Solid Oral & Non-Oral Modified-Release Dosage Forms

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What are MR (modified-release) solid oral drugs?

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formulation of dosage form with modified drug release features and are usually tablets, capsules, and granules

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Can any drug be made into XR?

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No, some drugs are too dangerous to have more than one dose due to MTC and drug drumming into circulation

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What is MR?

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Drug release based on time, course, location of therapy, effect or convenience

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Terminology for Modified-Release

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CR, SR, TR, SA, PA, ER, XR, LA

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MR dosage forms provide 2 things:

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1) delayed-release of drugs: release is not prompt, time-based or environment based
2) extended-release of drugs: system allows for reduction in dosing frequency

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2 types of delayed-release forms

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1) repeat action: one dose for immediate release + another dose for delayed release --> multiple layered or tablet-within-a-tablet
2) targeted release: release is directed toward specific tissue or site --> enteric coated

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MR are what type of delivery systems?

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Rate-controlled, rate of drug delivery controlled by features of device

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What are the main rationale for XR products?

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1) drugs with no long-lasting effect (nothing with short t1/2 or long t1/2)
2) Have an immediate and a gradual release doses
3) prevents night dosing
4) non-oral XR: patches, inserts, implants
5) want to maintain constant drug concentration in blood similar to blood concentration of IV --> decrease amount of peaks and valleys seen in blood concentration

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5 Advantages of solid oral MR

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1) reduction in drug blood level fluctuations
2) frequency reduction in dosing
3) enhanced convenience and compliance
4) reduction in side effects
5) reduction on health care costs

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2 Disadvantages of solid oral MR

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1) no flexibility in adjusting drug dose and/or dosage regimen
2) dose dumping into circulation can cause drug to exceed MTC levels

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4 good drug candidates for XR products

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1) neither very slow (long t1/2) or very fast (short t1/2) rates of absorption and excretion
2) uniformly absorbed from GI tract
3) administered in relatively small doses, less excipients
4) wide therapeutic index

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What is therapeutic index?

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MTC/MEC
Narrow: not good for XR, incase of drug dumping
Wide: good for XR, low risk for reaching MTC

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4 main characteristics of oral XR products

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1) provide immediate release of one dose (loading/priming dose) for prompt effect followed by gradual release of additional doses (maintenance dose) over period of time
2) additional maintenance doses released at a rate correspondent to amount being metabolized and excreted
3) dissolve in GI fluids, #1 step for absorption
4) maintain sufficient GI residence time by being buoyant

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Coated beads, granules or microsphere XR technology (3)

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1) sugar + starch or microcrystalline cellulose beads coated in solution of drug and can be coated in additional coatings of lipid material (beeswax, aqua coat, sure lease)
2) uncoated beads mixed with coated beads
3) variation in thickness of coats and coat material vary rate of drug release rates

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Examples of coated beads, granules, microsphere technology

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Prochlorperazine for nausea + vomiting or Toprol XL tabs

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Multitablet system XR technology (3)

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1)very small spheroid or square compressed mini-tablets of drug that can be coated or uncoated
2) coated in gelatin capsule shell
3) drug release rates vary depending on mixture of coated and uncoated mini-tabs

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Example of multitablet systems

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Eric: enteric coated pellets of erythromycin base

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Microencapsulated drug XR technology (3)

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1) particles of solid, liquids or gases coacervated (liquid droplets) with gelatin or polymers surrounded by wall-material coating made from gelatin, synthetic polymers, or gums
2) coating allows microcapsules to be free-flowing
3) changing core-to-wall ratio, type of polymers used, method of micro encapsulation vary drug release rate

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Example of micro encapsulated drugs

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Micro-K extencaps,

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Drug embedded in slowly eroding or hydrophilic matrix XR technology (3)

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1) drug + matrix excipients mixed to become slowly eroding in body fluids mixed with normal drug granules
2) matrix excipients: hydrophlilic cellulose polymers or wax
3) can have multiple layered tablets, for different release rates of drugs

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MOA of drug embedded in hydrophilic matrix (4)

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1) material wetted by gastric fluid, untreated granules released for prompt effect
2) polymer begins to hydrate and gel layer forms
3) water permeates into gel to release drug by diffusion through layer
4) buoyant in gastric fluid = extension in gastric fluids

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Examples of drugs embedded in hydrophilic matrix

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Valrelease: slow release diazepam
Slow-K: sugar coated KCL tablet in wax matrix

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Drug embedded in inert plastic matrix XR technology (4)

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1)similar to hydrophilic matrix MOA
2) drug is granulated with inert plastic material (polyethylene, polyvinyl acetate, polymethacrylate)
3) buoyant in gastric fluids
4) plastic matrix retains shape during drug leaching, ghost excreted

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Example of drug embedded in plastic matrix

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Desoxyn gradumet tablets of methamphetamine HCl for ADD

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Complex formation XR technology

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drug form complexes with other chemical agents that slow solubility of drug in body fluids (depends on pH)

Use of tannic acids and tannates to effect drug release rates

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Examples of complex foramations

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Rynatan: mixture of phenylephrine tannate, chlorpheniramine tannate, and pyrilamine tannate

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Ion-exchange resins XR technology (3)

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1) cationic drug + ion-exchange resin (resin product usually has suffix -stirex) = resin-drug complex
2) drug release dpenedend on pH and electrolytes in GI (environment based release)
3) polymer coating and bead technology also used in addition

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Examples of ion-exchange resins

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Tussionex Pennkinetic XR Supsension: hydrocodone polisterex + chlorpheniramine polistrex

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Osmotic pump OROS system XR technology (6)

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1) tablet contains osmotic drug core surrounded by semi-permeable membrane with single hole for drug in solution exit
2) buoyant in gastric fluids
3) Water in gastric fluids passes through membrane and reaches core to dissolve drug, pressure increases in core of drug, dissolved drug pushed out through hole, 1-2 drops per hour
4) drug rate release not effected by GI pH, motility or feed conditions
5) drug rate release effected by: changing surface area or composition of membrane and diameter of orifice
6) ghost excreted

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Examples of Osmotic systems (4)

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1) OROS: polymeric osmotic push compartment
2) MODAS: multidirectional osmotic drug absorption system
3) GITS: gastrointestinal therapeutic system
4) COER: controlled-onset extended release system

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Repeat Action Tablets (5)

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1) tablet within a tablet or multiple layered tablets
2) initial dose from shell or coating
3) second dose from inner core separated by slowly permeate barrier coating exposed 4-6 hours later
4) suitable for chronic conditions, drug must have low dosage + rapid rate of absorption and elimination
5) Ex: polaramine repetabs: antihistaminic

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Enteric Coating delayed release oral dosage forms (5)

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1) protect drug from GI, protect GI from drug to decrease gastric distress, facilitate GI transit for drugs better absorbed in intestine
2) release of drug intentionally delayed
3) pH dependent coating (most common), time-based coating, moisture-eroding coat ing, enzyme dependent coating
4) fats, fatty acids, waxes, shellac, cellulose phthalates used
5)Ex: prilosec (omeprazole)

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USP requirements and FDA guidelines for MR solid oral dosage forms (4)

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1) drug release based on drug dissolution over time
2) uniformity in dosage units through weight variation and content uniformity
3) in-vitro-in-vivo correlations for predictive models
4) additional labeling requirements: tabs are enteric coated, state if XR, hint of tech. used

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Clinical considerations for MR solid oral dosage forms

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1) products should not be used interchangeably with prompt release drugs
2) not crushed or chewed
3) enteral nutrition: coated pellets mixed with water and administered
4) ghost tablets: normal

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Non-Oral MR Systems: TDDS

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Transdermal delivery systems: patches

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Non-oral MR systems: parenteral

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1)drug in slowly absorbed vehicles that usually contain phospholipids
2) increased particle size of drugs in suspensions
3) matrix carrier systems: biodegradable materials: insoluble collagen
4) dlowly eroding microspheres of phopholipids + drug = liposomes (most commonly used)
5) if mixed with PEG (pegylated liposome): slower drug release

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Example of parenteral Non oral MR

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Depo-provera contraceptive injection: water insoluble drug in aqueous microsuspension

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Non-oral MR system: vaginal inserts

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1) cervidil vaginal insert: polymeric pouch containing prostaglandin E2 for labor induction
2) also include bioadhesive vaginal gels and vaginal rings

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Non-oral MR systems: sub dermal and other implants

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special injectors or sugrical incision that deliver drug with less side defects and slow release of drug over time
Ex: Zoladex implant: goserelin acetate for SQ injection for advanced prostatic cancer

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Non-oral MR systems: Ocular

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1) viscosity increasing agents: help coat eye for longer release of drug: pilopine HS gel that cross-links with acrylic acid and forms gel upon contact with tears
2) opthalmic inserts: ocusert systemc,
Ex: alza: pilocarpine system for treatment of glaucoma and lacrisert: hydroxypropyl cellulose for dry eyes