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DEPOT PREPARATIONS

SUBMITTED TOProff.M.VIDYAVATHI M.Pharm.,PhD

SUBMITTED BYKASARANENI.DIVYA SHANTHI,PHARMACEUTICS,2015MPH4008.

CONTENTS:INTRODUCTIONAPPROACHESTYPES OF DEPOT

PREPARATIONSDEVELOPMENT OF DEPOTSCONCLUSIONREFERENCES

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INTRODUCTION:Definition: Depot is a formulation which is aqueous or oleaginous

suspension (or) oleaginous solution administered by parental route i.e.

by sub-cutaneous or intra muscular.

Depot is a drug reservoir that releases the drug molecule continuously

at a rate determined to a large extent leading to prolong absorption of

drug molecule from formulation

The ingredient used for depot formulation should be sterile, pyrogen

free, non-irritating, bio-compatible, bio-degradable and non toxic

compounds

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Improved patient convenience and complianceProlonged steady state drug plasma concentrationMaximum utilization of drug Less frequency of dosingReduction in health care cost through improved therapy

ADVANTAGES:

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Decreased systemic availabilityPoor invitro- invivo co-relationPossibility of dose dumpingRetrieval of drug is difficult in case of toxicity,

poisoning or hypersensitivity reactionsReduced potential for dosage adjustmentsHigher cost of formulations

DISADVANTAGES:

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APPROACHES:1) Use of viscous, water-miscible vehicles, such as aqueous

solution of gelatin or polyvinylpyrrolidone.

changes in solubility of drug

changes in time release once drug is administered

changes in state of drug post administration

2)Utilization of water-immiscible vehicles such as

vegetable oils, water repelling agents such as aluminium

monostearate 6

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3)Formation of thixotropic suspensions structural break point

change in flow properties change in dissolution characteristics

4)Preparation of water insoluble drug derivatives such as

salts, complexes and esters. chemical modification without affecting therapeutic activity kinetics were influenced stability enhanced

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5)Dispersion in polymeric microspheres or microcapsules

such as lactide-glycolide homopolymers or copolymers

use of surface active agent

polymerization insitu or through reaction

microcapsule using various techniques

6)Co-administration of vasoconstrictors

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TYPES OF DEPOT PREPARATIONS:

Depot formulation may be classified on the basis of the process used for controlled drug release as follows: A)Dissolution-controlled depot formulation

B)Adsorption-type depot formulation C)Encapsulation-type depot formulation D)Esterification-type depot formulation

DISSOLUTION-CONTROLLED DEPOT FORMULATIONS:

The rate of dissolution is controlled by slow dissolution of the drug particle in the formulation or tissue fluid surrounding the formulation

The rate of dissolution can be determined mathematically as Q/t = SDC/ h Q/t = rate of dissolution S = surface area of drug particle D = diffusion coefficient C = saturation solubility H = thickness of hydrodynamic diffusion layer

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Two approaches to control dissolution are:

a) Formation of salt or complexes with low aqueous

solubility:

A water soluble basic or acid drug can be

rendered effective as a depot by transforming it into a salt

with an extremely low aqueous solubility.

EX: Aqueous suspensions of benzathine pencillin G

(c=2mg/ml) and procaine pencillin G (c=4mg/ml) from

water soluble alkali salts of acidic pencillin G.01/05/2023 11

b) Suspension of macro crystals: Large crystals are known to dissolve more slowly than small crystals. It is called the macro crystal principle and can be applied to control the rate of drug dissolutionEX: aqueous suspension of testosterone isobutyrate for I.M injection

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Suspension of macro crystals is having exception in case of

Pencillin G procaine suspension in gelled peanut oil for I.M injection. This is due to possibility that micronized particles may reach the interface of tissue fluid and gelled suspension at a significantly slower rate than the larger particles.

Drawbacks: Release of drug molecules is not of zero order kinetics as expected

from the theoretical modelSurface area of drug particles diminishes with time The saturation solubility of the drug at the injection site cannot be

easily maintained.01/05/2023 13

ADSORPTION-TYPE OF DEPOT PREPARATIONS:This depot preparation is formed by the binding of drug

molecules to adsorbents.In this case only the unbound, free species of the drug is

available for absorption.The equilibrium concentration of free, unbound drug

species (C)f is determined by the Langmuir relationship,

(C)f/(C)b = 1/a(C)b,m+(C)f/(C)b,m

EX: Vaccine preparations in which antigens are bound to highly dispersed aluminium hydroxide gel to sustain their release.

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ENCAPSULATION-TYPE DEPOT PREPARATIONS:This type of depot formulation is prepared by encapsulating

drug solids within a permeation barrier or dispersing drug

particles in a diffusion matrix

Both of these are made from either bio-degradable or bio-

absorbable polymers. such as gelatin, dextran, polyactate ..etc..Release of drug is controlled by rate of penetration across the diffusion barrier rate of biodegradation of barrier macro molecules.

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EX: Naltrexone pamoate -releasing biodegradable microcapsules, liposomes

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ESTERIFICATION-TYPE DEPOT PREPARATIONSThis depot preparation is produced by synthesizing the bio-

convertibles esters of a drug and then making up an injectable formulation.

This formulation forms a drug reservoir at the site of injection.Rate of absorption is controlled by interfacial partitioning of drug esters from reservoir to tissue fluid. rate of bioconversion of drug esters to regenerate active drug molecules.EX: Fluphenazine enanthane,testosterone17β cypionate in oleaginous solution

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DEVELOPMENT OF INJECTABLE CONTROLLED RELEASE FORMULATIONS: Long acting vitamin B12 preparations Long-acting antipsychotic preparations Long-acting pencillin preparations Long-acting insulin preparations Long-acting adrenocorticotropic hormones

preparation Long-acting steroid preparations Long-acting antimalarial preparations Long-acting contraceptives preparations

LONG ACTING VIT-B12 PREPARATION:

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Reasons for preparation of long acting vitB-12 preparation:

VitB-12 which was given by the oral route is mediated by gastric intrinsic factor of castle which is secreted by the gastric parietal cells

This gastric intrinsic factor is easily saturated by vitB-12 and forms vitB12-intrinsic factor complex.

Attachment of vitB12-intrinsic factor complex to receptors on the ileal surface requires calcium and a ph>6. After a delay of several hours at or with in ileal mucosa, the vitamin is transported by the blood stream to the liver and other organs

It is responsible for over whelming majority of the megaloblastic anemias

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VitaminB-12 is rapidly and quantitatively absorbed from intramuscular and subcutaneous sites of injection

The plasma level of vitamin B12 reaches its peak concentration within 1hr of intramuscular injection

VitB12 which was given by these routes is the medication of choice for the treatment of pernicious anemia

The usual maintenance treatment of patients with pernicious anemia is by monthly injections of vitamin B12(0.03-1.0mg)

Unfortunately, much of the injected doses were lost through urine

Different approaches were developed for formulation of vitaminB12

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First approach to the development of a parental controlled vitaminB12:

VitaminB12 in a concentrated partially hydrogenated gelatin (32%) solution.

Drawback: No sustained release behaviour was obtained on human testing

Second approach to the development of a parental controlled vitaminB12:

Crystalline vitaminB12 was suspended in seasame oil gelled with aluminium monostearate (2%)

Drawback: Urinary excretion of this vitamin was unacceptable

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Third approach to the development of a parental controlled vitaminB12:

VitaminB12-zinc-tannate complex was prepared and suspended in sesame oil gelled with aluminium monostearate (2%).

This preparation achieved a significant prolongation of the absorption of vitB12 when compared to former two approaches

Urinary loss was significantly reduced.

MARKETED PRODUCT: Depinar(armour pharma) which consists of combination

of readily absorbable vit-B12 and sustained release vit-B12 with zn-tannate.

Adequate maintenance therapy has been provided when given at a dose of 1mg/ml at interval of 8-12 weeks.

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LONG ACTING ANTIPSYCHOTIC PREPARATIONS:Phenothiazines were the most prescribed antipsychotic

drugs Fluphenazine, is the most potent derivative of

phenothiazines due to its potency, prolonged duration of action.

Prolongation of the antipsychotic activity of fluphenazine can be accomplished by esterification

EX: Fluphenazine decanoate, fluphenazine enanthateEsterification of fluphenazine with enanthate moiety

prolongs its activity

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Parental(IM or SC) administration of either ester in sesame oil produces anti-psychotic action for an average duration of 2 weeks

Onset of action generally takes 24-72 hrs and effect on psychotic symptoms becomes significant within 48-96hr.

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Long acting antibiotic preparations: Aqueous solubility of penicillin is reduced by converting penicillin to penicillin G procaine (aq. solubility 4mg/ml) EX: DuracillinLong acting insulin preparations: plasmat1/2 of insulin = 40min insulin-protamine complex has isoelectric point at pH 7.3 and therefore it is insoluble in body fluid which shows sustained release upto 24hrs,stability issues arises but solved by adding zinc chloride.

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Long acting adrenocorticotropic hormone preparations: When given parentally ACTH gets disappeared due to its shorter t1/2 i.e.; 15min. By the addition of partially hydrolysed gelatin solution into injectable ACTH solution shows prolonged release. Gelatin inhibits protein binding of ACTH and enhances response.Long acting anti-narcotic preparations: Gelled oleaginous suspension of narcotic antagonist – salt complex shows sustained release for 72hrsLong acting contraceptive preparations: Norethindrone in a biodegradable polymer beads Norgestrel 17β-fatty acid esters in oleaginous solution.

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EVALUATION FOR DEPOTS:ViscosityDrug content In vitro release studySterility testing

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POLYMERS USED…….Generally Biodegradable polymers are used because as

they gets degraded in the body NATURAL: Albumin, starch, dextran, gelatin, fibrinogen,

haemoglobin.SYNTHETIC: Poly ethyl-poly alkyl cyanoacrylates, poly

amides, poly acryl amides, poly amino acids, poly urethane.

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PROPERTIES: Depot systems should have the following propertiesIt should be safe from accidental releaseIt should be simple to administer and removeIt should be inert and biocompatibleIt should be capable of achieving high drug loadingIt should be easy to fabricate and sterilizeIt should be free of leachable impurities

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CONCLUSION: Depot preparations or parental controlled drug delivery

system is designed to achieve a desired pharmacological

response in a sustained manner at a selected site without

undesirable interactions at the other sites.

Extended release parental products are complex dosage

forms, requiring careful development of test methods

and acceptable criteria for the specifications.

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REFERENCES: Chien Y.W., Novel drug delivery systems;

Drugs and pharmaceutical sciences(2nded,vol-50).

Lachman L.& Lieberman H. & kanig J www.wikipedia.org www.pharmatutor.org/articles/review-parenta

l controlled drug delivery systems.

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