Sustained release dosage forms

April 10, 2023 1

• Introduction-definition• Concept• Objectives• Advantages and disadvantages• Dose considerations• Formulation• Types of SR systems

Diffusion systems Dissolution systems

Ion exchange sysApril 10, 2023 2

• Oral SR delivery systems design and types• Parentral SR dosage forms types and routes• References

April 10, 2023 3

IDEAL DRUG DELIVERY SYSTEM

• should deliver drug at a rate dictated by the needs of the body over the period of the treatment.

• should channel the active entity solely to the site of action.• This is achieved by development of new various modified

drug release dosage forms, like-

Control release dosage forms Time release dosage forms Sustained release dosage forms Site specific or targeted drug delivery systems etc.

April 10, 2023 4

“Drug Delivery systems that are designed to achieve prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose.”

Basic goal of the therapy to achieve steady state blood level that is

therapeutically effective & non toxic for an

extended period of time.

April 10, 2023 5

Sustained release drug profile

April 10, 2023 6

Objectives of drug delivery

• Temporal drug delivery: controlling the rate or specific time

of drug delivery to the target tissue.

• Spatial drug delivery: targeting a drug to a specific organ

or tissue.

April 10, 2023 7

Reduction in fluctuation in steady state levels

Increased safety of high potency drugs

Total amount of dose is decreased

Improved patient compliance

advantages

Poor in vivo-in vitro correlation

Possibility of dose dumping

Retrieval of drug is difficult

Dose adjustments is difficult

disadvantages

April 10, 2023 8

• Biopharmaceutical properties:

Molecular size less than 600 Daltons Aqueous solubility more than 0.1 mg/ml Partition coefficient between 1 to 2 Dissociation constant pka acidic drugs pka>2.5 Basic drugs pka<11 Absorption mechanism passive but not through Window Ionisation at physiological pH NMT 95%

April 10, 2023 9

Pharmacokinetic properties

• Absorption rate constant ka high(btw 0.17- 0.23/hr)

• Elimination half life t1/2 2-6 hrs• Metabolism rate not too high• Dosage form index(ratio of cssmax /css min) One

April 10, 2023 10

Pharmacodyanamic properties

Dose max 1.0g (in a controlled release form)Therapeutic range wideTherapeutic index wide PK/PD relationship good

April 10, 2023 11

• Divided into two considerations

1.Release rate consideration Release rate consideration :-In conventional dosage form Kr>Ka - release of

drug from dosage form is not rate limiting step.

April 10, 2023 12

(Kr>>Ka) in immediate release non immediate (Kr<<<Ka) i.e. release is rate limiting step.

The release should follow zero order kinetics(clinically equivalent to constant release in many cases) Kr = rate in = rate out = Ke.Vd.Cp

Ke = Elimination rate constant (first order kinetics).

Vd = Total volume of distribution. Cp = Plasma drug concentration. Kr = zero order release rate constant

April 10, 2023 13

b)Dose consideration:for zero order release

a) Initial (primary) dose Di b)Maintenance dose Dm = kr .Td

Td=total time required for extended release dosage form

therefore, total dose W W= Di + Dm W=Di +Kr.Td

April 10, 2023 14

coreMaintenance dose

Immediate release component

If maintenance dose begins to release the drug during dosing t=0 then,

W = Di + K r. Td – Kr.Tp

Tp = time of peak drug level.

April 10, 2023 15

First order release

Dm=ke.Cp.Vd/kr W=Di+Dm W=Di+(keCp/kr)Vd kr= first order release rate constant ke=elimination rate constant Cp=plasma drug concentration If drug begins to release maintenance dose at T=0 W=Di+(keCp/kr)Vd - DmkeTpTp= time of peak plasma drug concentrationApril 10, 2023 16

rate in=rate out Dm.kr=ke.Cp.Vd

Diffusion systems• Porous matrix controlled system Rate controlling element-water swellable material e.g.

xanthan gums ,guar gum , high viscosity grades of HPMC,HPC, alginates or non- swellable water insoluble polymers such as ethylcellulose

April 10, 2023 17

• Porous membrane controlled system rate controlling element – non-swellable

water insoluble polymer e.g. ethylcellulose, PMA. Drug release controlled through micropores.

April 10, 2023 18

• Can be in following ways:- Slow dissolution of drug1. Drug with inherently slow dissolution rate.2. Drugs that transforms into a slow dissolving form.

Slow dissolution rate of reservoir memb. & matrix

1. Embedment in slowly dissolving, degrading erodible matrix.2. Encapsulation or coating with slowly dissolving degrading erodible

subs.

April 10, 2023 19

• slowly soluble and erodible materials:- Ethylcellulose, PVP with cellulose PMA(eudragits), Waxes(glyceryl monostearate)

April 10, 2023 20

Erosion controlledPolymer or wax degradation brought about by: enzyme, pH change osmotic pressure

• Bulk erosion(A) homogeneous erosion• Surface erosion(B) heterogenous erosion when water penetration is restricted to surface

April 10, 2023 21

ORAL SUSTAINED RELEASE DESIGN • Continuous release systems-release drug

continuosly over extended period of time.• Pulsatile release systems:- characterize by a lag time then rapid &

complete /extended release. Advantages:-1. Drugs with extended first pass e.g. Propranolol2. Targeting e.g. in intestinal inflammations3. Protection of gastric or upper intestinal mucosa from

irritating drugs.April 10, 2023 22

Following methods can be used to prepare sustained release oral preparation:-

• Increasing the particle size of the drug

• Embedding the drug in a polymeric matrix.

• Coating the drug or dosage form containing drug(microencapsulation).

• Forming complexes of the drug with material such as ion exchange resins.

April 10, 2023 23

1)Increasing the particle size of the drug

• Increasing particle size decreases the surface to volume ratio slow the rate of drug availability.

•This method is limited to poorly soluble drug .

April 10, 2023 24

2) Embedding the drug in matrix• Matrix is a uniform dispersion of drug with polymer

matrix

• Continuous external phase of the dispersion effectively impede the passage of the drug from the matrix.

• Drug release through-diffusion

• Least complicated approaches to manufacture sustained release dosage form involves the direct compression of drug, materials & additives to form a tablet .

April 10, 2023 25

polymers

•Insoluble, inert - polyethylene, polyvinyl chloride, methyl acrylate, ethylcellulose.

•Insoluble, erodible – carnauba wax, stearyl alcohol, castor wax.

•Hydrophilic – methyl cellulose, hydroxyl ethyl cellulose, sodium carboxymethyl cellulose, sodium alginate.

April 10, 2023 26

3) Microencapsulation• method for retarding drug release by coating its

surface with a material(polymers) that retards penetration by the dispersion fluid.

• it is a means of applying relatively thin coating to small particles of solid or droplets of liquids and dispersion.

Can be done by- spray congealing spray drying

April 10, 202327

Polymers:• Polyvinyl alcohol• Polyacrylic acid• Ethyl cellulose(pH sensitive)• Polyethylene• Polymethacrylate• Poly (ethylene-vinyl acetate)• Cellulose nitrite• Silicones• Poly (lactide-co-glycolide)

April 10, 2023 28

3)Ion exchange resins• Sustained delivery of ionizing acidic & basic drug

can be obtained by complexing them with insoluble non-toxic anion exchanger & cation exchanger resin respectively.

• Release by diffusion .

• The complex can be prepared by incubating the drug-resin solution or passing the drug solution through a column containing ion exchange resin.

April 10, 2023 29

Advantages

• Resinates prevent dose dumping• Uniform release of drug• Flexibity in designing various dosage forms

April 10, 2023 30

Types of resinates• Simple resinates• Microencapsulated or coated resinates-rate

controlling membrane of polymers(EC,waxes etc)

April 10, 2023 31

polymer

Drug+resin

polymer

• Pennkinetic systems drug resinate is pre treated with PEG 400

Coated with water insoluble polymerPEG-controls rate of swelling of resinate mixture in water.

EC-modifies diffusion pattern of ions in & out.

• Hollow fibre systems-resinates filled into hollow fibres of suitable polymeric materials

April 10, 2023 32

ADVANTAGES

April 10, 2023 33

• Convenience and ease of administration• Flexibility in DFD• Ease of production.

April 10, 2023 34

INJECTABLES

April 10, 2023 35

SOLUTIONS Both aqueous & oilyaqueous solution• High viscosity solutions• For cmpds more than ml wt 750• For water soluble drugs• Gelling agents & viscosity enhancers are used

drug release is controlled by:-• By increasing viscosity of vehicle by mc,cmc

pvp• Forming a complex with macromolecules• Forming complex & decreasing solubility of

drug

April 10, 2023 36

Oil solutions• Release drug by partioning the drug between

oil &aqueous body fluid.

• Vegetable oils like-arachis oil,cottonseed oil

April 10, 2023 37

• Emulsions- o/w, adm of liquid oily drugs (i.v, s.c,i.m)

• Suspensions-solid particles in aqueous vehicle solid content 0.5%-5.0%, size <10μ (s.c,i.m) for drugs insoluble in water

• Microspheres-polymeric particles, site specific delivery

April 10, 2023 38

• Liposomes- liquid based vesicles diameter range 25nm-10000nm phospholipids i.v,s.c,i.m,intra-CSF

• Nanoparticles-polymeric liquid particles biodegradable polymers i.v,s.c, i.m

• Niosomes- surfactant vesicles non-ionic surfactant i.v,i.m,s.c

April 10, 2023 39

Drug loading-immersing in buffered hypotonic solution

Resealing-restoring isotonicity & incubation at 37

Target organs-liver &spleen • Advantages biodegradable & non-immunogenic carry large doses targeted drug delivery

April 10, 2023 40

• Leon lachman – The theory and practic of industrial pharmacy

• D.M. Brahmankar and Sunil B. Jaiswal, Biopharmaceutics and Pharmacokinetics: A Treatise. 1995, 1st Edn, Published by M. K. Jain for Vallabh Prakashan

• .Remington, The science and practice of pharmacy, 21st Edition.

April 10, 2023 41

April 10, 2023 42