Parenteral drug delivery

Parenteral drug delivery

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  PARENTERAL PRODUCTS
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   Definitions relatedto the topic: Parenteral Products Sterilization & Sterile Product Pyrogen SVP LVP Light Resistant Containers Well closed containers Tightly closed containers Single dose container Multiple dose container Hermetically sealed container
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  PARENTERALS para: outside enteron: intestine(i.e. beside the intestine) These are the preparations which are given other than oral routes. Injections: These are  Sterile,  Pyrogen free preparations intended to be administered parenterally (outside alimentary tract).
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  DEFINITION Parenteral preparation orinjectables are the sterile solutions or suspensions of drug in aqueous or oily vehicles meant for introduction into the body by means of an injection under or through one or more layers of the skin or mucous membrane.
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  •Based on typesof packaging 1)Single dose units: ampoules, infusions and prefilled disposable syringes 2)Multiple dose units: multiple dose vials •Based on the production and control a)Small volume parenterals: volume < 100 ml b)Large volume parenterals: volume ≥ 100 ml Classification of parenteral preparations
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  •Based on clinicaluse a)Solutions for irrigation b)Ophthalmic solution c)Dialysis solution d)Diagnostic agent e)Allergenic extracts f)Implants •Based on physical state of product a)Sterile solutions b)Sterile suspensions c)Sterile emulsions d)Sterile solids
• 7.
  Small volume parenterals: Volumeof these parenterals varies from fractions of Milli liter to several hundred milliliters i.e. 1ml to 500ml Example: Injections :- Furosemide, Heparin, Cimetidine, Iron dextran etc Large volume parenterals: Volume of these parenterals varies from 500ml and above. They are administered as single dose injections at a slow rate. Example: Infusion Fluids, Total parenteral nutrition solutions, patient controlled anlgesia, dialysis fluids etc.
• 8.
  Why Parenteral? Parenteral RouteIs Used bcoz 1) Rapid action 2) Oral route can not be used 3) Not effective except as injection 4) Many new drugs particularly those derived from new development in biotechnologically can only be given by parenteral coz they are inactivated in GIT if given orally. 5) New drugs require to maintain potency & specificity sodium that they are given by parenteral.
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   Advantages:  Quickonset of action  Suitable for the drugs which are not administered by oral route  Useful for unconscious or vomiting patients.  Duration of action can be prolonged by modifying formulation.  Suitable for nutritive like glucose & electrolyte.  Suitable for the drugs which are inactivated in GIT or HCl (GI fluid)
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   Disadvantages:  Onceinjected cannot be controlled (retreat)  Injections may cause pain at the site of injection  Only trained person is required  If given by wrong route, difficult to control adverse effect  Difficult to save patient if overdose  Sensitivity or allergic reaction at the site of injection  Requires strict control of sterility & non pyrogenicity than other formulation.
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   Necessities ofParenteral preparations:  Sterility (must)  Pyrogen (must)  Free from particulate matter (must)  Clarity (must)  Stability (must)  Isotonicity (should)  Solvents or vehicles used must meet special purity and other standards.  Restrictions on buffers, stabilizers, antimicrobial preservative. Do not use coloring agents.  Must be prepared under aseptic conditions.  Specific and high quality packaging.
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  Parental Routes ofAdministration: Most Common: 1. Subcutaneous (SC; SQ ;Sub Q) 2. Intramuscular (IM) 3. Intravenous (IV) Others: 4. Intra-arterial (IA) 5. Intrathecal 6. Intraarticular 7. Intrapleural 8. Intracardial 9. Intradermal (Diagnostic)
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  Routes of ParenteralAdministration Intradermal Intramuscular IntravenousSubcutaneous Dermis Intra arterial Vein Artery Muscle Epidermis Subcutaneous tissue
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  Subcutaneous (SC; SQ;Sub Q):  The injection is given under the skin  Need to be isotonic  Upto 2 ml is given  Using ½ to 1 inch 23 gauge needle or smaller needle  Given:  Vaccines  Insulin  Scopolamine  Epinephrine
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   Intramuscular (IM): Striatedmuscle fibre 0.5 to 2 ml sometimes upto 4 ml 1 to 1.5 inch & 19 to 22 gauge needle is used Preferably isotonic  Principle sites: Gluteal (buttocks) Deltoid (upper arms) Vastus lateralis (lateral thigh)  Given: Solutions Emulsions Oils Suspension
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  Intravenous (IV): Into thevein 1 to 1000 ml 1 inch ,19 to 20 gauge needle with injection rate 1ml/ 10 sec. for volume upto 5 ml & 1 ml/ 20 sec. for volume more than 5 ml. Given: Aqueous solutions Hydro alcoholic solutions Emulsions Liposome
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   IV infusionof large volume fluids (100- 1000 ml) has become increasingly popular. This technique is called as Venoclysis.  This is used to supply electrolytes & nutrients to restore blood volume & to prevent tissue dehydration.  Combination of parenteral dosage forms for administration as a unit product is known as an IV admixture. Lactated Ringer Injection USP NaCl Injection USP (0.9 %)– (replenish fluid & electrolyte) Dextrose Injection USP (fluid & electrolyte)
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   Intra-arterial (IA): Direct into the artery  2 to 20 ml  20 to 22 gauge  Solutions & emulsions can be administered  Given:  Radio opaque media  Antineoplastic  Antibiotics
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   Intrathecal:  Alsocalled intra-spinal  Directly given into the spinal cord  1 to 4 ml  24 to 28 gauge  Must be isotonic  Given:  LA  Analgesics  Neuroleptics
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   Intraarticular:  Givendirectly into the joints  2 to 20 ml  5 inch 22 gauge  Must be isotonic  Given:  Morphine  LA  Steroids  NSAID’s  Antibiotics
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   Intrapleural:  Givendirectly into the pleural cavity or lung  Used for fluid withdrawal  2 to 30 ml  2 to 5 inch, 16 to 22 gauge needle  Given:  LA  Narcotics  Chemotherapeutic agents
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  Intracardial:  Directly giveninto the heart  0.2 to 1 ml  5 inch , 22 gauge needle Given:  Cadiotonics  Calcium salts as a calcium channel blockers
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   Intradermal:  Alsocalled as diagnostic testing  0.05 ml  ½ inch, 25 to 26 gauge needle  Should be isotonic  Given:  Diagnostic agents
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  Official Types ofInjections: 1. Solutions of Medicinal Example: Codeine Phosphate Injection Insulin Injection 2. Dry solids or liquid concentrate does not contain diluents etc. Example: Sterile Ampicillin Sodium 3. If diluents present, referred to as.....for injection Example: Methicillin Sodium for injection
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  Parenteral drugs areformulated as solutions, suspensions, emulsions, liposomes, microspheres, nanosystems and powders to be reconstituted as solutions. Formulation mainly consists of two components •Contents •Container Formulation principles:
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  CONTENTS A.Vehicles 1.Water 1.water for injection 2.sterilewater for injection 3. bacteriostatic water for injection 2. Non-aqueous vehicles water miscible vehicles water immiscible vehicles
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  1.Solutes or addedsubstances 1.Antimicrobial preservatives 2.Antioxidants 3.Solubilizers, wetting agents or emulsifiers 4.Buffers 5.Bulking substances or tonicity modifiers 6.Suspending agents 7.Chelating agents 8.Stabilizers 9.Local anaesthetics 10.Antioxidants 2.reducing agents 3.blocking agents 4.synergists 5.chelating agents
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  a. It ismost frequently used in the large scale manufacturer of injections. b. Water of suitable quality for compounding and rinsing product contact surfaces may be prepared either by distillation method or reverse osmosis, to separate adequately various liquid, gas, and solid contaminants and undissociated substances such as pyrogens present in the absence of ions from water. c. It is not required to be sterilized and pyrogen free. d. It is intended to be used within 24 hours after collection. e. The water should be collected in sterile and pyrogen free containers. f. It contains total solid contents not more than 1 mg/100 ml. VEHICLES Water for injection:
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  Sterile water forinjection: a.It must be pyrogen free but an allowable endotoxin level is not more than 0.25 USP endotoxins units per milliliter. b.It may not contain any added substance like antimicrobial agent. c.It is packed in single dose containers not larger than 1 liter. d.This water is intended to be used as solvent, vehicle or diluent for already sterilized and packaged injectable medications. e.It is mainly used for reconstitution of multiple antibiotics. f.It contains more slightly more total solid contents than the water for injection because of the leaching of solids from the glass lined tanks during sterilization.
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  a. It issterile water for injection containing one or more suitable antimicrobial agents. b. It is packaged in prefilled syringes or in vials containing not more than 30 ml of the water. c. It is used as a sterile vehicle in the preparation of small volumes of the injectable preparations ( in large volumes, excessive and toxic amounts of bacteriostatic agents such as benzyl alcohol may cause gasping syndrome(multiorgan failure)). d. Presence of bacteriostatic agent in small volumes may provide flexibility for multiple-dose vials. e. This water is specifically labeled as per the USP requirements as “NOT FOR USE IN NEONATES”. Bacteriostatic water for injection:
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  1.Total solids content-a gravimetric evaluation of the dissociated and undissociated organic and inorganic substances present in the water. 2.Electrolytic measurement of the conductivity- immersing electrodes in the water and measuring the specific conductance, a measurement that depends on the ionic content of water. Conductance may be expressed by the meter scale as 1.conductivity in micromhos 2.resistance in megohms 3.ionic content in ppm of sodium chloride Water for injection should not have a conductivity of more than 1 micromho, 1 megohm and approximately 0.1 ppm sodium chloride Quality tests for Water for Injection:
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  a) These aremainly used to eliminate water entirely or impart from the vehicle, primarily because of the solubility factors or hydrolytic reactions. b) It must be non-irritating, non-toxic or non-sensitizing and it must not exert an adverse effect on the ingredients of the formulation. c) It must not exert a pharmacological activity of its own and it may not adversely affect the activity of the medicinal agent. d) It physical and chemical stability at various pH levels e) It has sufficient viscosity which must be such as to allow ease of injection. f) It has Fluidity, which must be maintained over a fairly wide temperature range g) It has a Boiling point, which should be sufficiently high to permit heat sterilization, miscibility with body fluids and low vapor pressure to avoid problems during heat sterilization. Non-aqueous vehicles
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  Two types ofsolvents are mainly used in combination with water are 1.water miscible solvents 2.water immiscible solvents Water miscible solvents Water immiscible solvents Dioxolanes Fixed oils Dimethylacetamide corn oil N-(β-hydroxyethyl)-lactamide cottonseed oil Butylene glycol peanut oil Polyethylene glycol 400 and 600 sesame oil Propylene glycol Ethyl oleate Glycerin Isopropyl myristate Ethylalcohol Benzyl benzoate
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  a.The most commonlyused solvents are Polyethylene glycol, Propylene glycol and fixed oils. b.Ethyl alcohol (40% ethanol with water) is particularly used in the preparation of solutions of cardiac glycosides. c.Glycols are mainly used in the solutions of barbiturates, certain alkaloids and certain antibiotics. d.The fixed oils must be of vegetable origin so that they will be 1.metabolized 2.liquid at room temperature 3.not become rancid readily 4.clear when cooled to 10°C to ensure the stability and clarity of the injectable product during refrigeration. 5.Not contain mineral oil or paraffin, as these are not absorbed by body tissues. 6.Having saponification value between 185 and 200 and an iodine value between 79 and 141
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  I)All substances addedto the preparation must improve its quality. II)An added substance may •Increase and maintain drug solubility. Examples include complexing agents and surface active agents. 1.Complexing agents include cyclodextrins, mainly Capsitol. 2.Surface active agents include : polyoxyethylene sorbitan monolaurate (Tween 20) and polyoxyethylene sorbitan monooleate (Tween 80). 2. Provide patient comfort by reducing pain and tissue irritation. Examples are Tonicity modifiers such as sodium chloride, dextrose and glycerin. 3. Enhance the chemical stability of a solution. Examples are antioxidants, inert gases, chelating agents and buffers. Solutes or added substances:
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  4. Enhance thechemical and physical stability of a freeze- dried product. Examples are cryoprotectants and lyoprotectants. 5. Enhance the physical stability of proteins by minimizing self aggregation or interfacial induced aggregation. Examples include surfactants. 6. Minimize protein interaction with inert surfaces such as glass, rubber and plastic by adding competitive binders such as albumin and surface active agents to the preparation.
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  1.Protect a preparationagainst the growth of micro organisms. Examples includes preservatives. 1.Sustaining or controlling the drug release by using controlled release polymers. 2.Maintaining the drug in a suspension dosage form by using the suspending agents includes polymers and surface active agents. 3.Maintaining the drug in an emulsified dosage form by using the emulsifying agents includes amphiphilic polymers and surface active agents. 4.Useful in the preparation of liposomes by using hydrated phospholipids.
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  1. Solubility 2. Meltingpoint 3. Polymorphism 4. Surface characteristics 5. Hygroscopicity 6. Partition coefficient 7. Dissolution 8. Bulk density and powder flow properties 9. Wetting PREFORMULATION FACTORS
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