Parenterals

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Slide 1:

Parenterals St. Peter’s Institute of Pharmaceutical Sciences Kakatiya University, Warangal, A.P Dr. Raju Jukanti

Slide 2:

Introduction Any drug or fluid whose delivery does not utilize the alimentary canal for entry into body tissues. Although drugs applied topically to the eye, ear & skin or even inhaled may be broadly interpreted as parenterals. Medical and pharmaceutical health care deliveries generally limit the definition to those drugs injected or infused directly into tissues, tissue spaces, vessels or body compartments. Parenteral products are injected through the skin or mucous membranes into the internal body compartments.

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History of Parenteral Therapy 1657: First recorded injection in animals – Sir Christopher Wren 1855: First subcutaneous injection of drugs using hypodermic needles – Dr. Alexander Wood 1920s: Proof of microbial growth resulting in infections – Dr. Florence Seibert 1926: Inclusion in the National Formulary 1931: Commercial Intravenous solution (Baxter) 1933: Application of freeze drying to clinical materials 1946: Organization of Parenteral Drug Association 1961: Development of laminar airflow concept 1965: Development of Total Parenteral Nutrition (TPN)

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Para enteron: Beside the intestine Circumvents : – GI enzymatic activity – GI instability – Low absorption – Variable absorption Provides : – Rapid and accurate dosage – Alternative to other routes of delivery Why Parenterals?

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Advantages of Parenteral Administration Useful for patients who cannot take drugs orally Useful for drugs that require a rapid onset of action (primarily iv admin) Useful for emergency situations Useful for providing sustained drug delivery (implants, im depot injections) Can be used for self-delivery of drugs (subcutaneous) Useful for drugs that are inactivated in the GIT or susceptible to first-pass Useful for injection of drugs directly into a tissue (targeted drug delivery) Useful for delivering fluids, electrolytes, or nutrients (TPN) Useful for providing precise drug delivery by iv injection or infusion utilizing pharmacokinetic techniques Can be done in hospitals, ambulatory infusion centers, and home health care

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Disadvantages of Parenteral Administration More expensive and costly to produce. Potential for infection at the site of injection, thrombophlebitis, fluid overload, air embolism, extravasation, sepsis Psychological distress by the patient Require specialized equipment, devices, and techniques to prepare and administer drugs. Potential for pain upon injection Potential for tissue damage upon injection Risk of needle stick injuries and exposure to blood-borne pathogens by health care worker. Increased morbidity associated with long-term vascular access devices. Disposal of needles, syringes, and other infusion devices requires special consideration.

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• Intradermal (I.D.) • Subcutaneous (S.C., S.Q., Sub-Q, Hypo) • Intramuscular (I.M.) • Intravenous (I.V.) • Intra-arterial • Intracardiac • Intra-articular (joint) • Intrasynovial (joint fluid area) • Intraspinal, Intrathecal (spinal fluid) Routes of Parenteral Administration

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Intradermal injection: 26 G,3/18 inch long needle is inserted at a 10°angle B. Subcutaneous injection: 25 G, ½ inch long needle C. Intramuscular injection: 20 - 23 G, 1 inch to 3 inch long needle is inserted into the relaxed muscle at a 90° angle D. Intravenous injection: the diameter and length of the needle used depend on the substance to be injected and on the site of the injection

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Small Volume Parenterals (25-50 ml) Requires little or no manipulation Extended stability Little wastage Do not offer flexibility in Quantity/concentration Primary uses of SVP Therapeutic injections Opthalmic products Diagnostic agents including Diagnostic radiopharmaceuticals Allergenic extracts Classification

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Large Volume Parenterals Flexible but requires manipulation Used for maintenance or replacement therapy Free of Preservatives Volume must not exceed 1L (except irrigation sols) Clinical Utilization of LVP Basic Nutrition Restoration of Electrolyte balance Fluid replacement Blood and blood products Drug carriers

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• Aqueous vehicles: – Frequently, isotonic (to blood). • Water-miscible vehicles: - primarily to effect solubility of drugs and/or reduce hydrolysis • Non-aqueous vehicles: Fixed oils (vegetable origin, liquid, and rancid resistance, unsaturated, free fatty acid content) – P eanut oil – Corn oil – Cotton seed oil (depo-testosterone) – Sesame oil – Soybean oil (source of fat in intralipid) – Ethyl oleate – Isopropyl myristate Vehicles for Parenteral Administration

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Active drug component Route of administration % (w/v) Cosolvent Reserpine IV/IM 10% Dimethyl acetamide 5% Polyethylene glycol Phenobarbital sodium IV/IM 10% Ethanol 40% Propylene glycol Digoxin IM/IV 10% Ethanol 40% Propylene glycol Diazepam IM/IV 10% Ethanol 40% Propylene glycol Phenytoin Sod IM/IV 10% Ethanol 40% Propylene glycol Lorazepam IV/IM 18% Polyethylene glycol 400 Hydralazine HCL IM/IV 10% Propylene glycol Multivitamin IV infusion 30% Propylene glycol Parenteral Products containing Co-solvents

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Water-Soluble Solvents and Surfactants in Commercially Available Injectable Formulations

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Oils Used in Commercially Available Parenteral Formulations

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Flow Chart of Suggested Order of Solubilization Approaches for Injectable and Oral Liquid Formulations

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Purified Water USP / Water for Injection USP High-purity water used as a vehicle for injectable preparations which will be subsequently sterilized. Stored for less than 24 hr at RT or for longer times at specific temperatures (5 or 8°C). Need not meet USP sterility test since used in products which will be sterilized. Needs to meet USP pyrogen test. Maximum 1mg/100 ml total solids. May not contain an added substance. Types of Water for Injection

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Sterile Water for Injection USP (SWFI) Appropriate type of water used for making parenteral solutions prepared under aseptic conditions and not terminally sterilized Needs to meet USP sterility test Can contain an added bacteriostatic agent when in containers of 30 ml or less Single-dose containers not exceeding 1000 ml

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Bacteriostatic Water for Injection USP SWFI containing one or more suitable bacteriostatic agents Multiple-dose containers not exceeding 30 ml Not the vehicle of choice (SWFI is) when need >5 ml due to toxicity of bacteriostatic agent Sterile Water for Irrigation Wash wounds, surgical incisions, or body tissues

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Types of Water described in USP

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• Sources of pyrogens - Water, Containers, Equipment, Solutes, etc. Products of metabolism of microorganisms - endotoxins, the most prevalent lipo polysaccharides from gram negative bacteria cell wall. • Can cause fever, malaise, muscle ache and in seriously ill patients shock-like symptoms. • Heating at high temperatures prevents pyrogens (210°C for 3 to 4 hours or heating at 650°C for 60 seconds. What are Pyrogens?

Slide 21:

Antibacterial Agents Required to prevent microorganism growth Limited concentration of agents - Phenylmercuric nitrate and Thiomersol 0.01% - Benzethonium chloride and benzalkonium chloride 0.01% - Phenol or cresol 0.5% - Chlorobutanol 0.5% Antioxidants Prevent oxidization by being oxidized faster than the drug or by blocking oxidization - Water soluble: ascorbic acid, sodium bisulfite, sodium metabisulfite, - Oil-soluble: BHT and BHA Displacing the air e.g. CO 2 and N 2 Parenteral Added Substances

Slide 22:

Buffers Added to maintain pH Results in stability Effective range, concentration, chemical effect – Citrate and Acetate buffer – Sodium benzoate and benzoic acid – Sodium titrate and tartaric acid – Phosphate buffer Tonicity Agents Reduce pain of injection Can include buffers – Sodium chloride – Potassium chloride – Dextrose – Mannitol – Sorbitol

Slide 23:

Other Parenteral Adjuncts Suspending or Viscosity Increasing Agents – Sodium cmc and gelatin – Polyvinylpyrrolidone – Methylcellulose Surfactants (Emulsifying, Solubilizing, Wetting Agents) – Egg yolk phospholipids (intralipidr) – Polysorbate 20, 60, 80 – Lecithin – Pluronic F-68 (oxypropylene polymer) (experimental) – Peg-400 Castor Oil

Slide 24:

Chelating Agents – ethylenediamine tetraacetic acid Inert Gases – N 2 (gentamicin sulfate injection) – CO 2 (sodium bicarbonate injection) Administration Aids – Local anesthetics: benzyl alcohol, xylocaine HCl, – Anti-inflammatory agents: hydrocortisone – Anti-clotting agents: heparin – Vaso-constrictors (prolong action): epinephrine – Increase tissue permeability: hyaluronidase (enzyme)

Slide 25:

• Effect solubility • Enhance physical and chemical stability (e.g. antioxidants, inert gases, chelating agents, buffers) • Preserve a preparation against growth of microorganisms • Provide patient comfort (e.g. tonicity agents) • To prolong action (e.g. vasoconstrictor in local anesthetic) Added Substances?

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Complete destruction of all living organisms and their spores or their complete removal from the preparation Steam sterilization Dry-heat sterilization need higher temperatures relative to moist heat sterilization Sterilization by filtration requires significant validation and monitoring Gas sterilization Sterilization by ionizing radiation (infrequently used) Freeze drying for biological products Sterilization of Parenterals

Slide 27:

Market inventory Projected sales Planning and Scheduling Functions Personnel Documentation control Equipment & Facilities Management Materials Management Purchasing Preparation of Facilitates Preparation, Equipment & Package Components Overview of Manufacturing Parenterals

Slide 28:

Manufacture of Product Sterilization of Product Aseptic subdivision & Sealing Online testing Capping (or) outer sealing Inspection Quarantine Finishing, Labeling & Packaging Warehouse Market

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Flow of Materials Through the Production Department Product storage Packaging Filling Sealing Sterilization Sterilization Cleaning Cleaning Compounding Filtration of Product Solution Ingredients Vehicles Solutes Processing Equipment Container Components

Slide 30:

Types of Glass Containers Type Description Type of Test General Use I II III NP Highly resistant Borosilicate Treated Soda Lime glass Soda lime glass General purpose Soda lime Powdered Glass Water Attack Powdered Glass Powdered Glass Buffered and unbuffered aqueous solutions All other uses Buffered aqueous solutions pH<7.0, Dry powders, Oleaginous solutions Dry powders, Oleaginous solutions Not for Parenterals. For tablets, oral solutions and suspensions, ointments and external liquids

Slide 31:

Used for medicine bottles and other commercial purposes Composition: 75% of SiO 2 , 15% of Na 2 O, 10% of CaO Aluminium oxide improves mechanical strength and chemical durability and makes melting easier. If MgO used in part of lime, it reduces the temperature required for manufacture of the glass and widens the temperature range over which the glass can be shaped in to containers. Manufactured at convenient temperature Easy to process Inexpensive Lime Soda Glass

Slide 32:

The defects of lime-soda glass can be largely over come by decreasing the proportion of alkali ( Ca & Sod.Oxides) and including boric oxide. Composition: 80% SiO 2 , 12% B 2 O 3 , 2% Al 2 O 3 , 6% Na 2 O It improves Heat resistance Confers great chemical durability Mainly chemical glass ware, oven ware and containers for alkali sensitivity preparations Expensive and difficult to melt and mould are the main draw backs Borosilicate Glass

Slide 33:

Neutral Glass Glass between borosilicate and lime soda in composition softer more easily manipulated than borosilicate good resistant to Autoclave the resistance is greater than lime soda glass Composition: 72-75% SiO 2 , 7-10% B 2 O 3 , 4-6% Al 2 O 3 , 6-8% Na 2 O 0.5-12% of K 2 O and 2-4% of BaO Large transfusion bottles are produced from neutral glass Lead monoxide is used in the manufacture of certain types of glass, but, Lead is cumulative poison. Lead free containers are desirable for pharmaceutical preparations, particularly those intended for liquids. Lead Free Glass

Slide 34:

Silicone Treated Containers Good resistance to heat, Oxidation Chemical inertness Freedom from color, odor and toxicity. Advantages They are not wetted by aqueous solutions or suspensions. With suspensions for example Aqueous Procaine penicillin, the quick drainage following shaking makes it easy. Foaming, which can make accurate measurement of the dose difficult is reduced.

Slide 35:

Thermoplastic Thermo setting on heating these are soften to a viscous fluid which hardens again on cooling. Their hardness when cold is influenced by the degree of cross – linkage between the long chain molecules. Example; nylon. When heated these may become flexible but they don’t become fluid usually their shape is retained right up to the temperature of decomposition. Because of high degree of cross-linking they are usually hard and brittle at room temperature Types of Plastics

Slide 36:

Plastic for Sterile containers & Equipment Thermoplastic types Polyethylene (Polyethene) Flexible, very light, , sterilization is difficult, MP 110-115°C . High Density Polyethene Walls can be thinner, handling and filling of containers is easy, sterilized by Autoclaving, and used for disposable syringes Polyvinyl chloride (PVC) Less flexible, high clarity, useful for – eye drops, eye ointment tubes, high clarity, some grades can be sterilized by autoclaving.

Slide 37:

Poly methyl methacrylate Hard, strong, glass clear material used for aseptic screens, contact lenses, heart, lung machines and bone replacement. Polystyrene Hard, rigid, light material, cheap, easy to mould, odorless and tasteless transparent or colored such items are bottles, tubes, jars, boxes and syringes Polypropylene Similar to polythene and it has greater heat resistance and melting point is 170°C Polyamides Excellent heat resistance, M.P is 200°C and can be Autoclaved repeatedly at 121°C Polycarbonates Similar to Polystyrene, very good heat resistance but poor chemical Resistance

Slide 38:

Thermosetting Types Phenol Formaldehyde Good heat and moisture resistance Outer caps of injection bottles and caps of eye drop bottles Urea Formaldehyde Less heat and moisture resistant than Phenol Formaldehyde. Pale or colorless, odourless and tasteless. Mainly used for closures Melamine Formaldehyde Advantages of both Phenol and Urea Formaldehyde

Slide 39:

Characteristics of Good Pharmaceutical rubbers Good ageing qualities Satisfactory hardness and elasticity Resistance to sterilization conditions Impermeable to moisture and air Examples: Butyl Rubbers Natural Rubbers Neoprene Rubbers Polyisoprene rubbers Silicone Rubbers Closures

Slide 40:

Types of Filling Equipment vial, ampoules, plastic containers, bottles syringe cartridges, plastic mini bags ,, vials, bottles, plastic mini bags. ,, Liquid products such as solutions, suspensions emulsions and solutions for freeze drying ,, Powders ,, Piston type (Cozzoli) Rotary chemical pump Time or pressure type Auger Vacuum Pressure displacement types of package Types of product filled Mechanism of filling

Slide 41:

All containers must receive a Primary sterile seal in a sterile area immediately after filling. In addition, some containers require secondary seal to assure the user that the primary seal has not been opened. Sealing Ampuls Ampuls are unique in that the primary and secondary seal are the same. Ampuls are sealed by melting a portion of glass in a flame. Pull seal – Slow, Reliable, powder or other types with wide opening Roll or Tip seal Sealing

Slide 42:

Sealing of Bottles, Cartridges and Vials Primary seal consisting of a tight rubber or plastic closure and secondary seal that holds the primary seal in place. Secondary seals are usually aluminum caps that are crimped on to a thread less container.

Slide 43:

Types of Packages

Slide 44:

Primary driving factors behind the growth of prefilled syringes include: Ease of administration; more convenient for healthcare professionals and end users. Easier for home use; easier in emergency situations. Reduction of medication errors, better dose accuracy. Increased assurance of sterility. Better use of controlled drugs such as narcotics. Lower injection costs - less preparation, Fewer materials, easy storage and disposal. Prefilled Syringes

Slide 45:

Avoids a multitude of disadvantages that are inherent in needle use: Risk of cross-contamination from needle-stick injury. Under- or overdosing resulting in poor injection technique of patients. Costs of sharps disposal. Needlephobia (up to 15% of people are clinically needle-phobic, and most people are apprehensive about receiving injections). Injection site pain. Poor compliance leading to long-term worsening of conditions. Increased costs due to patients visiting hospitals/ physicians’ offices for injections. Parenterals: Needle free systems

Slide 46:

The Intraject device. A prefilled, disposable, needle free injector. The three steps involved in using a prefilled, disposable device

Slide 47:

TPN: Intravenous administration of calories, nitrogen and other nutrients to achieve tissue synthesis and anabolism. Lecithin is used as a stabilizer. Indicated for patients who are unable to ingest food; carcinoma, extensive burns, anorexia, geriatrics, etc. Other ingredients; amino acids, electrolytes, medications, etc. Total Parenteral Nutrition

Slide 48:

Intravenous Fat Emulsion Composition Soybean oil Safflower oil Egg Phospholipids Soybean phospholipids Soybean lecithin Glycerol Glucose Sorbitol Pluronic F 68 DL –Tocopherol Water for injection

Slide 49:

Quality Control of Parenterals Leaker test Clarity test Clarity is tested by visual inspection of containers under light and viewed against a black and white background. Instrumental methods of evaluation is based on the principles of light scattering, light absorption and electrical resistance which are used to count particle and particle size distribution. Coulter-counter method and filtration method are used for monitoring particulate matter. Pyrogen test - In vivo rabbit test - In vitro LAL test

Slide 50:

In vitro testing/LAL test LAL is cell lysate of amebocytes of Limulus Polyphemus (horse shoe crab). Solution of the preparation is made with WFI and LAL reagent is added to it ,incubate at 37°C for 1h. Firm gel formation indicates presence of Pyrogens Sterility testing/microbiological tests The medium selected for culturing should extremely support the growth of the microbes. The protocol contains +ve control to check the ability of the medium to support growth and –ve control to ensure sterility of the media. Safety testing Particularly for biological products

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