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Parenteral Controlled Release Drug Delivery Systems: 

Parenteral Controlled Release Drug Delivery Systems Presented by: Mr. Patel Ritesh kumar K. Department Of Pharmaceutics 1 st year M. Pharm Srinivas College of Pharmacy Mangalore.

Introduction : 

Introduction Parenteral drug delivery results in easy access of the drug in to the systemic circulation. Drug absorption is very rapid and complete through this route because the drug is directly injected in systemic circulation

Approaches: : 

Approaches: Pharmaceutical formulation approaches may be applied to the development of Parenteral controlled release or sustained release formulations. Use of viscous, water miscible vehicles such as an aqueous solution of gelatin or poly vinyl pyrrolidine . Use of water immiscible vehicles such as vegetables oil plus water repelling agent such as aluminum mono stearate . Formation of thixotropic suspensions. Preparation of water insoluble drug derivatives such as salts, complexes and Esters. Dispersion in polymeric micro spheres or microcapsules such as Lactideglycolide homopolymer or copolymer. Co administration of vaso constrictors.

PowerPoint Presentation: 

Depot formulation may be classified on the basis of the process used for controlled drug release as follows: - 1. Dissolution controlled depot formulation:- In this depot system the rate of absorption is controlled by the slow dissolution of the drug particles in the tissue fluid surrounding the formulation or in the formulation. The rate of dissolution (Q/t) d under sink condition is defined by, (Q/t) d = Sa.ds.cs / hd Where, Sa= surface area of the drug particles in contact with the medium ds = diffusion coefficient of drug molecules in the medium Cs= saturation solubility of the drug in the medium hd = thickness of the hydrodynamic diffusion layer surrounding each drug

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2. Adsorption type depot formulation :- The binding of drug molecule to adsorbents forms this type of depot preparation. In this only the unbound, free species of the drug is available for adsorption. Unbound drug molecules are absorbed a fraction of the bound drug molecule is released to maintain equilibrium. E.g. vaccine preparations in which the antigens are bound to highly dispersed aluminium hydroxide gel to sustain their release and hence prolong the duration of stimulation of antibody formation.

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The Langmuir determines the equilibrium concentration of unbound drug relationship, Cf / Cb = 1/a(c) bm +(c)f/(c) bm Where, Cf = equilibrium concentration of unbound drug Cb = amount of drug (mg) absorbed by 1 gm adsorbent Cbm = is maximum amount of drug (mg) absorbed by 1 gm of adsorbent

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3. Encapsulation type depot formulation :- Encapsulating drug solids within a permeation barrier or dispensing drug particles in a diffusion matrix prepares this type of depot formulation. Both permeation matrix barrier and diffusion matrix are fabricated from biodegradable or bioabsorbable macromolecules such as gelatin, dextran , polylactate , lactide glycolide , co polymers, phospholipid and long chain fatty acid and glycerides . E .g. Naloxone pamoate releasing biodegradable microcapsules. The release of drug molecules is controlled by the rate of permeation across the barrier and the rate of biodegradation of the barrier controlled by macromolecules.

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4. Estrification type depot formulation :- This depot preparation is produced by esterifying a drug to form bioconvertable pro drug type ester and then formulating it in an injectable formulation this formulation forms a drug reservoir at the site of injection. E.g.: - fluphenazine enanthate , testosterone 17  cypionate in oleaginous solution.

Injectable Controlled-Release Formulations: 

Injectable Controlled-Release Formulations Includes:- Long-acting Penicillin Preparations Long-acting Insulin Preparations Long-acting Vitamin B 12 preparations Long-acting Adrenocorticotropic Harmone Preparations Long-acting Steroidal Preparations Long-acting Antipsychotic Preparations Long-acting Antinarcotic Preparations Long-acting Contraceptive Preparations Long-acting Anti-malarial Preparations

Long-acting Penicillin Preparations:: 

Long-acting Penicillin Preparations: Penicillin in the form of water-soluble Na or K salt is rapidly absorbed from subcutaneous & intramuscular sites of parentral administration. Intramuscular route of administration is preferred because of its rapid absorption & high peak serum levels. The high serum penicillin concentrations then decline rapidly as a result of the rapid urinary excretion, following its absorption from the site of injection.

PowerPoint Presentation: 

The earliest approach was to reduce the aqueous solubility of penicillin by converting the water-soluble Na or K salt into salts with extremely low aqueous solubility. E.g : Pencillin G procaine in a vegetable oil produces a depot effect that sustains the therapeutic blood level of penicillin for 24-48 hr. Gelation of this oil suspension with 2% aluminium monostearate further prolongs the therapeutic blood level of penicillin to 96 hr.

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Another approach is to prepare an aqueous suspension of relatively water-insoluble salts but it has achieved only limited success in sustaining the therapeutic blood levels of penicillin during initial stages of development. Further development has resulted in the preparation of long acting thixotropic suspensions of penicillin G procaine such as: Oleaginous suspensions Aqueous suspensions

Long acting Insulin preparations: : 

Long acting Insulin preparations: Due to its extensive 1 st pass metabolism, it is given by parenteral administration via sub cutaneous route. Improper injection techniques have been found to be responsible for poor bioavailability of insulin. APPROACHES : Insulin molecule reacts with zinc ion & precipitates as a water insoluble Zn-insulin complex. Depending upon pH of solution, it may precipitate as an amorphous or a crystalline solid.

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Ultra- Lente Insulin Insulin crystals can be precipitated from acetate buffer at pH 5-6. This crystalline insulin-zinc complex is absorbed very slowly & has a prolonged normoglycaemic activity. After s.c injection of these Zn-Insulin crystals as a suspension in buffer, the insulin is slowly released , absorbed & retains its activity for more than 36 hrs. Semi- Lente Insulin Amorphous Zn-Insulin complex is precipitated at higher pH (6-8 ) This amorphous insulin has low Zn content & is absorbed more readily & achieves duration of action shorter than that of ultre-lente .

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When administered subcutaneously, the Insulin in amorphous Zn-Insulin suspension is quickly released , absorbed & has shorter duration of normoglycaemic activity. Lente -Insulin It is a combination of 7 parts of crystalline & 3 parts of amorphous insulin-zinc complexes. It provides an intermediate acting form of insulin.

Long-acting Vitamin B12 Preparations:: 

Long-acting Vitamin B 12 Preparations: By oral administration the systemic bioavailability of vitamin B 12 is limited & variable. Vitamin B 12 is rapidly & quantitatively absorbed from intramuscular & subcutaneous sites of injection. On administration of intramuscular or deep subcutaneous injection, the peak plasma level of Vitamin B 12 reaches its peak concentration within 1 hr, which is the choice of medication in case of pernicious anemia & other vitamin B 12 deficiency states. Unfortunately, much of the injected doses is lost in the urine. For these reasons , it becomes necessary to develop a parenteral controlled-release formulation for Vit-B 12 .

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The first approach to the development of a parentral controlled vitamin B 12 release formulation was to formulate the Vitamin B 12 in a controlled partially hydrolyzed gelatin 32% solution. However, no sustained-release behavior was observed in human testing. The second approach , crystalline Vitamin B 12 was suspended in sesame oil gelled with 2% aluminum monostearate . This approach achieved a significant prolongation of the absorption of Vitamin B 12 compared to an aqueous solution of Vitamin B 12 .

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The third approach was to synthesize an insoluble derivative of Vitamin B 12 , the Vit-B 12 zinc- tannate complex, & then suspend it in sesame oil gelled with aluminum monostearate 2%. This preparation achieved a significant prolongation of the absorption of Vitamin B 12 & urinary loss was significantly reduced.

Long-acting Adrenocorticotropic Hormone Preparations: 

Long-acting Adrenocorticotropic Hormone Preparations ACTH is a polypeptide hormone that stimulates & regulates the secretion of adrenal steroids, mainly the corticosteroids, from the adrenal cortex. The adrenocorticotropic activity of ACTH is easily destroyed by proteolytic enzymes in the gastrointestinal tract, exogenous ACTH is therefore ineffective when given orally. On the other hand, ACTH is readily absorbed from parentral sites of administration & is usually administered by intramuscular injection & occasionally by i.v infusion.

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Following i.v administration, ACTH rapidly disappears from the systemic circulation with a plasma half-life of only 15 min in the human . 10-20% of the activity can be found in the non-target organ, the kidneys. ACTH is commercially prepared from bovine, porcine & ovine pituitaries. This hormone shows a great affinity to tissue proteins. The adsorption onto tissue proteins was responsible for low effectiveness of ACTH in aq solution by single administration of subcutaneous or intramuscular injection.

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Gelatin was found to inhibit the protein binding of ACTH. Addition of a partially hydrolyzed gelatin into the injectable ACTH solution was found to enhance adrenal ascorbic acid responses in hyposectomized rats. The results of this investigation provided the foundation for the development of a repository corticotropin injection, a long acting injectable formulation that contains a highly purified preparation of ACTH in 16% gelatin solution. This preparartion is active for 24hr, over the regular corticotropin injection, which has a duration of action of only 8 hr.

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The subcutaneous absorption & biological activity of ACTH can also be sustained to varying degrees by adsorption onto aluminum phosphate or by suspension in sesame oil gelled with aluminum monostearate, or by formation of ACTH-Zn- Tannate complex. The ACTH-Zn- Tannate complex in gelatin solution was found to produce the most efficient & long acting adrenocoticotropic effect.

Long acting Anti-malarial preparation: 

Long acting Anti-malarial preparation They are classified broadly into 2 distinct groups. 1. The first group are rapid in their schizontocidal action & non specific in their mechanism of action & make it difficult for original sensitive strains to develop resistance. They interact with and alter the properties of the DNA in both parasite and host without discrimination. 2.The second group is characterized by a schizontocidal effect that is slow in onset & dependant upon the stage of multiplication of the parasite.

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Cycloguanil Pamoate: It is the active metabolite of choloroguanide , whose antimalarial action is related to the binding & inhibition of plasmodial dihydrofoliate reductase . Clinically it was observed that with the co-administration of acedapsone the duration of anti-malarial protection of cycloguanil pamoate is extended. Acedapsone : It is produced by acylation from 4,4 ΄ - diaminophenyl sulfone . It shows prolong action and useful in the treatment of P.faliciparam in humans for upto 42 days after a single IM injection.

Long acting anti psychotic preparation: 

Long acting anti psychotic preparation In the management of psychotic disorder, patient compliance has presented a major problem. Development of this long acting preparation will provide a solution to this non compliance problem. Prolongation of this antipsychotic activity of Fluphenazine can be achieved by esterification, exemplified by development of fluphenazine deconoate , fluphenazine enanthate .

Long acting Steroid preparation : 

Long acting Steroid preparation Sustained drugs activity can also be accomplished by esterification of drugs to form water-insoluble but oil soluble prodrugs . E.g. Estrogenic Steroids Estradiol benzoate( Progynon benzoate) Estradiol 17-valerate( Delestrogen )

Estradiol benzoate(Soluna): 

Estradiol benzoate(Soluna) This is prepared by benzoylation of 3-hydroxyl group of estradiol. An oil soluble ester from which the active β -estradiol is slowly released from the oleaginous formulation at the site of IM injection providing a sustained therapeutic level of estrogen for several days.

PowerPoint Presentation: 

Parenteral administration (IM or SC) of ester in sesame oil produces anti psychotic action for duration of 2 weeks. Onset of action appears between 24-72hrs after injection, and the effects of drug on psychotic symptoms significant within 48-96hrs. These drugs are used for management of schizophrenia and other psychotic disorder, and they are particularly effective in modifying psychotic pattern & ameliorating such symptoms as agitation, delusions and hallucinations

Long acting Contraceptive preparation: 

Long acting Contraceptive preparation It is a progestational steroid, such as natural progesterone, in high doses suppress pituitary release of luteinizing hormone(LH) and the hypothalamic release of LH-releasing factor(LRF) & thus preventing ovulation. Successful results have been obtained in preclinical or clinical studies with the following preparations: Medroxyprogesterone acetate in aqueous suspension. Norethindrone in a biodegradable polymer bead. Norethindrone enenthate in oleaginous solution. Norgestrol 17 β -fatty acid esters in oleaginous solution.

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Depo – Provera C-150: It is an aqueous suspension of microcrystalline medroxyprogesterone acetate(150mg). It is recommended for intramuscular injection deep into gluteal muscle, one dose every 3 months. Deproxone : It is once a month IM contraceptive preparation. It is composed of dihydroxyprogesterone acetophenide (150mg) & estradiol enanthate (10mg).

References: : 

References: Novel drug delivery systems, 2 nd edition by Yie.W.Chien , Topic: Parenteral drug delivery systems, Page no 381-528.