parenteral drug delivery

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PARENTERAL PRODUCTS

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Page 1: Parenteral drug delivery

PARENTERAL PRODUCTS

Page 2: Parenteral drug delivery

Definitions related to the topic: Parenteral ProductsSterilization & Sterile Product PyrogenSVPLVPLight Resistant Containers Well closed containersTightly closed containersSingle dose containerMultiple dose container Hermetically sealed container

Page 3: Parenteral drug delivery

PARENTERALSpara: outsideenteron: 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 or injectables 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 types of packaging1)Single dose units: ampoules, infusions and prefilled disposable syringes2)Multiple dose units: multiple dose vials

•Based on the production and controla)Small volume parenterals: volume < 100 mlb)Large volume parenterals: volume ≥ 100 ml

Classification of parenteral preparations

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•Based on clinical usea)Solutions for irrigationb)Ophthalmic solutionc)Dialysis solutiond)Diagnostic agente)Allergenic extractsf)Implants

•Based on physical state of producta)Sterile solutionsb)Sterile suspensionsc)Sterile emulsionsd)Sterile solids

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Small volume parenterals: Volume of these parenterals varies from fractions of Milli liter to several hundred milliliters i.e. 1ml to 500mlExample: 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.

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Why Parenteral? Parenteral Route Is Used bcoz 1) Rapid action2) Oral route can not be used3) Not effective except as injection4) 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: Quick onset 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: Once injected 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 of Parenteral 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 of Administration: 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 Parenteral Administration

IntradermalIntramuscular

Intravenous Subcutaneous

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):Striated muscle fibre0.5 to 2 ml sometimes upto 4 ml1 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: SolutionsEmulsionsOilsSuspension

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Intravenous (IV): Into the vein 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 solutionsHydro alcoholic solutionsEmulsionsLiposome

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IV infusion of 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: Also called 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: Given directly 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: Given directly 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 given into 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: Also called 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 of Injections:1. Solutions of Medicinal Example: Codeine Phosphate Injection Insulin Injection2. Dry solids or liquid concentrate does not

contain diluents etc. Example: Sterile Ampicillin Sodium3. If diluents present, referred to as.....for

injection Example: Methicillin Sodium for injection

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Parenteral drugs are formulated 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.Vehicles1.Water

1.water for injection

2.sterile water for injection

3. bacteriostatic water for injection

2. Non-aqueous vehicleswater miscible vehicleswater immiscible vehicles

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1.Solutes or added substances1.Antimicrobial preservatives2.Antioxidants3.Solubilizers, wetting agents or emulsifiers4.Buffers5.Bulking substances or tonicity modifiers6.Suspending agents7.Chelating agents8.Stabilizers9.Local anaesthetics10.Antioxidants

2.reducing agents3.blocking agents4.synergists5.chelating agents

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a. It is most 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.

VEHICLESWater for injection:

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Sterile water for injection:

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 is sterile 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 micromhos2.resistance in megohms3.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 are mainly 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 of solvents are mainly used in combination with water are

1.water miscible solvents

2.water immiscible solvents

Water miscible solvents Water immiscible solvents

Dioxolanes Fixed oilsDimethylacetamide corn oilN-(β-hydroxyethyl)-lactamide cottonseed oil

Butylene glycol peanut oilPolyethylene glycol 400 and 600 sesame oil

Propylene glycol Ethyl oleateGlycerin Isopropyl myristateEthylalcohol Benzyl benzoate

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a.The most commonly used 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 be1.metabolized2.liquid at room temperature3.not become rancid readily4.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 added to 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 the chemical 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 preparation against 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. Melting point3. Polymorphism4. Surface characteristics5. Hygroscopicity6. Partition coefficient7. Dissolution8. Bulk density and powder flow

properties9. Wetting

PREFORMULATION FACTORS

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