Lecture 15 - Parenteral Products PDF

Lecture 15: Parenteral Product & Sterilization Allen , Popovich, and Ansel 1  Parenteral Medications  Small- and large- volume injectable preparation  Irrigation fluid to bathe body wounds or surgical opening  Dialysis solutions ...

Lecture 15: Parenteral Product & Sterilization Allen , Popovich, and Ansel 1  Parenteral Medications  Small- and large- volume injectable preparation  Irrigation fluid to bathe body wounds or surgical opening  Dialysis solutions  Biological preparations – vaccines, toxoids, antitoxins  Blood replenishment products 2  Advantages  Unconscious  Not active orally  Rapid acting  Nutrition  Depots  Implantable pumps 3  Disadvantages  Difficult to make/cost  Specific equipment  Hard to retrieve  Pain damage 4  Injections  Sterile – absence of living microorganisms  Pyrogen-free – pyrogens are fever-producing organic substances arising from microbial contamination  Administered parenterally by health professions (except insulin) 5 Parenteral Routes of Administration  Intravenous Injections – directly into the circulation  Intramuscular Injections – muscle mass – mid-deltoid area and gluteus medius  Subcutaneous Injections – subcutaneous tissue beneath the skin layers – e.g. arm or thigh  Intradermal Injections – the most superficial skin layer 6 Parenteral Routes of Administration 7  Intravenous Injections  Bolus – single, small-volume injection  Infusion – slow, large-volume  Aqueous Solutions – no precipitated drug after injection (emboli) – fat emulsion for caloric sources and essential fatty acids (vs glucose)  Aqueous Emulsions 8 Intralipid 9  Intramuscular Injections  Deep into skeletal muscles – gluteal or lumbar muscles – minimized hitting nerve or blood vessel  Solutions (aqueous or oleaginous) & Suspensions – low drug solubility – sustained drug action – suspension of penicillin G benzathine (7-10 days of effect) 10  Subcutaneous Injections  Loose subcutaneous tissue – small volumes (2 mL or less)  Sites – forearm, upper arm, thigh etc.  Aqueous Solutions  Suspensions – depot or repository for prolonged action  Pellets – implantation (e.g., Norplant; Zoladex) 11  Intradermal Injections  Corium of Skin  Very Small Volume (~0.1 mL)  Sites – arm and back  Diagnostic Measures – tuberculin testing – allergy testing 12  Official Types of Injections  “Drug Solution Injection” – Insulin Injection, USP  “Sterile Drug Powder” – Sterile Ampicillin Sodium, USP  “_Drug Powder for Injection” – Methicillin Sodium for Injection, USP  “Sterile _Drug Suspension” – Sterile Dexamethasone Acetate Suspension, USP  “Sterile Drug Powder for Suspension” – Sterile Ampicillin for Suspension, USP 13  General Categories of Injections  Solutions ready for injection – Insulin Injection, USP  Dry solids products ready to be combined with solvents (solution) – Sterile Ampicillin Sodium, USP  Suspensions ready for injection – Sterile Dexamethasone Acetate Suspension, USP  Dry solids products ready to combined with solvents (suspension) – Sterile Ampicillin for Suspension, USP  Emulsions (Propofol emulsion, Intralipid emulsion) 14 Solvents and Vehicles for Injections  Water (distillation, filtration, others) – Water for Injection, USP – Sterile Water for Injection, USP – Bacteriostatic Water for Injection, USP  Sodium Chloride – Sodium Chloride Injection, USP – Bacteriostatic Sodium Chloride Injection, USP  Ringer’s Injection, USP – NaCl, KCl and CaCl (physiologic fluids) 2 – Lactated Ringer’s Injection, USP  Dextrose 15  The solutions and suspensions of drugs intended for injection are prepared in the following manners: 1. Solvents and vehicles must meet special purity and other standards ensuring their safety by injection. 2. The use of added substances, such as buffers, stabilizers, and preservatives, fall under specific guidelines of use and are restricted in certain parenteral products. The use of coloring agents is strictly prohibited. 3. Parenteral products always sterilized, meet sterility standards, and must be pyrogen-free. 4. Must meet the compendial standards for particulate matter. 5. Must be prepared in environmentally controlled areas. 6. Be packaged in special hermetic containers of specific and high quality. 16  The solutions and suspensions of drugs intended for injection are prepared in the following manners: (con’t) 7. Each container is filled to a volume in slight excess of the labeled volume to be withdrawn. 8. The volume of injection permitted in multiple-dose containers is restricted. 9. Specific labeling regulations apply to injections. 10. Sterile powders intended for solution or suspension immediately prior to injection are frequently packaged as lyophilized or free-dried powders to permit ease of solution or suspension upon the addition of the solvents or vehicles. 17  Nonaqueous Vehicles for Injections  Fixed oils – must be of vegetable origin – must be liquid at room temperate (unsaturated) – Free of acids (muscle irritation) – corn oil, cottonseed oil, peanut oil, sesame oil  Water miscible substances – glycerin, polyethylene glycols, propylene glycol, alcohol  Others (lesser used) – ethyl oleate, isopropyl myristate, dimethylacetamide 18  Added Substances  Drug  Isotonic agents – NaCl, dextrose  Buffer agents – chemical degradation  Antimicrobial (preservatives) – thimerosal, benzoyl alcohol  Antioxidants – sodium bisulfite (aqueous) – ascorbic acid (aqueous) 19  Mode of Preservative Action Preservatives interferes with microbial growth, multiplication, and metabolism through one or more of the following mechanisms: 1. Modification of cell membrane permeability and leakage of cell constituents. 2. Lysis and cytoplasmic leakage 3. Irreversible coagulation of cytoplasmic constituents 4. Inhibition of cellular metabolism 5. Oxidation of cellular constituents 6. Hydrolysis 20  Probable Modes of Action of Some Preservatives  Benzoic acid, Boric acid, p-Hydroxybenzoates: Denaturation of proteins  Phenols and Chlorinated phenolic compounds: Lytic and denaturation action on cytoplasmic membranes  Alcohols: Lytic and denaturation action on membranes  Quaternary compounds: Lytic action on membranes  Mercurials: Denaturation of enzymes by combining with thiol (-SH) groups. 21  Sterilization  Sterility – the absence of life  Sterilization – complete destruction of all viable organisms  Disinfectant – a substance used on inanimate objects to render them noninfectious  Antiseptic – a substance used to prevent sepsis  Pyrogen – fever producing substance 22  Considerations in Sterilization  Application of an adequate sterilization treatment  Verification that the materials are sterile  Protection of the sterile material  Delivery, opening, and use of the sterile material without entrance of contamination 23  Methods of Sterilization  Steam Sterilization  Dry-heat Sterilization  Sterilization by Filtration  Gas Sterilization  Sterilization by Ionizing Radiation 24  Steam Sterilization  Moist heat in the form of saturated steam under pressure (autoclaving)  Most reliable method for the destruction of all forms of microorganisms  Kills by the result of coagulation of some protein in the cell (bacteria easier than spores)  Typical conditions 121°C for 20 min, 15 psi  Types of products this can be used for  Advantages/disadvantages (oils/fats, oleaginous preps) powders 25 Tabletop Autoclave 26  Application of Steam Sterilization  In general, steam sterilization is applicable to pharmaceutical preparations and materials that can withstand the required temperatures and are penetrated by but not adversely affected by moisture.  Solutions in sealed container, such as ampuls, are readily sterilized by this method.  Sealed empty vials can be sterilized by autoclaving only if they contain small amount of water.  Applicable to bulk solutions, glassware, surgical dressings and instruments  Not useful for oils, fats, oleaginous preparations, other preparations not penetrated by the moisture or for exposed powders that may be damaged by the condensed moisture. 27  Dry Heat Sterilization  Sterilizing ovens  Microorganism death by oxidation process  Good for dry glassware, petroleum jelly, mineral oils, talcum powder, some dry powders  Typical 170°C for > 1hr  Advantages and disadvantages  Not all drugs stable at this temp 28  Sterilization by Filtration  For solutions that cannot be heated  Sterilization is usually accomplished by filtration employing one of the several bacterial filters  These filters work by virtue of interlacing pores bacteria or particles become entrapped in these pores and thus are removed  Advantages/disadvantages (flaws) (amphotericin B, adsorption, suspensions)  0.22 micron (viruses less than 0.025 micron) 29 Membrane Filters 30 MILLEX Filter Unit 31 Millipore Sterilization 32 Filter Unit 33  Methods of Sterilization  Gas Sterilization – destruction of all living microorganisms with a chemical in a gaseous or vapor state (e.g., ethylene oxide, propylene oxide) – advantages/disadvantages (penetrates)  Sterilization by Ionizing Radiation – UV light – gamma radiation – advantages and disadvantages 34  Pyrogens  Cause febrile reactions  Gram negative bacteria – endotoxins, lipopolysacchride  Gram positive bacteria – exotoxins  Can be destroyed – heating at high temperature (250°C for 4 hr) – potassium permanganate/barium hydroxide filter  Other methods for removal 35  Pyrogen Testing  USP Rabbit Test  Limulus Amebocyte Lysate (LAL) Test: – Extract from the blood cells of Horse-crab (Limulus polyphemus) contains an enzyme and protein that coagulates in the presence of low levels of lipopolysaccharides (Pyrogen) 36 USP Rabbit Test 37  Containers  Types of dosing – Single-dose containers – Multiple-dose containers  Types of packaging – Ampuls – Vials – Pre-filled syringes 38 Packaging of Injections (Multiple-Dose Vials) 39 Mix-O-Vial 40 ADD-Vantage System 41 Packaging of Injections (Ampuls) 42  Ampuls  The oldest type of parenteral product containers and made entirely of glass  Intended for single use only – opened by breaking the glass at a score line on the neck  Product must be filtered before administration – because glass particles may become dislodged during ampul opening 43 Packaging of Injections (Vials) 44  Vials  Glass or plastic containers closed with a rubber stopper and sealed with an aluminum crimp  Advantages over ampuls – multiple doses (with a bacteriostatic agent) – easier to remove the product – eliminate the risk of glass particle contamination during opening  Disadvantages – rubber stopper may become cored – multiple withdrawals may result in microbial contamination 45  Glass Containers  Type I (borosilicate) – chemical resistant, low thermal coefficient of expansion  Type II (soda-lime treated glass) – lower concentration of migratory oxides than Type III – treated with sulfur oxide to dealkalize the internal surface – solution pH less than 7  Type III (soda-lime glass) – good for anhydrous liquids or dry substances 46  Plastic Containers  Plastic polymers – polyvinylchloride (PVC) – polyolefin  PVC is flexible and nonrigid.  Polyolefin is semi-rigid and can be stored upright  Advantages over glass – unbreakability – easier storage – reduced weight – and improved safety 47  Packaging of Injections (Pre-Filled Syringes and Cartridges) 48  Pre-Filled Syringes and Cartridges  Designed for maximum convenience  Administered in an emergency – e.g., atropine, epinephrine are available for immediate injection  Improved sterility and accuracy – e.g., Tubex are ready-to-use parenteral packages – consist of a metal or plastic cartridge holder – a prefilled medication cartridge with a needle attached – medication is premixed and premeasured 49 Tubex Injector 50 Administration via Tubex Injector 51  Packaging of Injections (Infusion Solutions)  Infusion solutions – for the intermittent or continuous infusion of fluids or drugs  Small volume parenterals (SVP) – volume less than 100 ml  Large volume parenterals (LVP) – volume of 100 ml or greater 52 Recommended Overages for Official Parenteral Products 53