contolled delivey of drug through parentral route

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Controlled release of drugs through parenteral products:

Controlled release of drugs through parenteral products Aakriti Nigam M.Pharm (PHARMACEUTICS) ADVANCE INSTITUTE OF BIOTECH AND PARAMEDICAL SCIENCES,KANPUR,UP


NEED OF PARENTRAL CONTROLLED RELEASE DRUG DELIVERY SYSTEM : Oral drug delivery in which the systemic bioavailability of drug is often subjected to variations in GIT and biotransformation in the liver system. An immediate physiological response can be achieved if neceesary which is of prime consideration in clinical conditions such as cardiac arrest,asthma and shock. Drugs for uncooperative,nauseous or unconscious patient must be administered by injection. It is required for drugs that are not effective orally or that are destroyed by digestive secretions such as insulin,some hormones and antibiotics.


DISADVANTAGES: It is difficult to reverse its physiological effect. The dosage form must be administered by trained personnel and requires more time than those administered by other routes. Parenteral administration requires strict adherence to aseptic procedures and some pain on injection is inevitable. The manufacturing and packaging requirements of parenteral products are more expensive than preparation given by other routes.


MAJOR ROUTES OF PARENTERAL ADMINISTRATION Subcutaneous Intramuscular Intravenous Intraperitoneal

Biopharmaceutics of sutained release products::

Biopharmaceutics of sutained release products: Drug particles dissolution Drug particles in solution partitioning Drug molecules in tissue fluid absorption Target tissue General circulation elimination

Factors affecting release rate of drug:

Factors affecting release rate of drug Particle size Polymorphism pH of the vehicle Viscosity of the medium: it is effected by Stokes einstein equation D kT / 6πηr Muscular activity

Biocompatibility of polymeric materials::

Biocompatibility of polymeric materials: Biocompatibility of polymeric material is described in terms of: (a)Acute inflammatory response (b)Chronic inflammatory response (c) Senstivity reactions (d)Infections



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After intravascular administration : Thrombus formation occurs Substantially limit the duration of therapy Local vascular constriction and thrombus formation can occur Venos statis Drug being infused into non perfused veins

Test for screening of polymers::

Test for screening of polymers : Platelet adhesion is not a good indicator of haemocompatibility and should not be used as the only test to screen polymers. Mean apparent volume of fibroblasts counted around the sub epidermal implant dependent on the initial surface energy and cleanliness of the implants. A high surface energy has greatest cellular adhesion. One potential method of improving the compatibility of polymers in the blood is to impergenate these polymers with heparin.



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HIGH VISCOSITY PRODUCTS : On increasing the viscosity of the vehicle,diffusion coefficient of the drug will be reduced, thereby delaying drug transfer. Examples: (a) methylcellulose (b) sodium carboxymethylcellulose (c) polyvinylpyrrolidine Delay also occurs if water soluble drug also undergo complexation with these macromolecules. Increasing viscosity of the medium not only decrease molecular diffusion but also localized the injected volume.

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COMPLEX FORMATION Drug action can be prolonged by forming dissociable complex of the drug with macromolecules such as- ethylcellulose , sodiumcarboxymethylcellulose . Complexes can be formed between drug molecules and other small molecules such as caffeine. There is third class of complexes which controls the release of drug not by dissociation but by decreasing solubility of the parent drug.

Aqueous suspensions:

Aqueous suspensions

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Parenteral suspension are dispersed, heterogeneous systems containing insoluble drug particle which, when resuspended in either aqueous or vegetable oil vehicles. They should be sterile, pyrogen free, stable, resuspendable , syringable , injectable , isotonic & non-irritating. Because of above requirements injectable suspensions are one of the most difficult dosage forms to develop in term of their stability, manufacture & usage. The parenteral suspension may be formulated as already to use injection or require a reconstitution step prior to use. They are usually administered by either subcutaneous (SC) or intramuscular route.

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Formation of salt complex with low aqueous solubility In this method aqueous soluble basic or acidic drug can be rendered depot effective by transformation into salts with extremely low aqueous solubility EXAMPLE aqueous suspension of penicillin G procaine. Suspension of micro crystals Adsorption type depot preparation Encapsulation type depot preparation Esterification type depot preparatio n

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Depot penicillin aqueous suspension Microspheres Microcapsules Magnetic microspheres



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It less elegent mechanism to achive parenteral controlled release is through the use of oil solutions. Dynamic equilibrium between drug in the oil phase and that in the aqueous phase with characteristic constant, the apparent partition co-efficient K.         K = drug concentration in oil /drug concentration in water         K = [Do] /[ Dw ] Where the drug concentration in water refers. To both ionized and unionized species of the drug.

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The volume of the oil phase Vo and that of aqueous phase Vw that total amount of drug Dt in the system at any time can be represented by            Dt = [ Dw ] [K Vo + Vw ] The fractional amount of the drug            F =1 (Kα+1)             Where, a = Vo/ Vw (3) Since absorption is driven by concentration, not amount and expression for the fractional concentration of drug that is in the aqueous phase f              f = (1 +a)/(l + Kα )(4)  There limiting cases, Case- I           For α < < 1, one obtains,f  =  1 / (1 + Kα ) Case -2 For α > > 1 one obtains ,f  =  α / (f + Kα )

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The fraction of drug that is available for absorption is controlled by the partition co-efficient and the ratio of the volume of two phase' a. That is remain constant as long as a is constant. Vw is constant since it is physiological parameter. So that the value of α is controlled solely by the volume of solution injected. Drug absorption occurs via the aqueous phase an expression describing the absorption rate {d[c]/ dt } similar to that for the complex formation.                              D [c] / dt = - Ka f' [c] Ka f ' can be obtain from this relationship. Usually an estimate of Ka is available so, that f can be determined. Given value of α, K can be estimated from the rearranged .                             K =[(I -f')/Vo] (f'/ Vw )+1/f 



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Liposomes are hydrated liquid crystals formed when phospholipids are allowed to swell in aqueous media. Advantages: Versatility in terms of size and electrical charge. Ability to encapsulate both lipophillic and hydrophillic drugs. Relative nontoxicity as compared to other carrier system. Ability to protect the labile drug from inactivation in the blood by isolating them from surrounding medium.

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Small unilamellar liposomes were cleared less rapidly than multilamellar ones. Neutral and positively charged unilamellar liposomes were cleared less rapidly than were negatively charged unilamellar ones. Because of their affinity for the phagocytic cells of the liver and spleen,liposomes have been Investigated to target drugs to those phagocytic cells which have been infested with parasites. In spite of their affinity for the reticuloendothelial system, it is possible to maximize the retention of liposomes at sites such as lung by manipulating the size and phospholipid composition of liposomes .

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