Parenteral drug delivery-INSULIN SEMINAR

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Parenteral controlled drug delivery system

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A SEMINAR ON PARENTERAL DRUG DELIVERY SYSTEMS :

A SEMINAR ON PARENTERAL DRUG DELIVERY SYSTEMS KRISHNAVENI.K.A I.M.PHARM PHARMACEUTICS PERIYAR COLLEGE OF PHARMACUTICAL SCIENCES TRICHY-21

INTRODUCTION:

INTRODUCTION In mucosal and transdermal drug delivery , in which the systemic bioavailability of a drug is always limited by its permeation barrier. In oral drug delivery , in which the systemic bioavailability of a drug is often subjected to variation in gastrointestinal transit and biotransformation in the liver by “first-pass” metabolism In Parenteral drug delivery , especially intravenous injection, can gain easy access to the systemic circulation with complete drug absorption and therefore reach the site of drug action.

SUMMARY:

INTRODUCTION CONTINUOUS IV INFUSION DEPOT TYPE PRINCIPLE RATE OF DRUG ABSORPTION ADVANTAGE INJECTABLE DRUG DELIVERY APPROCHES DEVELOPMENTS SUMMARY

CONTINUOUS IV INFUSION:

CONTINUOUS IV INFUSION ADVANTAGE: It is a superior mode of systemic drug delivery system Maintain a constant and sustained drug level within a therapeutic concentration range for as long as required for effective treatment. It also provides a means of direct entry into the systemic circulation for drugs that are subjected to hepatic first-pass metabolism and/or suspected of producing gastrointestinal incompatibility.

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DISADVANTAGE: Entails certain health hazards and therefore necessitates continuous hospitalization during treatment and requires close medical supervision. Insulin that is not properly injected into the subcutaneous region, where the normal absorption of insulin can take place, may be come temporarily trapped, resulting in areas of lumpiness or swelling The lumpiness also tends to occur when injections are given in the same region for several days, resulting in adverse insulin reaction.

DEPOT TYPE PARENTERAL CONTROLLED RELEASE FORMULATION:

DEPOT TYPE PARENTERAL CONTROLLED RELEASE FORMULATION To duplicate the benefits of intravenous drug infusion without its potential hazards , the development of DEPOT TYPE PARENTERAL CONTROLLED RELEASE FORMULATIONS has been invested. These developmental efforts have generated a number of injectable depot formulation. Example : Penicillin G- procaine suspension Cynocobalamin-Zn- tannate suspension Medroxyprogesterone acetate suspension Adenocorticotropin - Zn- tannate suspension Insulin zinc suspension, etc

PRINCIPLE:

PRINCIPLE Parenteral administration of a drug in depot formulation, which is an aqueous or oleaginous suspension or an oleaginous solution, into subcutaneous or muscular tissue results in formation of depot at the site of injection. This depot acts as a drug reservoir that releases the drug molecules continuously at a rate determined to a large extent by the characteristics of the formulation.

RATE OF DRUG ABSORPTION:

RATE OF DRUG ABSORPTION Rate of drug absorption and duration of therapeutic activity depends on, Nature of the vehicle, either aqueous or oleaginous, used in the formulation Physicochemical characteristics of the drug (or its derivatives). The interactions of the drug with vehicle and tissue fluid

ADVANTAGE:

ADVANTAGE The sustained or controlled release of the drugs from Parenteral depot formulations reduces the inherent disadvantages of conventional “immediate release” Parenteral dosage form. Relatively constant and substantially sustained therapeutic drug level with a reduction in the frequency of injection . Reduced drug dosing Decreased side effects Enhanced patient compliance Improved drug utilization.

INJECTABLE DRUG DELIVERY :

INJECTABLE DRUG DELIVERY APPROACHES Use of viscous, water-miscible vehicles , such as aqueous solution of gelatin or polyvinylpyrrolidone Utilization of water-immiscible vehicles , such as vegetable oils, plus water repelling agents such as aluminum monostearate. Formation of thixotropic suspension. Preparation of water-insoluble drug derivatives such as salts, complexes and esters. Dispersion in polymeric microspheres or microcapsules such as lactide-glycolide homopolymers or copolymers. Coadministration of vasoconstriction .

DEPOT FORMULATIONS:

DEPOT FORMULATIONS They may classified on the basis of the process used for controlled drug release as follows. Dissolution-Controlled Depot Formulations Adsorption-type Preparations Encapsulation-type Preparations Esterification-type Preparations

DISSOLUTION-CONTROLLED DEPOT FORMULATION:

DISSOLUTION-CONTROLLED DEPOT FORMULATION In the depot formulation the rate of drug absorption is controlled by the slow dissolution of drug particles in the formulation or in the tissue fluid surrounding the formulation. The rate of dissolution under sink conditions is defined by, Q S a D s C s t d h d where S a – surface area of the drug particles in contact with the medium, D s - diffusion coefficient of drug molecules in the medium, C s - saturation solubility of the drug in the medium h d - thickness of the hydrodynamic diffusion layer surrounding each drug particle.

APPROACHES:

APPROACHES Basically, two approaches can be utilized to control the dissolution of drug particle to prolong the absorption and hence the therapeutic activity of the drug Formation of Salt or Complexes with Low Aqueous Solubility Suspension of Macrocrystals

FORMATION OF SALTS OR COMPLEXES WITH LOW AQUEOUS SOLUBILITY:

FORMATION OF SALTS 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. Examples: Preparations of Penicillin G procaine (C s =0.2mg/ml) and Penicillin G benzathine (C s =4mg/ml) from the highly water-soluble alkali salts of Penicillin G Preparations of Naloxone pamoate and Naltrexone -Zn-tannate from the water-soluble hydrochloride salts of Naloxone and Naltrexone

SUSPENSION OF MACROCRYSTALS:

SUSPENSION OF MACROCRYSTALS Large crystals are known to dissolve more slowly than small crystals. This is called the macrocrystal principle This is applied to control the rate of drug dissolution. Example: Aqueous suspension of Testosterone isobutyrate for intramuscular administration Diethylstilbestrol monocrystals for subcutaneous injection

ADSORPTION-TYPE DEPOT PREPARATION:

ADSORPTION-TYPE DEPOT PREPARATION This depot preparation is formed by the binding of drug molecules to adsorbents. Here only unbound, free species of the drug is available for absorption. As soon as the unbound drug molecules are absorbed a fraction of the bound drug molecules is released to maintain equilibrium. The equilibrium concentration of free, unbound drug species (C) f is determined by the Langmuir relationship, (C) f 1 (C) f (C) b a(C) b,m (C) b,m where, (C) b – amount of drug(mg) adsorbed by 1g adsorbent (C) b,m – maximum amount of drug(mg) adsorbed by 1g adsorbent Linearity is obtained by slope value from the graph plotting (C) f /(C) b versus (C) f and a is a constant and can be determined from the intercept and (C) b,m Eg ., Vaccine preparations in which the antigens are bound to highly dispersed aluminum hydroxide gel to sustain their release and hence prolonged the duration of stimulation of antibody formation.

ENCAPSULATION-TYPE DEPOT PREPARATION:

ENCAPSULATION-TYPE DEPOT PREPARATION This depot preparation is prepared by encapsulating drug solids within a permeation barrier or dispersing drug particles in a diffusion matrix , both are fabricated from biodegradable macromolecules such as gelatin, dextran, polylactate, lactide-glycolide copolymers, phospholipids and long-chain fatty acids and glycerides. E.g., Naltrexone pamoate-releasing biodegradable microcapsules, liposomes and norethindrone-releasing biodegradable lactide-glycolide copolymer beads.

ESTERIFICATION-TYPE DEPOT PREPARATIONS:

ESTERIFICATION-TYPE DEPOT PREPARATIONS The depot preparation is produced by esterifying a drug to form a bioconvertible prodrug-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, Nandrolone decanoate in oleaginous solution

DEVELOPMENT OF INJECTABLE CONTROLLED-RELEASE FORMULATION:

DEVELOPMENT OF INJECTABLE CONTROLLED-RELEASE FORMULATION Long-acting Penicillin Preparation Long-acting Insulin Preparation Long-acting Steroid Preparation Long-acting Contraceptive Preparation Long-acting Vitamin B Preparation Long-acting Adrenocorticotropic hormones Preparation Long-acting Antipsychotic Preparation

LONG-ACTING INSULIN PREPARATION:

LONG-ACTING INSULIN PREPARATION SUMMARY INTRODUCTION DIABETIS MELLITUS HUMAN INSULIN HUMAN STRUCTURE BIOSYNTHESIS PREPARATION OF INSULIN LONG ACTING INSULIN PREPARATION EXAMPLE STORAGE

INTRODUCTION:

INTRODUCTION WHO, May-June, 1991 says there are more than 50 million peoples in the world who suffer from diabetes . Clinically they need regular administration of exogenous insulin for the control of their HYPERGLYCEMIA. Insulin is the primary hormone which is responsible for controlling the storage and utilization of cellular nutrients. Insulin works by regulating the absorption and storage of glycogen (blood glucose) in the cells of the liver, fat tissue and muscle, and by accelerating the oxidation of sugar in cells. Some people suffer from conditions like diabetes or insulinoma in which they cannot produce this hormone naturally and must rely on synthetic insulin preparations Insulin inhibits catabolic processes such as the breakdown of glycogen, fat and protein, whereas the overall effect of insulin is hypoglycaemia.

DIABETES MELLITUS:

DIABETES MELLITUS Deficiency of effective insulin in the body causes a disease called Diabetes mellitus (meaning in Greek is excessive thirst) which alters the metabolism of lipids, carbohydrates and proteins. This results in hypoglycaemia and glycosuria . Clinically diabetes mellitus occurs in 2 forms Type I (insulin dependent DM) , this condition occurs when the beta cells of the pancreatic islets of langerhans are destroyed, such that insulin production is deficient Type II (non-insulin dependent diabetes mellitus) , this is frequently associated with obesity; serum insulin level will be normal or elevated.

HUMAN INSULIN:

HUMAN INSULIN Insulin consists of two peptide chains A and B , which are connected by two disulphide bonds. The chain A composed of 21 amino acids and has one intra chain disulphide bonds; the chain B has 30 amino acids.

INSULIN STRUCTURE:

INSULIN STRUCTURE

BIOSYNTHESIS OF INSULIN:

BIOSYNTHESIS OF INSULIN Insulin is synthesized by the beta-cells of islets of Langerhans of the Pancreas (named after Paul Langerhans) from a precursor Proinsulin. Once the food enters the body, it immediately detected and the insulin mRNA is translated as a single chain precursor called Preproinsulin in the pancreas. By the removal of its single peptide during insertion into the endoplasmic reticulum, Proinsulin is generated. Proinsulin in order to eventually make the insulin hormone Preproinsulin Proinsulin Insulin

ANIMAL AND HUMAN INSULIN:

ANIMAL AND HUMAN INSULIN SPECIES CHAIN A – 8 CHAIN A-10 CHAIN B-30 HUMAN Thr Ile Thr Porcine Thr Ile Ala Bovine Ala Val ala

PREPARATION OF INSULINS:

PREPARATION OF INSULINS Insulin types usually fall into one of four categories based on their commonly reported actions: short-acting insulin, rapid-acting analogs, intermediate-acting insulin and long-acting analogs. Doctors typically base their choice of insulin on the time course desired for the level of the illness under treatment. Factors that contribute to the choice of insulin include length of time to the onset of medication and the effective duration of medication.

LONG ACTING INSULIN PREPARATION:

LONG ACTING INSULIN PREPARATION Protamine - insulin complex Protamine – Zn – insulin complex Isophane insulin suspension USP Globin – Zn – insulin injection USP Ultra- lente insulin Semilente insulin Lente insulin

PROTAMINE INSULIN COMPLEX:

PROTAMINE INSULIN COMPLEX The prolongation of insulin’s activity was made by complexing insulin with protamine. It is a water soluble, strongly basic simple protein isolated from the sperm or the mature testes of fish. This protamine insulin complex has an isoelectric point at pH 7.3 and therefore relatively insoluble in tissues fluids at physiological pH When injected subcutaneously it slowly releases the insulin for a prolonged period of time( up to 24hr .)

PROTAMINE–ZN–INSULIN COMPLEX:

PROTAMINE–ZN–INSULIN COMPLEX When injected into the loose subcutaneous tissue the protamine-Zn-insulin suspension provides a prolonged normoglycemic activity for over 36hr . Demerits : The protamine-Zn-insulin preparation has a slow onset of action and the normoglycemic action of insulin is not usually evident until 6-8 hr after administration and takes 14-20 hr to reach its peak level.

ISOPHANE INSULIN SUSPENSION USP:

ISOPHANE INSULIN SUSPENSION USP Similar to protamine-Zn-insulin but fairly rapid onset (1-1.5 hr) and moderate duration of activity (24 hr) It is also know as NPH; Neutral pH Protamine Hegedron (the developer of the product), adding neutral protamine (nuclear proteins) to regular human insulin in order to decrease the amount of injections required to control food-related blood sugar levels. This type of insulin is administered by subcutaneous injection or by a prefilled pen device. NPH insulin begins to work in 2-4 hours and is most effective for 10 to 16 hours. Its maximum duration is 14 to 18 hours.

GLOBIN-ZN-INSULIN INJECTION USP:

GLOBIN-ZN-INSULIN INJECTION USP It is a typical example of a protein-Zn-insulin complex prepared from zinc chloride and globin, a conjugated protein isolated from beef blood. It provides an insulin release pattern, in term of the onset and duration of action, similar to that of Isophane insulin suspension USP.

ULTRA-LENTE INSULIN:

ULTRA-LENTE INSULIN Depending upon the pH of the solution, it may precipitate as an amorphous or a crystalline solid. Insulin crystals (10-40um with a high zinc content) can be precipitated from acetate buffer at pH 5-6. This crystalline insulin-zinc complex is absorbed very slowly has a prolonged normoglycemic activity. After subcutaneous injection of these Zn-insulin crystals as a suspension in buffer (pH 7.3), the insulin is slowly released and absorbed (4-8hr to the onset of action) and retains its activity for more than 36hr.

SEMILENTE INSULIN:

SEMILENTE INSULIN The amorphous Zn-insulin complex precipitated at a higher pH (pH 6-8) This amorphous insulin has a low zinc content and is absorbed more readily and achieves a duration of action shorter than that of Ultralente suspension. When administered subcutaneously the insulin in the amorphous Zn-insulin suspension (with a particle size <2um) is quickly released and absorbed with onset of action within 1hr and has a shorter duration of normoglycemic activity (12-16 hr)

TYPES OF DM PATIENTS:

TYPES OF DM PATIENTS Patients can be classified according to the promptness of their response to an insulin injection as Fast Medium Slow reaction types These three types of diabetic patients responds very differently to the same kind of insulin preparation. The blood glucose response of a diabetic patients also depends upon the activity range of the insulin preparation used. Clinical studies say, Fast reaction patients need a relatively slow-acting insulin preparation to maintain the blood glucose level within the range of 100-200mg/dl Slow-reaction patients requires a relatively fast-acting insulin preparation

LENTE INSULIN:

LENTE INSULIN One of the advantages is that the Ultralente and Semilente insulin preparations are mutually miscible and because of this a range of activity can be formulated. A typical combination is Lente insulin which consists of 7parts of crystalline and 3parts of amorphous insulin-zinc complexes . It provides an intermediate-acting form of insulin. Its effect is evident in approximately 1-1.5 hr, reaches its peak level within 8-12 hr, and has a duration of action of 24 hr

NORMOGLYCEMIC ACTIVITY AND DURATION OF SOME COMMERCIAL INSULIN PREPARATION:

NORMOGLYCEMIC ACTIVITY AND DURATION OF SOME COMMERCIAL INSULIN PREPARATION INSLIN PREPARATION ONSET (hr) PEAK (hr) DURATION (hr) Insulin injection, USP 0.5-1.0 2-3 4-8 Insulin-zinc complex Semilente insulin 0.5-1.0 5-7 12-16 Lente insulin 1.0-1.5 8-12 24 Ultralente insulin 4.0-8.0 16-18 >36 Insulin- Zn-protein complex Globin- Zn-insulin injection, USP 2.0 8-16 24 Isophane insulin suspension, USP 1.0-1.5 8-12 24 Protamine – zn insulin suspension, USP 4.0-8.0 14-20 36

STORAGE CONDITION:

STORAGE CONDITION Insulin in powder form should be stored in airtight containers protected from light. Storage at low temperature is also recommended. The injection is required to be stored in the refrigerator at 2  and 8  and not to be allowed to freeze.

MARKETED PRODUCT:

MARKETED PRODUCT

EXAMPLES:

EXAMPLES

REFERENCES::

REFERENCES: NOVEL DRUG DELIVERY SYSTEM BY Y.W.CHIEN, MARCEL DEKKER , INC MEDICINAL CHEMISTRY-II BY ILANGOVAN

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