AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER

LARGE VOLUME PARENTERALS

 

* Para-other than ; enteron-intestine(1)

* According to I.P “parenterals are injectable preparations, sterile products intended for administration by injection, infusion or implantation in to the body.”(2)

* Parenterals should be free of physical, chemical and biological contamination. With the development in the field of bio-technology there is a development in the number of drugs administered parenterally.(1) parenteral route is the best, when oral route is not suitable.(3)

* In the middle of 19th century,the hypodermic needles came into the scenario.(3)

ROUTES OF ADMINISTRATION: (3)
They are:
* Intravenous
* Intramuscular
* Subcutaneous
* Intradermal
* Epidural
* Intra-articular
* Intrathecal

NOTE:
* We should not use preservatives in the parenteral formulations which create toxicity in the body.(3 )
* Port devices are used to deliver the drug in case of intravenous and intraarterial drugs whereas needle and syringe are used to deliver drugs in case of sub-cutaneous ,intramuscular and intradermal preparations(3).
* Colouring agents should not be used in parenteral preparations.(3)
* Basilica and cephalic veins are the main targets for insertion of peripheral infusions.(3)

TYPES

Based on the volume they are classified as:
SMALL VOLUME PARENTERALS(INJECTIONS):
These are supplied in single or multiple doses. The volume is generally less than or equal to 100 ml.(3)

LARGE VOLUME PARENTERALS: These are supplied for single dosE having more than 100 ml. These are delivered through IV route. These generally provide electrolytes, nutrition to the body.(3)

Generally small volume parenterals are used to dispense most of the drugs.

CLASSIFICATION (3)

* DRUG INJECTION: It is a liquid preparation consisting of drug.

* DRUG FOR INJECTION: The drug is present in the form of powder and solvent is added to form solution that have the properties of injection.

* DRUG INJECTABLE SUSPENSIONS: As the name suggests, the drug particles are suspended in suitable vehicle.

IDEAL PROPERTIES OF PARENTERALS (1)
* Every ingredient must be free from micro-organisms and pyrogenic materials.
* Almost all the parenterals should be isotonic with body fluids, and other parenterals should be near to isotonicity.

FORMULATION:
Parenterals will be dispensed in several forms including solutions, suspensions, emulsions, nanosystems and powders (which are made in to injection by addition of solvent.) (1)

VEHICLES:
WATER FOR INJECTION:
No material is added and water is treated by distillation or reverse osmosis. It has no smell and color. (1)

BACTERIOSTATIC WATER FOR INJECTION: Addition of 1 or 2 antimicrobial agents to water for injection results in bacteriostatic water for injection. Make sure that the anti microbial agent is compatible with the API which will be added in future. (1)

WATER FOR PARENTERALS:
Is is simply water for injection which is sterilized without having antimicrobial agent.it is used as a vehicle for all the aqueous parenterals. (1)
STERILE WATER FOR INJECTION:
It is also water for injection, which is sterilized and doesnot contain any anti microbial agent or any other substance. As the parenteral preparations are dilute vehicle occupies the larger part in parenteral preparation. (1)
WATER MISCIBLE VEHICLE: As name suggest, this occupies some part of the vehicle and it helps in decreasing hydrolysis and to solubulise some drugs. Ex: Ethyl alcohol, Propylene glycol. (1)
NON AQUEOUS VEHICLES:Generally fixed oils are used as non aqueous vehicles. According to USP vegetable oils should be used as they can metabolise and they will remain in liquid state at room conditions. Ex: Corn oil, Peanut oil, Cotton seed oil. These are used for harmone and vitamin preparations. (1)

ACTIVE INGREDIENTS
Other excipients should be pure enough to dispense them as parenterals. The non pyrogenic materials increase it’s characteristics by the end of process. Chemically the drug molecule should be pure and the microbes, endotoxins should be within the limits. Even the trace amount of impurities cause instability. (1)
ADDED SUBSTANCES:
These include the substances that safeguard the purity of the formulation. (1)
COMPLEXING AGENTS AND SURFACTANTS:
They enhance the solubility of the drugs. Ex: Cyclo dextrins, Tween twenty and Tween eighty are complexing agents and Surfactants respectively.
Tonicity adjusters make the preparation isotonic to body fluids to prevent irritation. Ex: Sodium Chloride, Dextrose. (1)
Buffers and Anti oxidants make the preparation chemically stable.
COMPETITIVE BINDERS:
They are used to prevent the interaction between proteins and glassware. Preservatives prevent the growth of micro organisms. Care must be taken while selecting the added substance as they can induce reaction that may inactivate API. (1)
BUFFERS:
Some substances like proteins degrade with the change in PH. So these are used for chemical stability of product. Capacity of buffer should be low. These are some instances where buffers induce degradation of API. (1)
TONICITY ADJUSTERS:
These are used to make solutions isotonic with the body fluids. small volume parenterals intended for the IV preparations need not be maintained but parenterals that deliver into spinal fluid and ophthalmic must be isotonic.for sub cutaneous preparations,isotonicity maintaince reduce irritation.
Ex:electrolytes and mono/di saccharides. (1)

ANTI-OXIDANTS:Many drugs are prone to oxidation and to protect them,antioxidants are used. (1)
Ex:sodium bisulfide
EDTA sodium salt increases the activity of antioxidants. (1)

Methods to prevent oxidation:
Removing the oxygen present in the soil by passing the inert gas. (1)
The containers in which the products will transform should be deaerated. (1)

CRYOPROTECTORS AND LYOPROTECTORS
These are the materials capable of protecting the substance during lyophilisation process. (1)
Ex;sugars-sucrose,trehalose
Aminoacid-glycine,lysine
Polymers-dextran,poly ethylene glycol

ANTI MICROBIAL AGENTS: (1)
USP suggests the addition of bacteriostatic and fungiststic antimicribials to parenteral formulations.A nd the concentration of parenterals should be enough that they should not allow micro organisms development when the product is drawed and during the usage.
Ex:phenyl mercuric acetate-0.01%
Thiomeral-0.01%
Benzothenium chloride-0.01%
Phenol and cresol-0.5%

Only solution and micro emulsions can be administered through IV route whereas micro particles and suspensions can be administered through sub cutaneous and intramuscular route.

PHARMACOKINETICS: Drug absorption, distribution, metabolism and excretion has to be considered while deciding the type of formulation.
Modified dosage forms are used in the case of drugs having rapid absorption, distribution, metabolism and secretion. (1)

If the drug is moved rapidly from the site of injection, viscosity enhancers should be added to slow down the movement. (1)

DRUG SOLUBILITY: Cosolvents are used if the drug is not completely soluble in water. (1)

DRUG STABILITY:
Freeze dryingis employed in case of drug that degrade when they remain in solution form.If the drug stored in cold conditions, care must be taken that the drug is soluble at low temperatures. (1)

DRUG COMPATIBILITY WITH EXCIPIENTS:care must be taken to avoid all kinds of incompatibilities between the drug and excipient. even the excipients must be free of impurities. (1)
Ex:proteins(sensitive to oxygen)will get degraded if the polymers contain peroxide impurties.

ADVANTAGES: (3)
-Drugs that cannot pass through first pass metabolism can be delivered through parenterals.

-Patients those cannot take the drugs orally ,parenterals are the sources to provide medication.
-Some drugs are self-injected
ex:insulin injections
-The onset of action of drug will be quick
-When the patient cannot take the food orally ,through LVP, nutrition and electrolytes can be supplied.

Large volume Parenterals, after hearing this word, the very first word comes in mind is Saline, isn’t?

Parenteral dosage form has a wide range of specialized large-volume solution.

Few important are explained over here.

  • Hyperalimentation Solution
  • Cardioplegia Solution
  • Peritoneal Dialysis Solution
  • Irrigating Solutions

 

Hyperalimentation Solution

Administration of large amount of nutrients to maintain a patient who is unable to take food orally for several weeks at caloric intake levels of 4000 kcal/day or more.
Development of Subclavian vein cannulation- infused fluid is rapidly diluted by the high blood flow in the subclavian vein.
Commonly consist of mixtures of dextrose, amino acids & lipids, added electrolytes, trace metals & vitamins
Administration of life-saving or life-sustaining nutrients to comatose patients or to patients undergoing treatment for esophageal obstruction, GI diseases (including cancer), ulcer.

 

Cardioplegia Solution

LVP used in heart surgery to help prevent ischemic injury to the myocardium during the time the blood flow supply to the heart is clamped off & during reperfusion.,
As well as to maintain a bloodless operating field & to make myocardium flaccid.
Are typically electrolyte solutions, where electrolyte composition is intended to maintain diastolic arrest.
These are solution are admixed by pharmacist in a hospital IV admixture program & are administered cold in order to cool the myocardium & minimize activity.
Solution are slightly alkaline & hypertonic in order to compensate for metabolic acidosis & to minimize reperfusion injury resulting from tissue edema.

 

Peritoneal Dialysis Solution

Are infused continuously into the abdominal cavity, bathing the peritonium & are then continuously withdrawn.
To remove the toxic substances from the body or to aid & accelerate the excretion function normal to the kidneys.
The process is employed to counteract some forms of drug or chemical toxicity as well as to treat acute renal insufficiency.
Solution contain glucose & have an ionic content similar to normal extracellular fluid.
An antibiotic is often added to these solution as a prophylactic measure.

 

Irrigating Solutions

Are intended to irrigate, flush, & aid in cleansing body cavities & wounds.
Although certain IV solutions, such as normal saline, may be used as irrigating solutions should not be used parenterally.
They must be sterile, pyrogen-free, & made & handled with the same care as parenteral solutions.

 

 

 

References:
1) Remington The Science and Practice of Pharmaceutical sciences, 21st edition Lippincott William Wilkins publishers, page no 802 to 805
2) Indian Pharmacopoeia 1996 volume1, Published by controller of Publications, page no. 395
3) Encyclopedia of Pharmaceutical technology, edited by James Swarbrick, third edition, page no 1001 to 1006
4) Remington The Science and Practice of Pharmaceutical sciences, 21st edition Lippincott William Wilkins publishers, page no 1070

QC

Parenterals are the sterile dosage forms intended for administration other than enteral route (parenteral = per+enteral) and exerts their action by directly entering into the systemic circulation.

The quality of parenterals is the sum of all parameters that contribute to safety, efficacy and therapeutic efficacy of the drug.

The USP compendial requirements has recommended the following tests for parenteral products 1

 

1. Weight variation or content uniformity
2. Particulate matter in injections
3. Bacterial endotoxin test
4. Pyrogen test
5. Sterility test

1. Weight variation or content uniformity test

This test is intended for sterile solids used for parenteral preparation. The weight of 10 individual sterile units is noted and the content is removed from them and empty individual sterile unit is weighed intern. Then net weight is calculated by subtracting empty sterile unit weight form gross weight. The content of active ingredient in each sterile unit is calculated by performing the assay according to the individual monographs. The content in 10 sterile units is calculated by performing the assay. The dose uniformity is met if the amount of active ingredient is within the range of 85-115.0% of label claim as determine by the content uniformity method or weight variation method. The dose uniformity is also met if the potency value is 100% in the individual monograph or less of label claim multiplied by average of limits specified for potency in individual monograph divided by 100 provided that the relative standard deviation in both the cases is equal to or less than 6.0%.If one unit is outside the range of 85-115.0%, and none of the sterile unit is outside the range of 75-125.0% and if the relative standard deviation of the resultant is greater than 6.0% then, the fore mentioned test is carried for 20 more sterile units. The sterile units meet the requirements if not more than one unit is out side the range of 85-115%, no unit is outside the range of 75-125.0% and the calculated relative standard deviation is NMT 7.8%.

2. Particulate matter in injections

The preparations intended for parenteral use should be free form particulate matter and should be clear when inspected visually. Two methods are described by USP according to the filled volume of the product to be tested.
For large volume parenterals (LVP’s), a filtration followed by microscopical examination procedure is used. For small volume parenterals (SVP’s)a light obscuration based sensor containing electronic liquid-borne particle counter system is used.
The USP standards are met if the LVP’s under test contain NMT 50 particles per ml of 10 um, and NMT 5 particles per ml of 25um in an effective linear dimensional fashion.
The USP standards are met if the SVP’s under test contain NMT 10,000 particles per container of 10 um, and NMT 1000 particles per container of 25um in an effective spherical diameter.

3. Bacterial Endotoxin test

LAL (Limulus Amebocyte Lysate) test is used to characterize the bacterial endotoxin that may be present. The USP reference standard contains 10,000 USP endotoxins per vial. The LAL reagent is used for gel-clot formation.The test is performed using stated amounts of volumes of products, standard, positive control, negative control of endotoxin. The tubes are incubated at 37+-1C FOR 60+-2 minutes.When the tubes are inverted at 180C angle, formation of firm gel confirms positive reaction. While formation of a viscous gel that doesn’t maintain its integrity or absence of a firm gel confirms negative reaction. The test is invalid if the standard endotoxin or positive product control doesn’t show end point within +-1 two fold dilution from label claim sensitivity of LAL reagent or if the negative control shows gel-clot end point.

4. Pyrogen test

It is performed by using rabbits as test animals.Initially 10 ml/kg body weigh of animal is injected through rat vein at 37+-2C within ten minutes from start of administration.The temperatures are recorded at 1, 2 and 3 hours after injection. The requirements of USP are met if the rise in temperature of individual rabbit is NMT 0.6C and the sum of rise in temperature of three rabbits is NMT 1.4C. If any one rabbit shows a rise in temperature of 0.6C and sum of rise in temperature of three rabbits exceeds 1.40C then the test is repeated using 5 rabbits. The requirements are met if 3 out of 8 rabbits shows an individual rise in temperature of NMT 0.6C and sum of maximum rise in temperature of 8 rabbits is NMT 3.7C.

5. Sterility test

Growth promotion medium and incubation conditions are selected based on the test microorganism according to USP and is listed in table 1. The sterility test is done using direct transfer and membrane filtration techniques. Membrane filtration technique is suitable for liquids, soluble powders with bacterio static or fungi static properties, oils, creams and ointments. Sterility test by direct transfer is performed by aseptic transfer of specified volume from test container (table 2) to culture medium and incubated for 14 days and visual observation of medium is done on 3rd, 4th, 5th, 7th, 8th and 14th day. A membrane filter with porosity of 0.45um with diameter of 47mm with flow rate of 55-75 ml of water per minute at a pressure of 70 cm of mercury should be used.The test meets the requirements when no growth is observed and if growth is observed then the test is repeated in the second stage and generally second stage is repeated with double the number of specimens tested in first stage when the test was found to be conducted under faulty or inadequate aseptic techniques.

Table 1. USP sterility tests growth promotion microorganisms

Medium

 

Test microorganisms Incubation
Temperature (C) Conditions
Fluid thioglycollate  Bacillus subtillis (ATCC No. 6633) 30 to 35 Aerobic
Candida albicans (ATCC No. 8482) 30 to 35
Bacteroides vulgatus (ATCC No. 8482) 30 to 35
Alternative thioglycollate Bacteroides vulgatus (ATCC No. 8482) 30 to 35 Anaerobic
Soybean-casein digest Bacillus subtillis (ATCC No. 6633) 20 to 25 Aerobic
Candida albicans (ATCC No. 10231 20 to 25

Table 2. Liquid quantities for USP sterility test

Container content (ml) Minimum vol taken from each container for each medium Minimum volume of each medium
Use for direct transfer of volume from each container (ml) Used for membrane representing total volume from the appropriate number of containers Number of containers per medium
Less than 100 1ml or entire contents if less than 1 ml 15 100 20 (40 if each does not contain sufficient vol for both media)
10 to less than 50 5 m l 40 100 20
50 to less than 100 10 ml 80 100 20
50 to less than 100 intended for i.v. administration Entire contents 100 10
100 to 500 Entire contents 100 10
>500 500 ml 100 10

 

“This book page doesn’t include any plagiarized material”

Reference:

1. Hanna SA, Quality Assurance. In: Avis KE, Lieberman HA, Lachman L, editors. Pharmaceutical dosage forms:Parenteral Medications.2nd ed. Vol. 1. Newyork: Marcel Dekker; 1996. p. 1-65.

 

PACKING

PARENTERAL
PACKAGING – PLASTIC

Plastic containers
are meant for using to packing of various types of sterile dosage forms which
includes ophthalmic preparations, infusion and dialysis fluids and few
injections.Plastic
containers are made up with thermoplastic polymers of high molecular weight1.

Plastic containers exhibits some advantages over
glass containers, which includes1

  • They
    are light in weight
  • They
    are non breakable
  • Exhibits
    low toxicity
  • Exhibits
    low reactivity

Plastic
containers are selected on the basis of physical and chemical properties of the
types of plastic used in its manufacture.

ADVANTAGES

  • Simple
    and clean manufacturing process
  • ,,Blow-Fill-Seal”
  • Break
    resistant
  • Design
    flexibility, very strict dimensional tolerances
  • Cheap

DISADVANTAGE

  • Low
    temperature resistance
  • Minor
    transparency with some polymers
  • Barrier
    properties inferior to glass
  • Interaction
    of material/additives
  • Moulds
    necessary

The commonly
useful polymers in parenteral packaging are2

  • Polypropylene and
  • Copolymer polyethylene
    polypropylene

Polypropylene is
most widely used,it exhibits

  • which is a linear polymer can be produced to be highly crystalline.
  • it
    has a high tensile strength,
  • high melting point,
  • lowpermeability to water vapour.

Fexible polyethylene
containers are used for ophthalmic solutions to be administered in drops

Fexible poly
vinyl chloride bags are used for intravenous solutions3

The
charecterstics of a rigid containers are utilized during handling and processing.

All of plastic
materials excluding low density polymers are an be sterilized by autoclaving.

EVALUATION4

  • Implanting small
    pieces of plastic material intramuscularly
    to rabbit
  • Injecting eluates
    using sodium chloride injection with and with out alcohol,intravenously to mice,and
    injecting eluates using PEG 400 and sesame oil intrperitoneally in mice and
  • Injecting all
    four eluates subcutaneously in rabbits.

The reaction from the test sample must not be
significantly greater than non reactive control samples.

References:

1) Remington The
Science and Practice of Pharmaceutical sciences, 21st edition Lippincott
William Wilkins publishers,

2) Indian
Pharmacopoeia 1996 volume1, Published by controller of Publications,

3) Encyclopedia of
Pharmaceutical technology, edited by James Swarbrick, third edition,

4) Remington The
Science and Practice of Pharmaceutical sciences, 21st edition Lippincott
William Wilkins publishers,

 

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