INTRODUCTION:

Parenteral preparations include injection gels, implants, emulsions for injection or infusion, powders for injection or infusion, solutions, and suspensions. These are sterile preparations that are intended to be injected straight into the systemic circulation of humans or animals.

Like other pharmaceutical dosage forms, they must be safe for the intended use and meet pharmacopeia-described pharmaceutical quality standards. Parenteral preparations need to be pyrogen-free as well as sterile¹.

While the pyrogen-free aspect will require, if no de pyrogenation process is used during the preparation of the sterile drug products, the use of pyrogen-free pharmaceutical ingredients; drug substances or API (Active Pharmaceutical Ingredient) and excipients; sterility can be achieved through various sterilization processes that should be appropriate to the formulations.

Parenteral preparations serve a crucial role in the direct administration of drugs, nutrients, and fluids into the bloodstream, making them an essential part of contemporary healthcare². When oral drugs are inappropriate or when quick therapeutic effects are necessary, this form of delivery becomes crucial. In this, we dig into the complex world of parenteral preparations, examining their various forms, many benefits, special difficulties, and crucial safety issues.

Parenteral preparations serve a crucial role in the direct administration of drugs, nutrients, and fluids into the bloodstream, making them an essential part of contemporary healthcare. When oral drugs are inappropriate or when quick therapeutic effects are necessary, this form of delivery becomes crucial. A variety of formulations, such as solutions, emulsions, suspensions, and lyophilized powders for reconstitution, are used in the administration of parenteral preparations ³. The most frequently used form, solutions, is made up of drug molecules that have been dissolved in an appropriate solvent to ensure quick and effective delivery.

Emulsions, on the other hand, use immiscible liquid phases to make it easier to administer lipid-based medications, some of which may not dissolve well in aqueous solutions.

Drugs that cannot be manufactured as solutions can be delivered using suspensions, which have solid particles suspended in a liquid media. Moreover, lyophilized Powders are perfect for some medications and treatments since they are stable and convenient to travel but require reconstitution before use. Comparing parenteral preparations to other drug delivery methods, there are many benefits.

TYPES OF PARENTERAL PREPARATIONS:

Parenteral preparations encompass a wide range of formulations, such as solutions, emulsions, suspensions, and lyophilized powders for reconstitution. Solutions, the most commonly used form consist of drug molecules dissolved in an appropriate solvent⁴. Emulsions, on the other hand, contain immiscible liquid phases and are employed for delivering lipid-based drugs. Suspensions involve solid particles suspended in a liquid medium, while lyophilized powders offer stability and ease of transport, requiring reconstitution before administration.

Parenteral preparations may be classified various types:

1. Solution ready for injection.

2. Suspension ready for injection.

3. Emulsion appropriate for parenteral administration.

4. Dry soluble product which are dissolved in an appropriate solvent directly before its administration.

5. Dry insoluble products which are shared with an opposite vehicle just before its administration.

ADVANTAGES:

· Subcutaneous and intramuscular routes have slower onsets of effect, lasting between three and five minutes.

· 100% bioavailability when administered intravenously.

· Intravenous can supply regular medicine, such as morphine for patients in chronic pain or saline drip and glucose for persons in need of fluids and nutrients. The suited for pharmaceuticals are not absorbed by the gut or those that are too irritating.

· Parenteral products are suitable for drugs that are inactivated by the gastrointestinal system or enzymes. Drug action can be prolonged by changing the formulation. Parenteral products are useful for unconscious and vomiting patients.

· When it comes to abusing drugs by injection, there is a considerable danger of addiction because the action starts quickly.

· The patient does not inject herself.

ROUTES OF ADMINISTRATION OF PARENTERAL PRODUCTS

1) Intradermal route (I.D)

2) Subcutaneous route (S.C)

3) Intramuscular route (I.M)

4) Intravenous route (I.V)

Intradermal route (I.D):

These are given in between dermis and epidermis. Skin of the left forearm is usually selected for given injection. Generally, 0.1 to 0.2ml of parenteral solution is injected by this route. The route is used for diagnostic purposes and for testing the sensitivity of the injectable⁵. For certain substances, administration via an ID route can result in a faster systemic uptake compared with subcutaneous injections, leading to a stronger immune response to vaccinations, immunology and novel cancer treatments, and faster drug uptake. Additionally, since administration is closer to the surface of the skin, the body's reaction to substances is more easily visible.

Subcutaneous route (S.C):

These are made under the skin, into the subcutaneous tissue. The volume of 1.0ml or less is usually injected into the upper arm⁶. This is most important route, because it is convenient for the patient and the doctor. In this type of injection, a short needle is used to inject a drug into the tissue layer between the skin and the muscle. Medication given this way is usually absorbed more slowly than if injected into a vein, sometimes over a period of 24 hours. This type of injection is used when other methods of administration might be less effective⁷. The subcutaneous administration route is widely used to administer different types of drugs given its high bioavailability and rapid onset of action. Apart from a direct effect of the drug itself, several factors can influence the sensation of pain: needle features, injection site, volume injected, injection speed, osmolality, viscosity and pH of formulation, as well as the kind of excipients employed, including buffers and preservatives. Short and thin needles, conveniently lubricated and with sharp tips, are generally used to minimize pain, although the anatomic injection site (abdomen versus thigh) also affects the sensation of pain.

Intramuscular route (I.M):

These injections are administered into the muscles. Typically, the buttock, thigh, or lower back muscles are chosen. This route is typically used to administer volumes up to 2.0ml, with a maximum capacity of 4.0 ml per site. By using this method, aqueous or oily suspensions and oily solutions can be supplied. It is one of several methods for parenteral administration of medications⁸. Intramuscular injection may be preferred because muscles have larger and more numerous blood vessels than subcutaneous tissue, leading to faster absorption than subcutaneous or intradermal injections.

Medication administered via intramuscular injection is not subject to the first-pass metabolism effect which affects oral medications. Common sites for intramuscular injections include the deltoid muscle of the upper arm and the gluteal muscle of the buttock⁹. In infants, the vastus laterals muscle of the thigh is commonly used. The injection site must be cleaned before administering the injection, and the injection is then administered in a fast, darting motion to decrease the discomfort to the individual. The volume to be injected in the muscle is usually limited to 2–5 milliliters, depending on injection site.

Intravenous route (I.V):

These injections are given into vein and therefore introduced directly into the blood steam. The median basilica vein near the anterior surface of the elbow is usually selected, because it is easily located and connects with the major veins of the arm¹⁰. Large volume of parenteral solutions ranging from 1 ml to 500ml or more than that can be injected. The parenteral solution should be isotonic with blood if the volumes of more than 15ml should be injected. The suspensions and oily injections cannot be injected by this route. There are about 40% of all the drugs administrated in the hospitals given in the form of injections and it’s used for increasing. The Part of this increase in parenteral therapy is due to the various uses of intravenous fluids¹¹. The IV fluids regular to remain as means of fluid alternate, electrolyte balance restoration, supplementary nutrition and they also used as vehicles for vary finding greater use as means of administering other drugs because of convenience the means to reducing the annoyance possible of drugs and the desirability for regular and intermittent drug therapy.

GENERAL PROCEDURE FOR THE PREPARATION OF PARENTERAL PRODUCTS:

Parenteral products must be free from particulate matter and microorganisms; therefore, room of preparation must be free from dust and microorganisms¹². This is achieved as follows:

● Fitting laminar air flow system to suck dust and microorganisms; UV radiation will kill microorganisms.

● Room walls and benches cleaned by antimicrobial agents.

● Workers should wear sterilized clothes and disinfected gloves and masks to protect their mouths and noses and wear plastic glasses to protect their eyes from UV lamps.

STEPS INVOLVED IN THE PREPARATION OF PARENTERAL PRODUCTS

● Cleaning: using automatic washing and rinsing machines.

● Sterilization: Dry or moist heat.

● Purity of ingredients: drugs, vehicles, additives. For water as solvent use water for injection.

● Compounding of the preparation: Add small quantity first then larger to form solution.

● Filtration: Use Millipore membrane composed of cellulose acetate filters, for thermo-labile solutions; removes microorganisms.

● Distribution of preparation into final containers: Bottles, ampoules, plastic bags. Glass preferred since its high temperature during sterilization. Amber colored glass used for photolabile drugs but this interferes with visual inspection for foreign material.

● Sterilization: Of filled and closed containers

● Labeling: Name and quantity of ingredients, storage conditions, manufacturing and expiry dates.

TEST FOR THE STERILITY OF THE PRODUCT:

Sterility testing assesses whether a sterilized pharmaceutical product is free from microorganism by counting all part of the product through a nutrient medium¹³. Due to the critical character of the test and the probabilities concerned in sample only a part of a batch, it is only probable to say that no contaminating microorganism have been found in the sample examined in the situation of the test. In other terms it is impossible to show sterility since sampling may fail to select nonsterile containers and culture techniques have limited sensitivity.

Types of Parenteral Devices:

· Syringe:

It's a tiny plastic tube with a needle pointing in one direction. Medication can be administered intravenously, intramuscularly, or intradermally using syringes¹⁴. Blood and other bodily fluids are also extracted with them for testing purposes. Needles-free syringes are helpful for administering drugs orally or via a feeding tube. The amount of liquid that syringes can hold is shown on the label. The capacity of a syringe is expressed in cubic centimeters for solids and milliliters for liquids¹⁵. Syringes come in capacities ranging from 1ml to 60ml.

Examples: medical syringe, insulin syringe, disposable syringe and tuberculin syringe.

· Needle:

A hub on one end of needles is connected to the syringe. Needles are available in a range of gauge sizes and lengths¹⁶. The needle's bevel or slope at the tip makes it easy for them to pierce tissues.

Examples: hypodermic needles, winged needles.

· Cannular:

A cannula is a tube that is placed within the body to take samples and remove or deliver fluids. To put it another way, a cannula extends the needle's useful length and facilitates operation by covering its surface¹⁷. They are available in a range of sizes and features and are also referred to as intravenous or IV cannulas. A variety of therapies and preventative care alternatives are made possible by IV cannulas. Once the cannula is implanted, the medical team utilizes it to directly inject medications, fluids, or blood into the vein¹⁸. With the use of the cannula, there is no longer a need to use and insert a fresh needle before every session or delivery. The two primary types of IV cannulas are peripheral and central line.

Examples: - Intravenous (IV) cannulation and Nasal cannulation.

· Catheter:

Catheters are used to enable appropriate bladder drainage in cases of physiological and anatomical abnormalities or obstruction of the lower urinary system, either temporarily or permanently¹⁹. Catheters are used for a number of reasons, such as ensuring bladder drainage during and after surgery or epidural anaesthesia to minimize or completely eliminate the risk of distension injuries, conducting investigations to measure urine output accurately and postmicturition residuals; administering treatments to relieve urinary retention or to install chemotherapy; and, as a last resort for containment, treating intractable incontinence.

Examples: Arterial catheter, Balloon catheter, Cardiac catheterization, Central venous atheter, Dialysis.

· Feeding Tube:

A feeding tube is a medical device that helps people who can't swallow securely or who need nutritional supplements to stay alive. The process of getting nutrition through a feeding tube is called enteral feeding, sometimes referred to as gavage or tube feeding. When treating acute illnesses, placement can be either temporary or permanent; when treating chronic disabilities, it can be either way. In medical practice, feeding tubes are used in multiples. Polyurethane or silicone are commonly used. A feeding tube's diameter is stated in French units. The diameter of the feeding tube is measured in French units, where ⅓ mm is equal to one French unit²⁰. The intended use and the site of insertion determine their classification.

Examples: - nasogastric and gastric feeding tube.

· Stents:

Small, expandable tubes called stents are used to treat arterial narrowing. They can treat a heart attack, open narrowed arteries, and lessen symptoms like chest pain in patients with coronary heart disease caused by plaque accumulation. Medical professionals refer to these devices as coronary stents. They are usually inserted into arteries after the artery has been widened through a procedure called angioplasty. They're made of metal wire mesh. No large incisions are made during the one-hour angioplasty procedure. Local anaesthetic and mild sedation are used during the procedure²¹. It might take longer if the patient needs more than one stent. Patients who receive stents recover faster and experience less discomfort than those who have coronary artery bypass surgery.

Examples: drug-eluting stents.

Parenteral therapy is used to:

· Create a localized effect.

· The oral route cannot be used for drug administration.

· Easily administration of drugs to the unconscious patient.

· Quickly accurate fluid and electrolyte imbalance.

· Accurate delivery of the drug to the target tissues

General steps involved in parenteral preparations:

· Cleaning: using automatic washing and rinsing machines.

· Sterilization: Dry or moist heat.

· Purity of ingredients: drugs, vehicles, additives. For water as solvent use water for injection.

· Compounding of the preparation: Add small quantity first then larger to form solution.

· Filtration: Use Millipore membrane composed of cellulose acetate filters, for thermo-labile solutions; removes microorganisms.

· Distribution of preparation into final containers: Bottles, ampoules, plastic bags. Glass preferred since its high temperature during sterilization. Amber colored glass used for photolabile drugs but this interferes with visual inspection for foreign material.

· Closing and sealing of containers.

· Sterilization: Of filled and closed containers.

· Visual inspection for clarity.

· Labelling: Name and quantity of ingredients, storage conditions manufacturing and expiry dates.

QUALITY CONTROL (OR EVALUATION) OF PARENTERAL PREPARATIONS

The following tests are done to ensure that the parenteral products meet the required standards of safety and effectiveness:

· Sterility test

· Clarity test

· Pyrogen test

· Leaker test.

· Sterility test:

All Parenteral products should be sterile. Sterility test is performed on randomly selected samples.

Principle of the test:

A quantity of the material is transferred to a suitable liquid culture medium contained in a tube. A number of culture media are used:

● Thioglycolate liquid medium: used to support the growth of anaerobic organisms. It is incubated for 7 days at 35 - 37C.

● Soybean-casein liquid medium: to support the growth of aerobic organisms. It is incubated for 7 days at 35 - 37C.

● Sabaraud liquid medium to support the growth of fungi, incubated at 25 - 27C.

Observations of the sterility test:

The tested material is sterile if no growth or turbidity in a, b, c, g, while d, e, f, show growth. If growth observed in a, b, c, g, or no growth in d, e, f, the test should be repeated with fresh sample. If there is growth repeat test. If still there is growth, then preparation is unsterile and is rejected.

· Pyrogen test:

Pyrogens are metabolic products which are produced by all microorganisms from their cell wall. They consist of liposaccharide and they are water soluble, filterable and thermostable. They are not removed after sterilization by moist heat or filtration. In the human body they cause febrile reaction (fever, headache, backache) ²². Major source of pyrogens is water which is used as a vehicle. Pyrogens can be removed by adding oxidizing agent (potassium permanganate + small quantity of barium) to oxidize pyrogens to non-volatile organic solids (filterable). It is performed on all aqueous parenteral preparations. Rabbits are used for the test since they show same response to pyrogens as humans.

Principle of the test:

Measuring the rise in temperature (fever) caused by pyrogens, using a thermometer placed in the rectum of the rabbit. The sample (10 ml/kg) is injected into the ear vein of 8 rabbits. The temperature is recorded before injecting and the after injecting at 1, 2, and 3 hours. The rectal temperature should not exceed 0.6^oC from normal recorded temperature.

· Clarity test

Clarity is defined as the freedom of parenteral preparations from any foreign matter. The clarity of solutions is visually inspected under strong light.

· Leaker test

This test is specific for ampoules to test that they are effectively sealed with no leak.

Steps:

● The ampoules are immersed in a tank containing dye solution (1% methylene blue).

● The tank is closed and the air inside is evacuated to form negative pressure inside the tank²³. The vacuum will create high pressure on the weak points on the ampoule seal and will also assist the passage of the dye into the leaking ampoule.

● The ampoules are washed and any leaking one will contain the blue dye and should be rejected.

PROCESS FOR STERILIZATION OF PARENTRAL PRODUCTS:

Based on a probability function, sterilization is the removal or killing of all living germs. Sterilization is the process of getting rid of all contaminants from a surface, a piece of equipment, food, or a medium for biological culture. This differs from disinfections, where a disinfectant merely eliminates germs that can spread disease. In general, all instruments that enter a portion of the body that is already sterile must be sterilized. This applies to tools like scalpels and hypodermic needles. The most crucial sterilizing procedure is autoclaving. While certain plastic devices that couldn't stay dimensionally stable in an autoclave were sanitized using alternative techniques including gas sterilization or radiation sterilization²⁴. Various methods of sterilization:

1. Autoclave sterilization: Usually to sterilize by autoclave a pressurized steam autoclave operates at 121ºC for at least 15 min.

2. Radiation sterilization: This method is very important for medical devices. That can withstand the attack of gamma rays’ bombardment. Radiation sterilization is only useful for the polymers which are sensitive to heat moisture or ethylene oxide.

3. Gas sterilization: Ethylene oxide is generally used as sterilant. It is nontoxic to most plastics. Ethylene oxide sterilization is used for most of the plastic syringe and needles.

STERILIZATION BY FILTRATION:

The sterilization by filtration sterilizes parenteral products by removing microbes, particulate matter, and viruses from the manufactured product²⁵. There are four primary filters used for sterilization: particulate filters, microfilters, ultrafilters, and nano-filters.

Particulate filters have the greatest porosity, while nano-filters have the smallest porosity. Microfilters are used to remove most bacteria and yeast, while ultrafilters remove most viral particles, in which about their details are given below²⁶. All in all, product sterility ensures that patients will not be at risk of infection following product use.

1) Particle filter: The porosity rating of particle filters ranges from 10 to 200 microns. Particle filters are used as prefilters to remove bulk dirt, pollen, some bacteria, and large particles.

Materials used for particle filters (sometimes called depth filters or surface filters) include cellulose, cellulose ester, heat-bonded polypropylene, diatomaceous earth, glass, sand, gravel, and polypropylene yarn²⁷. Prefilters are traditionally used to prevent the membranes of microfilters from clogging too quickly.

2) Microfilters: Most microfilters have a porosity of 0.22 microns or smaller. However, microfilter porosity ranges from 0.1 to 10 microns. Microfilters are used to remove all bacteria and yeast. Microfilters also remove colloidal forms in suspension.

As the industry’s classic sterilizing filter, microfilters have narrow pore distribution resulting from the creation of controlled polymeric structures. Some combination filters use microfilter pore sizing along with a particle filter. These combination filters are ubiquitously used as final filters for syringes before product administration.

3) Ultrafilters: -Ultra filter porosity ranges from 0.001 to 0.1 microns. Ultra filters are viral filters designed to filter viral particles and large organic compounds.

4) Nanofilters: -Nano-filter porosity is less than 0.001 microns and is used to remove small organic compounds and ionic particles. Nano-filters are used in reverse osmosis systems. Nano-sized activated alumina particles bonded to glass fibre matrices, polycarbonate, electro spun Nylon 6 fibres, polyether sulfone, and other polymers are used to create nano-filters. Note that polymeric filter materials are either hydrophilic or hydrophobic. Hydrophilic filters wet spontaneously and are used in sterile filtration of solutions. Hydrophobic filters don’t wet spontaneously²⁸. Thus, hydrophobic filters are used to filter gases, solvents, and strongly acidic or alkaline solutions.

VEHICLES USED IN PARENTAL PREPARATION:

Aqueous vehicles: Since aqueous treatments are well tolerated by the body and are the safest to employ, water is the most popular and appropriate parenteral delivery system.

TYPE OF WATER USED:

· Water for injection.

· Sterile water for injection.

· bacteriostatic water for injection.

Sterile water for injection:

It is water for injection which has been sterilized and packaged in single dose containers having a volume not exceeding 1 liter. It is pyrogen-free and does not contain an antimicrobial agent²⁹. For example: an injectable solution may be prepared from dry powder of sterile Ampicillin sodium by adding sterile water for injection.

Non-Aqueous vehicles:

· Water soluble.

· Water-resistant Water for injection

It is obtained by de-ionizing and distilling water. It should contain no more than 1 mg/100 ml of total solids. It must be pyrogen free but it is not required to be sterile.

Aqueous vehicles are preferred for parenteral preparations but it is sometimes necessary to eliminate water from certain preparations for one of the following reasons:

● To enhance the solubility of certain poorly water-soluble drugs by replacing water with other non-aqueous vehicles³⁰.

● To protect certain drugs from hydrolytic reactions.

Properties of non-aqueous vehicles used in parenteral preparations:

● Nontoxic, non-irritant and inert.

● Stable a compatible with other ingredients used.

● Should have suitable viscosity to be easily withdrawn from the container and easily injected.

CONCLUSION:

It was concluded that parenteral route of administration is the most effective route for the delivery of the active pharmaceutical substances with narrow therapeutic index, poor bioavailability especially for those drugs, prescribed to unconscious patients. The present article describes that route of administration, types of parenteral products, advantages, test for sterility, steps for preparation of parenteral, sterilization, filling and sealing of parenteral. It is more significant to produce good quality of parenteral. Parenteral are the pyrogen free liquids these are manufactured and stored according to GMP guidelines. Proper area environmental control, personnel observation will give excellent parenteral products and attain their described therapeutic effect.

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Received on 10.11.2023 Modified on 04.12.2023

Asian J. Pharm. Tech. 2024; 14(1):36-42.

DOI: 10.52711/2231-5713.2024.00008