sustained release dosage form

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SUSTAINED RELEASE DOSAGE FORMS Presented by: Sujit R. Patel, 1 st M. pharm. DEPARTMENT OF PHARMACEUTICS, Maratha Mandal’s College OF PHARMACY, Belgaum - 590 010. June 6, 2022 1 M.M.C.P.

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Sustained release dosage form

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Page 1: Sustained release dosage form

SUSTAINED RELEASE DOSAGE FORMS

Presented by:

Sujit R. Patel,

1st M. pharm.

DEPARTMENT OF PHARMACEUTICS,Maratha Mandal’s College OF PHARMACY,

Belgaum - 590 010.

April 10, 2023 1M.M.C.P.

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INTRODUCTIONDrug delivery systems refer to the technology utilized to present the drug to the desired body site for drug release and absorption.

Newer discoveries and advancements in technology has lead to various new techniques of delivering the drugs for maximum patient compliance at minimal dose and side effects.

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IDEAL DRUG DELIVERY SYSTEM

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

Second it 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

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SUSTAINED RELEASE DRUG DELIVERY: Any of the dosage form that maintains the therapeutic blood or tissue levels of drug by continuous release of medication for a prolonged period of time, after administration of a single dose. In case of injectable dosage forms it may vary from days to months.

SITE SPECIFIC AND RECEPTOR TARGETINGSITE SPECIFIC AND RECEPTOR TARGETING : : Targeting a drug directly to a certain biological location .For site specific release the target is the adjacent to or in the diseased organ or tissue, for receptor release the target is the particular drug receptor within an organ or tissue.

CONTROLLED RELEASE DRUG DELIVERY :Delivery of the drug at a predetermined rate and /or to a location according to the needs of the body and disease states for a definite period of time.

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REPEAT ACTION DOSAGE FORMREPEAT ACTION DOSAGE FORM: contain 2 or 3 full doses which are so designed that the doses are released sequentially one after the other.

OTHER NOVEL(NEW) DOSAGE FORMS:OTHER NOVEL(NEW) DOSAGE FORMS:

includes- Microspheres, Nanoparticles,, Trans-dermal delivery systems, Ocular drug delivery, Nasal drug delivery, Implants etc.

TIMED RELEASE OR DELAYED RELEASETIMED RELEASE OR DELAYED RELEASE: : These are the systems that use repetitive, intermittent dosing of a drug from one or more immediate release units incorporated into a single dosage form or an enteric delayed release systems e.g. Repeat action tablets and capsules and enteric coated tablets where time release is achieved by barrier coating, or wherein the release of the drug is intentionally delayed until it reaches the intestinal environment.

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Sustained release dosage forms

(SRDF’S)

timeApril 10, 2023 6M.M.C.P.

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INTRODUCTION

Sustained release describes the release of drug substance from a dosage form or delivery system over an extended period of time. Also referred to as prolonged-release (PR),

slow release (SR), sustained action (SA), prolonged action (PA) or extended-release (ER).

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COMPARISION OF DRUG RELEASE PROFILES

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Differences between sustained and controlled drug delivery system

Sustained release Sustained release dosage formdosage form

•Constitutes dosage form that Constitutes dosage form that provides medication over provides medication over extended period of timeextended period of time

•SRDF generally do not SRDF generally do not attain zero order release attain zero order release kinetics kinetics

•Usually do not contain Usually do not contain mechanisms to promote mechanisms to promote localization of the drug at localization of the drug at active site. active site.

Controlled release Controlled release dosage formdosage form

•Constitutes dosage form that Constitutes dosage form that maintains constant drug levels in maintains constant drug levels in blood or tissue blood or tissue

•Maintains constant drug levels in Maintains constant drug levels in the blood target tissue usually by the blood target tissue usually by releasing the drug in a zero order releasing the drug in a zero order pattern.pattern.

•Controlled dosage forms contain Controlled dosage forms contain methods to promote localization methods to promote localization of the drug at active site.of the drug at active site.

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Merits of SRDF Reduction in blood level fluctuations of drug, thus

better management of the disease. Reduction in dosing frequency. Enhanced patient convenience and compliance. Reduction in adverse effects(both systemic and local),

esp. of potent drugs, in sensitive patients. Reduction in health care costs. Improved efficiency of treatment. Reduces nursing and hospitalizing time. Maximum bioavailability with a minimum dose.

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  Minimize drug accumulation with chronic dosing.

  Cure or control condition more promptly.

 Make use of special effects, e.g. Treatment of Arthritis.

Constant blood levels achieve desired effect and this effect is maintained for an intended period of time.

  Drug susceptible to enzymatic inactivation or by bacterial decomposition can be protected by encapsulation in polymer system suitable for SR.

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Limits of SRDF

 Administration of sustained release medication dose not permit prompt termination of therapy. Immediate changes in the drug if needed during therapy when significant adverse effects are noted cannot be accommodated.

The physician has less flexibility in adjusting dosage regimen, as it is fixed by dosage form design.

Sustained release dosage forms are designed for normal population i.e. on basis of average biologic half-life. Consequently, disease states that alter drug disposition, significant patient variation, and so forth are not accommodated.

More costly process and equipment are involved in manufacturing many sustained release dosage forms. 

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Dose dumping

Unpredictable and poor in vitro and in vivo relationship.

Effective drug release time period is influenced and limited by GI

residence time. Need additional patient education.(such as not to chew or crush the

dosage form before swallowing) Drugs having very short half life or very long half life are poor

candidates for sustained release dosage forms. For Ex: diazepam. Delayed onset of action, hence sometimes not useful in acute

conditions

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Characteristics of Drugs Unsuitable for Peroral SRDF

I. Those which are absorbed and excreted rapidly; short biological half life(<1 hr). Ex- Penicillin G , Furosemide.

II. Those with long biologic half life(>12 hrs). Ex- Diazepam, Phenytoin.

III. For those which require large doses(>1 gm) Ex- Sulfonamides.

IV. Extensive binding of drugs to plasma proteins will have long elimination half life and such drugs generally do not require to be formulated to SRDF.

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V. Those with cumulative action and undesirable side effects. Ex-Phenobarbital

VI. Those with low therapeutic indices. ex- Digitoxin.

VII. Those requiring precise dosage titration for every individual. Ex- Warfarin, Digitoxin.

VIII. In general a very highly soluble drug or a highly insoluble drug are undesirable for formulation into SRDF product.

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Materials Used in Coating of Sustained Release Dosage Forms (Encapsulation)

Mixtures of waxes [bees wax, carnauba wax, etc] with glyceryl monostearate , stearic acid , glyceryl mono palmitate and cetyl alcohol.These provide coatings that are dissolved slowly or broken down in the GIT.

Shellac and zein – polymers that remain intact until the PH of the GI contents become less acidic

Ethyl cellulose , which provides a membrane around the dosage form and remains intact throughout the GIT. However, it does permit water to permeate the film, dissolve the drug , and diffuse out again.

Acrylic resins , which behave similarly to ethyl cellulose as a diffusion controlled drug release coating material.

Cellulose acetate [di acetate and tri acetate] Silicone elastomers.

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Polymers for Micro-encapsulation

Water-soluble resins

Water-insoluble resins

Waxes and lipids

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Water-soluble resins

Gelatin

Povidone (PVP)

CMC

HEC

MC

PVA

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Water-insoluble resins

Ethyl cellulose

Polyamide (Nylon)

Polyethylene

Cellulose nitrate

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Waxes and lipids

Paraffin

Carnauba

Beeswax

Stearic acid

Stearyl alcohol

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Physicochemical Properties of Drug Candidate:–

DoseDose sizesize

DoseDose sizesize

Molecular size Molecular size and diffusivityand diffusivity

Molecular size Molecular size and diffusivityand diffusivity

Protein bindingProtein binding Protein bindingProtein binding

Drug Drug stabilitystabilityDrug Drug

stabilitystability

Partition Partition coefficientcoefficientPartition Partition

coefficientcoefficient

Aqueous Aqueous

solubility and pka solubility and pka

Aqueous Aqueous

solubility and pka solubility and pka

Physicochemical Physicochemical propertiesproperties

Physicochemical Physicochemical propertiesproperties

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Physicochemical properties:–

1) Aqueous solubility & PKaː– Aqueous solubilityː–

A drug with good aqueous solubility, especially if pH independent, serves as a good candidates

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

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Noyes Whitney Equation

dc = KDACs dt

where ,dc/dt= dissolution rate.

KD = Dissoltion rate constant. A = total surface area of drug.

Cs = aqueous saturation solubility.

Drugs with low aqueous solubility have low dissolution rate and have oral bioavailability problems.

E.g.: Tetracycline.

Drugs with high aqueous solubility are undesirable to formulate SRDF’s.

E.g.: Paraacetamol

.

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PKaː–

The aqueous solubility of weak acids & weak bases is governed by the pKa of the compound and pH of the medium.

FOR WEAK ACIDSt = So(1+Ka\[H ] =So(1+10pH-pKa)

where, St – Total solubility of the weak acid So – Solubility of the un-ionized form Ka – Acid dissociation constant H - Hydrogen ion concentration

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

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FOR WEAK BASES

St = So(1+[H ] \Ka) =So(1+pKa-pH)

Where, St – Total solubility of both conjugate and free base form of weak base.

So– Solubility of the free base.

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

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2) Partition coefficientː– Between the time a drug is administered and is eliminated from the body, it must diffuse through a variety of biological membranes.

• Oil/Water partition coefficient plays a major role in evaluating the drug penetration.

K=Co/Cs

where, Co= Equilibrium concentration in organic phase. Cs= Equilibrium concentration in aqueous phase.

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According to ‘Hanch correlation’ a parabolic relationship between the log of its partition coefficient has with that of the log of its activity or ability to be absorbed.

Drugs with extremely high partition coefficient are very oil soluble and penetrates in to various membranes very easily.

Log K

Log

acti

vit

y

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There is an optimum partition coefficient for a drug in which it

permeates membrane effectively and shows greater activity.

Partition coefficient with higher or lower than the optimum are

poorer candidates for the formulation

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Values of partition coefficient below optimum result in the

decreased lipid solubility and remain localized in the first aqueous

phase it contacts.

Values larger than the optimum , result in poor aqueous

solubility but enhanced lipid solubility and the drug will not

partition out of the lipid membrane once it gets in.

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3) Drug stabilityː– 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.

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4) Protein bindingː– Drug binding to plasma proteins (albumins) & resulting retention of the

drug in the vascular space. Drug -protein complex can serve as a reservoir in vascular

space.

Main forces for binding are Vander Waal forces, hydrogen bonding , electrostatic forces.

Charged compounds has greater tendency to bind proteins than uncharged ones.

Extensive binding of plasma proteins results in longer half-life of elimination for the drug.

E.x..95% binding in Amitriptyline , diazepam , diazepoxide.

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5) Molecular size & diffusivityː–

The ability of a drug to diffuse through membranes is called diffusivity which is a function of molecular weight.

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.

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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.

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6) Dose sizeː– For those drugs requiring large conventional doses, the

volume of sustained dose may be too large to be practical.

The compounds that require large dose are given in

multiple amounts or formulated into liquid systems.

The greater the dose size,greater the fluctuation.

So the dose should have proper size.

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Name Marketer Dosage form Indication

Carbotrol

Glucotrol Xl

Adderall XR

Procardia Xl

Ortho Evra

Dura gesic

Shri Us

Pfizer

Shri US

Pfizer

Ortho – Mcneil

Janssen

Oral capsule

Oral TabletOral Tablet

Oral Capsule Oral Capsule

Oral TabletOral Tablet

Trans Dermal PatchTrans Dermal Patch

Trans Dermal PatchTrans Dermal Patch

Epilepsy

Hyperglycaemia

ADHD

Angina / Hypertension

Contraceptive

Chronic pain

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REFERENCEː–1) Remington’s pharmaceutical sciences.

2) Sustained and controlled release systems.

-James W Robinson.

3) Theory and Practice of Industrial Pharmacy.

-Lachmann and Liebermann.

4) Biopharmaceutics And Pharmacokinetics A Treatise. - D.M. Brahmankar.

5) www.google.com

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