STERILE DOSAGE FORMS

STERILE DOSAGE FORMS

Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D

Department of PharmaceuticsFaculty of Pharmacy

Omer Al-Mukhtar UniversityTobruk, Libya.

E-mail: [email protected]

2014/06/10 1Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya.

CONTENTS• Introduction• Routes of parenteral administration• Components of parenteral products• Antioxidants• Antibacterial• Buffers• Chelating agents• Inert gases• Surfactants• Solvents systems• Non-aqueous vehicles• Containers and closures• Formulation of parenterals (solution)• Suspensions• Emulsions• Dry powders• Sterilization• Radiopharmaceuticals• Radiation protection• Ophthalmic preparations• Packaging of ophthalmic products• References


Introduction

• The human eye is a remarkable organ and the ability to see is one of our most treasured possessions. Thus the highest standards are necessary in the compounding of ophthalmic preparations and the greatest care is required in their use. It is necessary that all ophthalmic preparations are sterile and essentially free from forign particle.

• Parenteral preparations are sterile preparations intended for administration by injection, infusion or implantation into the human or animal body.


Routes of parenteral administration

• Intravenous injections and infusions

• Subcutaneous injections

• Intramuscular injections

• Intradermal injections

• Intra-arterial injections

• Intracardic injections

• Intraspinal injections

• Intra-articular injections


2014/06/10 Faculty of Pharmacy, Omer Al-Mukhtar University, Tobruk, Libya. 5

Routes of parenteral administration

Components of parenteral products

• Vehicles

• Stabilizers

• Buffering agents

• Tonicity factors

• Solubilizers

• Wetting, suspending, emulsifying agents

• Antimicrobial compounds


Antioxidants

• Many drugs in aqueous solutions are easily degraded by oxidation. Small-volume parenteral products of these drugs often contain an antioxidant.

• Bisulphites and metabisulphites are commonly used antioxidants in aqueous injections.

• Antioxidants must be carefully selected for use in injections to avoid interaction with the drug.

• Antioxidants have a lower oxidation potential than the drug and so are either preferentially oxidized or block oxidative chain reactions.


Antibacterial

• Antibacterials may be divided into two groups according to their speed of action and residue production:

• The first group contains those that act rapidly to destroy bacteria, but quickly disappear. E.g. alcohols, chlorine, peroxides, and aldehydes.

• The second group consists mostly of newer compounds that leave long-acting residues on the surface to be disinfected and thus have a prolonged action. E.g. triclocarban, and benzalkonium chloride.


Buffers

• The ideal pH of parenteral products is pH 7.4.

• If the pH is above pH 9, tissue necrosis may result, whilst below pH 3 pain and phlebitis in tissues can occur.

• Buffers are included in injections to maintain the pH of the packaged product.

• pH changes can arise through interaction between the product and the container.

• Acetate, citrate and phosphate buffers are commonly used in parenteral products.


Chelating agents

• Chelating agents such as disodium edetate may be included to chelate the metal ions and thus enhance stability.

• It is seen that disodium edetate is a very useful adjuvant to ophthalmic preparations at concentrations of up to 0.1 % w/v to enhance antibacterial activity and chemical stability.

• It has also been used at higher concentrations as an eye drop for the treatment of lime burns in cattle.


Inert gases

• An inert gas is a gas which does not undergo chemical reactions under a set of given conditions.

• Inert gases are used generally to avoid unwanted chemical reactions degrading a sample.

• The term inert gas is context-dependent because nitrogen gas and several of the noble gases can be made to react under certain conditions.

• Purified nitrogen and argon gases are most commonly used as inert gases.


Surfactants

• Certain compounds, because of their chemical structure, have a tendency to accumulate at the boundary between two phases, such compounds are termed surfactants.

• The adsorption at the various interfaces between solids, liquids and gases results in changes in the nature of the interface which are of considerable importance in pharmacy.

• Surfactants are generally classified according to the nature of the hydrophilic group.



Surfactants

Solvents systems

• The drug is generally present in an injection in low concentration.

• The vehicle provides the highest proportion of the formulation and should not be toxic nor have any therapeutic activity.

• The first choice of solvent is obviously water.

• However, although the drug may be freely soluble, it may be unstable in aqueous solution.


Non-aqueous vehicles

• Water-miscible co-solvents, such as glycerin and propylene glycol are used as vehicle in small-volume parenteral fluids.

• They are used to increase the solubility of drugs and to stabilize drugs degraded by hydrolysis.

• Metabolizable oils are used to dissolve drugs that are insoluble in water. E.g. steroids, hormones and vitamins are dissolved in vegetable oils.

• These formulations are administered by intramuscular injection.


Large-volume parenteral fluids are packed into:

• Glass bottles

• PVC collapsible bags

• Semi-rigid polythene containers

The containers and closures that are used for packaging parenteral products must;

• Maintain the sterility of the packed fluids

• Withstand sterilization

• Be compatible with the packed fluid

• Allow withdrawal of the contents


Containers and closures



Containers

• Parenteral preparations are usually supplied in glass ampoules, bottles or vials, plastic bottles or bags, and prefilled syringes, which are coloured in the case of light-sensitive substances.

• Containers should be made from material that is sufficiently transparent to permit the visual inspection of the contents.

• They should not adversely affect the quality of the preparation, allow diffusion of any kind into or across the material of the container.


Closures

• Closures for parenteral preparation containers should be equipped with a firm seal to prevent entry of microorganisms and other contaminants.

• They should not be made of components that react with the contents, nor should they allow foreign substances to diffuse into the preparation.

• Plastic materials or elastomers of which the closure is composed should be sufficiently firm and elastic to allow the passage of a needle with the least possible shedding of particles.




Formulation of parenterals (solution)

• Aqueous solutions

– High viscosity solutions• For compound with mol. wt. more than 750

• For water solution drugs

• Gelling agents or viscosity enhancers are used

– Complex formulations• Drug forms dissociable complex with macromolecule

• Fixed amount of drug gets complexed

• Given by I.M. route


• Oil solutions

– Drug release is controlled by controlling partitioning of drug out of oil into surrounding into aqueous medium

– For I.M. administration only

– No. of oils are limited

• LVP usually contains one or more electrolytes

– Potassium chloride is the most common additive

– Other salts of potassium, magnesium, or sodium can be added

• Additives to IV solutions can also be multivitamins or trace elements

Formulation of parenterals (solution)


Solution• The vehicles most commonly used for IV infusions

are:

– Dextrose in water

– NS solution

– Dextrose in saline solution

• The two main types of IV solutions are:

– small-volume parenterals (SVPs) of 50 or 100 mL

– large-volume parenterals (LVPs) of more than 100 mL


Suspension

• Suspension for injection contain less than 5% of drug solids with a mean particle diameter within the range 5-10m.

• During the manufacture of suspension for injection, the components are prepared and sterilized separately, then aseptically combined.

• The final product cannot be filter sterilized owing to the presence of particles in the formulation.

• Powders for use in sterile suspensions can be sterilized by gas residues must be avoided.


Suspensions• Aqueous suspensions

– Given by I.M. or S.C. routes

– Concentration of solids should be 0.5 to 5 %

– Particle size should be < 10 μm

– Drug is continuously dissolving to replenish the lost.

– For oil soluble drugs

– Only crystalline and stable polymorphic drugs are given by this form

– Viscosity builders can be used.

– E.g., crystalline zinc insulin


• Oil suspensions

– Given by I.M. route.

– Process of drug availability consists of dissolution of drug particles followed by partitioning of drug from oil solution to aqueous medium.

–More prolong dug action as compared to oil solution and aqueous suspension.

– E.g., Penicillin G procaine in vegetable oil

Suspensions


Emulsions

• Can be given by I.M., S.C., or I.V. routes

• O/w systems are not used due to large interfacial area and rapid partitioning.

• W/o emulsions are used for water soluble drugs.

• Multiple emulsions are used generally such as w/o/w and o/w/o since an additional reservoir is presented to the drug for partitioning which can effectively retard its release rate.


Emulsions

• Release of water soluble drugs can be retarded by presenting it as oil suspension and vice versa.

Aqueous phase

Oil phase

Water soluble drug

e.g., 5-Fluorouracil

Oil soluble drug

e.g., lipidol


Dry powders

• Dry sterile powder is aseptically added to a sterile vial.

• The dry drug powder is reconstituted with a sterile vehicle before use.

• Powders for injections are solid substances, distributed in their final containers and which, when shaken with the prescribed volume of the appropriate sterile liquid, rapidly form either clear and practically particle-free solutions or uniform suspensions.


Sterilization

• Products to a process to a process whereby all viable life forms are either killed or removed.

• The sterilization process is usually the final stage in the preparation of the product.

• The methods of sterilization in regular use include exposure to: saturated steam under pressure, dry heat, ionizing radiation, ethylene oxide or passage through a bacteria retaining filter.

• When possible, exposure to saturated steam under pressure is the sterilization method of choice.


Radiopharmaceuticals

• Radiopharmacy is concerned with the manufacture of radioactive medicines known as radiopharmaceuticals.

• These have two main applications in medicine:

1. As an aid to the diagnosis of disease (diagnostic radiopharmaceuticals)

2. In the treatment of disease (therapeutic radiopharmaceuticals)


• Diagnostic radiopharmaceuticals may be classified into two types:

1. Radiopharmaceuticals used in tracer techniques for measuring physiological parameters (e.g. 51Cr-EDTA for measuring glomerular filtration rate)

2. Radiopharmaceuticals for diagnostic imaging (e.g. 99mTc-methylene diphosphonate (MDP) used in bone scanning).


Radiopharmaceuticals

Radiation protection

• There are three basic principles to radiation protection:

1. Shielding: By placing shielding around the radioactive source the radiation dose rate may be reduced.

2. Distance: The radiation dose from a radioactive course is inversely proportional to the square of the distance.

3. Time: Minimizing the time spent handling a radioactive source will reduce the radiation dose.


Ophthalmic preparations

• Eye drops

• Eye lotions

• Eye ointments

• Ophthalmic inserts

• Contact lenses and their solutions

• Solutions

• Suspensions

• Emulsions

• Ointment

• Gels

• Erodible inserts • Non-erodible inserts


• Eye drops including solutions and suspensions of active medicaments for instillation into the conjunctival sac.

• Eye lotions for irrigating and cleansing the eye surface, or for impregnating eye dressings.

• Eye ointments, creams and gels containing active ingredients for application to the lid margins and/or conjunctival sac.

• Contact lens solutions to facilitate the wearing and care of contact lenses.

• Parenteral products for intracorneal, intravitreous or retrobulbar injection

• Ophthalmic inserts placed in the conjunctival sac and designed to release active ingredient over a prolonged period


Ophthalmic preparations

Packaging of ophthalmic products

• Contact lens solutions are usually packed in plastic containers.

• It is imperative that the low concentrations of antimicrobials present in these products are not reduced to ineffective levels due to sorption effects with the plastic.

• Contact lens storage cases are also of importance to the contact lens wearer.

• It is important that these containers are kept in a hygienic conditions.


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STERILE DOSAGE FORMS