Sustained Release Formulations

M.Phil. Pharmaceutics

What is an ideal drug delivery system?

• it should deliver drug at a rate according to the needs of the body over the period of the treatment.

• It should direct the active ingredient solely to the site of action.

• This is achieved by development of new various modified drug release dosage forms, like-

• Control release dosage forms• Repeat action dosage forms.• Sustained release dosage forms• Extended release dosage forms etc

Some important definitions are

• CONTROLLED RELEASE DOSAGE FORMS:

• Dosage forms release drug at a constant rate and provide plasma concentration that remains invariant with time.

• REPEAT ACTION DOSAGE FORMS.• an individual dose is released fairly soon after administration , and second or third

doses are subsequently released at intermittent intervals.

• SUSTAINED RELEASE DOSAGE FORMS.

• an initial release of drug sufficient to provide a therapeutic dose soon after administration , and then a gradual release over an extended period.

• EXTENDED RELEASE DOSAGE FORMS.

• These release drug slowly , so that plasma concentration are maintained at a therapeutic level for a prolonged period of time usually between 8-12 hours

• MODIFIED RELEASE DOSAGE FORMS.• According to USP these are those dosage forms whose drug release characteristics

of time course and/ or location are choosen to accomplish therapeutic or conveniences objectives not offered by conventional dosage forms.

Sustained release dosage forms (SRDF’S)

Introduction

• Sustained release ,sustained action, prolonged action ,extended action, time release depot , repository dosage forms are the terms used to indicate a drug delivery systems that are designed to have a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.

ADVANTAGES OF SRDF OVER OTHER CONVENTIONAL DOSAGE FORMS

• Decreased local and systemic side effects reduced gastrointestinal irritation.

• Reduction in dosing frequency. • Improved patient compliance and reduced

patient care time. • Reduced fluctuations in circulating drug levels• Reduced cost.

DISADVANTAGES OF SRDF

• Unpredictable or poor in-vitro and in-vivo correlation.

• Dose dumping. • Reduced potential for dosage adjustment. • Poor systemic availability in general

CANDIDATES FOR SRDF

• In general the drugs best suited for SRDF having following characteristics

• Have neither very short (less than 2 hours) Nor very Long Half life (more than 8 hours)

• with Desirable absorption and solubility characteristics• Are administered in relatively small doses• Possess a high therapeutic index• Are used in the treatment of chronic rather than acute

conditions.

Techniques used in SRDF

• There are two type of methods used for development of SRDF

1. based on drug modification 2. based on dosage form modification

DRUG MODIFICATIONIt can be done by eithera. Complex formation.• Cationic exchange resins • Tacid complexes• Alginic acid complexes

b. Drug adsorbate formation.• It is the special case of complex formation in which the drug is essentially insoluble.• e.g. clays like bentonite

c. Pro- drug formation.• Pro-drugs are therapeutically inactive that regenerate the parent drug on metabolism .• For pro-drug Kd and Ke must be less than its parent drug.

DOSAGE FORM MODIFICATION

A. Embedded matrix principle.• In which drug is embedded in a matrix of a retardant material

and compressed into tablets. The retardant materials may be • Skeleton matrix forming e.g. PVC• Water insoluble but potentially erodible e.g.

1.stearyle alcohol 2.carnuba wax

• Polymers forming hydrophilic matrices e.g. methyl cellulose sodium car boxy methyl cellulose.

B. Barrier principle

• A layer of retardant material is imposed between the drug and elution medium ( the formulation may be in the form of granules or tablets.

• Coating used are I. Solid hydroxylated lipid ( hydrogenated castor

oil / glyceryl hydroxyl stearate) mixed with modified cellulose.

II. Formalized gelatin

c. Osmotic principle

• The drug is covered with a semi permeable membrane that allows the water to move inside thus building up an osmotic pressure and forcing the drug to exude out of tiny hole made by laser.

MECHANISM OF RELEASE OF DOSAGE FROM SRDF

1. Dissolution controlled system• Easy to design• Formulated by slowing dissolution rate of drug

in GIT through incorporating it into an insoluble polymer and coating with diff. material of varying thickness.

• Rate limiting step in such DDS is diffusion of drug across boundary layer.

Contd.

The rate of dissolution is given by following equation dm/dt = ADS/hWhereS= aq. Solubility of drugA=surface area of tabletD=Diffusivity of drugh= thickness of boundary layer

continued

• Dissolution control can be achieved in following ways:-

• Slow dissolution of drug• Drug with inherently slow dissolution rate.• Drugs that transforms into a slow dissolving form. • Slow dissolution rate of reservoir membrane & matrix• Embedment in slowly dissolving, degrading erodible

matrix.• Encapsulation or coating with slowly dissolving

degrading erodible substances.

Types of dissolution Controlled System

1. Matrix dissolution Controlled System• it consists of a drug mixed with a polymer such as

bees wax or carnuba wax and from which the drug is then released slowly depending upon the porosity of the tablets.

2. Reservoir dissolution Controlled System• In this type the drug is coated with polymer

material such as Cellulose and PEG and the release of drug depends upon solubility and thickness of coating.

MECHANISM OF RELEASE OF DOSAGE FROM SRDF

2. Diffusion Controlled System:• In this system the rate controlling step is diffusion of the drug across the

physical barrier.• This system always follows first order kinetics• This DDS can be prepared either by encapsulating the drug in polymer or

dispersing the drug in the matrix The rate of diffusion is given by following equation dm/dt = ADK ▲C/ l Where K= Partition co-efficient of drug between drug core and membrane A= surface area of tablet D= Diffusion co efficient l= Diffusion path length ▲C= Concentration differnce across membrane

Types of diffusion Controlled System

• Porous matrix controlled system• Rate controlling element is water swellable material e.g. xanthan gums ,guar gum , high viscosity grades of

HPMC,HPC, alginates

• Porous membrane controlled system• Rate controlling element is non-swellable water

insoluble polymer • e.g. ethylcellulose, PMA. Drug release controlled

through micropores.

Methods Using ION Exchange

• Resins are water insoluble compounds having both anionic and cationioc groupps

• Complex is formed upon prolong exposure of ionic solution of drug with ionic resins

• Drug is slowly released when this complex comes incontact with the gastric acid.

• E.g Nicorette is nictione in complex with COOH group of resin.

Methods using Osmotic pressure

• In this design a semipermeable membrane is placed in a tablet around the drug which allows the inward movement of water and pumping out drug at a zero order rate through a small hole. E.. Procardia XL (Nifedipine)

• There are two types of this design• Type A has drug in a osmotic core• Type B has drug in flexible bad with

surrounding osmotic core.

pH independent Formulation

• Different buffers such as salts if amino acids like citric acid,phthalic acid and phosphoric acid are used in formulation to maintain a Ph thus not affecting drug release.

• Formed by mixing the drug with buffering agent/s and the granulating with suitable excipients ad then coating with GIT juices resistant polymer.

Factors Governing the Design of SRDF

• Physico-Chemical Properties1. Molecular Size and Diffusivity2. Aqueous Solubility3. pKa - Ionization Constant4. Partition Coefficient5. Stability

Molecular Size and Diffusivity•

• The ability of a drug to diffuse through a polymer is called diffusion coefficient of that drug and depends upon the molecular size

• In most polymers it is possible to relate log D to some function of molecular size as,

• Log D = - Sv log v + Kv = - SM log M + Km• where,• V – Molecular volume.• M – Molecular weight.• Sv, Sm, Kv & Km are constants.• The value of D is related to the size and shape of the cavities, as well

as the drugs.• The drugs with high molecular weight show very slow kinetics.

Aqueous Solubility

• A drug with good aqueous solubility, serves as a good candidate for SRDF.

• Drug to be absorbed it first must dissolve in the aqueous phase surrounding the site of administration and then partition into absorbing membrane.

• The dissolution if drug is greatly affected by the aqueous solubility and the relation is clear by following relation

• dc/dt = KDA.cs Where• dc/dt is dissolution rate• A is total surface area of drug• C is aq. Saturation solubility of drug thus the intial rate is directly propotional to the solubility of drug

pKa - Ionization Constant

• Pka is the measure of strength of an acid or a base and determines the presence of a charge on a molecule at any given pH.

• Since all the drugs are either weak acids or weak bases thus the presence or absence of charge on a molecule is very important for its ability to cross the membrane and hence determines its dissolution.

Conti.

• Weakly acidic drug exist as unionized form in the stomach absorption is favored by acidic medium.

• Weakly basic drug exists as ionized form in the stomach hence absorption of this type is poor in this medium.

Partition Coefficient

• Between the time a drug is administered and is eliminated from the body, it must diffuse through a variety of biological membranes.

• As the membranes are lipid in nature Oil/Water partition coefficient plays a major role in evaluating the drug penetration

• K=Co/Cs• Drugs with extremely high partition coefficient are very oil

soluble and penetrates in to various membranes very easily an stay there for longer times

• Drugs with low partition co-efficient have low bioavailability

Stability

• Solid state undergoes degradation at much slower rate than in the suspension or solution etc..

• Drugs stable in stomach gets released in stomach and which are unstable gets released in intestine.

• Drugs with stability problems in any particular area of G.I.T are less suitable for the formulation.

• Drugs may be protected from enzymatic degradation by incorporation in to a polymeric matrix.

EXAMPLES OF PHARMACEUTICAL TECHNOLOGYS USED IN SRDF

• Oral Drug delivery systems• These SRDF systens mostly involve diffusion or

dissolution or both to facilitate slow release of drug in GIT.