Parenteral dosage form

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Presentation Transcript

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Sterile products are dosage forms of therapeutic agents that are free of viable microorganism Principally these include parenteral, opthalmic

Parenteral products : 

Parenteral products Derived from Greek words Para – Beside Enteron – Intestine So parenteral administration includes the administration of drugs by any route other than intestine. Definition:- in pharmaceutical practice however parenteral products are considered to be the sterile drugs,solutions,suspension or emulsions that are administrated by hypodermic injection either in the form in which they are supplied or after the adition of suitable solvent or suspending agent. These are unique among dosage forms of drugs because they are injected through skin or mucus membrane into the body compartments.

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The parenteral products by passes the 1st line of body defence , the skin and mucus membrane they must be free from Toxic components Microbial contamination High level of purity All component and process involved in the preparation of these products must be Selected and designed to eliminate as much as possible contamination of all types whether of physical, chemical or microbial origin.

The steps to be given important : 

The steps to be given important The organizational divisions normally responsible for the preparation of sterile products in the pharmaceutical industry are Product development production Control Packaging

Product development : 

Product development Formulation goals: Adequate conc. of the drug at the site of action IV route – absence of absorption I.V. – adequate solubility, minimize probability of precipitation at site of injection I.M. and S.C. – absorption from the site of injection

Active drug : 

Active drug Thorough evaluation of properties of active drug/s is highly essential for safe and stable dosage form Solubility and rate of absorption. Aqueous solubility of the drug for dissolution Physical state of the drug – crystalline /amorphous, particle size, formulation pH

Chemical modification of the drug : 

Chemical modification of the drug Improvement of the properties of the drug may be achieved by the chemical modification of the parent drug Preparation of ester, salt, or other modification may be employed to increase stability, alter solubility, enhance depot action, avoid formulation difficulties, decrease pain on injection Prodrug – modified drug converts back into the active parent structure – in body system or after reconstitution Antibiotic prodrugs – benzathine penicillin, procaine penicillin, metronidazole phosphate, chloramphenicol sodium succinate Steroids- methyl prednisolone formulated as methyl prednisolone sodium succinate, hydrocortisone as hydrocortisone sodium succinate

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a drug is prepared for parenteral use by the mfg. depend on :- The physical & chemical properties of the drug Therapeutic consideration If a drug is unstable in solution it may be prepared as prepared as suspension of drug particle Dry powder intended for reconstitution with the proper solvent at the time of administration. If a drug is unstable in presence of waterthatsolvent may be replaced in part or totally by a solvent in which the drug is insoluble. If a drug is insoluble in water prepared a s an :- Aqueous suspension Solution of drug in an suitable non aqueous solvent The onset & duration of a drug is increased by:- Chemical form of the drug used Physical state of injection (solution or suspension) vehicle employed

Added substances (excipients) : 

Added substances (excipients) Purpose: Provide safe and efficacious parenteral product Stability Control product attributes Ensure sterility Aid in parenteral administration Every attempt should be made to choose added substances that are accepted by regulatory agencies.

Types of excipients : 

Types of excipients Antioxidants Antimicrobial agents Buffers Chelating agents Inert gases Solubilizing agents Tonicity contributors

Selection of excipients : 

Selection of excipients Addition of any additive should have a clear purpose /function/ justification Meet the regulatory requirements all over the world since most pharmaceutical development is international in scope Most formulators continue to depend on materials already being used in marketed products because extensive pharmacological and toxicological data is required to obtain approval for any new additive

Antioxidants : 

Antioxidants Salts of sulphur dioxide, including bisulphite, metabisulphite, and sulphite are commonly used. The antioxidants mainly function in 2 ways:- By oxidised itself(acting as reducing agent). By blocking an oxidative chain reaction . Certain antioxidants act as synergistic which increases the effectiveness of other antioxidants particularly those blocking reactions. Certain other group are there which form complex with catalyst and acclerate the reaction. On oxidation sulphites may be converted to sulphates and other species Sulphites can also react with drugs like epinephrine Sulphites reported to cause allergic reactions in some asthmatics. Alternatives may be considered

Preservatives : 

Preservatives Used in Multidose containers and Single dose products that are not terminally sterilized. Used to inhibit the growth of microorganism. the formulation scientist must be aware of Interactions between preservatives and other components . Proteins can bind with thimersol reducing the efficacy Benzalkonium chloride which is positively charged are incompatible with products containing anionic drugs and excipient. Partitioning into a micellar phase or an oil phase in an emulsion can reduce the effective concentration of preservative Preservative efficacy testing be done on proposed formulation to assure on effective preservative concentration. Rubber closures and other containers used are incompatible with preservatives

Buffers : 

Buffers Many drugs requires a certain pH range to maintain product stability. Drug stability also depend on pH Parenteral products formulated to possess sufficient buffer capacity to maintain proper pH Factors influencing pH include: Product degradation Diffusion of gases through the closure Effect of gases in the product Weak base and salt of a weak base or weak acid and salt of a weak acid are normally used Eg:-Acetates, citrates, phosphates Amino acid are increasingly used for polypeptide injectable.

Chelating agents : 

Chelating agents Form complexes and inactivate metals such as copper, iron and zinc that catalyze oxidative degradation of drug molecules Sources of metal contamination: Raw material impurities Solvents such as water Rubber stoppers Containers and Equipment Most commonly used are Edetate disodium , citric acid and tartaric acid

Inert gases : 

Inert gases The air within an injectable product is frequently replaced with an inert gas such as nitrogen to enhance the stability of the product by preventing chemical reaction between the oxygen in the air and the drug. Butyl rubber stock is used with rubber stoppered products that are sensitive to oxygen because It provides better resistance to gas permeation than other rubber stocks.

Tonicity adjustment agents : 

Tonicity adjustment agents IV solutions isotonic must be required. Hypotonic causes haemolysis of RBC Hypertonic causes crenation Dextrose, Sod. Chloride, pot. Chloride are commonly used to adjust isotonicity

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C. Vehicles : 

C. Vehicles Water for injection:- Contains not more 1 mg per 100 ml water for injection. Not require to sterile but must be pyrogen free. Free from ions Must be useeeeeed within preparation of 2 hours. Sterile water for injection:- Sterilized & sitabely packaged in a closed container not exceeding 1000 ml capacity.& not containing bacteriostatic agent. Free from pyrogen & used inn the vials to prepare the desired injection. Bacteriostatic water for Injection:- A sterile water of injection containing one or more bacteriostatic agent. Boiling of water makes it free from atmospheric gases & such water should be stored suitably so that reabsorption of oxygen should not be possible. It is packaged in prefilled syringes or in vials containing not more than 30 ml of vials. The water is employedb as a sterile vehicle in the preparation of small volume of injectable preparation. Theoritically presence of bacteriostatic agent gives theflexibility of multiple dose vials.

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In addition to water some co-solvents are used to replace portion of water in certain formulation. These co-solvents must be used either to increase the solubility of drug or to reduce its hydrolytic degradation. commonly used water miscible solvents are ethyl alcohol,Glycerine,PPG,PEG and Dimethyl acetamide

Nonaqueous vehicles : 

Nonaqueous vehicles WHY NON AQUEOUS VEHICLE? Water precluded in a formulation due to limited water solubility of medicinal substance or susceptible to hydrolysis. The solvent must be nonirrigating,Non-toxic and mustnt exert pharmacological activity of its own. Physical & chemical properties of solvent must be considered. Other consideration are :- Viscosity-which allow ease of injection(syrengebility) Fluidity-must be maintained over a wide range of tempreature boiling point– high to permit heat of sterilization Imiscibility-- with the body fluid Purity and Standarddisation No single solvent free o f limitation. Mainly fixed vegetable oils are used Restriction of Fixed oil:- Must remain vclear when cooled to 10 celsius to ensure stability and clarity or injectable product upon storage under refrigereation. Oils mustnt contain mineral oil such as paraffin as these materials are not absorbed by body tissue. Must meet official requirement of saponification value & Iodine value.

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Vegetable oil:- Toxicity is less but some persons show allergic reaction so the label state the specific oil present. Most commonly used are corn oil, cottonseed oil,peanut oil,sesam oil.castor oil, and olive oil. oleagenous injections are given I.m but not I.V because the oil globules will occlude the pulmonary circulation.

D. Types of parenteral dosage forms : 

D. Types of parenteral dosage forms Solutions Suspensions Emulsions Dry powders Protein formulation Novel formulation

Solutions : 

Solutions Most injectables are solution. Solution of drugs suitable for parenteral administration are refered as injection. According to USP injections are separated into [Drug] Injection Eg:- Insulin [Drug] for Injection Eg:-Cefamandole sodium [Drug] injectable emulsion Eg:- Propofol [Drug] injectble suspension Eg:-Methyl prednisolone acet [Drug] for Injectable suspension Eg:-Imipenem Dissolve the drug, excipients, adjust pH, sterile filter through 0.22micron membrane filter PROCESS:- Mix all ingredients ? Filter all the resultant solution in 0.22 µm membrane filter ? If possible autoclave the final product

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Sterile filtration with subsequent aseptic filling is common because of heat sensitivity of many drugs LVPs and SVPs with no preservatives should be terminally sterilized The formulator must be aware of the potential for binding when filtering protein solutions

Dry powders : 

Dry powders Many drugs are too unstable either physically or chemically in an aqueous medium to allow formulation as a solution,suspension or emulsion. Instead, the drug is formulated as a dry powder that is reconstituted by addition of water before administration. The reconstitution product is usually an aqueous solution but occasion it may be aqueous suspension. Eg:-Ampicillin Trihydrate Freeze drying is the most common form of sterile water.

Suspensions : 

Suspensions Solid content ranges from 0.5 to 5%. But may goes as high as to 30% in some antibiotic preparation. Easy resuspendability, Passage through 18-21 gauge needle To achieve this: Proper particle size distribution It is very important because of Drug release predictable rate of dissolution Uniform rate of sedementation Various technique used for this purpose are Micropulverization Spray drying Fluid energy grinding Dry milling

Main problems associated : 

Main problems associated Solid granules forms cake Surface active agent may reduce the interfacial tension between particle and vehicle Eg:-Polysorbate 80,lecithin,emulphor EL-620 Hydrocolloid like sodium CMC increases the effect of surfectant Stability sometime increase by increasing viscosity:- By adding some amount of protective colloid By adding compound such as sorbitol. Syringeability– Related to viscosity Injectability – pressure required to inject, Syringeability and injectability are related to viscosity and particle characteristics that is amount of solid.

Emulsions : 

Emulsions The main problem is attainment and maintaince of uniform oil droplets of 1-5µ size as internal phase. The important aspect is selection of emulgent. The emulsion must be stable to autoclaving. Elevated tempreature tend to produce coalscence of dispersed phase & excessive shaking cause accleration of rate of creaming. Small amount of gelatin,dextran & microcrystalline cellulose added to stabilize the emulsion. Preparation of parenteral emulsion is troublesome becoz of control of particle size control to prevent emboli in blood vessel by the limited choice of emulsifier and stabilizer of low toxicity & difficult to prevent the rancidity of oil phase.

Novel Formulation : 

Novel Formulation Used to prepare sustained & control release formulation. Carrier system like microsphere,liposomes,monoclonal antibodies & emulsions are used. Drugs are incorporated into these system to increase the duration of action & to provide selective delivery of the drug to a specific site or organ. Unwanted side effects & adverse reaction are reduced Because of selective delivery.

Protein formulations : 

Protein formulations The first biotech derived is human insulin approved by FDA. Special problems with formulation and processing of proteins arise from the hierarchy of structural organization of proteins In addition to primary structure, proteins have secondary structure , tertiary structure and in some cases quaternary structure and disruption of this higher order structure can lead to loss of biological active and leads to exposure of hydrophobic amino acid residue which cause problem in manufacturing process or in primary package. Disruption of the higher order structure can lead to loss of biologically active or native conformation which may also cause physical and chemical instability Suitable aspects of mfg. is important in protein preparation:- Vigorous agitation causes foaming & air water interface which is excellent site for denaturaion & precipitation. Loss of protein byadsorption tosurfaces when filter used in Mfg. process. Maintaince of St. during process like temp., solvent

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Stabilization strategies include:- Addition of additives such as other proteins (serum albumin), amino acids, and surfactants to minimize adsorption to surfaces Modification of protein structure to enhance stability by genetic engineering methods Chemical modification of protein such as formation of a conjugate with PEG