PARENTERAL DOSAGE FORMS
Parenterals 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 parenterals
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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