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PARENTERAL PRODUCTS

PARENTERAL PRODUCTS
PHC 426 PHARMACY PRACTICE II Meor Mohd Redzuan

Definition (BP) Parenteral preparations are sterile preparations intended for administration by injection,infusion or implantation into human or animal body May require the use of excipient, for eg to make the preparation isotonic with blood, to adjust the pH, to increase solubility,to prevent deterioration of the active ingredient or to provide adequate antimicrobial properties but not to adversely affect the intended medicinal action of the preparation or at the concentrations used to cause toxicity or undue local irritation

PARENTERAL PRODUCTS
Parenteral products are products that are administered to the body by injection. Because this route of administration bypasses the normal body defence mechanisms, it is essential that these products are prepared with a higher degree of care and skills than utilised in preparing conventional oral or topical products

PARENTERAL PRODUCTS
Sterile formulations must : a. Sterile b. Particulate material c. Pyrogen free d. Stability e. pH f. Osmotic pressure

PARENTERAL PRODUCTS
The parenteral products is often used for drugs which cannot given orally. due to patient intolerance instability of drug poor absorption if given by oral route

In practice - injected - implanted - infused Directly into blood vessels, tissues, or other body compartments. Usually admit at hospital Patient can admit their own medication (insulin)

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Parentral therapy is used to: (advantages) - produce localized effect - administer drugs if the oral route cannot used - deliver drugs to the unconscious patient - rapidly correct fluid and elecrolyte imbalances - ensure delivery of the drug to the target tissues

Disadvantages Expensive Required trained personnel Difficult to remove if adverse or toxic reaction Patient acceptability-pain acceptability Introduction of microorganism/toxic potentially fatal (especially as patient often already very sick) Thrombosis,hemolysis,precipitate in the vein tissue/nerve damage

Administration
The three major routes of administration
Subcutaneous Intramuscular Intravenous

Subcutaneous Injection
Injected into the loose connective and adipose tissue immediately beneath to skin Typically volume not more than 1 ml .. Abdomen, the upper back, the upper arms and lateral upper hips more rapidly and predictable adsorb than oral less rapidly and predictable than intramuscular drugs that cannot deliver orally

Other routes
Intra dermal IntraIntra-arterial Intra cardiac Intraspinal IntraIntra-articular

Intramuscular Injection
Aqueous solution, solutions in oil and suspension Easier administration than IV Slower onset but prolonged action than IV, aqueous solution to be adsorb quickly should be slightly hipertonic Limited volume 2-5ml 2 Solutions, suspension,emulsion,oil base vehicle Muscle sites
The gluteal muscle in the buttock (larger volume can tolerate for adult) The deltoid muscle in the shoulder (rapid absorption) The vastus lateralis of the thigh (suitable for children and infant)

Intravenous Injection and Infusion

Small volume for IV to produce a rapid effect. Complete bioavailability Less irritation Volume 50ml 1L infusion Selection of vein
Size of needle or catheter The type and volume of fluid to be admit The rate of admit of fluids

The fluids are admit into a superficial vein at the back of the hand or in the internal flexure of the elbow. It must not be used to admit emulsion and suspension.

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IntraIntra-dermal Injection
Small volume: 0.1 ml Injected into the skin between the epidermis and the dermis. Absorption is slow < 0.1 0.2ml Used for diagnostic test for allergy and immunity Administration of vaccines

IntraIntra-arterial Injections
The drug injected directly to the artery Fast flow of blood, drug rapidly dispersed throughout blood system. Manipulatives difficulties restrict the use To target specific organ/tissue served by the artery Mainly for diagnostic procedures

Intracardiac Injections
Aqueous solutions are injected directly to cardiac or ventricle in emergency case only for local effect.

Intraspinal Injections
Less than 20 ml of Aqueous solutions are injected into particular areas of the spinal column. Use for spinal anaesthetics & antibiotics Must be isotonic Categorized:
Intrathecal into spinal fluid Subarachnoid Epidural PeriduralPeridural-into peridural space

Specific gratify of these injections may be adjusted to localize the site of action of drug

IntraIntra-articular Injections
Aqueous solutions or suspension injected into synovial fluid in a joint cavity. Local administration of anti inflammatory drugs.

Type of parenterals
Large volume parenteral Small volume parenteral
Single dose ampoules Multiple dose vials Pre-filed syringes Pre-

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The British Pharmacopoeia (B.P.) Definition

SINGLE DOSE PREPARATIONS single dose preparations as: The volume of the injection in a single dose container is sufficient to permit the withdrawal and administration of the nominal dose using a normal technique. MULTIPLE DOSE PREPARATIONS (BP 2004) Multidose preparations are multidose aqueous injections which contain a suitable antimicrobial preservative at an appropriate concentration except when the preparation itself has adequate antimicrobial properties.

Single dose ampoules

Small volumes in ampoules or small vials Glass ampoules are made of Type I borosilicate glass. Packaging: filled and heat sealed. Prepared in clean room conditions and must be sterile and free of particles. Great concern relates to the hazards of opening the ampoules (contaminated by glass particle) Ampoules neck have a painted dot marker (weakened neck). Plastic ampoules: Blow -fill-seal Blow-fillHave reliable seal Single use without antimicrobial agents. Must contain small excess of product.- to allow nominal injection product.volume to be drawn into a syringe

Multiple dose vials

Thick walled class container is sealed with a rubber closure and held by an aluminum seal which is crimped to the neck of the glass vial. These closures are then covered with a plastic cap Dose flexibility and economical Disadvantages: fragment of closure & Interaction between product & closure Possibility of microbial contamination Antimicrobial agents Eg : Insulin

Prefilled syringes
The injection solution is aseptically filled into sterile syringes It has high level of sterility insurance Without any antimicrobial agents. Immediate use Expensive.

Advantages of Pre-filled Syringe Pre For self-injecting patients self High degree of flexibility and independence Simple handling the discrete appearance of the injector and reduction of injuries Point of view of pharmaceutical companies and physicians Product differentiation in the market Cost savings from optimized drug use due to low overdosing requirements in pre-filled syringes in precomparison to vials Reduced material requirement; simple storage and disposal Better patient compliance

Simplified drug administration Simple administration and great convenience for hospital personnel Fewer needle injuries Reduced risk of microbiological contaminations Reduction of cross-infections (since re-use of crossrethe needle is not necessary) Reduction of misidentification since systems are labelled High dosage accuracy and sterility assurance due to machine filling

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FORMULATION OF PARENTRAL PRODUCTS

During the formulation of parenteral products, the following factors are critical: (a) The vehicle in which the drug is dissolved or dispersed (b) Volume (dose) of the injection (c) Adjustment to isotonicity (d) Adjustment of pH (e) Stabilisers (f) Preservatives (g) Adjustment of specific gravity (for spinal anaesthesia) anaesthesia) (h) Concentration units

FORMULATION OF PARENTRAL PRODUCTS Vehicle for injections

Provide higher proportion Should be inert, non-toxic & no therapeutic nonactivity Mains water; always containing contaminant such as electrolytes, organisms, particulate matter and dissolved gases (CO2 and Cl) Called water for injection. It can be use for ophthalmic preparation

Water for injections

Extensively use in parentral formulation It is well tolerated in the body Ionazable electrolytes readily dissolve in water It must bee free from pyrogen a high level of chemical purity BP 1993; water from distillation process EP 1997; water prepared by distillation, reverse osmosis and ultrafiltration

Preparation of water for injections

The usual method is distillation Consistent quality of product Source: potable water Contaminated with suspended mineral and organic substances, mineral salts,m/o,endotoxin and chemicals.

To improve the quality of the end product the source of water may be pretreated by
Chemical softening Filtration Deionisation pH adjustment Then treated by reverse osmosis This water was used as the feed water for distillation A boiler containing feed water A heater A headspaces A condenser

Distillation set

Conductivity of the water is not more 2microS/cm. Usually free of microbial contaminants. It should contain fewer than 10 bacteria per 100 ml and no pseudomonas species It must be free of pyrogens with less than 0.25 endotoxin unit (EU) per ml (endotoxin test) Chemical quality of the freshly collected distillate should be comply with the limit tests for purified water.

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Quality limits of water for injection

Chlorides Ammonia Heavy metals Oxidizable substances Residual on evaporation pH less than 0.5 parts (ppm) 0.1 ppm 0.1 ppm less than 5 ppm less than 0.001% 5.0 7.0

Care is required in handling the freshly collected distillate water as it subject to microbial contamination during storage and distribution. Two systems are commonly used for the storage of water for injection:
Batch storage Dynamic storage

Batch storage
WFI stored as a batch QC tests are performed on this batch. Batch release after identification. Provides maximum product accountability before use. Expensive storage system

Dynamic storage
A surge tank Quality polished stainless steel. As the level of water falls more WFI produced and filled into the tank. Cheaper. Disadvantages: Contamination through corrosion of the steel tank. Gram negative bacterial contamination. Storage at 80 degree C to prevent bacteria growth.(steam heated jacket) Surge tank need sterilisation at interval of time

Distribution of water for injection

The water in the stainless steel pipes is constantly circulated from the tank to avoid stagnation and to maintain the temperature. Disadvantage : Although water is constantly circulated, POU normally will have dead leg (stagnant water) which can promote m/o growth.

Sterilised water for injection

Packed in seal container, sterile and free from pyrogen. It use to dissolve and dilute parentral preparation before administration to the patient.

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PYROGEN
Water source of pyrogen( fever producing substance) . Pyrogens must be removed from the water before use as water for injection. It can be achieved by distillation process. After injection water contains pyrogens can increase body temperature. Free pyrogen water describe as apyrogenic

Microbial pyrogens arise from components of Gram-negative and Grampositive bacterial, fungi and viruses. Non-microbial pyrogens; steroid and Nonpyrogens; plasma components. The most important pyrogen in pharmaceutical product is high molecular weight endotoxins. endotoxins. They are found in the outer membrane of gram negative bacteria.

Freshly prepared parenteral products must not be contaminated with microorganism that could produce pyrogen. Contaminated solutions will become more pyrogenic with the passage of time. These products must be sterilised shortly after preparation. Endotoxins produce significant physiological changes when injected. Their detection and elimination are very important for manufacturers of parenteral products.

Nature of Endotoxins
Endotoxins isolated from the outer membranes of Gram negative bacteria are compose of three areas.
The inner region is composed of lipid A that is linked to a central polysaccharide core. Polysaccharides core is joined to long projections known as the O-antigenic Oside chains. Lipid A responsible for most of the biological activity of endotoxin. It is not soluble in water, however, it is joined to a core polysaccharide by an eight carbon sugar that acts as a solute carriers for the lipid A in aqueous solutions.

The molecular weight of endotoxin is important to determine the biological activity. In a pure aqueous solutions, endotoxin has a relative molecule mass of about 106. Equivalent to a virus RMM. In the presence of Mg and Ca, the endotoxin form a bilayer or vesicles with diameter 0.1 micron. Can easily pass through 0.22 micron filter.(commonly used in parenteral product preparation)

Biological activity of Pyrogens

The injections of endotoxins and pyrogens can produce many physiological effects. The most important effect from parentral products contaminated with pyrogen is pyrogenic effect. Lipid A directly affect the thermoregulatory centres in the brain.

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NonNon-aqueous solvents
At high dose levels of endotoxin will also: Activate the coagulation system. Alter carbohydrate and lipid metabolism. Produce platelet aggregation. Produce shock and ultimately death. The effect is serious. Therefore the detection & elimination are very important Water miscible co-solvents co Glycerin and propylene glycol are use as vehicle in small volume parenteral fluids. They are use to increase solubility of drugs and stabilised drug from degradation (hydrolysis)

Metabolizable oils are used to dissolve drugs that are insoluble in water.
Hormones and vitamins (IM)

Particulate matter
Solutions for parenteral use and injections with a volume of 100mL or more must comply with the BP test for the absence of particulate matter. Particles >50 microns can be detected by visual inspection. Examples of such particulate materials are cellulose, glass, rubber cores, cloth or cotton fibres. fibres. Suitable filtration media for removal of particulate materials are sintered glass filters or membrane filters with a pore size of 0.45-1.2m. 0.45-

ADDITIVES
The purpose additive required in parenteral formulation is to produce a safe and elegant product.
Antimicrobial agents Antioxidants Buffers Tonicity adjusting agents

Antimicrobial agents
Multidose parentral product.
Multidose vials

AA are not use in large volume injection or if the drug formulation itself has sufficient antimicrobial activity
Methohexital sodium injection

AA must be stable and effective in the parentral formulation. AA was added to inhibit microbial growth accidently contaminated during use. Precautions AA are more effective in free form and their activity greatly reduce by interaction with components of injection. Rubber closure can take up AA from the solution

AA uptake is more on natural and neoprene rubber and less with butyl rubber closure. Aims Small amount and effective use of AA is necessary. AA effectiveness challenge test with selected m/o. The test procedure in BP (2001)

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Examples of antimicrobial preservatives used in aqueous multiple dose injection Antimicrobial preservative Benzyl alcohol Chlorocresol Cresol Methyl hydroxybenzoate Phenol Thiomersal Concentration (%w/v) 1-2 0.1 0.3 0.25 0.5 0.1 0.25 0.6 0.01

Antioxidants
Many drugs easily degrade (oxidation) in aqueous solution Small volume of parentral product of unstable drugs in aqueous often contain antioxidant. Eg of antioxidants: Bisulphites and metabisulphites Avoid interaction with drugs. Parenteral product also contain chelating agents; to remove trace elements which can catalyse oxidative degradation eg: EDTA or citric acid eg:

Buffers
The ideal pH for parenteral product is 7.4 > pH 9; tissue necrosis < pH 3; pain and phlebitis in tissue In certain cases however, acidic or alkaline solutions may be needed to solubilize drugs. The acceptable pH range is 3-9 for IV preparations and 4-9 for other routes 34The function : to maintain pH in parenteral products. Precautions : pH change can arise through interaction between the product and the container. The buffer used in the injection must allow the body fluid to change the product pH after injection. Eg of buffer used: Acetate, citrate and phosphate buffers.

TonicityTonicity-adjusting agents
Isotonic solution have the same osmotic pressure as blood plasma and do not damage the membrane of red blood cells Hypotonic solutions have a lower osmotic pressure than blood plasma and cause blood cells swell and burst. Hypertonic solutions have a higher osmotic than plasma; as a result the red blood cells lose fluids and shrink. BP stated : large volume infusion liquid, aqueous fluid for SC,ID,IM, intra thecal must be isotonic

Sodium chloride, glucose, or mannitol Additive that could effect the tonicity;
Buffers and antioxidants Another additive which are presence in low concentration, have a little effect on the tonicity.

Isotonic calculation
W = 0.52-a b W = percentage concentration of adjusting substance in the final solution a = Freezing point depression of the unadjusted hypotonic solution b = freezing point depression of a 1% w/v concentration of the adjusting substance

Isotonic solution; 0.9% NaCl. Freezing point depression. to determine required dilution

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Special Injection
Complex formulations Suspensions
Contain less than 5% of drug solid with a mean particle diameter within the range 5 10 micrometer.

DRIED INJECTION
Dried powder /granules aseptically added to a sterile vial Drug reconstitute with water for injection before use. (make sure all of the powder dissolve before use)

More difficult to sterilised than solution Components sterilise separately during manufacture, and then aseptically combined. The final product cannot be filter sterilised due to the presence particle in the formulation Powder can be sterilised by gas, but the gas residues must be avoided.

NON-AQUEOUS INJECTION NON Formulated in arachis and sesame oil, which are easily metabolized

LARGELARGE-VOLUME PARENTRAL PRODUCTS

Single dose injections that are administered by IV infusion Sterile aqueous solution or emulsions with water for injection as the main component Free particle During administration of this fluids additional drugs are often added to the fluids.
Small volume parentral products Small volume infusion product

Large-volume parentral products include: Large Infusion fluids TPN solution IV antibiotics PatientPatient-controlled analgesia Dialysis fluids Irrigation solutions

Large-volume parentrals are variously Largeformulated and packaged and have been use to:
Restore fluids and electrolyte imbalance in patients suffering from dehydration, shock or injury Provide nutrition in circumstances where patients are malnourished, e.g. TPN Act as a vehicle for administration of medicines Perform dialysis Allow irrigation of body parts

Large-volume parentrals must be terminally Largeheat sterilised. While water for injections is the main component of these products they also incorporate other ingredients including:
Carbohydrates (dextrose, sucrose and dextran) Amino acids Lipid emulsions which contain vegetable or semi synthetic oil Electrolytes such as sodium chloride Polyols, (glycerol, sorbitol and mannitol)

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Most of large volume parentral products are clear solution, except for O/W emulsions. O/W emulsions production is specialized as they destabilised by heat. Heat can affect droplet size of emulsions Therefore have to use other sterilazation method

Production of largelargevolume parentral products

Manufactured in high-standard clean room. high Automation filling machine system in the production In line membrane filter (to remove particulate matter) before fill in the bottle (glass or plastic) After filling sealed with rubber closure crimped with aluminium Plastic bag aseptically filled and heat sealed or blow-fillblow-fillseal system Products are examined for particulate matter and the integrity of container closure established. Moist heat should be use to sterilised parentral products, irrigation solutions and dialysis fluids wherever possible.

Container and Closures

Large volume parentral fluids are package into: Glass bottles PVC collapsible bags Semi-rigid polythene container Semi-

The containers and closures that are used for packaging parentral products must:
Maintain the sterility of the packaged fluids Withstand sterilisation Be compatible with the packed fluid Allow withdrawal of the contents.

Type I glass Type I glass for products that have a high pH Transparent and chemically inert. It can be use for drugs that incompatible with plastic bags. Disadvantage are heavy and brittle, and also require an air inlet during the administration. To equal inside and outside of the bottle. Problem; contamination.by glass particle,pressure imbalance between internal and external environment

PVC plastic bags are widely used to package infusion fluids. They are design with a port for the attachment of the administration set and additive port for the addition of smallsmallvolume parentral fluids.

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PVC collapsible bags are:

Resistance to impact Flexible and collapse during fluid administration and so do not require an air inlet system

The disadvantages of the plastic bags are:

They are a high moisture penetration They are adsorb some drugs They are require and extended sterilization time due to the heat resistance of the PVC Moist heat sterilization requires air ballasting to avoid pouch explosion.

Semi rigid plastic containers

Semi rigid plastic containers are use for 100 ml for electrolyte solutions 3 L for TPN Up to 5 L for dialysis solutions

Semi rigid containers Are more drug compatible than PVC container Are difficult to break Do not fully collapse Need extended heat sterilisation Need air equilibration

Semi rigid are design with two ports; One for attachment of administration set The other port permits the addition of small volume parenteral product or small infusion fluids. Single use. They have graduated scale

Labelling
Product identity Solution strength in terms of the amount of active ingredient in a suitable dose-volume dose Batch number and product expiry date Storage requirements For TPN solutions, the name of the patient, the unit number, ward and infusion rate.

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Labelling
The name and concentration of any added substance e.g., antioxidant, anti-microbial preservative anti Indication that a single dose preparation should be discarded after first use Special labelling requirements for particular product e.g., powders for reconstitution prior to use, concentrated solutions requiring dilutions prior to use The date after which the preparation is not intended to be used (expiry date) The conditions under which the preparation should be stored

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