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

Absorption & elimination

As something gets absorbed, it also gets eliminated at the same time, but not necessarily at the same rate
Drug plasma concentration (mg/ml)

Rapid absorption i.e. t1/2 = 15 minutes Slower Elimination i.e. t1/2 = 60 minutes

Time (minutes)

Absorption & elimination

Rapid absorption i.e. t1/2 = 15 minutes Drug plasma concentration (mg/ml)

Slower Elimination i.e. t1/2 = 60 minutes

Time (minutes)

If a drug has a wide therapeutic window: - the difference between effective and toxic thresholds is large - control in drug plasma levels is not critical - conventional formulations may be suitable If a drug has a narrow therapeutic window: - the difference between effective and toxic concentrations is small - control is critical to the blood plasma levels - 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, assumption made that equilibrium between cs and cp.

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

Bioavailability
Faster rate, same AUC Slower onset, 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

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

Why may oral controlled release be necessary?

Biological factors - pharmacokinetics following oral dosing - site of action - toxicity at specific gi sites Physico-chemical factors - acid lability Therapeutic requirement - timing - chronotherapy
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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, thereby improve patient compliance Maintain therapeutic efficacy, for long periods e.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, 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.d. dosing)

Physiology Of GIT
Stomach residence is variable
Solutions and pellets (<2 mm) empty from the stomach rapidly (ca. 30 mins) Larger formulations (>7 mm) reside for longer (ca. 3 hours, 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. 8 15 hours

Variability in drug permeability along GIT

Physicochemical properties
Biopharmaceutical Classification Scheme (BCS)
Class I high solubility, high permeability Class II low solubility, high permeability Class III high solubility, low permeability Class IV low solubility, low permeability

Key factors:
Aqueous solubility, crystal & salt form, RMM, partition coefficient (log P), pKa & ionisation Should be highly soluble (where?) and have high permeability

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

Examples of oral constant-release formulations

MST Continus, morphine b.d. rather than every 4 hours Adalat LA, nifedipine o.d. rather than t.d.s Ventmax SR salbutamol, b.d. rather than t.d.s. or q.d.s. Concerta XL, methylphenidate, o.d. rather than t.d.s.

Note that some of these are b.d. rather than once a day because of time taken for dosage form to go through body
17

Examples of oral enteric-coated formulations

Voltarol - diclofenac sodium Salazopyrin - aminosalicylic acid Colpermin - peppermint oil

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Rate controlled release mechanisms

Diffusion controlled Dissolution controlled Osmosis controlled Bio-responsive control Time control

Terminology
Zero order release, the release rate does not vary with time: the delivery system maintains constant effective drug level in the body for prolonged periods. M 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

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 t Approximation: true for <60% release

Matrix systems
Has one basic principle that has proved extremely important, as it works when diffusion is dominating process

Amount released

Time Amount released

Mt K t M
K is proportionality constant, M is release at infinite time (i.e. total release) Square root relationship between release and time

Time1/2

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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

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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 - C) = dt h

Dissolution controlled release dosage forms

Reservoir
Disintegrating coatings Differently coated beads e.g. SODAS

Matrix

Drug release controlled by dissolution of the matrix, 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

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

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

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

Calculated and experimental release rates of KCl

Osmotic pump for nifedipine

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, and issues could lead to dose dumping and/or ineffective release

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.

Bioresponsive systems
pH controlled systems Enteric coat can be applied to a formulation (ie pellets, tablets or capsules) Most common materials used are the Eudragits, which are a family of copolymers of methacrylic acid and methylmethacrylate. These materials are insoluble in the acid conditions in the stomach, but will dissolve at higher pHs, each Eudragit being designed to dissolve at a different pH.

For example, capsules of sulphasalazine coated with Eudragit-S, soluble above pH 7, survive the gastric and proximal small intestine environment intact, but break down in the terminal ileum and colon.
35

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 37C.
Al-Taani BM, Tashtoush BM. AAPS PharmSciTech. 2003; 4(3): article 43.

Bioresponsive systems
Microbially-activated systems Relies on colonic flora possessing different enzymatic activity to flora in the rest of the GI tract. Delivery system is in some way degraded by the colonic bacteria releasing the drug at the appropriate site. Utilisation of colonic bacterial azoreduction Classically, sulphasalazine in treatment of inflammatory bowel diseases. Consist of a molecule of 5-aminosalicylic acid (5-ASA) linked via an azo bridge (-N=N-) to a sulphapyridine molecule. 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. 5ASA exerts its therapeutic effect locally and is essentially 37 unabsorbed

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. More complex dosage form studied - an azolinked polymer-drug complex was incorporated into a hydrogel system. As the pH of the gi tract increased, swelling of the gel increased, thus allowing access to the azo bonds, with subsequent cleavage and release of drug.

38

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

39

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, thus exposing the drug formulation for dissolution
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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, which in the body slowly erodes until the core is exposed for drug dissolution

41

Design of MR formulations
Considerations:
Physiology of the GI tract/alternative route of administration
i.e. pH, barrier issues

Physicochemical properties of the drug

i.e. pKa, log P, MW, etc.

Design of the MR system

The mechanism of drug release from the formulation (i.e. preferential partition)

Biological properties of the drug

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

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 - drug released via a gel layer formed on contact with water Hydrophobic may also be used, particularly for implants rather than oral systems.

44

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.g. HPMC, MC, carbopol, 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, triglycerides, ethylcellulose

Hydrophilic matrix
Most commonly used material is HPMC (hydroxypropyl methyl cellulose) Cheap, safe, may be compressed into tablets easily High degree of swelling on contact with water/biological fluids
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Lipid Matrix
Simple, easy and cheap to manufacture
A blend of powdered components
Lipids (usually, 20 40% hydrophobic solids); remain intact during the release process The drug A channelling agent
Such as sodium chloride or sugars They leach from the formulation, forming pores and channels

Drug is released through these aqueous capillaries, and release is usually not zero order

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, 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, i.e. the Fero-Gradumet Film-tab

Insoluble polymer matrix

Rate of release:

Mt = K . t0.5
Where Mt is the drug released at time t The square root of time the reaction slows as the diffusion front recedes.

Soluble polymer matrix

Rate of release:

Mt/M = K . tn
Where Mt/M is the drug released at time t expressed as a fraction If n = 1/2, release is by diffusion (see Higuchi) However if n = 1, release is controlled by the rate of swelling/erosion (i.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

Swellable polymer matrices

Compressed mixture of water-swellable hydrophilic polymer and drug Drug release mechanisms:
The polymer swells, 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.e. the degree of cross-linking) The viscosity of any entrapped fluid

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. PAAs), ion bridges (i.e. alginate, calcium, tetracaine and PMVE/MA) and complex secondary bonds, 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, and not the bulk rheology of a particular system

Swellable polymer matrices

Where a gel/system is not cross-linked:
Weaker, non-permanent associations exist between polymer chains
This is simple, secondary bonding (i.e. HPMC or alignate) Bonds are neither covalent nor ionic

Such a system will gradually erode, the erosion being a function of bond equilibrium Drug release is related to the bulk rheology, and may be a useful QC test.

Swellable polymer matrices

Hydrophilic matrix formulations have clear advantages:
Simple concept Different types of release rates possible Well-established technology Easy to manufacture

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, especially with regard to the production and scale-up of matrix-forming agents Must be optimised for each drug

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

Formulation
Single unit systems:
Different from conventional tablets, cores must not disintegrate, but must dissolve:
With minimal changes in osmotic pressure There are, however, risks of membrane rupture e.g. 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, followed by diffusion out of the matrix

Formulation
Multiple unit systems:
Contain more than one discrete unit
Discrete spherical beads, individually coated with rate-controlling membrane Encapsulated in a hard gelatin shell (i.e. Contac 400, Feospan) or, compression into a tablet (e.g. Suscard)

Extrusion spheronisation
A conventional matrix system, and more commonly in use

Formulation
Advantages:
Multiple units have more consistent GI transit rate Multiple unit systems unlikely to suffer from dose-dumping , or cause localised GI Multiple unit systems may be used for combination therapies, optimised for more than one drug Straight forward to include immediate release and modified release portions e.g. Equasym XL and Medikinet XL Patients with swallowing difficulties

Disadvantages:
Specific membrane control is often difficult Manufacture: filling multiple unit capsules electrostatic interactions

Some practical examples

Some practical examples

Some practical examples

Some practical examples

Non oral controlled release devices

Ocusert: membrane

Deponit NT: matrix

Nuvaring

Nexplanon

Learning outcomes
Know and understand what controlled release is; 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, regulation, quality assurance and control, stability and application