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DEVELOPMENT OF INJECTABLE CONTROLLED- RELEASE FORMULATIONS Presented to Dr. Hemant.K.S.Yadav Dept. of Pharmaceutics, JSSCP,Mysore . Presented by, S . S wetha 1 st M.Pharmacy, Pharmaceutics.

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

1. Long-acting Penicillin Preparations::

1. 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.

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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

2.Long acting Insulin preparations: :

2.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 . When administered subcutaneously, the Insulin in amorphous Zn-Insulin suspension is quickly released , absorbed & has shorter duration of normoglycaemic activity.

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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.

2. Long-acting Vitamin B12 Preparations::

2 . 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.

3. Long-acting Adrenocorticotropic Hormone Preparations:

3. 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.

References: :

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

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