国上K秋特 “-风 国生 ®1.Introduction Parenteral Products 2.Routes of parenteral administration 3.Formulation of parenteral products School of Pharmacy ©4.Packaging Chen Jian 2013.4 ®5.Stability chenjian@sjtu.edu.cn 6.Sterilization methods 周7.Quality assurance 国丛生 圈上秋建一 ④1.Introduction ®l.Introduction ·Parenteral: ·Advantages not via the digestive tract. ·rapid onset; As a practical matter,the parenteral route ·predictable effect, encompasses injectable formulations,though very high bioavailability; implants are also included .avoid individual difference, rectal administration would not fall under the .Disadvantages definition of parenteral other non-oral dosage forms also are excluded .Pain (epicutaneous,ocular,otic,nasal,pulmonary) ·Discomfort very hard to counteract an incorrect drug or dose 国活人生 国生一 ©l.Introduction 2.Routes of parenteral administration Special significant under the conditions: Subcutaneous route(SC) Very inefficient or unreliable GIT Intramuscular route(IM) absorption .Intravenous route(IV) Extensive mucosal or first-pass effect when oral: ·Intradermal(ID) .Clinical need for rapid,assured high concentration: 1
1 Parenteral Products School of Pharmacy Chen Jian 2013.4 chenjian@sjtu.edu.cn Shanghai Jiao Tong University 1. Introduction 2. Routes of parenteral administration 3. Formulation of parenteral products 4. Packaging 5. Stability 6. Sterilization methods 7. Quality assurance Shanghai Jiao Tong University 1. Introduction • Parenteral : • not via the digestive tract. • As a practical matter, the parenteral route encompasses injectable formulations, though implants are also included • rectal administration would not fall under the definition of parenteral • other non-oral dosage forms also are excluded (epicutaneous, ocular, otic, nasal, pulmonary) Shanghai Jiao Tong University 1. Introduction • Advantages • rapid onset; • predictable effect; • very high bioavailability; • avoid individual difference; • Disadvantages • Pain • Discomfort • very hard to counteract an incorrect drug or dose Shanghai Jiao Tong University 1. Introduction • Special significant under the conditions: • Very inefficient or unreliable GIT absorption • Extensive mucosal or first-pass effect when oral; • Clinical need for rapid, assured high concentration; Shanghai Jiao Tong University 2. Routes of parenteral administration • Subcutaneous route (SC) • Intramuscular route (IM) • Intravenous route (IV) • Intradermal (ID)
国丛生 m 2.Routes of parenteral administration Subcutaneous route(SC) Site:beneath the skin in the loose interstitial tissue Volume 0.5-2ml Characteristic:slower onset,less total abs. Formulation Constraints:not irritating Precautionary Notes:ensure that the needle is not in a vein. 国生一 圈上人生 2.Routes of parenteral administration 2.Routes of parenteral administration Intramuscular route(IM) Site:striated muscle fibers,1.5 inches Intravenous route(IV) Volume:0.5-2ml .IV injection Characteristic:rapid onset;drug depot, sustained-release:factors affecting the ·IV infusion diffusion process control the release rate; .Formulation Constraints:nearly all drug classes Precautionary Notes:potential muscular or neural damage 国生一 国生一 2.Routes of parenteral administration 2.Routes of parenteral administration Intravenous route(IV) Intravenous route (IV) IV infusion(venoclysis) .IV injection vein puncture) -Site:vein -Volume 100-1000ml -Site:large proximal veins Volume 1-100ml LVP:to provide energy,water and dilution effect Drug:provide continuousand prolonged effect -Characteristic:extremely rapid and predictable response -Formulation Constraints: -Formulation Corstraints:solutions,emulsions,liposomes solutions and some emulsions normally need to be isotonic -Precautionary Notes:Drug shock:too rapid abs control the injection rate 2
2 Shanghai Jiao Tong University 2. Routes of parenteral administration • Subcutaneous route (SC) • Site : beneath the skin in the loose interstitial tissue • Volume : 0.5~2ml • Characteristic : slower onset, less total abs. • Formulation Constraints : not irritating • Precautionary Notes : ensure that the needle is not in a vein. Shanghai Jiao Tong University 2. Routes of parenteral administration • Intramuscular route (IM) • Site : striated muscle fibers, 1.5 inches • Volume : 0.5~2ml • Characteristic : rapid onset; drug depot, sustained-release; factors affecting the diffusion process control the release rate; • Formulation Constraints : nearly all drug classes • Precautionary Notes : potential muscular or neural damage Shanghai Jiao Tong University 2. Routes of parenteral administration • Intravenous route (IV) • IV injection • IV infusion Shanghai Jiao Tong University 2. Routes of parenteral administration • Intravenous route (IV) • IV injection ( vein puncture) – Site : large proximal veins – Volume : 1~100ml – Characteristic : extremely rapid and predictable response – Formulation Constraints : solutions, emulsions, liposomes – Precautionary Notes: Drug shock: too rapid abs. control the injection rate Shanghai Jiao Tong University 2. Routes of parenteral administration • Intravenous route (IV) • IV infusion (venoclysis) – Site : vein – Volume : 100~1000ml – Characteristic : » LVP: to provide energy, water and dilution effect » Drug: provide continuous and prolonged effect – Formulation Constraints : » solutions and some emulsions: » normally need to be isotonic – Precautionary Notes : IV admixtures: must avoid incompatibility; sterility
国生 国生 2.Routes of parenteral administration 3.Formulation of parenteral products ·Intradermal(ID) .Site:beneath epidermis,anterior forearm Physicochemical properties of the drug ·Volume:0.05-0.lml The added substances; .Characteristic:detect hypersensitivity reations Formulation Constraints:isotonic The vehicle(the delivery media) ·Precautionary Notes 国我生一 圈生 3.Formulation of parenteral products 3.Formulation of parenteral products The added substances; Physicochemical properties of the drug ·Antioxidants Crystal characteristics Antimicrobial agents Buffers Chemical modification of the drug Chelating agents Inert gases Polymorphism Solubilizing agents and surfactants pH and pKa Tonicity adjustment agents Protectants 国丛生一 国我生一 3.Formulation of parenteral products 3.Formulation of parenteral products The added substances: The added substances; ·Antioxidants .Antimicrobial agents -Antioxidants maintain product stability by being -Required in all multiple-dose parenteral preferentially oxidized and gradually consumed products over the shelf life of the product. -Salts of sulfur dioxide,including bisulfite, -try to avoid using it in all single-dose metasulfite,and sulfite parenteral products 3
3 Shanghai Jiao Tong University 2. Routes of parenteral administration • Intradermal (ID) • Site : beneath epidermis, anterior forearm • Volume : 0.05~0.1ml • Characteristic :detect hypersensitivity reations • Formulation Constraints : isotonic • Precautionary Notes Shanghai Jiao Tong University 3. Formulation of parenteral products • Physicochemical properties of the drug • The added substances; • The vehicle( the delivery media) Shanghai Jiao Tong University 3. Formulation of parenteral products • Physicochemical properties of the drug • Crystal characteristics • Chemical modification of the drug • Polymorphism • pH and pKa Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Antioxidants • Antimicrobial agents • Buffers • Chelating agents • Inert gases • Solubilizing agents and surfactants • Tonicity adjustment agents • Protectants Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Antioxidants – Antioxidants maintain product stability by being preferentially oxidized and gradually consumed over the shelf life of the product. – Salts of sulfur dioxide, including bisulfite, metasulfite, and sulfite Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Antimicrobial agents – Required in all multiple-dose parenteral products – try to avoid using it in all single-dose parenteral products
国生一 国生 3.Formulation of parenteral products 3.Formulation of parenteral products .The added substances; .The added substances; ·Buffers Chelating agents -A certain pH range are required to maintain -Chelating agents are added to complex and drug stability and solubility. inactivate metals such as copper,iron,and -acetates,citrates,phosphates,and amino zinc that generally catalyze oxidative acids degradation of drug molecules. -EDTA derivatives and salts 国我生一 圈上秋生 3.Formulation of parenteral products 3.Formulation of parenteral products The added substances; The added substances; .Solubilizing agents ·Inert gases -Ethanol,glycerin,propylene glycol, -Displacing the air in the solution with inert polyethylene glycol,lecithin gases to enhance the product integrity of ·Surfactants oxygen-sensitive medicaments -Wetting and preventing crystal growth in a suspension -Nitrogen or argon -Solubilizing hydrophobic drugs in emulsion 国活人连 Micrographs of osmotic pressure 3.Formulation of parenteral products on red blood cells The added substances; Tonicity adjustment agents Hypertonic Isotonic Hypotonic -Osmotic pressure changes can cause hemolysis or crenation of red blood cells if given in quantities larger than 100 mL -Hypertonic:higher osmotic pressure -Hypotonic:lower osmotic pressure http://en.wikipedia.org/wiki/File:Human_Erythrocyt es_OsmoticPressure_PhaseContrast_Plain.svg 4
4 Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Buffers – A certain pH range are required to maintain drug stability and solubility. – acetates, citrates, phosphates, and amino acids Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Chelating agents – Chelating agents are added to complex and inactivate metals such as copper, iron, and zinc that generally catalyze oxidative degradation of drug molecules. – EDTA derivatives and salts Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Inert gases – Displacing the air in the solution with inert gases to enhance the product integrity of oxygen-sensitive medicaments – Nitrogen or argon Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Solubilizing agents – Ethanol, glycerin, propylene glycol, polyethylene glycol, lecithin • Surfactants – Wetting and preventing crystal growth in a suspension – Solubilizing hydrophobic drugs in emulsion Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Tonicity adjustment agents – Osmotic pressure changes can cause hemolysis or crenation of red blood cells if given in quantities larger than 100 mL – Hypertonic: higher osmotic pressure – Hypotonic: lower osmotic pressure Hypertonic Isotonic Hypotonic Micrographs of osmotic pressure on red blood cells http://en.wikipedia.org/wiki/File:Human_Erythrocyt es_OsmoticPressure_PhaseContrast_Plain.svg
国生 国生 3.Formulation of parenteral products Osmolality and tonicity .The added substances; Some solutions are isosmotic but not .Tonicity adjustment agents isotonic.This is because the cell membrane -Normal serum:285mOsm/L of the red blood cell is not semipermeable -Glucose to all drugs. -Sodium chloride 国我生一 圈丛生 3.Formulation of parenteral products 3.Formulation of parenteral products The added substances; The added substances; ·Protectants ·Tonicity adjustment -Added to a formulation to protect against -Sodium chloride equivalent loss of activity -Cryoscopy -Cryoprotectants -Lyoprotectants -Prevent loss of active substance by adsorption 国生 国生一 3.Formulation of parenteral products 3.Formulation of parenteral products The vehicle(the delivery media) ·Aqueous vehicles .The vehicle(the delivery media) -Water for injection (WFI) To eliminate:microorganisms,dissolved organic and inorganic substances,particulate ·Aqueous vehicles contaminants,pyrogen -Sterile and bacteriostatic water for injection .Nonaqueous and mixed Vehicles Must be sterile; In small volume container 5
5 Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Tonicity adjustment agents – Normal serum: 285mOsm/L – Glucose – Sodium chloride Shanghai Jiao Tong University Osmolality and tonicity • Some solutions are isosmotic but not isotonic. This is because the cell membrane of the red blood cell is not semipermeable to all drugs. Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Tonicity adjustment – Sodium chloride equivalent – Cryoscopy Shanghai Jiao Tong University 3. Formulation of parenteral products • The added substances; • Protectants – Added to a formulation to protect against loss of activity – Cryoprotectants – Lyoprotectants – Prevent loss of active substance by adsorption Shanghai Jiao Tong University 3. Formulation of parenteral products • The vehicle( the delivery media) • Aqueous vehicles • Nonaqueous and mixed Vehicles Shanghai Jiao Tong University 3. Formulation of parenteral products • The vehicle( the delivery media) • Aqueous vehicles – Water for injection (WFI) » To eliminate: microorganisms, dissolved organic and inorganic substances, particulate contaminants, pyrogen – Sterile and bacteriostatic water for injection » Must be sterile; » In small volume container
国生 国生 3.Formulation of parenteral products 3.Formulation of parenteral products ·Pyrogen Properties of pyrogen .A pyrogen is a substance that induces fever-endotoxin. ·Thermally stable The bacterial substance lipopolysaccharide(LPS), ·Small size present in the cell wall of some bacteria LPS could leads to release of pro-inflammatory ·Water soluble cytokines and nitric oxide,which may lead ultimately Nonvolatile to fatal consequence. ·Adsorbable ·Fever,chll, 圈以丝 圈上人堂一 3.Formulation of parenteral products 3.Formulation of parenteral products .Pyrogen removal in water(depyrogenation) The vehicle(the delivery media) ·Activated charcoal .Nonaqueous and mixed vehicles ·Distillation -Stabilize drugs that are readily hydrolyzed ·Ion exchange by water ·Reverse osmosis -Improve solubility of hydrophobic drugs Ultrafiltration 国活人生 国生 3.Formulation of parenteral products 3.Formulation of parenteral products The vehicle(the delivery media) The vehicle(the delivery media) ·Nonaqueous vehicles -Nonirritating .Nonaqueous and mixed vehicles -Nontoxic -Fixed vegetable oils -Not sensitizing >corn oil,peanut oil,sesame oil -Inert pharmacologic activity >never be administered intravenously -Chemical stable restricted to IM use. -Proper viscosity -Suitable fluidity -Water-miscible solvents -High boiling point >glycerin,ethanol,propylene glycol,and -Miscible with body fluid PEG -Constant purity 6
6 Shanghai Jiao Tong University 3. Formulation of parenteral products • Pyrogen • A pyrogen is a substance that induces fever-endotoxin. • The bacterial substance lipopolysaccharide (LPS), present in the cell wall of some bacteria • LPS could leads to release of pro-inflammatory cytokines and nitric oxide, which may lead ultimately to fatal consequence. • Fever, chill, Shanghai Jiao Tong University 3. Formulation of parenteral products • Properties of pyrogen • Thermally stable • Small size • Water soluble • Nonvolatile • Adsorbable Shanghai Jiao Tong University 3. Formulation of parenteral products • Pyrogen removal in water (depyrogenation) • Activated charcoal • Distillation • Ion exchange • Reverse osmosis • Ultrafiltration Shanghai Jiao Tong University 3. Formulation of parenteral products • The vehicle( the delivery media) • Nonaqueous and mixed vehicles – Stabilize drugs that are readily hydrolyzed by water – Improve solubility of hydrophobic drugs Shanghai Jiao Tong University 3. Formulation of parenteral products • The vehicle( the delivery media) • Nonaqueous vehicles – Nonirritating – Nontoxic – Not sensitizing – Inert pharmacologic activity – Chemical stable – Proper viscosity – Suitable fluidity – High boiling point – Miscible with body fluid – Constant purity Shanghai Jiao Tong University 3. Formulation of parenteral products • The vehicle( the delivery media) • Nonaqueous and mixed vehicles – Fixed vegetable oils » corn oil, peanut oil, sesame oil » never be administered intravenously » restricted to IM use. – Water-miscible solvents » glycerin, ethanol, propylene glycol, and PEG
