PARENTERAL DOSAGE FORMS
Parenteral preparation:
Parenterals preparations are sterile preparations intended for administration under or through one or more layers of skin or mucous membranes.
General requirements:
1. Parenterals preparations should be free from living microbes
2. Parenterals should be free from microbial products such as toxins, pyrogen
3. It should be free from physical contaminants such as particulate matter, fibres
4. It should be matching osmotic qualities with respect to body fluids
5. It should be free from chemical contamination
6. It should be matching specific gravity with respect to some body fluid.
Classifications of parenteral preparations
1. Small volume Parenterals
1. Solutions of medicaments
a) Aqueous
b) Oily
2. Suspensions
3. Emulsions
4. Dry solids to be dissolved in a suitable vehicle before use
5. Dry solids to be suspended in a Suitable vehicle before use.
2. large volume Parenterals
1. Aqueous volume
2. 10% I.V fat emulsion
Advantages and disadvantages of parenterals preparations:
Advantages:
1. Exact dose-can be administered
2. Purity and sterility of the medicament are ensured
3. Stability of the drug is prolonged
4. Numerous incompatibilities are over come
5. Quick therapeutic response of a drug
6. Unconscious and in vomiting patient this route is possible
7. Substances like in-activated or not absorbed by GIT can be administered
8. Physiologic action is localized when desired.
Disadvantages:
1. Painful and un-comfortable
2. Dependent – administered by physician
3. More expensive, more danger than other dosage forms
4. Difficult to correct toxic effect.
Various vehicles used in parenterals.
Pyrogen free water is commonly used as vehicle for injections. Non-aqueous vehicle (Eg: oil) can also be used as vehicle when the medicament is insoluble in water and when a depot effect is desired. Vehicles are three types. They are
1. Aqueous vehicles:
There are three types of aqueous vehicle, namely
a) Water for injection free from pyrogen: If water for injections contains pyrogen, it produces rise in body temperature so pyrogen should be removed.
b) Water for injection free from CO2 : If waters contain Co2, the sodium salt of drugs (Eg-barbiturates and sulphonamides) may decompose and free base is precipitated. So Co2 should be eliminated by boiling water for injection for 10min.
c) Water for injection free from dissolved air: If water contains air, oxidation of the medicaments may take place. So dissolved air should be removed by boiling water for 10 minutes. They are isotonic vehicles Ex: Nacl Inj, lactated ringer’s Inj, Ringer’s Inj, Dextrose and Nacl Inj, Dextrose Inj
2. Water miscible vehicles:
To effect solubility of drug, to reduce hydrolysis
Ex: Ethyl alcohol, Propylene glycol, Polyethylene glycol – 400,600, Glycerine.
3. Non-Aqueous Vehicle:
The non – aqueous vehicles are used when the use of water is contra-indicated in one way or the other. It is used
due to following reasons
1. When the medicament is insoluble or slightly soluble in water
2. To increase the stability of the preparation.
3. To prolong the duration of action of a drug
. These oil should be free from rancid odour and taste. Ex: Fixed oil, Sesame oil, Cotton seed oil, peanut oil.
Fixed oil is used in certain hormone preparations. Propylene glycol is used in injection of phenobarbitone. Non aqueous vehicle should be non-toxic, non-irritating and compatible.
Different additives employed in the formation parenterals preparations.
Additives: Additives are other than the active medicament, added to a preparation to improve the quality of the product. The additives act to prevent the physical, chemical or biological degradation of a product.
Properties: They should be non-toxic, they should be non-irritant, they should be compatible with many ingredients, they should not interfere with the therapeutic effect of the preparations, and they should be physically stable and chemically inert.
Additives are as follows:
1. Vehicles: It is required to dissolve or suspended the medicament. It must meet the special purity and the other standards assuring its safety by injection. They are two types
a) Aqueous Vehicle: Water is used; it should be free from irons and pyrogen, O2 and Co2
b) Non-Aqueous vehicles: Depending on the physical and chemical factor, limit of solubility of hydrolysis of medicament in water, a non-aqueous vehicle is used. Ex: Fixed oil, Propylene glycol.
2. Solubilizers: Purges with poor solubilties may have to be solubilised with the acid of solubilisers or co-solvents. Ex: Propyl glycol or glycerin, tweens, is used as solidifiers to increase the solubility.
3. Anti-oxidants: Anti oxidants are used to protect the active medicament from oxidation. Anti-oxidants act by blocking an oxidative chain reaction. Ex: Sodium Meta bisulphate, Ascorbic acid, Propyl gallate.
4. Chelating agents: The presence of trace of metal ion causes destructive changes in medicaments. The chelating agents produce oxidation or decomposition of medicament. These effects can be prevented by adding a chelating agent. The chelating agent combines with metal ion to form a soluble co-ordination compound and thereby it suppresses the effect of metal ion. Ex: EDTA, Citric acid, ca EDTA.
5. Buffers: Buffers are added to maintain the PH of the products. A change in PH affects the therapeutic effect of the preparation. Change in PH may be due to
a) The dissolution of the glass constituents in the product during storage.
b) Dissolution of gases from the atmosphere.
c) Release of constituents from rubber closure or plastic containers to the product.
Ex: Acetate, citrate and phosphate buffers are commonly used to maintain the PH of the product.
6. Isotonicity contributors: All injections should be made isotonic in order to minimize tissue damage, irritation, to reduce haemolytic of blood cells and to prevent electrolyte imbalance injection are made isotonic by using 0.9% w/v of sterile Nacl.
7. Preservatives: Preservatives are essential in parenterals preparations in order to prevent contamination and to maintain the stability of the preparation. Preservatives may not be included to intravenous injections of large volume.
Ex: Phenol, Cresol, Chlorocresol, Phenyl mercuric nitrate, phenyl mercuric acetate.
Flow chart of the area for the manufacture of sterile products:
| Stock Room |
| Finishing Goods Room |
The production for parenterals is divided into 8 sections:
1. Stock room
2. Clean up area
3. The preparation room
4. Sterilization room
5. Aseptic room
6. Quarantine room
7. Packing and finishing room
8. Finished goods room
Preparation/ formulation of parenterals products:
Aseptic procedure should be followed in preparing the parenterals products. The area where parenterals products are prepared are made bacteria free through the use of ultra-violet light, a filtered air supply, sterile manufacturing equipments such as flasks, connecting tubes and filters and sterilized clothing worn by the personal in the area.
The following steps are involved in the preparation of parenterals preparation:
1. Selection of ingredients
2. Formulation of parenterals products
3. Filtration
4. Filling
5. Sealing
6. Sterilization
1. Selection of ingredients: Vehicles and other additives are carefully selected. They should be compatible with medicament. They should be chemically stable and physiologically inert they should be non-toxic and free from pyrogen.
2. Formulation of parenterals products: The medicament is dissolved or suspended in water for injection or in non-aqueous solvent. Then required ingredients are added to vehicle containing medicament.
3. Filtration: The solution so obtained is passed through bacteria proof filter.
Ex: Sintered glass filter, Sintered glass filters grade No.3&4 having pore size from 25-40 and 5-10 micron respectively are used for filtration by applying positive or negative pressure.
4. Sealing: It should be done immediately as soon as possible to prevent the contamination ampoules are sealed manually or a small scale by melting a portion of glass by melting a portion of glass neck with.
Fire jet of flame: For rapid sealing, a high temperature gas oxygen flame is most suitable a variety of automatic sealing device are available today for making full seal.
The vials and transfusion bottles are sealed by closing its opening with a rubber closer. The rubber closers are held in place by crimping the aluminium caps. The criping is done manually or by
mechanical means.
5. Filling: After filtration, the solution is transferred as rapidly as possible under aseptic conditions. The containers and closures must be properly cleaned, sterilized and made available for use in the process of small scale. Filling is done manually by using hypodermic syringe or needle. A large scale filling is done by automatic filling machine. The sterile powders are filled into containers by weighting or semi-automatic machine.
6. Sterilization: The parenterals products are sterilized immediately after sealing in its final container. The method of
sterilization depends on the nature of medicament. Thermostable medicaments are sterilized either by autoclave at 120OC for 30 minutes or by heating in hot own over at 1600 for 1 hour. Only injections are sterilized by heating in hot air oven and aqueous injections are generally sterilized by autoclaving. Themolabile medicaments are sterilized by non-thermal methods. These are generally sterilized by filtration through bacteria proof filters which contain a suitable Bacteriostatic agent to prevent the growth of micro – organism.
Pyrogen:
1. Pyrogen are metabolic by product of micro-organism. It consists of lipo-poly saccharine. Generally gram negative organisms produce potent pyrogenic substances.
2. Pyrogen are soluble filterable, thermostable and non-volatile
3. When pyrogens injected in human being, they cause chills, fever, headache, backache and discomfort.
4. Major sources of pyrogens are water anti-biotic. Produced by fermentations and equipments.
5. Pyrogens can be destroyed by heating at 1750 C for 3 hours in presence of acids, alkali or oxidising agents.
6. Pyrogens are removed by adsorbent like charcoal, asbestos pad and aluminium hydroxide gel.
Quality control tests on parenterals products:
Quality control test for parenterals products are:-
1. Pyrogen test:
i) Rabbit test: Pyrogen test is performed for all aqueous parenterals preparations. The suitable amount of sample to be tested is injected into the marginal vein of the healthy rabbit. The thermo meter is inserted into the rectum the temperature of the animal as recorded for 3 hours. If the temperature is raised more than 0.6OC above the normal sample fails to pass the test. If there is no rise in temperature the sample passes the test.
ii) Leukocyte count test: The sample to be tested in injected. After several hours, the blood is examined. If the sample contains pyrogens they cause changes in the white cell picture.
Ex: Fall in small lymphocytes and a rise in young neutrophills.
2. Sterility test:
The sterility test is performed as per specification of the drugs and cosmetics act and rules. The entire test is performed aseptically.
a) The sample to be tested is transferred to culture tubes containing a measured volume of a suitable culture medium. Ex: Aerobic medium, Nutrient agar medium, anaerobic medium, Thioglycollate medium.
b) The tubes are plugged with sterilized cotton wool and incubated for 7 days at 30-350C
c) If there is no growth of micro-organisms in the tube, the sample is said to be sterile.
d) If there is any growth of micro-organisms, the test may be repeated third time very carefully.
e) If the second test also shows growth, the test may be repeated third time very carefully.
f) If the third test also shows growth, then the sample is said to be contaminated and the whole preparation is to be discarded.
3. Leaker test:
Ampoules which have been sealed by fusion to ensure that there should not be any leakage in them. It is intended to defect incompletely sealed ampoules.
Method:
Sealed ampoules are dipped in coloured dye (methylene blue 1%) solution and vacuum (-ve pressure) is produced for 15minutes. When vacuum is released the coloured solution will enter inside ampoules. Defective ampoules will contain coloured solution (blue).
4. Clarity test:
The presence of any solid particles in injections causes serious effect. The contents of the containers are inverted, rotated and the solution is examined in front of strongly illuminated light for the presence of dust or any foreign particles. If any particles are visible, the sample is rejected.
5. Assay:
Quantitative estimation is done to check the stated quantity of medicament present in the parenterals preparation. It is done according to method prescribed in monograph mentioned in the pharmacopoeia.
Total parenterals nutrition (TPN):
Large amounts of nutrients (Eg. Proteins, amino acids, carbohydrates vitamins) are administered intravenously to a patient who is unable to take food orally so as to maintain the patients for a period up to several months without any major deterioration in their physical conditions.
Method of administration: Total parenterals nutrition involves continuous administration of the nutrient solution into the superior venacava by means of an indwelling catheter.
Contents of total parenterals nutrition: It contains
Glucose -20%
Fibrin hydrolysate -5%
Amino acid
Vitamins
Mineral
Electrolytes
Traces of elements like Zn, cu
Uses: Total parenterals nutrition is used as life saving or sustaining nutrients. It is used to comatose patients undergoing treatment for esophageal obstruction, GIT diseases (including cancer, ulcerative colitis, hepatic failure, renal failure and burns.
Dialysis fluids:
Dialysis fluids are sterile solutions used to remove toxic substances and excessive body waste and serum electrolyte and thereby make the excretory function of the kidney to normal.
Composition of dialysis fluids: Dialysis fluids contain 1.5% to 4.5% dextrose with any one or more additives namely tetracycline’s heparin and Kcl dialysis fluids are made hypertonic to plasma with Nacl in order to avoid absorption of water into the intravascular compartment.
Types of dialysis fluids:
1. Peritoneal dialysis solutions:
1. Peritoneal dialysis solutions are administered directly into the peritoneal cavity. This solution is permitted to flow into the abdominal cavity (peritoneal cavity) continuously and it remains in the cavity for 30-90min. afterwards it is drained by a siphon. This procedure is repeated many times.
2. A patient may require 30-50 litre solution for daily treatment.
3. Peritoneal dialysis solution is used to remove toxic substances. Excessive body waste and serum electrolytes from the blood and thereby allow the kidneys to regain their excretory function normal.
2. Haemodialysis solution:
1. In haemodialysis, dialyzing machine acts as an artificial kidney is used. In the dialyzing machine, dialyzing membrane and dialysis fluids are present.
2. Through a cannula, the blood from the artery entered into the dialyzing machine. The toxic substances and other body waste from the blood diffuse into the dialyzing fluid through the dialyzing membrane. The required substances (electrolytes) present in the dialyzing fluid are transfused into the blood through the dialysis membrane by the process of osmosis. Thus toxic substances and other body wastes are removed from blood. Through other cannula, the purified blood enters into the vein.
3. Haemodialysis solution is used to remove toxic substances and other body wastes from the blood and thereby allow the kidneys to regain their excretory function normal.
3. Isotonic solutions:
1. To minimise tissue damage and irritation, to reduce haemolysis of blood cells and to prevent electrolyte imbalance, all injections should be made isotonic.
2. Solutions having same osmotic pressure as that of blood plasma are said to be isotonic.
3. Solutions having lower osmotic pressure than that of blood plasma is said to be hypotonic.
4. Solutions having higher osmotic pressure than that of blood plasma is said to be hypertonic.
5. Both hypotonic and hypertonic is said to be paratonic.
6. When hypotonic solutions are injected, they cause haemolysis. When hypotonic solutions are injected, they cause shrinkage of cells.
7. Hence isotonicity is essential for injections. Solutions are made isotonic by using 0.9 % w/v of sterile sodium chloride solution.
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