be used • Manufactured drug products - Consider presence of excipients - Instant Release dosage forms Levels of Compounding USP <1075> ito increasing process/facilities reqs: 1. Nonsterile Topical Creams 2. Nonsterile Topical Ointments 3. Nonsterile Flavoring Addition 4. Sterile Immediate Injection Reconstitution 5. Nonsterile Oral Dosage Forms 6. Sterile Opthalmics/Otics 7. Sterile Injections-Many Patients-Not for Immediate Use-TPN 8. Chemotherapeutic Injections/Implants 9. Sterile Radiopharmaceuticals USP <795> Overview • Personnel - Qualified • Education, including CE - Capable • Training and Demonstration • Facility • Equipment • Records Equipment - Appropriate size and design - Suitable for intended use - Inspected, maintained, and validated at appropriate intervals • e.g., electronic balances, pipets, pH meter - Clean promptly to avoid cross-contamination Facility - Designated Area - Separate Non-sterile from Sterile - Clean - Environmental Controls (HVAC) - No Cross-Contamination Records - Formulation Record (Master Batch Record) - Compounding Record (individual Rx) • Ingredients lot no., date prep., compounder, lot or Rx no., assigned exp date, etc. - SOP (implied, standard operating procedure) - MSDS (safety data sheet) - Quality Control Results (e.g., weight checks on capsules) - Equipment and Facility Logs • Maintenance and Calibration Pharmaceutical Compounding of Sterile Preparations USP <797> Applies to any Pharmacy practice setting • More detailed requirements than USP <795> • Approaching manufacturing requirements - More testing and reporting! - More systems! API= biologics= always expiration date but api (in general?)= can retest and good=can continue to use it -expiration date for drug pdt= need to discard; "in the original packaging unopened" -beyond use date= compound term; don't use beyond this date, conservative based on literature, experience, etc USP <797> Overview Pharmaceutical Compounding - Sterile Preparations Examples of Additional Requirements: • Personnel - Annual didactic review and written testing - Media fill testing (w/o contamination) • Facility - Stringent air controls - Buffer zone of intermediate air quality - Certification every 6 months • Equipment - Sterilized • Records - Adverse event reporting - Complaint procedures - Periodic review of QC documents (SOPs) Examples of Additional Systems • QA Program - Formalized in writing - Monitoring and evaluation activities - Reporting results and corrective actions • QA Practices - Routine disinfection - Material management program • Patient and Caregiver Training - Formalized program • Storage, handling, and use of product • Administration techniques There are several fundamental techniques useful for pharmaceutical compounding. • Comminution - mechanical reduction of particle size • Trituration - comminution using a mortar and pestle • Levigation - use of a liquid to make a paste followed by trituration or spatulating on a slab • Pulverization by Intervention - use an "intervening" solvent (e.g., alcohol) that dissolves the powder then evaporates quickly • Geometric Dilution - mixing of equivalent amounts of materials starting with the smallest quantity General Procedures and Tips for Compounding (1) 1. Calculate the required quantity of each ingredient for the amount to be prepared. 2. Accurately weigh or measure each ingredient. 3. Record weights immediately. 4. Double-check all calculations and recordings. 5. Double-check Label. 6. Do a REALITY check. "Does this sound right?" 7.Comminute insoluble materials to a very fine state of subdivision. 8. Levigating agents used for comminution must be compatible with the active ingredient and the vehicle. 9. For ingredients that build up electrostatic charges, a few drops of a levigating agent works well. 10. For maximum preparation stability, try to keep the product anhydrous. 11. Geometric dilution will enhance uniformity of distribution of the active ingredient in the vehicle. 12. Geometric dilution techniques will actually speed up the preparation time. 13. If a preparation is too stiff, decrease the proportion of waxy components and if an emulsion, increase the proportion of water. 14. Humectants can be added to cream/lotion formulations to increase their hydrating properties. 15. Solvents with low vapor pressures, such as water, glycerin and propylene glycol should be used in place of alcohol and higher vapor pressure solvents (which will evaporate and may lead to crystallization of the drug). 16. When fusion is used and volatile substances are to be incorporated, allow the melt to cool before adding the volatile ingredients. 17. When preparing bases using fusion, melt the ingredient with the highest melting point first, followed by those with decreasing melting points. 18. Aqueous systems should be heated for as short a time as possible to minimize water loss due to evaporation. 19. Mix creams and ointments using butcher paper to simplify cleanup. The preparation can easily be placed in a tube by rolling the paper into a funnel shape and squeezing the contents into the package. 20. Transfer semi-solids to a plastic bag, snip off the corner, and squeeze into a tube. Products Should be Packaged in Appropriate Containers • Primary Container - In direct contact with product - May be clear, but normally tinted • White - Titanium dioxide • Amber - Iron oxide (glass) - Closure is part of primary container • Secondary Container - Encloses one or more primary containers - Cardboard box, aluminum wrap, plastic tray The primary container can be used to obtain protection from destabilizing influences. • Tinted for light protection • Glass and Foil are superior gas and moisture barriers • Plastic is a satisfactory alternative - Bottles - Jars - Tubes Expiration Date of compounded products Determined by the Pharmacist • Beyond-use date • Assign conservatively • Base on literature when available • Base on information from manufacturer • Base on pharmaceutical education and experience • Follow recommendations in USP sections USP <795> Recommendation for Beyond-Use Dating (1) • For non-aqueous liquids and solid formulations where active ingredient is: (1) from a commercial product (ex: tablet already manufactured)- The earliest of 6 months or 25% of the time remaining until the product's expiration date= whichever is shorter (2) a USP or NF substance (ex: you ordered acetaminophen and API and mix, etc) - Not later than 6 months For water containing formulations prepared from ingredients in solid form - Not later than 14 days when stored at cold temperatures • For all other formulations - The earliest of 30 days or the intended duration of therapy USP <797> Recommendation for Beyond-Use Dating (1) The Beyond-Use date is assigned based on Risk Categories - Low Risk • All compounding under Class 100 conditions • Only use sterile ingredients and devices • Promptly conducted, simple procedures - Medium Risk • No broad spectrum bacteriostatic agent present even though administration is over several days • Complex aseptic manipulations (e.g., TPN) • Multiple doses in one container • Unusually long procedure - High Risk • Nonsterile ingredients or devices used before a terminal sterilization • Sterile ingredients exposed to air quality inferior to Class 100 • Terminal sterilization, but no endotoxin testing Maximum Beyond-Use Date Storage Condition Low Risk Preparations, Medium Risk Preparations , High Risk Preparations Room Temp 48 hours, 30 hours, 24 hours Refrigerated 14 days, 9 days, 3 days Frozen 45 days or less

Lect. 11

There are essentially four environmental factors that cause pharmaceutical product instability. • Water • Heat • Light • Oxygen The Pharmacist's first responsibility is proper storage of pharmaceutical products and to provide storage information to the consumer. Product stability can be divided into three categories. • Chemical - Potency (90% Label Claim) - Purity - 5 year maximum expiration date • FDA CVM - Center for Veterinary Medicine • Physical - Product Specifications - Pass/Fail • Microbiological - Preservative Effectiveness - Sterility Testing Determination of chemical stability is not limited to the active ingredient. • Active Pharmaceutical Ingredient • Excipients • Degradation product(s) Excipients are often added to improve stability. Antioxidants may be added to liquid or solid dosage forms. The chemical stability of liquid products may be affected by solution pH. Buffer agents are used to control pH and stabilize the formulation. There are many physical product attributes that are important to product quality. Physical stability: • Appearance • Color • Odor • Taste • Dissolution • Moisture content • Friability • Polymorphism • Hydrate formation • Solution Clarity • Solution pH • Aggregation • Precipitation • Settling/Redistribution Viscosity • Particle size distribution • Crystal growth • Crystallization • Cake collapse • Reconstitution time • Extractables/Leachables • Protein unfolding (denaturation) • Adhesion and Peel • Leakage • Absorption • Adsorption • Compatibility Manufacturers and Pharmacists both have stability related requirements. • Industry Requirement - Product Testing • Preclinical toxicology studies • Clinical trials (IND phase) • Commercial products (NDA phase) • Pharmacist Requirement - Proper Storage - Label • Commercial products • Extemporaneously compounded products The expiration date of the dispensed prescription typically depends on the source. • Commercial Products - Use manufacturer's expiration date - Institutional guidelines or SOP's - Note: Reconstitution is not compounding • Compounded Products - RPh can not "manufacture" - RPh not required to conduct stability tests - USP has Guidelines • Section <795> Nonsterile Preparations • Section <797> Sterile Preparations • Section <800> Hazardous Drugs The manufacturer's expiration date applies to the packaged product. • Based on - Unopened Container - Labeled Storage Conditions • Once opened - "No" Obligation - Some exceptions • Reconstituted products - Injections, oral antibiotics • Multi-dose units (pen injections) • Change of allowed storage condition • Labeled as Month and Year (no day) - good through the last day of the month Pharmacists are required to properly store products according to the manufacturer's labeling. The temperature ranges are defined by the USP. • -25°C to -10°C Freezer • 8°C or less Cold • 2°C to 8°C Controlled Cold Temperature (Refrigerator) • 8°C to 15°C Cool • 20°C to 25°C Controlled Room Temperature Industry stability testing is conducted as part of the development process and during commercialization. • Stability studies required by cGMP Regulations • Regulated by FDA • Guidelines published by FDA - First (?) guideline published in 1987 - Multiple guidance documents are currently available • Published on-line at FDA.gov • Many are ICH guidelines - International Council for Harmonisation - Guidelines not Regulations - "Negotiated" during IND and NDA submission Guidance documents are available on FDA.gov • Search for "stability" identifies 18 documents • Perhaps the one, best starting document - ICH Q1A(R2) - Stability Testing of New Drug Substances and Products • Final guidance • Nov 2003 The stability guidelines list several key ideas for the protocol design. • Representative product • Duplicate samples from original (unopened) container • Pooling of individual dosage units allowed • Bracketing of containers and dosage strengths allowed Storage conditions are specified in the stability guidelines. • -20°C +/- 5°C • 5°C + 3°C • 25°C + 2°C/60%RH + 5%RH • 30°C + 2°C/65%RH + 5%RH • 40°C + 2°C/75%RH + 5%RH Test frequency is listed in the stability guidelines. • Accelerated Conditions - Minimum of three (3) test points - 0, 3, and 6 months • Intermediate Conditions - Minimum of four (4) test points - 0, 6, 9, and 12 months - Studies required if a 'significant change' is observed under accelerated conditions • Significant change is defined by the guideline - A 5 percent change in assay from its initial value - Others related to degradation products, pH, dissolution, and physical stability parameters • Long Term Conditions - 0, 3, 6, 9, 12, 18, 24, 36, 48, and 60 months -product shelf-life stability is NOT det. by accelerated conditions> accelerated conditions is ONLY to get an early read; product shelf-life stability is det by real time data w/ real life conditions Testing at elevated temperatures is used during development to accelerate reactions and predict chemical stability at lower temperatures. • Arrhenius theory is used to model temperature effects 𝑘 = 𝐴e^-Ea/RT k = rate constant T = temperature (°K) • "Constants" - A = Pre-exponential factor (also - frequency factor) - Ea = Activation Energy - R = Molar gas constant • Model holds for many reactions over small temperature ranges Model used to predict an expiry period. • The Arrhenius equation can be linearized 𝑙nK = 𝑙nA− (𝐸𝑎/R) ∗ 1/𝑇 • Determine rate constants at high temperature • Plot ln k versus 1/T • Extrapolate to temperature of interest to predict rate constant • Use rate constant to determine t90 The expiry period is determined by statistical analysis of data for product stored at its intended storage condition./temp Lyophilization is a manufacturing process used to remove water from a solution product. The main objective is to obtain a product that has a longer shelf-life. The process is primarily carried out on frozen solution and is also called freeze drying • There are three distinct stages - Freezing - Primary Drying • Sublimation of ice (solid>gas) - Secondary Drying • Desorption of "bound" water • The drying steps are conducted at low pressure to facilitate the process -basically freeze drying: liquid solution> freeze> dec pressure> inc temp to get gas> water evaporates leaving only API Water is removed from the frozen material leaving a dry, porous matrix. • Drug chemical stability is enhanced in the solid state • Fast reconstitution times achieved from porous cake Improperly dried product • Pharmaceutical elegance is lost • Stability may be compromised • Reconstitution is often difficult Over 400 Lyophilized Products Approved by FDA=but expensive, only for pdts with stability problems • Powders for Injectable Solutions • Powders for Injectable Suspensions • Oral Melt Tablets (over 30) - Loratidine, piroxicam, loperamide HCl, risperidone, lorazepam, olanzapine, others • Liposomal Injections (6) - Amphotericin B, doxorubicin citrate Pharmacist's Responsibilities • Storage Conditions - Product - Reconstituted product • Visual Inspection - Discoloration - Product Collapse • Reconstitution Volume • Reconstitution Vehicle - WFI - BWFI - Special Diluent • Reconstitution Procedure - Addition of vehicle to protein products - Time for dissolution -lyophilized products= the process removes frozen water via absorption as a means to improve product stability to hydrolysis reactions

Lect. 8

Suppositories • Solid dosage forms for insertion into the rectum, vagina or urethra. • Formulation: usually made with either a fatty or water miscible base (can also be hand molded or made by compression. • Usually made in a plastic or metal mold. • Suppository sizes: - Rectal ~ approx 2 gm - Vaginal ~ 3-5 gm - Urethral ~ 2 gm female, 4 gm male • Urethral suppositories were formerly called bougies. Advantages of Suppositories • Local and systemic delivery both possible. • Avoid first pass metabolism • Delivers medication systemically when the patient can not take the medicine orally or by injection. 1) Ingredients are melted and placed in a suppository mold 2) Suppository mold is separated after it is cooled down. 3) Suppositories are removed from the mold Suppositories can be molded into packages for direct use Typical Suppository Vehicles are: Cocoa Butter, Witepsol, and Glycerinated Gelatin Shapes Depend On Material and Intended Use Suppository Base • Selection based on: - Drug substance characteristics. - Desired release pattern. • Solid at room temperature - Melt or soften at body temperature - Dissolve in body fluids. Release Profile • Fatty or oleaginous base: lipophilic drugs release slowly, hydrophilic drugs release rapidly. - Cocoa butter (limited due to polymorphism) - Hydrogenated vegetable oil bases. • Water soluble base: hydrophilic drugs have moderate release rate. - PEG - Glycerinated gelatin bases Rectal Drug Delivery • Alternate to oral route if patient has nausea, vomiting or convulsions, if patient is uncooperative or if oral intake is restricted. • Local and systemic delivery. • Absorption is passive diffusion, as in upper GI tract. • Rectal epithelium similar to that in upper GI tract and highly vascularized. - Inferior and middle hemorrhoidal or rectal veins drain into systemic circulation. - Superior hemorrhoidal or rectal vein drains directly into portal circulation. Issues in Rectal Delivery • Alternative to IV, relatively painless, convenient to use (esp. for pediatric patients). • High concentration can be achieved. • Intersubject and intrasubject variability in absorption. - Physiologic conditions (pH, fluid content) differ substantially from upper GI. - Wide range of pH (mean 7.2 in adults, 9.6 in children) - Difficult to predict absorption. • Patient compliance - reluctance to use rectal form. Rectal Suppositories • Most popular in the US for non-traditional patients. - Patient unwilling or unable to take medication by mouth or injection • Popularity is greatest in Europe and Japan. • Rectal preparations are ideal for young infants, debilitated patients, or those who can not tolerate oral intake. • The shape of the suppository determines how it will be inserted. • Packaging must be thoroughly removed prior to insertion Rectal Suppositories • Commonly used for laxative purposes. • Local applications include the treatment of hemorrhoids, itching, inflammation, and infections. • Systemic applications promote rapid onset of action for antinauseants, antiasthmatics, antipyretics, analgesics, and hormones. • Sensation of tenesmis (sense of fullness) may affect the dwell time of the suppository Enemas or Rectal Irrigations • Aqueous or oily preparations. • Administration from squeeze-pack or by lavage for either retention or evacuation. • Solutions, suspensions or emulsions are all available as enemas. • For cleansing, diagnostic (e.g. barium), or therapeutic uses. • Administration may be pulsed or for extended retention. • Systemic administration can be used for antibiotic or anti-asthmatic drugs. • Surfactant agents, (oils or fecal softeners) are used for mechanical promotion. Other Dosage Forms • Foams: contain inert, pressurized gas propellants. - Retained better than enemas - More uniform coating and better patient acceptance - Drug in foam or enema can spread over wider area than drug in suppository • Ointments and creams: small contact time, so no significant systemic absorption. - Usually to deliver steroids, anti-inflammatory agents and local anesthetics for local conditions (hemorrhoids or anal itching or swelling) Vaginal Drug Delivery • Ideal target for local delivery and excellent route for systemic drug delivery. • Large surface area (approx. 60 cm2), dense network of blood vessels. • Similar to buccal mucosa. • Presently, only a limited number of drugs are available for delivery by this route. • Thickness of epithelium varies with age and hormonal activity. • pH 3.5-4.5 in women of reproductive age, but neutral or slightly basic in postmenopausal women and prepubescent girls. Vaginal Drug Delivery • Ideal target for local delivery and excellent route for systemic drug delivery. • Large surface area (approx. 60 cm2), dense network of blood vessels. • Similar to buccal mucosa. • Presently, only a limited number of drugs are available for delivery by this route. • Thickness of epithelium varies with age and hormonal activity. • pH 3.5-4.5 in women of reproductive age, but neutral or slightly basic in postmenopausal women and prepubescent girls. Vaginal Flora - Many microorganisms are living in balance with each other and their hostess. • Acidic Environment • Some women will have Lactobacillus virginals as a useful bacterium. - Lactobacilli (lactic acid bacteria) are named after their property to produce lactic acid. - They largely determine the acidity and the normal antisepsis of the vaginal environment. Normal Biochemistry of Vagina May Affect Drug Disposition • Depends on: - Cellular Uptake - Metabolism - Enzyme Activities • Life Cycle of the Woman • Menstrual Cycle • Sexual Activity • Infection Advantages and Disadvantages • Absorption not affected by GI disturbances, and 1st pass effect is avoided. • Convenience of self-administration, painless application, discreet use. • Lower doses of hormones can be delivered locally, and reduce systemic side effects. • Variations of epithelium and pH. • Systemic absorption can be erratic and unpredictable, and may be undesirable. • Formulation may leak or slip out leading to soiling of clothing. • Local irritation. • Patient reluctance. Vaginal Formulation Factors • Physicochemical factors associated with the drug. - Solubility / dissolution rate, ionization characteristics, molecular size, aggregation. • Drug release from the dosage form, limited amount of vaginal fluid. • Effective area of contact (vaginal cavity = 60 cm2). - Hydrophilicity, spreadability, viscosity. • Residence time. - Bio-adhesion and phase change polymers External factors can cause a disbalance in the vaginal environment. • Can be subdivided into four categories: - mechanical - hygienic - chemical factors - sexual intercourse Vaginal Formulation Strategies • Semi-solids: + Gels, cremes: Prolonged residence, inexpensive, ease of manufacture, spreadability. - Messy, frequent applications, difficult to remove, preservatives. • Tablets: + Ease of insertion. - More expensive, frequent applications, spreadability. • Pessaries / Suppositories: + Ease of insertion, relatively inexpensive. - Frequent applications, poor retention in vagina, spreadability. Controlled Release • Intravaginal rings - Estring - Femring - NuvaRing • Microspheres - In development • More expensive • Patient compliance Urethral Suppositories • Urethra ~17.5 - 20 cm in males, 4 cm in females. • Called "bougies" - slender, cylindrical, tapered, vary in length dependent on sex. • Typically more rigid and with a higher melting point • Formulation considerations are the same as for rectal suppositories. • Almost all urethral suppositories are made by molding. • A suppository applicator is often used to insert the urethral suppository. Commercially-Available Urethral Suppository • Only one: Muse® which contains alprostadil. • Called "pellet" - 1.4 mm in diameter, 3 or 6 mm long depending on dose strength. • Administered using intraurethral applicator device provided by manufacturer. • Used to treat erectile dysfunction. • Alprostadil delivered across urethra into erectile tissue, causes vasodilation. • Not Common.

Lect. 15

Tablets - Size range: 4mg (1.5mm) to 1.5g (oval) • Advantages - Low cost - High quality: stable, uniform - Tamper resistant - Convenient, high patient compliance - Versatile (chewable, effervescent, etc.) with controlled release: • Sustained release • Delayed release (e.g., enteric, colonic) • Pulsed release • etc. Choice of tablet shape is based on many factors: Market identity Manufacturability Swallowability Functional - Ease of breaking - Release rate "Trade Dress" refers to physical appearance (size, shape, color, etc.) which is important for product safety considerations and corporate brand loyalty • Unique identifier minimizes errors - Yearly, ~50 million medication errors occur per 3 billion prescriptions (1.6%) - ~7,000 people die each year as a result of medication errors - The FDA has a specific guidance addressing such errors and product design Atypical Tablet Shapes/Imprints Bullet shaped compacts for veterinary use (private, USDA/FS) Solid unit inserted into a remote delivery system, RDS casing dissolves, releasing drug (antibiotic, contraceptive, etc.). Air gun accuracy to 25 yards Tablet Nomenclature Caplet Shaped Tablets: Anti-Twinning Curvature= basically less SA on side to accidently stick two caplets together Useful for caplets with wide bands to prevent cohesion during film coating. tablet nomenclature: -diameter -total thickness= up and down if think lozenge on side= also minor axis or width -band= side to side if think lozenge on side= also major axis or length -face= like think coin face Tablet Nomenclature Summary • Round tablets - Diameter - Face - Thickness (or gauge) - Band • Oval or Caplet Shape - Major/Minor axis - Anti-twinning curvature • Tablet Markings - Engraved - Embossed (rare) - Score bar Tablet Tooling Nomenclature Key required for non-round dies Punches - Barrel =the middle of like needle - Head=the flat head - Upper Punch Key - Tip=literally tip • Die - Bore=inside - Face=like coin face outside Considerations in the design of a tablet formulation: Phys/chem attributes of active component - Solubility; crystallinity; purity; particle size; hygroscopicity; compatibility/stability • Potency or mg dosage per tablet (1mg vs. 1000mg) - Lower drug load per tablet favors properties of excipients • Biopharm considerations - BDCS designation (low/hi solubility/permeability) • Trade Dress / Marketing - Shape, color, size, for • ease of dosing ~ patient compliance • Identification: minimizes medication errors; increases brand loyalty - Sales regions/territories re storage temperature, humidity • Maximize Intellectual Property - Wellbutrin™ had only 3 yrs of market exclusivity at launch • Special formulations (composition patent) or manufacturing process (process patent) hinder competition Ideal tablet and manufacturing characteristics Granulation process nontoxic and not flammable - avoid alcoholic or acid/alkaline granulations • Powder/granule free flowing • Reduce dust - Mixes with machine lubricants creating black specks on tablets - Work hazard • Good compression characteristics • Tablet surface is good substrate for coating - Avoid deep engravings • Quality Attributes - Reproducible drug release (disintegration, dissolution) - Robust tablet: hard and non-friable - Appearance (no chipped edges, striations, etc.) - Physically and chemically stable over the shelf-life Typical Excipient Categories: Fillers (diluents) - Function: bulk up fill; impart cohesiveness; enhance flow • Binders and granulating fluids - Function: densify powders during granulation • Disintegrants - Function: swelling action to enhance disintegration • Lubricants - Function: reduces friction of tablet during ejection from die hole • Glidants and antiadherants - Function: increases fluidity; reduces adhesion [less "picking"] • Coloring, inks, flavor and polishing agents - Function: appearance, id, and palatability (consider pediatrics) tablet Picking (like hole in ur tablet): Adhesion forces > Cohesion forces Fix by: Increase compression force Slow down press Alter formulation Capping/Lamination(basically split tablets by sides): generally elastic deformation Fix by: Slow down press to increase dwell time Decrease compression force Alter: formulation, tooling/tablet shape, etc. Typical Manufacturing Processes Objective: ideal powder/granule for compaction Wet granulation: Component sieving Blending Wet-massing Drying Milling Lubricant blending Compressing Direct Compression Component sieving Blending - - - (these missing ones=saving money) Lubricant blending Compressing FitzMill Comminution (mill) the dried granulate to a particle size Granule Characteristics Compressibility Index: a measure of flow Compressibility Index (50 taps) = [(T-B)/T ] x 100% B T = [(0.62-0.54)/0.62] x 100% = 12.9 % ~13% compressibility is decent flow Granulated sugar < 5% (excellent flow); Confection sugar > 30% (terrible!) Manufacturing Equipment The Manual Carver Press - Bench Top=Up to 100 tablets / hour. Useful for preformulation and toxicology studies. Occasionally for GMP (human clinicals) such as with expensive drugs. The Rotary Tablet Press - Lab / Development Scale=18k/hr The Rotary Tablet Press - Full Production Scale=The "double-sided" Korsch PH 800/85 produces up to 1 million tablets / hour with single tip punches > 4 million / hr with multiple tip punches Rotary press nomenclature: Upper Turret - Upper punches • Turret Table - Dies - Lower punches • Hopper • Feed Frame - Gravity vs. forced feed • Precompression Rollers • Main Compression Rollers - Upper - Lower -process: die filling> mass/weight adjustment (to fill more/less)> volume reduction/compaction> dwell time (the actual press)> tablet ejection Tablet hardness increases to a maximum then decreases with elastic rebound (lamination and capping likely) hardness tester=Hardness units: Kiloponds, 1.0 kp = 9.8 N Typical hardness: 5kp (small tablets) to 15kp (large tabs) Tablet Quality Attributes Assay / Impurity Profile by HPLC testing: USP <621> Tablet Friabilaty Apparatus: USP <1216> Friability = % weight loss in tablets after testing Disintegration Apparatus: USP <701> Disintegration = time for dosage unit to pass through 10 mesh screen Dissolution Equipment: USP <711> Dissolution Flask - with Paddles [USP<711> Type 2] Basket: Type 1 apparatus Paddles: Type 2 apparatus Dissolution • Necessary for In Vivo absorption • Critical attribute in formulation development and manufacturing process • Uniform Rate of Dissolution over expiry date • Useful for Generic approvals ~ to waive in vivo BAV / BE studies! Tablet splitting: Advantages • Ease of swallowing • Dose flexibility - geriatrics, pediatrics - dosing as needed • Cost savings Disadvantages • Difficulty splitting tablets • Unequal parts • Loss of mass • Patient confusion Take Home Points: • Not all tablets should be split. Coated CR tablets should never never be split • Generally, if not scored, then consider the consequences of splitting (manufacturers may avoid scoring to increase sales of lower strength product) • If split in the pharmacy: document on the patient's file and on the label... (best to avoid splitting in pharmacy to avoid confusion & complaints) • Note: large caplets can easily be split between spoons... but not small tablets Tablet Quality Attributes Initial Release Testing (first 3=most important) • Tablet Appearance Conforms • Assay 90-110% LC • Purity - Impurity profile Meets ICH • Weight and/or Content Uniformity < 3 % RSD • Hardness ~ 10 Kp • Thickness (gauge) ~ 4 mm • Friability (uncoated tablets) < 1 % loss • Moisture Content < 2 % • Disintegration < 5 min • Drug Release Meets USP - Dissolution Testing Q75 in 45 min