STERILE DOSAGE FORMS

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STERILE DOSAGE FORMS

• Dr. Basavaraj K. Nanjwade M. Pharm., Ph. D
• Department of Pharmaceutics
• Faculty of Pharmacy
• Omer Al-Mukhtar University
• Tobruk, Libya.
• E-mail nanjwadebk_at_gmail.com

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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

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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.

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Routes of parenteral administration

• Intravenous injections and infusions
• Subcutaneous injections
• Intramuscular injections
• Intradermal injections
• Intra-arterial injections
• Intracardic injections
• Intraspinal injections
• Intra-articular injections

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Routes of parenteral administration
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Components of parenteral products

• Vehicles
• Stabilizers
• Buffering agents
• Tonicity factors
• Solubilizers
• Wetting, suspending, emulsifying agents
• Antimicrobial compounds

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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.

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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.

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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.

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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.

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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.

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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.

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Surfactants
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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.

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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.

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Containers and closures

• 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

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Containers and closures
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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.

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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.

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Containers and closures
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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

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Formulation of parenterals (solution)

• 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

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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

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Suspension

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

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Suspensions

• Aqueous suspensions
• Given by I.M. or S.C. routes
• Concentration of solids should be 0.5 to 5
• Particle size should be lt 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

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Suspensions

• 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

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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.

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Emulsions

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

Water soluble drug e.g., 5-Fluorouracil
Oil soluble drug e.g., lipidol
Aqueous phase
Oil phase
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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.

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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.

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Radiopharmaceuticals

• Radiopharmacy is concerned with the manufacture
  of radioactive medicines known as
  radiopharmaceuticals.
• These have two main applications in medicine
• As an aid to the diagnosis of disease (diagnostic
  radiopharmaceuticals)
• In the treatment of disease (therapeutic
  radiopharmaceuticals)

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Radiopharmaceuticals

• Diagnostic radiopharmaceuticals may be classified
  into two types
• Radiopharmaceuticals used in tracer techniques
  for measuring physiological parameters (e.g.
  51Cr-EDTA for measuring glomerular filtration
  rate)
• Radiopharmaceuticals for diagnostic imaging (e.g.
  99mTc-methylene diphosphonate (MDP) used in bone
  scanning).

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Radiation protection

• There are three basic principles to radiation
  protection
• Shielding By placing shielding around the
  radioactive source the radiation dose rate may be
  reduced.
• Distance The radiation dose from a radioactive
  course is inversely proportional to the square of
  the distance.
• Time Minimizing the time spent handling a
  radioactive source will reduce the radiation dose.

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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

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Ophthalmic preparations

• 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

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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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THANK YOUe-mail nanjwadebk_at_gmail.com