Parenteral Product Administration Definition: Advantages disadvantages Route Compounds formulation drug:preformulation: yehicle:WFI Route Form Subcutaneous, Important added substances Intravenous Parenteral Products Intramuscular In what kind of Form Solution,Suspension,Emufsion Epidermal Dosage Forms Prep Dry powder,Liposome (aseptic filling) Xiaohui Wei Sterilization Method Injection formulations: xhwei@sjtu.edu.cn Route Form Method Selection Validation Sterility Testing: Quality Control Pyrogen Testing; GMP To build the Leaker Testing Sealing Verification; Quality into the Product Clarity and Particulate Testing 1.Introduction 1.Introduction Parenteral ÷Advantages. para(beside)+enteron(intestine)or not via the rapid onset;predictable effect;very high bioavailability;avoid individual digestive tract. difference; As a practical matter,the parenteral route encompasses injectable ÷Disadvantages: formulations.though implants are also included pain,discomfort,very hard to counteract an incorrect drug or dose. rectal administration would not fall under the definition of parenteral Special significant under the conditions: other non-oral dosage forms also are excluded (epicutaneous. 1.very inefficient or unreliable GIT absorption ocular,otic,nasal,pulmonary) 2.extensive mucosal or first-pass effect when oral; 3.Clinical need for rapid,assured high concentration; 1
1 Parenteral Parenteral Products Products Xiaohui Xiaohui Wei xhwei@sjtu.edu.cn Parenteral Parenteral Product In what kind of Form Administration Administration Route Solution, Suspension, Emulsion Dry powder, Liposome (aseptic filling) Compounds & formulation drug : preformulation; vehicle : WFI Important added substances Sterilization Method Injection formulations: Method Selection & Validation Quality Control Quality Control Sterility Testing; Pyrogen Testing; Leaker Testing & Sealing Verification; Clarity and Particulate Testing Dosage Forms & Prep Subcutaneous, Intravenous Intramuscular Epidermal Definition: Advantages & disadvantages GMP：To build the Quality into the Product Route & Form Route & Form 1. Introduction 1. Introduction Parenteral Parenteral : para (beside) + (beside) + enteron (intestine) or not via the (intestine) or not via the digestive tract. digestive tract. z As a practical matter, the As a practical matter, the parenteral parenteral route encompasses route encompasses injectable formulations, though implants are also included z rectal administration would not fall under the definition of would not fall under the definition of parenteral parenteral z other non-oral dosage forms also are excluded (epicutaneous epicutaneous, ocular, ocular, otic, nasal, pulmonary) 1. Introduction Introduction Advantages: Advantages: rapid onset; predictable effect; very high bioavailability; avoi rapid onset; predictable effect; very high bioavailability; avoid individual d individual difference; difference; Disadvantages: pain, discomfort, very hard to counteract an incorrect drug or dose. ug or dose. Special significant under the conditions: Special significant under the conditions: 1.very inefficient or unreliable GIT absorption ; 1.very inefficient or unreliable GIT absorption ; 2. extensive mucosal or first-pass effect when oral; 3. Clinical need for rapid, 3. Clinical need for rapid, assured high concentration; 1
Needle-free Injection Device 2.Routes of parenteral administration Primary Routes: Subcutaneous route:SC,SQ,Sq Intramuscular route:IM P IOLET BUBCTEUn Intravenous route:IV 品高密，n 。Other Routes: Intradermal,intra-arterial,intrathecal etc. Details please find: http://www.cdc.gov/nip/dev/jetinject.htm Skin Structure Free narvo Hair root For each route of administration, Smail blood describe 1.Where the drug is administered 2.Volume limitations Dermis 3.Formulation constraints Smooth muscle Adipoee tissue Sweat gland Nerve Receptors Copyngt 2001 Birjamn Cummng an iernt of Adsson Woily Longmir,ine 2
2 Needle-free Injection Device Details please find: http://www. cdc.gov/nip/dev/jetinject.htm 2. Routes of 2. Routes of parenteral parenteral administration administration Primary Routes: Primary Routes: Subcutaneous route: SC, SQ, Sq Intramuscular route: IM Intravenous route: IV Other Routes: Other Routes: Intradermal Intradermal, intra-arterial, arterial, intrathecal intrathecal etc. For each route of administration, describe 1.Where the drug is administered 2.Volume limitations 3. Formulation constraints Skin Structure 2
2.1.Subcutaneous Route Site:superficial fascia,5/8 inch ÷Volume:~2ml Characteristic:slower onset,less total abs. Formulation Constraints:not irritating Precautionary Notes: ensure that the needle is not in a vein. http://www.pharmacy.wsu.edu/courses/PharS531/Parenterals201.htm 2.2.Intramuscular Route 2.3.Intravenous Route Site:striated muscle fibers,1.5 inches Two types:IV injection and IV infusion needle or cannulation Volume:1~3ml,10ml sometimes ÷Characteristic: Type I IV injection(vein puncture) rapid onset: Site:large proximal veins drug depot,sustained-release; ÷Volume:1~100ml factors affecting the diffusion process control the release rate; Characteristic:extremely rapid and predictable response Formulation Constraints:nearly all drug classes Formulation Constraints: ÷Precautionary Notes: solutions and some emulsions potential muscular or neural damage ÷Precautionary Notes: Drug shock:too rapid abs.control the injection rate Thrombosis 3
3 http://www.pharmacy.wsu.edu/courses/PharS531/Parenterals20I.htm 2.1. Subcutaneous Route 2.1. Subcutaneous Route Site : superficial fascia, 5/8 inch Volume : ~2ml Characteristic Characteristic : slower onset, less total abs. slower onset, less total abs. Formulation Constraints : not irritating Precautionary Notes : Precautionary Notes : ensure that the needle is not in a vein. ensure that the needle is not in a vein. 2.2. Intramuscular Route 2.2. Intramuscular Route Site : striated muscle fibers, 1.5 inches striated muscle fibers, 1.5 inches Volume : 1~3ml, 10ml sometimes Characteristic : rapid onset; rapid onset; drug depot, sustained-release; release; factors affecting the diffusion process control the re factors affecting the diffusion process control the release rate; lease rate; Formulation Constraints Formulation Constraints : nearly all drug classes Precautionary Notes : Precautionary Notes : potential muscular or neural damage 2.3.Intravenous Route 2.3.Intravenous Route Two types: Two types: IV injection and IV infusion needle or needle or cannulation cannulation Type I_IV injection( vein puncture) Type I_IV injection( vein puncture) Site : large proximal veins Volume : 1~100ml 1~100ml Characteristic Characteristic : extremely rapid and predictable response extremely rapid and predictable response Formulation Constraints Formulation Constraints : solutions and some emulsions Precautionary Notes : Precautionary Notes : Drug shock: too rapid abs. control the injection rate Drug shock: too rapid abs. control the injection rate Thrombosis 3
2.3.Intravenous Route(continued) 2.4.Other Routes Type ll_IV infusion(venoclysis) Intra-arterial route: ◆Site:vein To administer radiopaque contrast agent,to perfuse ·Volume:100-1000ml antineoplastic agent targetly; ·Characteristic LVP:to provide energy,water and dilution effect *Drug:provide continuous and prolonged effect Intrathecal route: Formulation Constraints: Must be especially carefully formulated; solutions and some emulsions: normally need to be isotonic Precautionary Notes: Intradermal route: IV admixtures:must avoid incompatibility;sterility Allergy test,isotonic Qualities of Parenteral Products 3.Compounds and Formulation Manageability of Dosing Volume The availability of the active drug in a parenteral product Comfort: is affected by: Isotonicity,Pyrogen free,pH Physicochemical properties of the drug: drug itself) Stability: chemical,physical,microbial resistance The added substances: ÷Convenience: modifications and assurance in stability,efficiency the least convenient of dosage forms.device improvement and convenience Release of Drug for Absorption: The vehicle(the delivery media) solution disperse systems; Devices give considerable control of release of drug 4
4 2.3.Intravenous Route ( 2.3.Intravenous Route (continued) Type II_IV infusion( Type II_IV infusion( venoclysis) Site : vein Volume : 100~1000ml 100~1000ml Characteristic Characteristic : LVP: to provide energy, water and dilution effect LVP: to provide energy, water and dilution effect *Drug: provide continuous and prolonged effect *Drug: provide continuous and prolonged effect Formulation Constraints Formulation Constraints : solutions and some emulsions: solutions and some emulsions: normally need to be isotonic Precautionary Notes : Precautionary Notes : IV admixtures: must avoid incompatibility; sterility 2.4. Other Routes 2.4. Other Routes Intra-arterial route: arterial route: To administer To administer radiopaque contrast agent, to perfuse contrast agent, to perfuse antineoplastic antineoplastic agent targetly; Intrathecal Intrathecal route: Must be especially carefully formulated; Must be especially carefully formulated; Intradermal Intradermal route: Allergy test, isotonic Qualities of Parenteral Products Manageability of Dosing Volume Comfort: Isotonicity, Pyrogen free, pH Stability: chemical, physical, microbial resistance Convenience: the least convenient of dosage forms, device improvement Release of Drug for Absorption: solution & disperse systems; Devices give considerable control of release of drug 3. Compounds and Formulation 3. Compounds and Formulation The availability of the active drug in a The availability of the active drug in a parenteral parenteral product product is affected by: is affected by: Physicochemical prope Physicochemical properties of the drug; rties of the drug; ( drug itself) ( drug itself) The added substances; The added substances; ( modifications and assurance ( modifications and assurance in stability ,efficiency in stability ,efficiency and convenience ) and convenience ) The vehicle( the delivery media) ( the delivery media) 4
Properties Effect on 3.1.1.Crystal characteristics Molecular structure and weight drug activity Melting point preparation method Of special importance for suspension powders Thermal profile thermal stability,prep method Particle size and shape solubility&stability ÷Including: Hygroscopicity potential hydration,prep.process design and storage lonization constant pH solubility stability Crystal form,habit,density size distribution Light stability stability evaluation method Great effect on the solubility and stability Optical activity Example:IM suspension pH solubility profile stability efficiency pH stability profile ÷Control: Polymorphism potential crystallization,solubility,stability Strictly crystallization control Solvate formation solubility,stability and activity pH,rate of addition,solvent conc.&purity,tem.,mixing rate 3.1.2.Chemical Modification 3.1.3.Polymorphism Parent drug modify new structure,new properties Definition: ÷Prodrug A given chemical has several crystal forms In vivo,modified drug converted into parent drug exhibiting different properties Commonly used:salts of organic compounds Dramatically increase solubility Significantly affect: Weak acids:sodium/potassium salts: Weak bases:hydrochloride/sulfate salts; Solubility,dissolution rate stability Water-insoluble salts: To enhance stability or to prepare a suspension Examples: 5
5 Properties Effect on Molecular structure and weight Molecular structure and weight drug activity Melting point Melting point preparation method Thermal profile t Thermal profile thermal stability, prep method hermal stability, prep method Particle size and shape Particle size and shape solubility& stability solubility& stability Hygroscopicity potential hydration, prep. process design and storage Ionization constant Ionization constant pH solubility & stability Light stability Light stability stability evaluation method Optical activity Optical activity pH solubility profile pH solubility profile stability & efficiency pH stability profile pH stability profile Polymorphism potential crystallization, solubility, stability tion, solubility, stability Solvate formation solubility, stability and activity lubility, stability and activity 3.1.1.Crystal characteristics 3.1.1.Crystal characteristics Of special importance fo Of special importance for suspension & powders r suspension & powders Including: Including: Crystal form, habit, density & size distribution Crystal form, habit, density & size distribution Great effect on the solubility and stability Great effect on the solubility and stability Example: IM suspension Control: Control: Strictly crystallization control Strictly crystallization control pH, rate of addition, solvent conc.& purity, tem., mix pH, rate of addition, solvent conc.& purity, tem., mixing rate 3.1.2. Chemical Modification 3.1.2. Chemical Modification Parent drug modify Parent drug modify new structure, new properties Prodrug: In vivo, modified drug converted into parent drug In vivo, modified drug converted into parent drug Commonly used: salts of organic compounds Dramatically increase solubility Weak acids: Weak acids: sodium/potassium salts; sodium/potassium salts; Weak bases: Weak bases: hydrochloride/sulfate salts; hydrochloride/sulfate salts; Water-insoluble salts: insoluble salts: To enhance stability or to prepare a suspension 3.1.3.Polymorphism Definition: Definition: A given chemical has several crystal forms A given chemical has several crystal forms exhibiting different properties Significantly affect: Significantly affect: Solubility, dissolution rate & stability Examples: Examples: 5