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Parentrals
- 1. PARENTERALS 1HINDU COLLEGE OFPHARMACY NARESH GORANTLA M.Pharm., (Ph.D) Assoc. Professor, Dept of Pharmaceutics, Balaji college of Pharmacy, Ananthapuramu
- 2. CONTENTS • Introduction • Routesof administration • Advantages • Disadvantages • Formulation • Manufacture • Filling • Packaging • Sealing • Sterilization • Quality control 2
- 3. INTRODUCTION DEFINITION “ Introduced otherthan by way of the intestine” According to IP “Parenterals are injectable preparations, sterile preparations intended for administration by injection, infusion or implantation into the body. 3
- 4. A BRIEF ABOUTPARENTERALS : • para: outside enteron: intestine • Any drug or fluid whose delivery does not utilize the alimentary canal for entry into body tissues. • Parenteral products are injected through the skin or mucous membranes into the internal body compartments. • These are the preparations which are given other than oral routes. 4
- 5. Requirements of Parenterals Sterility Non pyrogenicity Clarity Isotonicity Stability 5
- 6. ROUTES OF ADMINISTRATION Threeprimary routes of parenteral administration • Subcutaneous • Intramuscular • Intravenous 6 Other routes : • Intra arterial • Intra thecal • Intra articular • Intra cardial • Intra dermal (Intracutaneous) • Intra pleural • Intra spinal • Intra cesternal
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- 8. Subcutaneous Route NMT2 ml Aspiration Absorption depending on blood flow Constant & slow absorption Prolonged effect Drugs Insulin Local Anaesthetics Vaccines
- 9. Subcutaneous Injection Sites Abdominal wall Thigh Arms
- 10. Intramuscular Route Solutions,emulsions, suspensions and powders 0.5 to 2 ml and upto 4 ml. Absorption depending on blood flow Slower onset & slower absorption Longer duration of action Drugs Glucagons Adrenaline
- 11. Intramuscular Injection Sites Gluteal muscles Deltoid muscles Triceps and thigh muscles
- 12. Intravenous Route Drugsin aqueous solutions, Hydro alcoholic solutions, Emulsions and Liposomes. 1 to 1000 ml Rapid immediate onset Administer slowly to avoid irritation. Drugs with shorter half life- IV Infusion Drugs that are too irritating in other routes- Nitrogen mustards.
- 13. Intravenous Injection Sites Large proximal veins In the side fore arm
- 14. • Parentrals areclassified into two types. They are 1. Small Volume Parenterals (upto 100ml) Single / multiple doses Primary uses of SVP • Therapeutic injections • Opthalmic products • Diagnostic agents • Allergenic extracts 14
- 15. 2. Large VolumeParenterals (100-1000ml) Clinical Utilization of LVP • Basic Nutrition • Restoration of Electrolyte balance • Fluid replacement • Blood and blood products • Drug carriers 15
- 16. ADVANTAGES • Quick onsetof action and complete bioavailability • Suitable for the drugs which are not administered by oral route • Useful for unconscious or vomiting patients. • Useful for patients who cannot take drugs orally • Useful for emergency situations • Duration of action can be prolonged by modifying formulation. • Can be done in hospitals, ambulatory infusion centers, and home health care 16
- 17. DISADVANTAGES • Pain oninjection. • Difficult to reverse an administered drug’s effects. • Sensitivity or allergic reaction at the site of injection. • Requires strict control of sterility & non pyrogenicity than other formulation. • Only trained person is required • Require specialized equipment, devices, and techniques to prepare and administer drugs. • More expensive and costly to produce. 17
- 18. FORMULATION 18 1. Vehicles 2. Preservatives 3.Buffers 4. Tonicity adjusting agents 5. Surfactants 6. Chelating agents
- 19. 19 Aqueous vehicle : WaterFor Injection(WFI) USP : • Highly purified water used as a vehicle for injectable preparations which wil be subsequently sterilized. • USP requirement include not more than 10 parts per million of total solids. • pH of 5.0 to 7.0 • WFI may prepared by either distillation or reverse osmosis. • Stored for less than 24hr at RT or for longer times at specific temperatures. • It may not contain any added substances. • Stored in chemically resistant tank.
- 20. Bacteriostatic Water forInjection (BWFI) : • This type of water used for making parenteral solutions prepared under aseptic conditions and not terminally sterilized. • Need to meet USP sterility test. • It can contain an added bacteriostatic agent when in containers of 30ml or less 20
- 21. Sterile Water forInjection USP • SWFI containing one or more suitable bacteriostatic agents. • Multiple-dose containers not exceeding 30 ml. • They are permitted to contain higher levels of than WFI because of the possible leaching of glass container. • Wash wounds, surgical incisions, or body tissues. 21
- 22. 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) – Peanut oil – Corn oil – Cotton seed oil (depo-testosterone) – Sesame oil – Soybean oil (source of fat in intralipid) – Ethyl oleate – Isopropyl myristate 22
- 23. OTHER ADDITIVES Antibacterial Agents •Limited concentration of agents - Phenylmercuric nitrate and Thiomersol 0.01% • Required to prevent microorganism growth - Benzethonium chloride and benzalkonium chloride 0.01% - Phenol or cresol 0.5% - Chlorobutanol 0.5% 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 23
- 24. Tonicity Agents Chelatingagents Reduce pain of injection – ethylenediamine tetraacetic acid Can include buffers - Sodium chloride - Potassium chloride Inert Gases - Dextrose N2 (gentamycin sulfate injection) - mannitol - sorbitol CO2 (sodium bicarbonate injection) Surfactants polyoxyethylene sorbitan monooleate sorbitan monooleate 24
- 25. MANUFACTURING STEPS 1.cleningcontainers, closures & equipment 2.collection of materials 3.preparation of parenteral products 4.filtration 5.filling the preparation in final containers 6.sealing the containers 7.sterilization 8.evalution 9.packing
- 26. FILLING 1. Filling ofliquids A. Small volume parentrals Syringe based system Retraction device B. Large volume parentrals By gravity By pressure By vaccum 26
- 27. 2. Filling ofsolids Scoop method Machine (Auger) method Problems Stratification Electrostatic charges Air pockets Clumping 27
- 28. 28 Types of FillingEquipment vial, ampoules, plastic containers, bottles syringe cartridges, plastic mini bags ,, vials, bottles, plastic mini bags. ,, Liquid products such as solutions, suspensions emulsions and solutions ,, Powders ,, Piston type (Cozzoli) Rotary chemical pump Time or pressure type Auger Vacuum Pressure displacement types of packageTypes of product filledMechanism of filling
- 29. PACKAGING Glass containers: 29 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
- 30. Plastic containers : Closures : 30 ThermoplasticThermosetting Polyethylene (Polyethene)High Density Polyethene Polyvinyl chloride (PVC) Poly methyl methacrylate Polystyrene Polypropylene Polyamides Polycarbonates Phenol Formaldehyde Urea Formaldehyde Melamine Formaldehyde Pharmaceutical rubbers Butyl Rubbers Natural Rubbers Neoprene Rubbers Polyisoprene rubbers Silicone Rubbers
- 31. PREFILLED SYRINGES : •Administration is more convenient for healthcare professionals and end users. • Reduction of medication errors, better dose accuracy. • Better use of controlled drugs such as narcotics. • easy storage and disposal. 31
- 32. SEALING Sealing Ampoules Ampoulesare unique in that the primary and secondary seal are the same. Ampoules 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 32
- 33. 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. 33
- 34. STERILIZATION Dry heatsterilization Steam sterilization Sterilization by filtration Gas sterilization Sterilization by ionizing radiation 34
- 35. QUALITY CONTROL Sterilitytesting Pyrogen test Clarity test Leakage test 35
- 36. Flow of MaterialsThrough the Production Department Product storage PackagingFilling Sealing Sterilization Sterilization Cleaning Cleaning Compounding Filtration of Product Solution Ingredients Vehicles Solutes Processing Equipment Container Components 36
- 37. 1. STERILITY TESTING A. Membrane filtration 37
- 38. 38 B. Direct inoculationof culture media
- 39. A. Invivo test(Rabbit test) • Pyrogenic - means producing fever Pyrogens - fever inducing substances Endotoxins Produced mostly by gram-negative bacteria Endotoxin - complex of pyrogenic lipopolysaccharide, a protein and inert lipid. 39 2. PYROGEN TEST
- 40. The result ofpyrogen test No.of Rabbits Individual Tempt. rise (°c) Temperature rise in group (°c) Result 3 rabbits 0.6 1.4 Passes If above not passes 3+5 = 8 rabbits 0.6 3.7 Passes 40 If above test not passes perform the test again If above test not passes, the sample is said to be pyrogenic and the test fails
- 41. B. Invitro test(LAL) . Limulus polyphemus = horseshoe crab Limulus - genera of crab Amebocyte - crab blood cell from which active component is derived The name of the test is also Limulus amebocyte lysate (LAL) test 41
- 42. Mechanism of LAL •The test is based on the primitive blood- clotting mechanism of the horse shoecrab enzymes located with the crab's amebocyte blood cells + endotoxins (pyrogens) ↓ incubated at 37°c initiation of an enzymatic coagulation ↓ proteinaceous gel (with in 60 mins) 42
- 43. Lysate -component is obtained by separating amebocytes from the plasma and then lysing them. The hearts of mature crabs are punctured and bled to collect the circulating amebocyte blood cells. Since amebocytes act as activators of the coagulation mechanism in the crab, an antiaggregating agent must be added to inhibit aggregation. N-Ethylmaleimade is the most commonly used anti- aggregant. LAL test is the combinationof 0.1 ml test sample with 0.1 ml LAL reagent. After 1 hour incubation at 37°C, the mixture is analyzed for the presence of a gel clot. 43 Commercially derived LAL reagents
- 44. Unwanted mobileinsoluble matter other than gas bubbles present in the given product. It may be dangerous when the particle size is larger than R.B.C. & may block the blood vessel. It can be done by the following methods. A. Visual method B. Light scattering & Light absorption C. Light blockage method D. Coulter current method 44 3. CLARITY TEST
- 45. A. Dye test(Ampoules) Immersing the ampoules in a dye solution 1% metylene blue solution The vacuum on the tank is then released as rapidly as possible to put maximum stress on weak seals. Defective ampoules will contain blue solution. B. Spark tester probe (Vials & Bottles) • Water hammer sound • When the space is evacuated then it releases blue spark 45 4. Leakage Test
- 46. CONCLUSION A widevariety of devices and new methods of drug delivery employed. Each has its advantage and disadvantages, which have to be carefully considered by the therapist. Parenteral dosage forms differ from all other drug dosage forms because they are injected directly into body tissues through primary protective systems of human body the skin and mucous membranes. They must be free of contaminating microorganism, harmful substances, free of pyrogenic contamination, free of particulate matter. In coming future we can expect much more advance technology in utilizing parenteral products for safety desirable effects in human being. 46
- 47. • Theory andpractice of Industrial pharmacy. Lieberman, Herbert A. Vol.1.Lachman, Third edition Pharmaceutical Dosage Forms. Avis, Kenneth E. Vol. 2: Parenteral Medications Pharmaceutical Dosage Forms. Avis, Kenneth E Vol. 3 : Parenteral Medications Pharmaceutical packaging technology. D A Deam , E R Evans, I H Hall Modern Pharmaceutics. Gilbert S. Banker, Christopher T. Rhodes. Fourth Edition. www.pharmaceuticalonline.com 47 REFERENCES
- 48.