Controlled Release 2013

Oral controlled release dosage formsDr Liam McAuley

http://upload.wikimedia.org/wikipedia/commons/0/00/FlattenedRoundPills.jpg

http://en.wikipedia.org/w/index.php?title=Gastrointestinal_tract&oldid=261906707

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



What difference does controlled release make?

Measure blood levels following administration

Standard release formulations

Max effective concentration

Min effective concentration

Time

Therapeutic window

Blo

od c

once

ntra

tion

http://upload.wikimedia.org/wikipedia/en/9/95/Blooddraw.jpg

Bioavailability

Cmax Maximum (peak) concentration of drug in blood

Tmax The time after dosing at which Cmax is reached

T1/2 Time for the drug concentration to reduce to 50%

AUC Area Under the Curve: Amount of drug received by the patient (Exposure)

Therapeutic window the drug plasma concentration over which the drug elicits a therapeutic effect without causing unwanted side effects

Duration of action the length of time the drug is therapeutically active following a given dose

Absorption & eliminationD

rug

plas

ma

conc

entr

atio

n (m

g/m

l)

Time (minutes)

As something gets absorbed, it also gets eliminatedat the same time, but not necessarily at the same rate

Rapid absorptioni.e. t1/2 = 15 minutes

Slower Eliminationi.e. t1/2 = 60 minutes

Absorption & elimination

Dru

g pl

asm

aco

ncen

trat

ion

(mg/

ml)

Time (minutes)

Rapid absorptioni.e. t1/2 = 15 minutes

Slower Eliminationi.e. t1/2 = 60 minutes

If a drug has a wide therapeutic window:- the difference between effectiveand toxic thresholds is large- control in drug plasma levels is notcritical - conventional formulations may besuitable

If a drug has a narrow therapeutic window:- the difference between effective andtoxic concentrations is small- control is critical to the blood plasmalevels- controlled/modified release may berequired

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

0

20

40

60

80

100

0 6 12 18 24time

con

cen

trat

ion

ab

sorp

tion Distribution

& elimination

AUC related to total amount absorbed

But ‘flip flop’ kinetics

Bioavailability

0

20

40

60

80

100

120

140

160

180

200

0 6 12 18 24time

con

cen

trat

ion

0

20

40

60

80

100

0 6 12 18 24time

con

cen

trat

ion

Faster rate, same AUCSlower onset, sustained effect

Lower extent

IV instantaneous administration of all the drug

Absorption phase, drug must cross various barriers which takes time & results in drug loss

Multiple dosing of standard release formulations

Ideal controlled release formulation

Maximum effective concentration

Minimum effective concentration

Blo

od c

once

ntra

tion

Blo

od c

once

ntra

tion

Maximum effective concentration


Theoretical plasma time profiles

0

25

50

75

100

0 12 24 36 48

time

con

cen

trat

ion

Thera

peuti

c ra

nge


Maximum safe concentration

Fast release

Prolonged release

Controlled release

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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

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

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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

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Examples of oral enteric-coated formulations

• Voltarol- diclofenac sodium

• Salazopyrin- aminosalicylic acid

• Colpermin- peppermint oil

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 α time• dm/dt = k

Am

ount

m

time

Blo

od

conc

entr

atio

n

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/hM α t½

Approximation: true for <60% release

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

• K is proportionality constant, M is release at infinite time (i.e. total release)

• Square root relationship between release and time

tKM

M t

Time1/2

Am

ount

rele

ase

d

Time

Am

ount

rele

ase

d

Matrix systems

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Membrane limited systems

• Drug is housed in reservoir and release is controlled by a rate-limiting 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

Dry tablet

Immersion

Hydrated film allows drug diffusion

dm/dt = DKDc/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

h

C) - DA(Cs =

dt

dMNoyes – Whitney equation

Dissolution controlled release dosage forms

Disintegrating coatingsDifferently coated beads

e.g. SODAS

Reservoir

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)

Osmotic core containing drug

Semi-permeable membrane

Delivery orifice

Osmosis controlled drug release

Osmotic pressure can be used to pump out a drug at a constant rate from the delivery system

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




• The core material (drug and excipients) will then undergo dissolution/suspension/ solubilisation

Osmotic Pump




• 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.

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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.

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.

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

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• Microbially-activated systemsRelies 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 azoreductionClassically, 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. 5-ASA exerts its therapeutic effect locally and is essentially unabsorbed

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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 azo-linked 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.

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Utilisation of colonic bacterial polysaccharidasesIn 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.

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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

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

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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.

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

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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

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:

• Where Mt is the drug released at time t

• The square root of time – the reaction slows as the diffusion front recedes.

Mt = K . t0.5

Soluble polymer matrix

• Rate of release:

• 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

Mt/M∞ = K . tn

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


Examples of entangled networks


Cross-linked systems


• 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


• 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.


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


• 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




Ocusert: membrane Deponit NT: matrix

Nuvaring

Nexplanon

Non oral controlled release devices

Learning outcomesKnow 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

Documents

Controlled Release 2013