Pharmaceutics II Exam 3

What color does an emulsion containing 0.1-1 micrometer droplets appear?

Blue-white

What is a disadvantage of an ophthalmic ointment?

Blurred vision due to ointment base melting and spreading across the lens

What is coalescence?

Droplets merge with each other to form large droplets Irreversible

What surfactant has the highest HLB?

sodium lauryl sulfate (40)

What is the most common packaging of ophthalmic solutions and suspensions? Why?

soft plastic containers with fixed built-in dropper facilitates easy administration and protects product from contamination

Rank the following formulations from most to least bioavailable: capsule solution suspension tablet

solution > suspension > capsule > tablet

What is a molecular dispersion?

*True solution* <1nm particle size invisible in electron microscope pass through semipermeable membrane rapidly diffuse e.g. ions, glucose

What are some examples of typical flocculating agents?

*surfactants* e.g. benzalkonium chloride and polysorbate 80 *hydrophilic polymers* e.g. xanthan gum, tragacanth *clay* e.g. bentonite *electrolytes* e.g. aluminum chloride, sodium chloride

What size droplets are in emulsions?

0.1 - 10 micrometers

What range of tonicities are appropriate for use in the eye?

0.6% - 1.8% NaCl

What is the particle size range for most pharmaceutical suspensions?

1-50 micrometers

What is a colloidal dispersion?

1-500nm particle size visible in electron microscope pass through filter paper do not pass through semipermeable membrane diffuse very slowly e.g. micro emulsions, nanoparticles, liposomes, polymers, milk, paint

What is the tear turnover for an eye following 1 drop instillation?

Approximately 30% per minute

What is the tear turnover for a nonirritated eye

Approximately about 15% per minute

What is absolute bioavailability?

The ratio of the AUC for the oral dosage form to the AUC obtained by intravenous (i.v.) administration F=(AUC)oral/(AUC)intravenous F: fraction, or bioavailability F=60% implies that 60% of the drug is systemically available form the oral dosage form F=100% for intravenous dosage form

Compare Cmax and efficacy

The same Cmax does not guarantee the same therapeutic effect Same Tmax does not guarantee the same effect

Explain what OASIS is

Ultrasonic nebuilizer more than 4 hours of continuous operation high deposition rate in alveolar area max nebulization = 4mL/min aerosol droplet size = 0.5-5 micrometers

How can penetration of water into the matrix be reduced?

Use hydrophobic polymers (e.g. poly methyl vinyl ether-maleic anhydride)

How can precorneal retention and duration of action be increased?

Use water-soluble matrices in which the drug is either dispersed or dissolved Delivery of drugs from hydrophilic matrices is fast because tear fluid rapidly penetrates into the matrix

Pilocarpine eye drops example

Used as a topical miotic agent to reduce intraocular pressure associated with glaucoma Acidic pH needed to increase the stability of pilocarpine Difference between pH of ophthalmic solutions of pilocarpine (4-5) and pH of tears (7.47) causes increased lacrimation and loss of drug Ocular bioavailability is very low (1-3% absorbed; 50% loss to systemic absorption from conjunctiva)

Why can't particle size be reduced below 1-50 micrometer?

fine particles have tendency to form a compact cake upon settling to the bottom; this is nearly impossible to re-disperse

How many compounds that enter preclinical testing make it to human tests as IND?

five in 5,000

What are the properties of a stainless steel container in an aerosol system?

for certain aerosols in which a great deal of chemical resistance is required

Explain how to create a multiple-phase emulsion (e.g. W/O/W)

formulate the W/O emulsion add the W/O emulsion to water/hydrophilic surfactant and mix

What factor is the efficacy of aerosols dependent on?

function of the aerosol system (container, valve, propellant, etc.) for the physical delivery of the drug in a proper form

To obtain the desired bioavailability, the dissolution rate of the drug must be _________ than the clearance of the dose from the conjunctival sac and ___________ the absorption rate

greater equal to

Why are buffers used in ophthalmic preparations?

greater comfort, greater stability, greater solubility, greater bioavailability, to maximize preservative efficacy

What are the three types of particle size reduction equipment that are most commonly used for oral and topical suspensions due to being rapid, convenient, and inexpensive?

hammer mill, ball mill, micro pulverizer

In 1984, ___% of Rxs were generic. In 2014, ___% were generic

12 84

Explain gas sterilization

Exposure to ethylene oxide gas in presence of moisture

What materials should be sterilized via gas sterilization?

Heat sensitive materials

most ocular formulations are applied as _________

eye drops

What are dendrimers?

'tree-like' polymers: extensive branching around a central core can be used for delivery of a variety of molecules including genes Dendrimer based gene delivery has been shown to reduce corneal transplant rejection In vitro studies demonstrate the effective nature of dendrimer based gene delivery to ocular tissues - further studies required Poly(amidoamine) dendrimers based topical solutions are found to be effective in increasing the ocular residence time of drugs following topical administration

What is a fine dispersion?

0.5 - 10 micrometer particle size same properties as coarse dispersion

List three methods to avoid the agglomeration of suspended particles.

1. mutual repulsion (high zeta potential) 2. absorption of small colloids on the surface of particles 3. steric hindrance via oriented non-charged molecules

CALCULATION OF AUC EXAMPLE

ANSWER ME!

Mechanisms that are thought to provide stable emulsifications include the I. formation of interfacial film II. lowering of interfacial tension III. presence of charge on dispersed droplets

ANSWER ME!

True/False: Anionic surfactants are commonly used for oral and parenteral emulsions

ANSWER ME!

USP/NF Dissolution Regulation

ANSWER ME!

Use drawings to describe the four different types of instability in emulsions

ANSWER ME!

What are the effects of lung disease on aerosol deposition?

ANSWER ME!

What are the different elements of formulations of a suspension?

API Wetting agent - disperse particles in the continuous liquid phase Flocculating agent - induce flocculation of suspended particles Suspending agent - to increase the viscosity of suspensions Dispersion medium Other ingredients: buffering agents, osmotic agents, coloring agents, preservatives

What are the elements of an emulsion formation?

API oil phase water phase emulsifying agent (e.g. surfactant) preservatives (esp. in O/W emulsions which are more susceptible to microorganism growth)

What are examples of natural emulsifying agents?

Acacia Lecithin *found in egg yolks* Pectin

What are some pharmacologic categories of ophthalmic drugs?

Anesthetics (tetracaine, cocaine, proparacaine), Antibiotics/antimicrobials (gentamicin, tetracycline, ciprofloxacin, polymixin, chloramphenicol) Antifungal agents (amphotericin B, natamycin, flucytosine) Antiinflammatory agents (steroidal agents such as fluromethalone, prednisolone, dexamethasone; NSAIDs such as diclofenac, flurbiprofen, ketorolac) Antiviral agents (trifluridine, idoxuridine, vidarabine) Astringents (zinc sulfate) Mitotics/glaucoma agents (pilocarpine, timolol, latanoprost) Mydriatics/cycloplegics (atropine, scopolamine, cyclopentolate, phenylephrine, tropicamide) Protectants/artificial tears (methylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol) Vasoconstrictors/ocular decongestants (naphazoline, oxymetazoline, pheneramine)

Most pharmaceutical suspensions have a particle size range of: A. 1-500 nm B. 500-1000 nm C. 1-50 um D. 50-1000 um

C

What molecule is a natural emulsifying agent? A. span B. tween C. acacia d. lactose

C - acacia

Pharmaceutical suspensions can be used for: A. oral administration B. parenteral administration C. topical administration D. rectal administration E. all of the above

E A is most common route

What is a required HLB (RHLB)?

Each lipophilic phase of an O/W emulsion has a required HLB allows one to use the least amount of surfactant to prepare a stable emulsion

15% of contact users wear these

RGPs

What is the relationship between sedimentation rate and stability?

Reducing sedimentation rate increases stability

What lens care products are available?

Wetting solutions (form hydrophilic coating over hydrophobic surface of the lenses; include viscosity imparting agent + surfactant + preservative; e.g. PVP, cellulose derivatives, polyvinyl alcohol, PEG derivatives) Cleaning solutions (remove surface contaminants such as films, crystals, protein aggregates, insoluble inorganic solts; commonly are nonionic surfactants; specific to lense material) Soaking solutions (store/hydrate/disinfect hard lenses; e.g. benzalkonium chloride and chlorhexidine)

What color does an emulsion containing >1 micrometer droplets appear?

White

Rigid gas permeable lenses (RGPs):

allow oxygen to pass through to the cornea less expensive, more durable, provide wearers with clearer, sharper vision requires less maintenance (do not contain water and proteins from the eye do not build up on the lens)

Explain what the hydrophilic-lipophilic balance (HLB) theory is?

an arbitraty scale of values that serves as a measure of the hydrophilic-lipophilic balance of surfactants *only calculated for nonionic surfactants* indicator of the solubility of a surfactant

3D printed pill dissolution?

employs the company's trademark "ZipDose" technology, which uses 3D printing to create a more porous pill (FDAapproved: September, 2015); structure means the pill dissolves more quickly on contact with liquid, making it much easier to swallow high doses than a conventional tablet

What are the three basic layers of the cornea? What are the role of each of these layers?

epithelium (lipophilic) - blocks passage of foreign material and absorbs oxygen and cell nutrients from tears stroma (hydrophilic) - composed of water (78%) and collagen fibers and functions in nutrient transport endothelium (lipophilic) - primary task is to pump excess fluid out of the stroma

What are some physiological factors that may affect a drug's bioavailability?

pH of GI/ionizations tatus, GI motility, metabolism during absorption process (e.g. first-pass effect), age, sex, disease status, transporters and efflux pumps

What are the effects of hypertonic solutions?

tissue shrinkage less severe as with hypotonic solutions

What tool can be used to help reduce contamination of ophthalmic solutions?

Eye cup

What is the main route of absorption?

Across the cornea

Explain the four types of contact lenses and their characteristics

*Hard, rigid and hydrophobic* (hard contact lens) - made of polymethyl methacrylate (PMMA) and have negligible gas permeability, low water content, and medium wettability *Soft, flexible, hydrophilic* (soft contact lens) - made of hydroxyethylmethylmethacylate (HEMA) and have high water content, low gas permeability, and good wettability *Flexible, hydrophobic* - made of silicone rubber and have good gas permeability and poor wettability *Rigid, hydrophilic* - made of silicone vinylpyrollidone, cellulose acetate butyrate and have good gas permeability and good wettability

Calculate the diffusion coefficient of a drug in an Ocusert with a release rate of 10-2 mg/h with a surface area of 2.8 cm2 and thickness of 1.4 cm, K=25 and solubility of the drug is 22 mg/ml?

(M/t) 10-2 mg/h = (s/h) 2.8/1.4 cm * D * (K) 25 * (Cs) 22mg/cm3 D = 1/110000 cm2/hr D = 1/110000 / 3600 = 2.52 * 10-9 cm2/sec

What are the 6 methods to ensure a stable emulsion?

1. correct emulsifying agent 2. small and uniform-sized droplets 3. optimize zeta potential 4. optimize phase-volume ratio 5. optimize viscosity 6. minimize density difference between internal and external phases

On average, it takes _____ years and costs _______ dollars to get one new medicine from Lab to Patient

10-15 years 802 million

What is the optimal viscosity range to reduce drainage loss when PVA or methylcellulose are used as viscosity enhancers?

12 to 15 cp

Explain the Ocusert system

1975 first controlled topical dosage form market for use in the eye device consists of a central core or reservoir of pilocarpine between two membrane surfaces, made of an ethylene- vinyl acetate copolymer, that control the rate of release of the drug. The oval device, slightly larger than a contact lens, is placed in the cul-de-sac under the upper or lower lid Pilocarpine is released at a zero order rate and is absorbed into the cornea of the eye The ocular delivery system was designed to overcome the inefficient delivery of pilocarpine from ophthalmic drops They are in close contact with the eye and release of drug from the Ocusert is continuous over a period of a week Only about one fourth dose of pilocarpine was required as compared to the dropper technique, and this reduction in dose overcomes toxicity and side effects. Further the release can be controlled by use of proper choice of membranes.

Explain the importance of the Hatch-Waxman Act

1984 created the generic drug industry

What are the steps for a patient to correctly use an MDI?

1: Shake the inhaler well before use (3 or 4 shakes) 2: Remove the cap 3: Breathe out, away from your inhaler 4: Bring the inhaler to your mouth. Place it in your mouth between your teeth and close you mouth around it 5: Start to breathe in *slowly*. Press the top of your inhaler once and keep breathing in slowly until you have taken a full breath 6: Remove the inhaler from your mouth, and *hold your breath for about 10 seconds*, then breathe out

Describe the proper usage of an MDI.

1: Shake the inhaler well before use (3 or 4 shakes) 2: Remove the cap 3: Breathe out, away from your inhaler 4: Bring the inhaler to your mouth. Place it in your mouth between your teeth and close you mouth around it 5: Start to breathe in slowly. Press the top of you inhaler once and keep breathing in slowly until you have taken a full breath 6: Remove the inhaler from your mouth, and hold your breath for about 10 seconds, then breathe out

What volume containers are ophthalmic solutions and suspensions commonly packaged in?

2, 2.5, 5, 10, 15, 30 mL

What is the desired viscosity in an ophthalmic solution?

25 and 50 cps

What is the maximum volume of the cul-de-sac?

30 microliters

What volume can be accommodated without spillage?

30 microliters

What is the thickness of the cornea?

30-50 micrometers

Most commercial eye drops range from ____ to ______ microliters.

50 - 75 microliters

What is the average estimated drop volume?

50 microliters

Example: calculate required HLB of the following oil mixture -mineral oil 50% (RHLB = 10.5) -caprylic/capric triglyceride 12.5% (RHLB = 5) -isopropyl isostearate 12.5% (RHLB = 11.5) -cetyl alcohol 25% (RHLB = 15.5)

50%(10.5) = 5.25 12.5%(5) = 0.625 12.5%(11.5) = 1.437 25%(15.5) = 3.875 sum of all = 11.2

What is the most widely used radioisotope?

60Co

What is the normal tear volume?

7 microliters

For maximum comfort, ophthalmic preparations should be at pH...

7.4

What is the pH of tear fluid?

7.4

What is a coarse dispersion?

>0.5 micrometer particle size visible under optical microscope do not pass through filter paper or semipermeable membranes do not diffuse e.g. most emulsions, suspensions, RBCs in blood plasma

What are the deposition profiles of aerosols with different particle sizes?

>5-10 µm: mainly deposited in the large conducting airways and oropharyngeal region 1-5 µm: deposited in the small airways and alveoli 3 µm: 50-60% being deposited in alveoli <0.6 µm: not deposited, but exhaled

What is an emulsion?

A two-phase system in which one liquid is dispersed throughout another liquid in the form of small droplets; the two phases are immiscible

Explain what caking is

Compact aggregates that sit on the bottom Irreversible Most difficult problem

Explain the AUC

AUC: Area Under the Concentration time Curve (the amount of systemic drug absorption is directly related to AUC) AUC represents the total amount of drug absorbed into the blood circulation If same doses of drug in two different formulations produce different AUC, differences exist in the extent of drug absorption between these two formulations Equivalent doses of the same drug, when fully absorbed, produce the same AUC

Define absorption

Absorption: the process of transporting the drug from the GI tract into the systemic circulation (not greatly dependent on product formulation and the manufacturing process, it is more dependent on the physical/chemical properties of the drug and the physiology condition)

What are common suspending agents?

Acacia, xanthan gum, caboxymethyl cellulose, methylcellulose

How can you minimize byproduct formation?

Aerate sterilized materials for at least 72 hours at 40-50 degrees C

What are commonly used wetting agents?

Alcohol, glycerin, propylene glycol, non-ionic surfactants, and other hygroscopic liquids

What is the difference of air autoclave over steam autoclave?

Allows pressure manipulations which permit the autoclave sterilization of materials that tend to deform (e.g. polypropylene containers)

What type of molecule is a surfactant?

Amphiphilic Contains both polar and nonpolar groups Have a tendency to self associate into aggregation polymers/micelles

Explain the factors related to the formulation that affect dissolution rate.

Binder (excessive binder = slow dissolution) Disintegrant (↑ dissolution) Lubricant (the property and quantity of lubricant may affect the dissolution rate) Hydrophilic excipients (↑ dissolution) Hydrophobic excipients (↓ dissolution) Coating may affect the dissolution

How do you determine a "compromise" pH?

Can be maintained by buffers Permits greater activity Maintains stability

Which of the typical flocculating agents are most commonly employed as the flocculating agent for oral suspensions?

Clays

What are the components of an aerosol system?

Container Propellant Concentrate containing the API Valve Actuator

List the five major components of an aerosol system

Container, propellant, API, valve, and actuator

What are the two types of valves used in pharmaceutical aerosol systems?

Continuous valve or metered valve

What are the advantages of pharmaceutical aerosols?

Convenient, easy to use Protects drug from oxygen, humidity, and microbial contamination due to *closed system* topical medication can be applied in uniform, thin layer to the skin without touching affected area (which can minimize irritation due to mechanical application) *remaining product not contaminated during use*

Explain the factors related to the API that affect dissolution rate.

Crystal forms: amorphous/noncrystalline = fast dissolution polymorphic forms/multiple crystalline forms have variable solubilities Salt forms always have higher solubility

What are some examples of surfactants?

Detergent, soap, emulsifiers, defoamers, dispersants, and wetting agents

Define dispersion

Dispersed phase is fragmented into small pieces and distributed in a continuous phase (dispersion medium or dispersing phase)

Explain the concept of drug delivery through contact lenses

Drug delivery systems that increase residence time of the drug in the eye, thereby reducing wastage and eliminating side effects Slow diffusion of the drug molecules through the particles and the lens matrix, drug-laden contact lenses can provide continuous drug release for extended periods Particle-laden lens contains enough drug to last approximately 3 to 4 days Nanometer-sized channels in a drug-laden contact lens may result in better delivery techniques and less waste

Explain the concept of bioequivalence

Drug products are considered bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered at the same molar dose under similar conditions e.g. theophylline formulation types

What are the steps of preparing a suspension?

Drugs are finely divided to uniform size Solids are wetting to separate individual particles and coat them with a layer of dispersion medium Suspending agents are added Preparation is brought to desired volume

Why use suspensions over capsules/tablets?

Easier to swallow good bioavailability

What is the most important factor that determines the type of an emulsion?

Emulsifying agent

What is the role of a viscosity enhancer in a pharmaceutical preparation?

Enables formulation to remain in the eye longer and gives more time for the drug to exert its therapeutic activity or undergo absorption

What factors affect drug dissolution?

Factors related to formulation types, manufacturing processes (high compression = high hardness = slow dissolution e.g.), factors related to API, and dissolution conditions (speed, medium, temperature

True/False: Continuous valve is mainly used for inhalation products

False

True/False: suspensions can be used for soluble and insoluble drugs

False - just used for insoluble drugs

True/False: increasing the viscosity of dispersion medium is the best strategy to improve the physical stability of a suspension

False - reducing particle size is the preferred method

True/False: suspension is a thermodynamically stable system

False - suspensions are thermodynamically unstable

What are some advantages of filtration?

Filters retain all particulate matter (microbial, dust, fibers, etc.)

Explain the properties of Intralipid

First approved parenteral emulsion O/W emulsion 10-20% soybean oil droplets 70-400 nm in size high negative zeta potential

What are the different types of instability in emulsions?

Flocculation --> creaming Coalescence --> breaking

What type of size reduction equipment produces the smallest sized particles?

Fluid energy/jet milling

What are the benefits of developing a brand drug?

Full patent life: 20 years: Effective patent life: 11~12 years "Market exclusivity": During the patent protection period, the company can set the price to maximize its profitability

What are the benefits of bringing a generic drug to market?

Generic companies may seek FDA approval before the expiration of the patent via the ANDA process Generic companies are not required to repeat expensive clinical trials performed by the innovator. Instead, generic companies need to prove that the generic drug is bioequivalent to the brand name drug

What is the ideal ratio of concentration to volume?

High concentration of drug in minimum drop volume

What is the relationship between HLB and hydrophilicity?

Higher HLB = more hydrophilic

Ingredients that may be used as suspending agents include I. methylcellulose II. acacia III. talc

I and II

Which of the following processes are reversible? I. Flocculation II. Aggregation III. Caking

I only

Emulsions can be used _____ I. to increase drug solubility II. to increase drug stability III. for parenteral dosage form

I, II, and III

Explain the difference between USP dissolution apparatus I (basket) and II (paddle)

I: 50~150 RPM; generally preferred for capsules and for dosage forms that tend to float or disintegrate slowly II: 25~100 RPM; generally the first choice for immediate release dosage forms

Sedimentation of particles in a suspension can be minimized by: I. Adding sodium benzoate II. Increasing the viscosity of the suspension III. Reducing particle size of the active ingredient

II and III

What is TPN?

IV administered calories, nitrogen and other nutrients to achieve tissue synthesis and anabolism indicated for patients unable to ingest food to get nutrition contains 20-60% dextrose, 3.5-10% protein (amino acids) and various amounts of fatty acids, electrolytes, vitamins and minerals *Medications can also be added*

What are some advantages of emulsions?

Increase drug solubility (insoluble drugs can be dissolved in the oil-phase of an emulsion) Increase stability (drugs are more stable when incorporated into the oil phase rather than an aqueous solution) Well accepted as parenteral nutrition Prolonged drug action Improves taste and appearance (palatability)

What are suspending agents used for?

Increase viscosity of suspensions

What are wetting agents used for?

Insoluble powder is generally not readily wetted and it is difficult to disperse insoluble powder in hydrophilic medium Function by displacing the air in the crevices of the particles, dispensing the powder, and allowing penetration of dispersion medium into the powder

What is drainage voume proportional to?

Instilled drug volume Larger instilled volume, more rapidly the instilled solution is drained from pre-corneal area

Explain what agglomeration is

Intermediate (between flocculation and aggregation) Settle rapidly

Differentiate between the internal and external phase of an emulsion

Internal = dispersed phase External = continuous phase

Why not use large particles in ophthalmic suspensions?

Large particles may drain away before dissolution takes place and thus decrease bioavailability

Most effective penetration is obtained with drugs with what property (properties)?

Lipid and hydrophilic properties

What is topical ocular administration used to treat?

Local diseases that affect the eye

Explain what flocculation is.

Loosely bound clusters Reversible Settle rapidly

What are the advantages of HFAs?

Low inhalation toxicity, high chemical stability, high purity, *no impact on ozone layer* less forceful (soft mist)

What type of size reduction equipment produces the largest sized particles?

Low speed

What are the three categories of size reduction equipment?

Low speed (roller mill, end-runner mill, ball mill, universal mill, hammer mill) High speed, with classifier (hammer mill, vibratory mill, stud mill) Fluid energy/jet mill

Release of sparingly soluble drugs from Ocusert can be calculated as:

M = (S*D*K*Cs)/h * t M: accumulative amount of drug released in time t S: surface area of the device D: diffusion coefficient of the membrane K: liquid-liquid partition coefficient of the ocusert membrane and the eye fluids Cs: aqueous solubility of the drug h: membrane thickness

What is the most widely used aerosol delivery device?

MDI

Explain what a specialty contact lens case is

Marietta Vision Specialty Contact Lenses distributes a contact lens case that has incorporated nanosilver. The lens case is designed so that these particles, which carry positive charges, collide with the cells of microorganisms, which carry negative charges

When would we use a suspension over a solution?

Medicinal agent is insoluble in the desired vehicle or is unstable in solution form or slower release/sustained effect of drug is needed

What are the disadvantages of HFAs?

Minor greenhouse effect, high cost, poor solvents

What are some physiochemical factors that may affect a drug's bioavailability?

Molecular weight, solubility, manufacturing variables (e.g. dissolution), properties of API (may not pass through biological membranes?)

What is a surfactant?

Molecule that adsorbs to interfaces to reduce interfacial tension

What is an emulsifying agent?

Molecules that lower interfacial tension and form a film at the interfae

What are the three methods of preventing agglomeration?

Mutual repulsion via high zeta potential Absorption of small colloids on the surface of particles Steric hindrance via oriented non-charged particles

Differentiate between an NDA and ANDA:

NDA for brand requires chemistry, manufacturing, controls, labeling, testing, *animal/preclinical studies, and clinical studies* ANDA for generic requires requires chemistry, manufacturing, controls, labeling, testing, *bioequivalence studies in vitro and in vivo*

Does pharmaceutical equivalence mean bioequivalence?

NO! Drug products are considered bioequivalent if they are pharmaceutical equivalents whose rate and extent of absorption are not statistically different when administered at the same molar dose under similar conditions Pharmaceutical/chemical equivalence indicates that two or more dosage forms contain the same quantities (plus or minus specified range limits) of the drug

Are emulsions thermodynamically stable?

No

Explain what aggregation is

Strongly bound particles Irreversible

What type of emulsion are most pharmaceutical preparations?

O/W

What type of emulsion do natural emulsifying agents work best for?

O/W

What are the properties of milk?

O/W emulsion Consists of a large number of fat droplets (raw milk ~10 micrometers; homogenized milk ~1 micrometer)

Differentiate between an oil-in-water emulsion and a water-in-oil emulsion

O/W: oil is dispersed phase, water is continuous phase W/O: water is dispersed phase, oil is continuous phase

What is the bioavailability of an ophthalmic ointment vs. an opthalmic solution?

Ointment > solution greater contact time --> prolonged drug levels and increased drug absorption

What surfactant has the lowest HLB?

Oleic acid (1)

List some applications of emulsions.

Oral (nutrition, mask unpleasant flavor, drug delivery of water insoluble drugs or proteins) Parenteral (nutrition/TPN, delivery of poorly soluble drugs, targeted drug delivery and controlled drug release) Topical (creams/lotions, can be O/W or W/O)

What patient population is most likely to use a suspension?

Pediatrics

What drugs are insoluble in water at pH 7.4?

Pilocarpine, ephedrine

Explain the role of nano and microparticles in ophthalmic drug delivery.

Polymeric nano and microparticles have been used to prolong the drug residence time in the eye Pilicarpine loaded nanoparticles increased the miosis time (up to 10 hrs) and AUC by 50 % Cyclosporine nanocapsules (poly caprolactone) increased corneal levels by 5 times compared to solution Various other drugs such as betaxolol, piroxicam, indomethacin have exhibited enhanced activity when administered as nanoparticles Micro/nanoparticles have also been used to deliver drugs such as acyclovir and 5-fluorouracil to the posterior segment of the eye

Why can viscosity not be too high in ophthalmic solutions?

Products must have negligible visual affects Products should be filterable

What enzymes of the conjunctival mucosa metabolize peptides administered by ocular route?

Proteases

What "bug" is not killed by the common preservatives in their dose ranges in ophthalmic formulations? How is this "bug" controlled?

Pseudomonas aeruginosa use preservative mixtures such as benzalkonium chloride 0.01% and polymixin B sulfate 1000units/mL

What are the methods to overcome the tendency of particles to group together due to large surface free energies while separate?

Reduce interfacial area by controlling particle size but not making the particles too small Reducing interfacial tension by using a surfactant Using controlled flocculation by using loose, weak interactions to decrease chance of development of stronger interparticle interactions

What is the function of a valve in an aerosol system?

Regulates flow of the therapeutic agent and propellant from the container

What else can determine the type of emulsion?

Relative phase volumes

What is the goal of controlled flocculation?

Repulsive forces must be decreased until weak attraction prevails

What is a major disadvantage of using MDIs?

Require hand-mouth coordination Patients must be trained

What temperature is filtration done at?

Room temperature

Explain the importance of implants?

Scleral and vitreal implants have been attempted Vitreal implant use associated with endophthalmitis Need replaced every 6 months Implants made from poly lactide/glycolide polymers can result in drug release over 5- 6 month period with out the need for replacement

How do you choose the most appropriate surfactant?

Select a surfactant with the required HLB (will give superior stability at low cost, which will save time and money) Toxicity of surfactants should be considered Use a blend of at least two surfactants (because mixing low HLB and high HLB surfactants gives better coverage at the interface and allows for better stability) Use 0.5-5% surfactants

What color does an emulsion containing 0.05-0.1 micrometer droplets appear?

Semi-transparent

The dissolution rate of large particles is ___________ than that of smaller particles.

Slower

Where does the drug go?

Small amount penetrates cornea Remaining drug leaves eye through tear drainage

What is the relationship between solubility and temperature?

Solubility decreases with increasing temperature Exothermic reaction - deltaH is negative

Which of the three types of conventional ocular drug delivery systems is most frequently employed?

Solution

What is an example of an emulsifying agent for W/O emulsions?

Span 80 (sorbitan oleate); nonionic

In what ways can drug be lost in ocular drug delivery?

Spillage Removal by naso-lacrimal apparatus Superficial absorption of drug through conjunctiva and rapid removal by peripheral blood vessels Precorneal loss of drug due to tear turnover (which dilutes the drug), drainage, systemic sbsorption, and in situ metabolism

What are the most important requirements?

Stability and preservation

How can you increase the ocular drug bioavailability?

Sustained drug delivery systems providing controlled and prolonged drug delivery (e.g. implants, inserts, colloids) Enhancing drug absorption by maximizing the contact time and minimizing the corneal drug loss due to drainage using viscosity enhancing agents, penetration enhancers, prodrugs that target various receptors on eye

Explain what the process of drug dissolution and absorption looks like.

Tablet/Capsule *disintegrates* into granules or aggregates which then *deaggregate* into fine particles Tablets/capsules, granules/aggregates, fine particles undergo *dissolution* and form drug in solution Drug in solution undergoes *absorption* to enter blood, other fluids and tissues Drug is *distributed* to other organs to exert action and be *metabolized* and *eliminated*

Why are suspensions thermodynamically unstable?

The particles have cumulatively very large surface area with surface free energies and thus have a tendency to group together

Explain in vivo bioequivalence testing

The standard bioequivalence study can be conducted using a two-treatment crossover study design including approximately 24 to 36 adults, which are randomly separated into test and reference drug groups. Single oral doses of the test and reference drugs are administered in both the fasting and fed states, and blood or plasma levels of the drug are measured over time. A food-effect study requires administration after an appropriate meal at a specified time before taking the drug, a so-called "fed" or "food-effect" study. The rate and extent of drug absorption are statistically measured. According to the FDA, two products are considered to be bioequivalent if the 90% clearance (CI) of the relative mean Cmax, AUC(0-t), and AUC(0-∞) of the generic drug to the brand-name drug is within 80% to 125% in both the fasting and fed states.

What are some applications of bioavailability?

Therapeutic comparisons 1. Compare the absorption of different formulations of the same drug 2. Compare the absorption of different routes of the same drug Oral, Parenteral, Rectal, Transdermal, Topical etc. 3. Compare the absorption of a generic drug to the original brand name drug

What kind of epithelium is the corneal epithelium?

Tight epithelium containing tight junctions (zonula occludens)

What is the most widely used container for aerosols?

Tin-plated steel

What is bioavailability?

To exert an optimal therapeutic action, an active moiety should be delivered to its site of action in an effective concentration for a desired period. "the rate and extent to which the active ingredient or active moiety is absorbed from a drug product and becomes available at the site of action the fraction of unchanged drug reaching the systemic circulation following administration through any routes

What is the goal of preservation of ophthalmic preparations?

To maintain sterility during use

What is the structure of the lung and the functions of these structures (in a nutshell)?

Trachea, main bronchi, lobar bronchi, small bronchi, and bronchiles = conducting airways; respiratory bronchioles, alveolar ducts, and alveolar sacs = where gas exchange occurs

What color does an emulsion containing <0.05 micrometer droplets appear?

Transparent

True/False: a blend of two or more surfactants is better for the stability of emulsions

True

True/False: a high HLB value indicates a molecule with more hydrophilic groups

True

True/False: suspensions have better bioavailability compared to capsules

True

Which have higher HLBs: SPAN or TWEEN surfactants?

Tween

What is an example of synthetic emulsifying agent for O/W emulsions?

Tween 80 (polyoxyethylene sorbitan oleate); nonionic

Explain the 3-stage dissolution acceptance test for immediate release dosage forms

USP29-NF24 Stage 1: The batch is acceptable if each of 6 tablets/capsules releases not less than Q+5%. If not all pass, then an additional 6 are added and studied in stage 2, Stage 2: If the average percentage (Q) released from all 12 (6+6) units is equal to or more than Q, and no unit has less than (Q-15)% released, then the batch passes. If not, additional 12 units are added for stage 3, and Stage 3: If the average percentage (Q) released from all 24 (6 from stage 1+ 6 from stage 2 + 12 for Stage 3) units is equal to or more than Q, and there are no more than 2 units with less than Q-15% released, and no single unit had less than Q-25% released at the specified time, then the batch passes. Otherwise, the batch fails and is unacceptable for distribution. *3 stages (6+6+12) Rules 1st stage: Each unit is not less than Q+5% 2nd stage: Average of 12 units (S1+S2) is equal to or greater than Q, No unit is less than Q-15% 3rd stage: Average of 24 units (S1+S2+S3) is equal to or greater than Q, No more than 2 units are less than Q-15% No unit is less than Q-25%* Q: the amount of dissolved active ingredient (expressed as % of the labeled dose) Q is about 75% in a 45-min dissolution test (defined by USP monograph) Continue testing through the three stages unless the results conform at S1 or S2 If S3 fails, the whole batch will be rejected and discarded.

How can ocular delivery of drugs from matrices be improved?

Using bioadhesive polymers

What is the bioavailability of ophthalmic solutions?

Usually low (due to barrier properties of both the conjunctiva and cornea, the loss of drug by processes such as precorneal loss of drug due to tear turnover, drainage, systemic absorption, and in situ metabolism)

What is Stoke's Law?

V = [2(r^2)g(Dp-Df)] /9u] V= velocity r = radius of the particle g= acceleration of gravity, 9.81 N/kg Dp = density of particles Df= density of fluid u = liquid viscosity Particles of a certain size will take a certain amount of time to fall.

Why is increasing the viscosity of the liquid phase not the preferred method of changing sedimentation rate?

Viscosity of the dispersion medium cannot be too high because you couldn't pour it, difficult to re-disperse, difficult to formulate

What are the requirements for a generic drug?

When compared to brand name product... Same API Same dosage form Same route of administration Same strength *all of the above = pharmaceutical equivalence* Same conditions of use

Explain when to use an ophthalmic ointment

When increased ocular contact time is necessary

Why is preventing agglomeration of suspended particles important?

While agglomeration is reversible, it can lead to aggregation/caking and thus is important to prevent

What amount of dose from an MDI is deposited where?

______ in lung ______ in orophayngeal region

What byproducts may be created when using ethylene oxide sterilization?

ethylene glycol ethylene chlorhydrin *irritating*

Explain a dry powder inhaler system

a device that delivers drugs to the lungs in the form of a dry powder eliminates coordination difficulties associated with MDI can be single or multiunit dose inspiratory flow rate is important - requires rapid inhalation to provide necessary energy for aerosolization *good choice for macromolecules*

What is required to form an emulsion?

a large increase in interfacial area requires a large amount of energy brought into the system during the emulsification process

Explain a metered dose inhaler system

a pressurized device that uses propellant to deliver a *metered dose (a specific amount of medication)* through the mouth piece upon the actuation of the valve aerosol is driven by expelling a metered dose of pressurized liquid propellants (CFC or HFA) containing drug thorugh a nozzle at high velocity

What are methods in which one could induce controlled flocculation?

add electrolytes (reduce electric barrier between particles and thus reduce zeta potential) add surfactants add hydrophilic polymers (adsorbed polymers can associate with each other and form bridges between particles)

How does a jet nebulizer work?

air from the compressor breaks the liquid medication into small breathable particles which form a mist; as you breathe in, the valve at the top opens and lets air in and speeds up mist generation; when you breathe out, the top valve closes which slows down the mist, and the mouthpiece flap opens letting your breath out

How is preservation of ophthalmic preparations done?

antimicrobial agents are added in the formulations

Beta-blocking agents example

e.g. propranolol, levobunolol effective in control of glaucoma loss of levobunolol due to systemic asborption about 46% - 12% converted to dihydrolevobunolol in ocular tissues

How are drugs absorbed from ocular administration?

either through the conjuctival sac or the corneal membrane

Explain what homogenization does in regards to the structure of the emulsion of milk?

before homogenization, casein micelles and fat globules are separate after homogenization, fat and casein micelles aggregate

What is the effect of homogenization?

before homogenization, wide range of sizes averaging at 8 micrometers after homogenization, narrow range of sizes averaging at 1 micrometer

What are common preservatives and dose ranges used in ophthalmic formulations?

benzalkonium chloride (0.004-0.01%) benzethonium chloride (0.01%) chlorobutanol (0.5%) phenyl mercuric acetate (0.004%) thimerosal (0.005-0.01%)

What are the different pehnomena and parameters to be investigated in regards to structure-based requirements of polymers for contact lenses?

chemical: stability, hydrolytic degradation, thermal stability, migration of impurities optical: refractive index, discoloration at storage surface: surface energy, contact angles, chemical structure, protein adsorption mechanical: modulus of elasticity, ultimate tensile strength, tear propagation, response to shear stress, environmental aging biologic: toxicity, carcinogenicity, sterility

Explain what a jet nebulizer is

compressed gas passes through a narrow orifice creating an area of low pressure at the outlet of the adjacent liquid feed tube, resulting in drug solution being drawn up from the fluid reservoir and shattered into small droplets in the gas stream

What are the types of propellants used in aerosol systems?

compressed gases (carbon dioxide, nitrogen, nitrous oxide) and liquified gases (CFC, HFA)

What anatomic structures of the face play a role in systemic absorption of ocularly applied drugs?

conjunctiva and nasal mucosa

Which site of ocular absorption is a more effective *barrier* for drug absorption?

corneal membrane

What equation is used to describe the free energy of the interface of an emulsion?

deltaW = sigma * deltaA deltaW = change in free energy of the interface = energy brought into the system during the emulsification process sigma: ultimate stability is only achieved when sigma approaches zero

Explain the phenomena of Ostwald Ripening

describes evolution of an inhomogenous structure over time dispersed particles have an equilibrium solubility that varies based on size: small particles are more soluble and have a finite tendency to solubilize; large particles will grow at the expense of small particles

What are collagen shields?

designed to be a disposable, short-term therapeutic bandage lens for cornea Antimicrobial, anti-inflammatory, antifungal, immunosuppressant, antiviral, wound healing agents have been delivered to the cornea by corneal collagen shields These shields can be used in patients who underwent corneal surgery for delivery of therapeutic agents without disturbing the eye Utility of collagen shields for posterior segment drug delivery is still under investigation

Explain a nebulizer inhalation system

device to administer medication to the lungs of patients in the form of a mist

Hard plastic lenses:

do not allow oxygen to pass through to the cornea require long adjustment period cannot be worn for more than 12 hours AKA high-maintenance lenses rarely used

What does the Noyes-Whitney equation tell us?

high solubility --> high dissolution rate smaller drug particles --> higher dissolution rate *reducing particle size is effective method to increase dissolution rate of poorly soluble drugs* but can be limited by agglomeration surface area per dose can be increased by reducing particle size

Why use inhalation route of administration?

highly vascularized tissue low intrinsic enzymatic activity large absorptive surface (>100 meters squared in humans - half the area of a tennis court) high permeability of the alveoli (due to alveolar thickness being 0.1-0.2 micrometers) great tolerance for foreign substances molecules absorbed in the lung bypass the portal circulation/first-pass metabolism

What are some commonly used viscosity enhancers?

hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol, polyvinylpyrrolidone

Absorption of the drug is inefficient due to...

impermeable surface small surface area

Define therapeutic equivalence

implies that one structurally different chemical can yield the same clinical result as another chemical. (also for the same drug from two or more dosage forms)

Where are ocular drugs normally administered?

in the cul-de-sac

Explain the dissolution test

in vitro laboratory test method to demonstrate how efficiently a drug is released from a solid dosage form standard method published by the United States Pharmacopeia (USP) : "To determine whether tablets or capsules disintegrate within the prescribed time when placed in a liquid medium" (USP 29) Does not provide any information on drug absorption across the GI tract (To assist with the determination of bioequivalence (generic drug vs. brand name drug): products after scale-up are the same (bioequivalent) as the originally approved formulation)

What is iontophoresis?

increased transport of ionic drugs by application of an external electric current Used in ophthalmic delivery of antibiotic, antiviral, antifungal, antimetabolite, steriod and dyes Vidarabine levels in the cornea were 3-12 times higher compared to simple topical administration Iontophoresis has been attempted for transcorneal and transscleral delivery of vancomycin. Transscleral iontophoresis was effective in delivering therapeutic levels of vancomycin, ketoconazole into the vitreous

Increasing viscosity _____ bioavailability of drugs

increases

What are aerosols used for in pharmaceuticals?

inhalations (most important application) topicals (anti-infectives, local anesthetics) vaginal (estrogenic substances and contraceptive agents) rectal (anti-inflammatory)

What types of products are metered valves used with?

inhaled products

What is the common buffer used in ophthalmic preparations?

isotonic phosphate buffer

Are filters more or less reliable than the autoclave?

less reliable

What are the properties of an aluminum container in an aerosol system?

lightweight, manufactured by extrusion, seamless, incompatible with some propellants and solvents

What are the two methods of sterilization by radiation?

linear electron accelerators (produce high energy electrons which may have little penetrating power) and radioisotopes

Define suspension

liquid preparation consisting of solid particles dispersed throughout a liquid phase in which the particles are not soluble

What are some examples of surfactants in the human body?

liver bile lung surfactant

What is the major constraint to ocular drug delivery?

loss of drug

What are the advantages of CFCs?

low inhalation toxicity, good solvent, high chemical stability, high purity

Explain the process of aerosol deposition in the lung.

lung has various defense mechanisms to prevent aerosol particles penetrating into deep lung oropharyngeal region and the bronchial tree are filters to remove particles from the inhaled air Biophysical parameters determine the particle deposition: Aerodynamic particle behaviors (e.g. size, density, shape, electrical charge), Breathing pattern of the patient (optimal deposition occurs with slow, deep inhalations followed by breath-holding prior to exhalation) Airway anatomy of the patient

What pieces of equipment are used to make emulsions?

magnetic stirrers heat plates homogenizers industrial mixers industrial homogenizers

What are disadvantages of sterilization by radiation?

may produce chemical changes (e.g. color change) in the product or in the packaging

What is a good way for scientists to demonstrate bioequivalence?

measure the time it takes the generic drug to reach the bloodstream and its concentration in the bloodstream in 24 to 36 healthy, normal volunteers.

What process can help decrease drug particle size? Why is this important

micronization minimizes eye irritation and scratching of the cornea

Explain polymer based implants

microspheres can deliver drugs over 60-90 days polymeric gels (PLGA + PEG) can result in depot formation at site of injection and thus controlled drug release Devices prepared from non-biodegradable polymers can be implanted permanently in the eye and their drug content replenished

What is creaming?

migration of droplets to the surface or to the bottom of emulsions Reversible undesirable because increases likelihood of coalescence

Corneal absorption is also affected by physicochemical properties of drug like

molecular weight, solubility, ionization state (unionized form greatly enhances the absorption), octanol-water coefficient

Describe fluid energy grinding.

most effective method to reduce particles below 10 micrometers uses shear action of high velocity streams of compressed air may cause high electrostatic charges on particle surface and cause difficulties in collection of the particles

Soft contact lenses are used for:

myopia (nearsightedness), hyperopia (farsightedness), astigmatism (irregular shaping of the cornea causing skewed vision)

What are the four types of emulsifying agents?

natural emulsifying agents surfactants (adsorbed at oil/water interfaces to form monomolecular films and reduce interfacial tension) hydrophilic colloids (form multimolecular films around the dispersed droplets of oil in an O/W emulsion Finely divided solid particles (adsorbed at the interface between two immiscible liquid phases)

What is the role of tears in preventing discomfort due to ophthalmic solution pH differences?

normal buffering action of tears (tears have some buffer capacity)

What is the "true dose" of a drug?

not the amount of drug administered, but the amount of drug available to exert its effect

Define clinical equivalence

occurs when the same drug from two or more dosage forms gives identical effects as measured by a pharmacological response or by control of a symptom or disease

What are the steps of preparing an emulsion?

oil phase heated until liquified oil soluble components dissolved in oil phase water-soluble components are dissolved in the aqueous phase and heated to the same temperature of the oil phase two phases are mixed until cool made to weight or volume

What is the major consideration of making an ophthalmic ointment vs. making a topical ointment?

ointment base must be sterile, non-irritating to eye, and have a melting or softening point close to body temperature

What fraction of INDs tested in humans are approved?

one in five

Explain the importance of clarity

ophthalmic preparations should be free from foreign particles normally achieved by filtration (can be done at same step as sterilization if filtration is used) both container and closure must be thoroughly clean, sterile and nonshedding and go through stability testing to prove this

What are the three types of conventional ocular drug delivery systems?

ophthalmic solutions, suspensions, and ointments

What routes can suspensions be administered?

oral, ocular, parenteral (IM), topical, rectal, otic

What are the effects of hypotonic solutions?

painful swelling

What is first pass effect?

phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced after first pass through the liver, thus greatly reducing the bioavailability of the drug before it reaches the systemic circulation

What are the factors affecting ocular bioavailability?

physical considerations corneal absorption

What are the disadvantages of suspensions?

physically unstable; difficult to give uniform/accurate dose (can be solved by packing in unit doses), difficult to formulate (must reduce particle size uniformly) and bulky to handle/transport

Pilocarpine as example of controlled ocular drug delivery

pilocarpine was released from PVM-MA polymers according to zero-order kinetics and was controlled by the erosion of the polymer surface Erodible and non-erodible dry films for sustained delivery of pilocarpine were prepared The polymers used in both cases were polyvinyl alcohol and carboxyl copolymer The in vivo miotic response was delayed longer than that of pilocarpine solutions.

Explain what Duro-Mist is

portable, easy to use ultrasonic neubilizer nebulizer rate = 0.5 mL/min aerosol droplet size = 1.5-5.7 micrometers

Describe Exubera inhaled insulin

powdered form of human insulin too big, too expensive, not very effective

How do you determine the required HLB of an uncommon lipophilic phase?

prepare eight emulsions each with the same amount of oil, water, and mixing - use the same amount of surfactant but with different HLB values select the most stable emulsion - the HLB value of the surfactant used in this emulsion is the required HLB for the lipophilic phase

Define dissolution

process of releasing the drug out of the solid formulations into solution within the GI tract (much dependent on product formulation and the manufacturing process)

Define pharmaceutical aerosols

products that are packaged under pressure and contain therapeutically active ingredients that are released upon activation of an appropriate valve system

Why are suspensions good for IM injections?

provide controlled release e.g. insulin complexed with zinc - effects begin 2.5 hours after injection and can last up to 22 hours

What are the disadvantages of CFCs?

reduce atmospheric ozone, contribute to greenhouse effect, high cost were banned on 12/31/2008

How can ocular residence time of a drug be prolonged?

reduce drainage (use viscosity enhancers, formulate suspensions or emulsions, use erodible and nonerodible matrices) enhance corneal penetration (use prodrugs and liposomes)

How can creaming be avoided?

reduce droplet size, reduce difference in density between the two phases, increasing the viscosity of the continuous phase

Which is the preferred method of reducing sedimentation rate for pharmaceuticals?

reduce particle size

How can you reduce sedimentation rate?

reduce particle size reduce density difference between the particles and the fluid increase viscosity of the fluid

What is breaking?

separation of internal phase from emulsion Irreversible

What are the desired properties of a suspension?

settle slowly and re-disperse upon gentle shaking particle size is uniform and remains fairly constant during storage pour readily and evenly palatable (pleasing taste, odor, and color) stable during storage

What methods are used to adjust tonicity (aka, to make something isotonic)?

sodium chloride equivalent method use of isotonic buffer

What properties of antimicrobial agents are necessary to be used for preservation?

stability, chemical and physical compatibility with formulation and containers

What are the four types of sterilization used to prepare ophthalmic preparations?

steam under pressure (autoclave) filtration gas sterilization radiation

What is the preferred method of sterilization according to USP?

sterile membrane filtration

Opthalmic preparations require special consideration with regard to...

sterility, preservation, clarity, isotonicity, buffering, and viscosity

What is a propellant in an aerosol system?

supplies the necessary pressure within an aerosol system to expel material from the container and, in combination with other components, to convert the material into the desired physical form

What are the five examples of dispersions?

suspension (solid particles in liquid) emulsion (liquid particles in liquid) smoke (solid particles in gas) cloud (liquid particles in gas) foam (gas particles/bubbles in liquid)

What are some limitations of aerosol delivery?

technically difficult expensive patients must learn specific inhalation techniques (and incorrect use may greatly affect therapeutic efficacy) safety hazard (due to flammable propellants, pressurized containers) only a small fraction (10-15%) of the dose reaches the small airway and alveoli high humidity in respiratory tract affects the aerosol particle size and distribution

What is the property of compressed gases that makes them not good over time?

tend to lose pressure over time

Explain the process of autoclaving

terminal sterilization method 121 degrees C for 15 minutes formulation must be have appropriate thermal stability

Define bioequivalence

the absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study Have same AUC, Cmax, and similar Tmax a drug in two or more similar dosage forms reaches the general circulation at the same relative rate and the same relative extent, ie, that the plasma (blood or serum) level profiles of the drug obtained using the two dosage forms are, within reason, superimposable. If two products are said to be bioequivalent it means that they would be expected to be, for all intents and purposes, the same

Define the term "aerosol"

the fine mist of spray that results from a pressurized system

What is an actuator in an aerosol system?

the fitting attached to an aerosol valve stem, which when depressed or moved, opens the valve, and directs the spray containing the drug preparation to the desired area *technically part of the valve assembly* product discharged through orifice in the actuator design of actuator affects physical form (mist, coarse spray, foam) of discharged product

What is the osmotic pressure of tears equal to?

the osmotic pressure of 0.9% NaCl *isoosmotic*

Are suspensions stable or unstable?

thermodynamically unstable

Explain the importance of isotonicity

to ensure isotonic solutions do not damage tissue or produce pain when administered

What types of products are continuous valves used with?

topical products

What does a container in an aerosol system look like?

uncoated or plastic coated glass, metal such as aluminum, stainless steel, or tin-plated steel, or plastic

Why use suspensions over solutions?

use for insoluble drugs when cosolvents, surfactants, and solubilizing agents are not available can increase stability make unpleasant taste

Explain what an ultrasonic nebulizer is

uses piezoelectric crystal vibrating at high frequency to generate a foundation of liquid in the nebulizer chamber, the higher the frequency, the smaller the droplet size; has poor delivery efficiency (~10% of the dose deposits in the lung) and there is a stability concern (marcromolecules may be degraded during the generation of small liquid droplets)

How can you avoid breaking?

using proper emulsifying agents and phase-volume ratio

Ocular bioavailability of topical drugs is ___________

very poor (<5%)

What is the pH profile of the majority of APIs used in ophthalmology?

weakly acidic with weak buffer capacity

When does removal by the naso-lacrimal apparatus begin?

when reflex tearing causes volume to exceed 7-10 microliters sends drug to GI tract, which can cause potential systemic effects and lead to a salty/bitter taste