Oral controlled release dosage forms

Dr Liam McAuley

Dosage forms,
For example; tablets, capsules suspensions

Standard/Immediate release,

Disintegrate within 15 mins, releasing drug for absorption

Controlled/sustained/extended release, The formulation limits the rate of drug release and thus absorption
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What difference does controlled release make?

Measure blood levels following administration

Standard release formulations
Max effective concentration Blood concentration

Therapeutic window

Min effective concentration

Time

Bioavailability Cmax Maximum (peak) concentration of drug in blood Tmax T1/2 AUC The time after dosing at which Cmax is reached Time for the drug concentration to reduce to 50% Area Under the Curve: Amount of drug received by the patient (Exposure) the drug plasma concentration over which the drug elicits a therapeutic effect without causing unwanted side effects the length of time the drug is therapeutically active following a given dose Therapeutic window Duration of action .

it also gets eliminated at the same time. but not necessarily at the same rate Drug plasma concentration (mg/ml) Rapid absorption i. t1/2 = 60 minutes Time (minutes) . t1/2 = 15 minutes Slower Elimination i.e.Absorption & elimination As something gets absorbed.e.

e.the difference between effective and toxic concentrations is small .Absorption & elimination Rapid absorption i. t1/2 = 60 minutes Time (minutes) If a drug has a wide therapeutic window: .e.conventional formulations may be suitable If a drug has a narrow therapeutic window: .control in drug plasma levels is not critical . t1/2 = 15 minutes Drug plasma concentration (mg/ml) Slower Elimination i.control is critical to the blood plasma levels .the difference between effective and toxic thresholds is large .controlled/modified release may be required .

Bioavailability • Rate & extent of absorption – Ideally measured as clinical response – Drug concentration at site of action (cs) • Often cannot be achieved. – cp vs time curves concentration 100 80 60 40 20 AUC related to total amount absorbed 0 0 6 12 tim e 18 24 absorption Distribution & elimination But „flip flop‟ kinetics . assumption made that equilibrium between cs and cp.

sustained effect 100 200 180 IV instantaneous administration of all the drug 160 80 concentration concentration 140 120 100 80 60 60 40 20 40 20 0 0 6 12 tim e 18 24 0 0 6 12 tim e 18 24 Lower extent Absorption phase. drug must cross various barriers which takes time & results in drug loss . same AUC Slower onset.Bioavailability Faster rate.

Multiple dosing of standard release formulations Blood concentration Maximum effective concentration Minimum effective concentration Ideal controlled release formulation Maximum effective concentration Blood concentration Minimum effective concentration .

Theoretical plasma time profiles 100 Maximum safe concentration Prolonged release Controlled release Therapeutic range 36 48 75 concentration 50 25 Minimum effective concentration Fast release 0 0 12 24 time .

acid lability • Therapeutic requirement .toxicity at specific gi sites • Physico-chemical factors .chronotherapy 11 .site of action .pharmacokinetics following oral dosing .Why may oral controlled release be necessary? • Biological factors .timing .

thereby improve patient compliance • Maintain therapeutic efficacy. for long periods e.Aims • To maintain drug plasma concentrations within a therapeutic range for extended (clinically relevant) periods OR to restrict drug release from the dosage form for a particular period of time • Improve treatment through improved control of drug plasma levels OR by releasing drug in the correct site in the GI tract • Reduce dosing frequency.g. Overnight .

Advantages of controlled delivery Can give better therapeutic outcomes (£££) Pharmacokinetics – minimise toxicity and ineffective concentrations Patient compliance Disease states worse in the morning Reduce total drug exposure Disadvantages of controlled delivery Danger of drug dumping.d. tablet crushing & localised GI effects Suitable drug candidates Cost Loss of dosing flexibility / prolonged side effects if wrong dose is given GI residence time (approximately 12 hours ? b. dosing) .

Physiology Of GIT • Stomach residence is variable – Solutions and pellets (<2 mm) empty from the stomach rapidly (ca. up to 10 hours with a heavy meal) • Transit through the small intestine takes 3-5 hours – Major site of absorption • Resident in the colon for ca. 30 mins) – Larger formulations (>7 mm) reside for longer (ca. 3 hours. 8 – 15 hours • Variability in drug permeability along GIT .

RMM.Physicochemical properties • Biopharmaceutical Classification Scheme (BCS) – – – – Class I – high solubility. crystal & salt form. pKa & ionisation – Should be highly soluble (where?) and have high permeability . high permeability Class II – low solubility. partition coefficient (log P). low permeability Class IV – low solubility. low permeability • Key factors: – Aqueous solubility. high permeability Class III – high solubility.

Classification • Modified Release: • Delayed Release – Delayed total drug release some particular time after administration • Repeat Action – Intermittent drug release in small aliquots • Sustained Release – Drug released slowly at a controlled rate governed by the drug delivery system • Controlled Release – Drug released at a constant rate which does not vary throughout the therapeutic window .

Note that some of these are b. Concerta XL. rather than every 4 hours Adalat LA. rather than once a day – because of time taken for dosage form to go through body 17 . nifedipine o.d. or q.d.d.d. rather than t.d. methylphenidate. rather than t.d. rather than t. o.s.s.d. b.d.s Ventmax SR salbutamol. morphine b.Examples of oral constant-release formulations MST Continus.d.s.

diclofenac sodium • Salazopyrin .Examples of oral enteric-coated formulations • Voltarol .peppermint oil 18 .aminosalicylic acid • Colpermin .

Rate controlled release mechanisms • • • • • Diffusion controlled Dissolution controlled Osmosis controlled Bio-responsive control Time control .

the release rate does not vary with time: the delivery system maintains constant effective drug level in the body for prolonged periods. • M α time • dm/dt = k Blood concentration Amount m time Not entirely clear what profile is ideal for a matrix system – used to be believed that zero order release was optimum but now complexity of rates of dissolution and absorption make this less certain .Terminology • Zero order release.

Diffusion controlled • Reservoir – Drug is surrounded by rate controlling membrane (non porous or micro-porous) • Matrix (monolith) – Drug is distributed throughout a continuous phase composed of lipid or polymer dm/dt = DKDc/h M α t½ Approximation: true for <60% release .

e.Matrix systems • Has one basic principle that has proved extremely important. M is release at infinite time (i. as it works when diffusion is dominating process Amount released Time Amount released Mt K t M • K is proportionality constant. total release) • Square root relationship between release and time Time1/2 22 .

Membrane limited systems • Drug is housed in reservoir and release is controlled by a ratelimiting membrane • Such systems do not tend to swell or erode • The core is coated with a film of suitable qualities • The most basic devices work on the principle of ‘water in. drug out’ • Drug is immobile until water penetrates membrane and forms a channel through which drug can diffuse out dm/dt = DKDc/h Immersion Dry tablet Hydrated film allows drug diffusion 23 .

C) = dt h .Dissolution controlled • Reservoir – Drug is surrounded by polymeric membrane which retains the drug. after a certain period of time membrane dissolves releasing the drug • Matrix – Drug is distributed throughout matrix which dissolves releasing the drug Noyes – Whitney equation dM DA(Cs .

g. SODAS Matrix Drug release controlled by dissolution of the matrix.Dissolution controlled release dosage forms Reservoir Disintegrating coatings Differently coated beads e. decrease in drug release can be compensated by constructing a non linear concentration profile (the core of the dissolution matrix contains more drug than the outer layer) .

Osmosis controlled drug release Osmotic pressure can be used to pump out a drug at a constant rate from the delivery system Delivery orifice Osmotic core containing drug Semi-permeable membrane .

and a water permeable but insoluble coating • In the presence of water. the core will solubilise and/or suspend the drug • Water permeates into the inner core across the outer membrane .Osmotic Pump • Contains a water-soluble core containing the active drug.

Osmotic Pump • Contains a water-soluble core containing the active drug. and a water permeable but insoluble coating • In the presence of water. the core will solubilise and/or suspend the drug • Water permeates into the inner core across the outer membrane • The core material (drug and excipients) will then undergo dissolution/suspension/ solubilisation .

Osmotic Pump • Contains a water-soluble core containing the active drug. and a water permeable but insoluble coating • In the presence of water. the core will solubilise and/or suspend the drug • Water permeates into the inner core across the outer membrane • The core material (drug and excipients) will then undergo dissolution/suspension/ solubilisation • Osmotic pressure rises and expels the drug .

and then released . and contains an aperture for drug release: • The aperture allows water to enter the core. and – if appropriate – a viscosity modifier and a solubiliser – The surface coating is permeable to water. whereafter the osmitic pressure rises and the drug is solubilised and/or suspended. excipients (fillers).Osmotic Pump • Summary: – The solid core consists of the active drug.

Calculated and experimental release rates of KCl .

Osmotic pump for nifedipine .

and issues could lead to dose dumping and/or ineffective release .Osmotic Pump • Advantages: – A wide range of drugs are compatible – Coating technology is cheap and widely used – Zero order release is possible • Disadvantages: – The size of the hole is very important. and precisely drilling it is expensive – Integrity and consistency of the coating is essential.

.Bio-responsive controlled drug release Bio-responsive controlled drug delivery systems modulate drug release in response to changes in the external environment For example drug release may be controlled by the way in which pH or affects the swelling of a polymeric delivery system.

capsules of sulphasalazine coated with Eudragit-S. 35 . survive the gastric and proximal small intestine environment intact. soluble above pH 7. These materials are insoluble in the acid conditions in the stomach. each Eudragit being designed to dissolve at a different pH. tablets or capsules) Most common materials used are the Eudragits.Bioresponsive systems • pH controlled systems Enteric coat can be applied to a formulation (ie pellets. For example. which are a family of copolymers of methacrylic acid and methylmethacrylate. but break down in the terminal ileum and colon. but will dissolve at higher pHs.

. 2003.Swelling and erosion of polymer. Effect of calculated microenvironment pH on the rate release of diclofenac sodium from buffer matrix tablet in dissolution medium at 37°C. AAPS PharmSciTech. Al-Taani BM. 4(3): article 43. Tashtoush BM.

Consist of a molecule of 5-aminosalicylic acid (5-ASA) linked via an azo bridge (-N=N-) to a sulphapyridine molecule. Delivery system is in some way degraded by the colonic bacteria releasing the drug at the appropriate site. Utilisation of colonic bacterial azoreduction Classically. 5ASA exerts its therapeutic effect locally and is essentially 37 unabsorbed . Sulphasalazine shows only limited digestion in or absorption from the stomach or the small intestine and > 85 % is presented intact to the colon The colonic bacteria then cleave the azo bond generating the independent 5-ASA and sulphapyridine molecules.Bioresponsive systems • Microbially-activated systems Relies on colonic flora possessing different enzymatic activity to flora in the rest of the GI tract. sulphasalazine in treatment of inflammatory bowel diseases.

thus allowing access to the azo bonds. 38 . swelling of the gel increased. More complex dosage form studied . As the pH of the gi tract increased.an azolinked polymer-drug complex was incorporated into a hydrogel system.Bioresponsive systems Azo-polymers with the polymer being linked to the active drug via an azo link used The drug-polymer compound would be administered in a conventional oral dosage form. with subsequent cleavage and release of drug.

pectin. guar gum.Bioresponsive systems Utilisation of colonic bacterial polysaccharidases In humans. the colon is the site of degradation of polysaccharides from the diet such as amylose. Two main methods have been used . chondroitin etc. 39 .formation of a hydrogel system or the use of a polysaccharide coat. it would be expected that colonic targetting could be obtained. By incorporating one or more of these materials into the dosage form.

thus exposing the drug formulation for dissolution 40 .Time delayed systems • Timed-release systems The average mouth-to-colon transit time can be used in the development of timed-release systems The Pulsincap consists of an insoluble capsule body containing the drug formulation and is sealed with a hydrogel plug After oral administration the hydrogel plug slowly hydrates and swells until it is expelled from the capsule body.

which in the body slowly erodes until the core is exposed for drug dissolution 41 .Time delayed systems The release of the drug formulation is controlled by the size of the hydrogel plug and its position within the Pulsincap The Timeclock consists of a drug-loaded solid core covered with a thick film coat containing hydrophobic materials and surfactants.

pH. – Design of the MR system • The mechanism of drug release from the formulation (i. MW.e. barrier issues – Physicochemical properties of the drug • i.Design of MR formulations • Considerations: – Physiology of the GI tract/alternative route of administration • i.e. preferential partition) – Biological properties of the drug . etc. log P.e. pKa.

Formulation for MR • Three major categories: – Monolithic/matrix – Reservoir/membrane controlled – Osmotic pump • Each may comprise: – – – – – – Active drug Release controlling agent(s) Matrix modifiers Drug modifiers Supplementary coatings Conventional formulation excipients .

drug released via a gel layer formed on contact with water • Hydrophobic may also be used. particularly for implants rather than oral systems. 44 .Monolith (Matrix) Devices • Classical form of oral controlled release • Term refers to a block of material through which drug is dispersed and release slowly (otherwise known as controlled release matrices) • May be hydrophobic or hydrophilic • Hydrophilic is much more common .

alginates • Or: – Drug particle dispersed in an insoluble matrix • The drug is available as the solvent enters the matrix (in the form of channels) and dissolves the particles • Usually a lipid matrix or an insoluble polymer matrix • Waxes.Monolithic Matrix Devices • Either: – Drug particles dispersed in a soluble matrix • The drug particles are available as the matrix swells or dissolves • Usually a hydrophilic colloid matrix • e. ethylcellulose . triglycerides. MC. carbopol. HPMC.g.

Hydrophilic matrix • Most commonly used material is HPMC (hydroxypropyl methyl cellulose) • Cheap. may be compressed into tablets easily • High degree of swelling on contact with water/biological fluids 46 . safe.

and release is usually not zero order . forming pores and channels • Drug is released through these aqueous capillaries. easy and cheap to manufacture – A blend of powdered components • Lipids (usually. remain intact during the release process • The drug • A channelling agent – Such as sodium chloride or sugars – They leach from the formulation.Lipid Matrix • Simple. 20 – 40% hydrophobic solids).

the “Fero-Gradumet Film-tab” . i. the particle size and the nature and type of excipients • The drug dissolves and diffuses out of the capillaries – Such devices were developed in the 1950s and are still in (limited) use today.Insoluble polymer matrix • The drug is embedded in an inert (insoluble) polymer – Drug release is by leaching • Fluid diffuses into the core of the device through capillaries that exist between that particles • Factors to influence kinetics include the compression strength.e.

.5 • Where Mt is the drug released at time t • The square root of time – the reaction slows as the diffusion front recedes. t0.Insoluble polymer matrix • Rate of release: Mt = K .

Soluble polymer matrix • Rate of release: Mt/M∞ = K . release is controlled by the rate of swelling/erosion (i. release is by diffusion (see Higuchi) • However if n = 1.e. it is the polymer not the drug movement that is controlling the process) • If n is in between these two extremes it is possible to calculate the relative contribution of the two processes . tn • Where Mt/M” is the drug released at time t expressed as a fraction • If n = 1/2.

e. the degree of cross-linking) – The viscosity of any entrapped fluid . forming a matrix layer This controls diffusion of water into the core of the gel And it also therefore controls diffusion of drug from the system The system may also erode and physically fall apart. affecting release • Depends on: – The tortuous nature of the gel (i.Swellable polymer matrices • Compressed mixture of water-swellable hydrophilic polymer and drug • Drug release mechanisms: – – – – The polymer swells.

Swellable polymer matrices Examples of entangled networks .

Swellable polymer matrices Cross-linked systems .

Swellable polymer matrices • Where a gel/system is cross-linked: – There exists a strong attraction between polymers: • Covalent bonds (i.e. tetracaine and PMVE/MA) and complex secondary bonds. and not the bulk rheology of a particular system . PAAs). such as helices in gelatin – Water swells to form a rigid gel network – Such a network is usually resistant to erosion – The rate of diffusion is related to the micro-rheology of the gel.e. alginate. calcium. ion bridges (i.

e. . non-permanent associations exist between polymer chains • This is simple. secondary bonding (i. and may be a useful QC test. the erosion being a function of bond equilibrium – Drug release is related to the bulk rheology. HPMC or alignate) • Bonds are neither covalent nor ionic – Such a system will gradually erode.Swellable polymer matrices • Where a gel/system is not cross-linked: – Weaker.

Swellable polymer matrices • Hydrophilic matrix formulations have clear advantages: – – – – Simple concept Different types of release rates possible Well-established technology Easy to manufacture .

especially with regard to the production and scale-up of matrix-forming agents – Must be optimised for each drug .Swellable polymer matrices • Disadvantages – Release mechanisms may be complex. with rates of diffusion relating to diffusion both into and out of the matrix • Erosion may lead to complex and unpredictable kinetics – May be sensitive to variation.

J Pharm Sci (2011) 100: 4745-4755

Formulation
• Hydrophilic matrix device – components:
– Active drug
• Is a high drug loading possible or necessary (i.e. saturation of drug concentration)

– Hydrophilic polymers
• These are often blends • 20 – 80% by mass

– Gel modifiers:
• Enhance drug diffusion, provide more rapid hydration (i.e. sugars), influence/facilitate cross-linking (i.e.ions/ionised dugs) and affect polymer ionisation (pH buffers)

Formulation
• Membrane-controlled systems:
– Consist of a rate-controlling membrane surrounding a drug reservoir
• The first membrane becomes permeable, usually via hydration, but it does not swell or erode (i.e. hydrophilic matrix device)

– The drug reservoir is essentially a conventional tablet (single unit) or a microparticle pellet (multiple unit), and it is usually best if it does not swell

60:40 lactulose:microcrystalline cellulose .and similar care should be taken in selecting other excipients – Diffusion is a two-phase process: • Diffusion into the matrix..Formulation • Single unit systems: – Different from conventional tablets. followed by diffusion out of the matrix .g. however. but must dissolve: • • • • With minimal changes in osmotic pressure There are. cores must not disintegrate. risks of membrane rupture e.

and more commonly in use . Feospan) • or. individually coated with rate-controlling membrane • Encapsulated in a hard gelatin shell (i.e.g. Suscard) – Extrusion spheronisation • A conventional matrix system. compression into a tablet (e. Contac 400.Formulation • Multiple unit systems: – Contain more than one discrete unit • Discrete spherical beads.

Formulation • Advantages: – Multiple units have more consistent GI transit rate – Multiple unit systems unlikely to suffer from dose-dumping . optimised for more than one drug – Straight forward to include immediate release and modified release portions e. or cause localised GI – Multiple unit systems “may” be used for combination therapies. Equasym XL and Medikinet XL – Patients with swallowing difficulties • Disadvantages: – Specific membrane control is often difficult – Manufacture: filling multiple unit capsules – electrostatic interactions .g.

Some practical examples .

Some practical examples .

Some practical examples .

Some practical examples .

Non oral controlled release devices Ocusert: membrane Deponit NT: matrix Nuvaring Nexplanon .

quality assurance and control. and what the different types of controlled release are Know and understand the different mechanisms which can be used to give controlled release Understand the advantages and disadvantages of using controlled release systems and be able to relate these to commercial examples Discuss the large-scale production of pharmaceutical dosage forms and the associated issues of health and safety. stability and application . regulation.Learning outcomes Know and understand what controlled release is.

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