Pharmaceutics - Hu Exam

passive diffusion

-%absorption is dose dependent -pH changes permeability -permeability increases with partition coefficient -molecular size restriction -favors lipophilic drug

Encapsulated Dissolution Drugs

-Ornade Spansules (phenylpropanolamine/chlorpheniramine) -contac 12-hour capsule (phenylpropanolamine/chlorpheniramine/others) -chlor-trimeton Repetabs (chlorpheniramine) -diamox sequels (acetazolamide) (lollipop)

V=PSC; *active transport*

-P is dependent on C -uptake transporter will impact absorption rate constant and Cmax and Tmax -when uptake transporter saturated, AUC will increase with dose but less than proportionally (non-linear MM kinetics)

enzymes

-break down nutrients -prevent entry of undesirable substances from entery our system intact

Osmotic shell

-cannot swell or dissolve -controls release rate; reproducible

chemical stability

-chemical changes in medication that change the composition (aspirin turns yellow if exposed to moisture)

enteric coating

-dissolve in intestine, not stomach -decrease stomach irritation -delayed release onset (less reliable) -increase stability of acid labile compounds (would otherwise become inactive in stomach acid)

osmotically controlled systems characteristics

-driven by osmotic pressure difference -water is the diffusing species which is easier to control than drug -drug independent release rate -constant release profile possible -size of hole is critical -laser drill is capital intesnsive -more stringent on coating requirements -dose dumping possible (could be dangerous to pt)

burst effect

-drug has been stored for an extended period -all of drug comes out as soon as drug is in water/liquid -diffusion/matrix system

disintegrant function

-ensure tablets rapidly break into smaller fragments when in contact with water (dissolution) -types: 1) facilitate water uptake (surfactants) 2) rupture the tablets (starch-particle/particle repulsion?, cellulose) 3) effervescent (not used in tablets to be swallowed) -expand in volume to break up tablet

Binder function

-ensure that tablets and granules can be formed with required mechanical strength types: 1) dry powder (added prior to wet granulation process) 2) solution (used in wet granulation process) 3) some binders added right before tabletting process that do not require liquid

time lag

-freshly made diffusion/matrix system -drug does not rush out

Reservoir Device

-has a rate controlling membrane - polymer -drug diffuses out of membrane -constant release rate possible -high cost to make -dose dumping possible -temperature dependent (don't leave pills in car) dm/dt=K -rate affected by the thickness of the reservoir membrane and properties of the membrane materials

Matrix device

-has polymer matrix -drug dissolves out of insoluble web matrix

digestive organs

-have their own rhythm and physiological characteristics that may be changed by diseases or drugs

efflux transporter

-higher dose = higher % of absorption -pH and PC probably not significant -molecular size restriction -structural size restriction -can be saturated

Excipients for capsules

-inactive ingredients that do not diminish the pharmacological activities of the active species -maintain appearance (color, capsule shell, sealant) -protect the active species (antioxidant, coating) -disguise the unpleasant taste/smell (sealants) -change the dissolution rates of active species (coating) -manufacturing (diluents, lubricants, glidant)

Filler function

-increase the bulk volume so the final product has proper volume for patient handling -inert, compatible, non-hydroscopic, soluble, cheap, compactable, tasteful(?)

excipients for tablets

-maintaining the appearance (color, consistency) -protecting the active species (antioxidants) -disguising the unpleasant taste/smell (sugar, flavoring agents) -changing the dissolution rates of active species (coating, matrix) -manufacturing (diluents, lubricants, glidant)

P-Glycoprotein

-most common efflux transporter -cloned by Victor Ling of U of Toronto 1976 -pump waste into lumen from cell

PepT1

-most important uptake transporter in gut for drug absorption -transport peptides -12 transmembrane domains

transporters

-only functional on live cells -they need energy -rely on organized cellular structures -impact drug exposure (present in all disposition organs) -membrane proteins with 12 transmembrane domain -saturable -inhibitable -follow non-linear MM kinetics

bioprecursor prodrug

-prodrug must undergo oxidation/reduction to become active

sustained release products

-reduce dosing frequency (improve compliance) -less side effects

uptake transporters

-take drugs into a cell, tissue and/or organ -transport endogenous molecules or nutrients -some are high affinity but low capacity (others opposite) -most are active and can concentrate substrates -isoforms may or may not have overlapping specificities -distribution of uptake transporter may dictate the cellular or organ concentration (exposure) of a substrate

coating

-to protect active ingredients -mask taste/smell -appearance -handling ease -special functions

how to make erosion/dissolution controlled sustained release

-use slowly soluble salt -coat dosage form with slowly dissolving materials -incorporate drug int solowly dissolving carrier -Noyes-Whitney Equation: dc/dt=(D/h)A(Cs-C) dc/dt = dissolution rate, D= diffusion coefficient A= surface area, Cs= solubility, C is concentration

S3P Rule

1) Stability - physical, chemical, microbial 2) Suitability - route, compliance 3) Solubility - rate and extent 4) Permeability - absorptive, secretory, stability, metabolic 5) Time profile

quality attributes of tablets

1) correct dose 2) consistent weight, size and appearance 3) expected and reproducible rate of drug release 4) biocompatible/safe 5) strength 6) chemical, physically, and microbiologically stable 7) invite compliance 8) safely packed

tablet compaction

1) granulation: wet granulating 2) direct compaction

enhancing permeability and absorption

1) increase lipophility -modify polar functional groups -add alkyl or aryl esters -increases bioavailability 2) carrier-mediated transport -peptide transporter -amino acid transporter

overcoming toxicity problems

1) site-selective prodrug activation - affects only the target tissue 2) physiological conditions of the target tissue can differ from conditions elsewhere -common in chemodrugs

3D printing

1) thin layer of powdered drug is spread 2) liquid dropped on to powder 3) particles selectively bound in a thin porous layer 4) process is repeated a specific number of times to add more layers based on the dosage

Tabletting process

1) weighing 2) mixing 3) granulation 4) tabletting 5) QA check 6) dissolution 7) coating 8) QC check

Osmotically controlled system design

1)core with drug 2)solution in a flexible bag characteristics: -driven by pressure difference -water is diffusing species which is easier to control (vs. drug) -drug independent release rate -constant release profile possible -size of hole is critical -laser drill is capital intesnsive -more stringent on the coating requirements -dose dumping

Motility and residence time

1. has preset rhythm 2. Contraction occur in more than 1 dimension 3. transit from stomach to intestine 4. depend on food intake amount and types 5. impacted by disease states and drugs -moves 1-2cm per minute ~5h in GI Tract *if you take a medication without food, it will take 1h to get out of stomach *drug must dissolve within residence time or it will be passed before it is absorbed

Superstructure of intestine

1. has villi and microvilli 2. has many types of cells 3. impacted by disease states and drugs 4. impacted by microbiome *chemotherapy drugs can have side effects in GI tract

Granulation Benefits

1. increase bulk density 2. improve flowability 3. improve homogeneity 4. improve comactability 5. ensure homogenous color 6. control dissolution rate

Mixing tablets via granulation

1. mixing 2. agglomeration (wet binder added here) 3. drying 4. milling 5. mixing (add in manufacturing aids here; dry binder added last) 6. tabletting

Direct Compaction

1. mixing (high shear mixer with filler) 2. mixing (double cone mixer with dry binder, other excipients) 3. tabletting

reasons drug may not reach minimum effective concentration

1st pass metabolism low absorption

mutual prodrug

2 drugs linked to each other -no promoiety

paracellular

Absorption pathway: -movement of materials between cells

Frances Kelsey

FDA scientist kept thalidomide off U.S. market for treating pregnancy-related data -safety first (FDA)

Reservoir Products

Nitro-bid (nitroglycerin) Nitrospan (nitroglycerin) Nico-400 nicotinic acid

V=PC(out)S-P(efflux)C(in)S *active transport*

P dependent on C -efflux transporter will impact absorption rate constant and Cmax -when efflux transporter is saturated, the AUC will increase more than proportionally with dose (non linear MM kinetics)

V=PSC; *passive diffusion*

P is independent of C V is dependent on C

Gordon L. Amidon

Pharmaceutical classification system -uses solubility and permeability -Classes I-IV

Matrix Products

Procan SR procainamide Fero-Gradumed ferrous sulfate Choledyl SA oxtryphylline

dissolution enhancer

forms a salt with the drug during dissolution increasing the dissolution rate

extended release

formulation in which drug is released over time

John Wagner

founding father of pharmacokinetics -Pharmacokinetics for the Pharmaceutical Scientist -time vs. concentration curve FDA bases all safety of products on -Genistein

wet/solution binders

gelatin, cellulose, cellulose derivatives, polyvinyl pyrrolidone, starch, sucrose, PEG

Erosion/dissolution controlled Sustained Release

hard (insoluble) center *lollipop* -inexpensive to make -easy to administer -difficult to control the actual release rate -cannot maintain constant release rate

regular capsules

hard gelatin soft gelatin

Transporter mediated uptake

higher dose = lower % absorption -pH and PC probably insignificant -molecular size restriction (absorption erratic of macromolecules) -structural restriction (erratic absorption of transporter-incompatible structures) -absorption competition by nutritional components

Matrix/diffusion controlled sustained release

hydrophobic core exterior membrane multiparticulate -homogenous dispersion of solid drug in a polymer mix -less expensive to make -can deliver high molecular weight product -cannot maintain constant release

disintegrating tablet

immediate delayed

glidant

improve the flowability of the powder or granules or both

filler examples

lactose, sucrose, glucose, mannitol, sorbitol, calcium phosphate, calcium carbonate, cellulose

sorbent

limited fluid sorbing in dry state

liver gut blood site specific (cancer cells)

location of conversion for prodrug to drug occur

cellular junctions

maintain healthy, normal epithelium -provide need for transporters

sugar coating

make it taste sweeter

film coating

mask taste (works better than sugar coating)

physical stability

no chips, crumbling etc -illegal to dispense

QA/QC tests

performed to assess physical, chemical and microbial stability of a product

P

permeability across the organ barrier

improving solubility

prodrugs that use phosphate esters (most common promoiety) -increase hydrophilicity

protecting from rapid metabolism and excretion

protect sensitive functional groups

effervescent

rapid drug action

subligual and buccal

rapid release without 1st pass metabolism

V

rate of absorption

antiadherent

reduce the adhesion btw the powder (granules) and the punch faces and thus prevent tablet sticking to the punches

osmotic pressure driven sustained release

semipermeable membrane with hole multidirectional

prodrugs can target a particular organ

site specific chemical modifies bio precursor drug to active drug (omeprazole- bypasses stomach, H+ in parietal cells modify it to active drug)

lozenges

slow release for local action sucking

Factors that affect s3p

solubility dissolution chemical stability pka crystal forms (physical) hygroscopic properties (physical stability) excipient compatibility and suitability

disintegrant examples

starch, cellulose, crosslinked polyvinyul pyrrolidone, sodium starch glycolate, sodium carboxymethyl cellulose

release rate (tablets)

subligual/buccal>rapid (IR)>susatained release (ER)>enteric coated *enteric could be released rapidly in the fasted state*

S

surface area of absorption organ

Bioavailability

the drug that has reached the blood

bioavailability (FDA)

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

Tablet QC and QA

uniformity of active ingredients *disintegration* -screened tubes mechanical strength *dissolution* -rotating blade -rotating basket

QA

weight appearance mechanical strength

Biological characteristics of target organs

determine the absorption area, permeability and dissolution rates of the drug substances

Absorption Pathways

diffusion facilitated transport active transport

tripartite

drug-linker-Promoiety -linker (ch2 is one)

Bipartite

drug-promoiety -most common -phosphate is a common promoiety

lubricant

ensures tablet formation and injection can occur with low friction between the solid and the die wall

chewable

facilitate disintegration ease of swallowing

types of tablet excipients

filler/diluent disintegrant solution binder dry binder glidant lubricant antiadherent color coating protective agents

matrix dissolution drugs

Dimetapp Extentabs (brompheniramine) mestinon timespans (pyridostigmine) tenuate dospan (diethylpropion) (hard core) dm/dt=k/t^(1/2) -rate affected by porosity, tortuosity and solubility of the drug in the matrix and diffusion coefficient

dry binders

cellulose, methyl cellulose, polyvinyl pyrrolidone, PEG

controlled release systems of capsules

coated granules coarse dispersion

C

concentration at the absorption organ

QC

content uniformity disintegration dissolution

matrix former

a polymer or lipid/ or a substance that forms a gel in contact with water - drug is dispersed in particulate form in the matrix solid hydrophobic materials at room and body temp wax matrix PEG HPMC

microbial stability

activity or resistance to microbial growth

absorption enhancer

additive that modulates the permeability of the intestine

improving formulation and administration enhancing permeability and absorption changing the distribution profile protecting from rapid metabolism and excretion

advantages of using a prodrug