PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 27th December 2012 KLE.
Download ReportTranscript PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 27th December 2012 KLE.
PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India. E-mail: [email protected] Cell No: 00919742431000 27th December 2012 KLE College of Pharmacy, Nipani 1 CONTENTS Introduction Objective Additives used in formulation Routes of administration Approaches for formulation Type of formulation Classification Approaches for formulations of Implants Infusion Devices References 27th December 2012 KLE College of Pharmacy, Nipani 2 Objectives Site-specific delivery Reduced side effects Increased bio-availability Increased therapeutic effectiveness 27th December 2012 KLE College of Pharmacy, Nipani 3 27th December 2012 KLE College of Pharmacy, Nipani 4 Advantages over conventional drug delivery system Improved patient convenience and compliance. Reduction in fluctuation in steady-state levels. Increased safety margin of high potency drugs. Maximum utilization of drug. Reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing 27th December 2012 KLE College of Pharmacy, Nipani 5 Disadvantages of controlled release dosage forms Decreased systemic availability Poor in vitro-in vivo correlation Possibility of dose dumping. Retrieval of drug is difficult in case of toxicity, poisoning or hypersensitivity reactions. Reduced potential for dosage adjustments. Higher cost of formulations. 27th December 2012 KLE College of Pharmacy, Nipani 6 Routes of administration Intravascular Intramuscular Subcutaneous Intradermal Intraarticular Intraspinal Intrathecal Intracardiac Intrasynovial Intravaginal Intraarterial 27th December 2012 KLE College of Pharmacy, Nipani 7 CHARACTERISTICS Free from living microbes Free from microbial products such as pyrogens Should match the osmotic nature of the blood Free from chemical contaminants Matching specefic gravity 27th December 2012 KLE College of Pharmacy, Nipani 8 ADDITIVES USED DURING FORMULATION OF PARENTRALS Vehicles Stabilizers Buffering agents Tonicity factors Solubilizers Wetting, suspending, emulsifying agents Antimicrobial compounds 27th December 2012 KLE College of Pharmacy, Nipani 9 APPROACHES FOR FORMUALATION 27th December 2012 KLE College of Pharmacy, Nipani 10 PARAMETERS MANIPULATED IN THE DESIGN OF PARENTRAL CONTROLLED FORMS Route of administration Vehicles Vaso-constriction Particle size Chemical modification of drug 27th December 2012 KLE College of Pharmacy, Nipani 11 Approaches Use of viscous, water-miscible vehicles, such as an aqueous solution of gelatin or polyvinylpyrrolidone. Utilization of water-immiscible vehicles, such as vegetable oils, plus water-repelling agent, such as aluminum monostearate. Formation of thixotropic suspensions. 27th December 2012 KLE College of Pharmacy, Nipani 12 Approaches Preparation of water-insoluble drug derivatives, such as salts, complexes, and esters. Dispersion in polymeric microspheres or microcapsules, such as lactide-glycolide homopolymers or copolymers Co-administration of vasoconstrictors. 27th December 2012 KLE College of Pharmacy, Nipani 13 TYPE OF FORMULATION Dissolution-controlled Depot formulations Adsorption-type Depot preparations Encapsulation-type Depot preparations Esterification-type Depot preparations 27th December 2012 KLE College of Pharmacy, Nipani 14 Dissolution type depot formulations Drug absorption is controlled by slow dissolution of drug particles. Rate of dissolution is given by ; ( ) SaDsCs Q t d = hd where, Sa – Surface area of drug particles Ds – Diffusion coefficient of drug Cs – Saturation solubility of drug hd – Thickness of hydrodynamic diffusion 27th December 2012 KLE College of Pharmacy, Nipani 15 Drawbacks Release of drug molecules is not of zero order kinetics as expected from the theoretical model. Surface area Sa of drug particles diminishes with time. The saturation solubility Cs of the drug at the injection site cannot be easily maintained. 27th December 2012 KLE College of Pharmacy, Nipani 16 Approaches Formation of salts or Complexes with Low solubility. Suspension of macro crystals. E.g., Aqueous suspensions of benzathine penicillin G. E.g., aqueous suspension of testosterone isobutyrate for I.M. administration. Exception Penicillin G procaine suspension in gelled peanut oil for I.M. injection. 27th December 2012 KLE College of Pharmacy, Nipani 17 Adsorption-type Depot Preparation Formed by binding of drug molecules to adsorbents. Only unbound, free species of drug is available for absorption. Equilibrium conc. of free, unbound drug species (C)f is determined by the Langmuir relationship. (C)f (C)b = 1 a(C)b.m + (C)f (C)b,m E.g., - Vaccine preparations 27th December 2012 KLE College of Pharmacy, Nipani 18 Encapsulation-type Depot Preparations Prepared by encapsulating drug solids within a permeation barrier or dispersing drug particles in a diffusion matrix. Membrane – biodegradable macromolecules or bioabsorbable Gelatin, Dextran, polylactate, lactide-glycolide copolymers, phospholipids, and long chain fatty acids and glycerides. 27th December 2012 KLE College of Pharmacy, Nipani 19 Encapsulation-type Depot Preparations E.g., Naltrexone pamoate-releasing biodegradable microcapsules. Release of drug molecules is controlled by Rate of permeation across the permeation barrier The rate of biodegradation of the barrier macromolecules. 27th December 2012 KLE College of Pharmacy, Nipani 20 Esterification-type Depot Preparation Esterifying a drug to form a bioconvertible prodrug-type ester. Forms a reservoir at the site of injection. Rate of absorption is controlled by Interfacial partitioning of drug esters from reservoir to tissue fluid. Rate of bioconversion of drug esters to regenerate active drug molecules. E.g., Fluphenazine enanthate, nandrolone decanoate, testosterone 17B-cyprionate in oleaginous solution. 27th December 2012 KLE College of Pharmacy, Nipani and 21 CLASSIFICATION INJECTABLES . IMPLANTS INFUSION DEVICES Solutions Suspensions and Emulsions Microspheres and Microcapsules Nanoparticles and Niosomes Liposomes Resealed Erythrocytes 27th December 2012 Osmotic Pumps Vapor Pressure Powered Pumps Intraspinal Infusion Pumps Intrathecal Infusion Pumps KLE College of Pharmacy, Nipani 22 Solutions Aqueous solutions High viscosity solutions For comp. with mol. wt. more than 750 For water sol. drugs Gelling agents or viscosity enhancers are used Complex formulations Drug forms dissociable complex with macromolecule Fixed amount of drug gets complexed Given by I.M. route 27th December 2012 KLE College of Pharmacy, Nipani 23 Solutions Oil solutions Drug release is controlled by controlling partitioning of drug out of oil into surrounding into aqueous medium For I.M. administration only No. of oils are limited 27th December 2012 KLE College of Pharmacy, Nipani 24 Suspensions Aqueous suspensions Given by I.M. or S.C. routes Conc. of solids should be 0.5 to 5 % Particle size should be < 10 μm 27th December 2012 KLE College of Pharmacy, Nipani 25 Suspensions Drug is continuosly dissolving to replenish the lost. For oil soluble drugs Only crystalline and stable polymorphic drugs are given by this form Viscosity builders can be used. E.g., Crystalline zinc insulin 27th December 2012 KLE College of Pharmacy, Nipani 26 Suspensions Oil suspensions Given by I.M. route. Process of drug availability consists of dissolution of drug particles followed by partitioning of drug from oil solution to aqueous medium. More prolong dug action as compared to oil solution and aqueous suspension. E.g., Penicillin G procaine in vegetable oil 27th December 2012 KLE College of Pharmacy, Nipani 27 Emulsions Can be given by I.M., S.C., or I.V. routes O/w systems are not used due to large interfacial area and rapid partitioning. W/o emulsions are used for water soluble drugs. Multiple emulsions are used generally such as w/o/w and o/w/o since an additional reservoir is presented to the drug for partitioning which can effectively retard its release rate. 27th December 2012 KLE College of Pharmacy, Nipani 28 Emulsions Release of water soluble drugs can be retarded by presenting it as oil suspension and vice versa. Water soluble drug e.g., 5-Fluorouracil Oil soluble drug e.g., lipidol Aqueous phase Oil phase 27th December 2012 KLE College of Pharmacy, Nipani 29 Microsphere Each microsphere is basically a matrix of drug dispersed in a polymer from which release occurs by first order process. Polymers used are biocompatible and biodegradable. Polylactic acid, polylactide coglycolide etc. Drug release is controlled by dissolution degradation of matrix. Small matrices release drug at a faster rate. 27th December 2012 KLE College of Pharmacy, Nipani 30 Microsphere For controlled release of peptide/protein drugs such as LHRH which have short half-lives. Magnetic microspheres are developed for promoting drug targeting which are infused into an artery. Magnet is placed over the area to localize it in that region. 27th December 2012 KLE College of Pharmacy, Nipani 31 Microcapsules Drug is centrally located within the polymeric shell. Release is controlled by dissolution, diffusion or both. For potent drugs such as steroids, peptides and antineoplastics. 27th December 2012 KLE College of Pharmacy, Nipani 32 Nanoparticles and Niosomes Nanoparticles are called as nanospheres or nanocapsules depending upon the position of drugs Polymer used are biodegradable ones. Polyacrylic acid, polyglycolic acid For selective targeting therapy. Nanosomes are closed vesicles formed in aqueous media from nonionic surfactants with or without the presence of lipids. 27th December 2012 KLE College of Pharmacy, Nipani 33 Liposomes Spherule/vesicle of lipid bilayers enclosing an aqueous compartment. Lipid most commonly used are phospholipids, sphingolipids, glycolipids and sterols. liposomes MLV OLV MUV 27th December 2012 KLE College of Pharmacy, Nipani ULV LUV GUV 34 Liposomes Water soluble drugs are trapped in aqueous compartment. Lipophilic ones are incorporated in the lipid phase of liposomes. Can be given by I.M., S.C., for controlled rate release. Can be given by I.V. for targeted delivery. 27th December 2012 KLE College of Pharmacy, Nipani 35 Liposomes 27th December 2012 KLE College of Pharmacy, Nipani 36 Resealed Erythrocytes Biodegradable, biocompatible, nonimmunogenic. Can circulate intravascularly for days and allow large amounts of drug to be carried. Drug loading in erythrocytes is easy. Damaged erythrocytes are removed by liver and spleen. 27th December 2012 KLE College of Pharmacy, Nipani 37 Ideal Characteristics Envionmentally stable Biostable Biocompatible Nontoxic and noncarcinogenic Nonirritant Removable Provide constant release 27th December 2012 KLE College of Pharmacy, Nipani 38 Advantages and Disadvantages Advantages More effective and more prolonged action Small dose is sufficient Disadvantages Microsurgery is required 27th December 2012 KLE College of Pharmacy, Nipani 39 Approaches to implantable drug delivery CDD by diffusion Activation process Feedback regulated Osmotic pressure Polymer Matrix membrane diffusion Microreservoir Vapour pressure Magnetically activated Bioerosion Bioresponsive Phonophoresis Hydration activated Hydrolysis activated 27th December 2012 KLE College of Pharmacy, Nipani 40 Polymer membrane permeation controlled DDS Reservoir is solid drug or dispersion of solid drug in liquid or solid medium. Drug enclosed in reservoir and reservoir is enclosed in rate limiting polymeric membrane. nonporous Polymeric membrane microporous semipermeable 27th December 2012 KLE College of Pharmacy, Nipani 41 Polymer membrane permeation controlled DDS Encapsulation of drug in reservoir can be done by encapsulation, microencapsulation, extrusion, molding or any other technique. E.g., Norplant Subdermal Implant. 27th December 2012 KLE College of Pharmacy, Nipani 42 Polymer Matrix diffusion controlled DDS Drug is homogeneously dispersed throughout polymer matrix. Polymers used are : Lipophilic polymers Hydrophilipic polymers Porous Decreasing release with time E.g., Compudose implant 27th December 2012 KLE College of Pharmacy, Nipani 43 Membrane-Matrix Hybrid type Drug Delivery Device Hybrid of first two Minimizes the risk of dose dumping Drug reservoir is homogeneous dispersion of drug solids throughout a polymer matrix, and is further encapsulated by polymeric membrane E.g., Norplant II Subdermal Implant 27th December 2012 KLE College of Pharmacy, Nipani 44 Microreservoir Partition Drug Delivery Device 27th December 2012 Drug reservoir is a suspension of drug crystals in an aqueous solution of polymer. Device is further coated with layer of biocompatible polymer. Polymer used for matrix : water soluble polymers Polymer used for coating : semipermeable polymer KLE College of Pharmacy, Nipani 45 Microreservoir Partition Drug Delivery Device 27th December 2012 KLE College of Pharmacy, Nipani 46 Controlled drug delivery by activation process Osmotic pressure activated Vapor pressure activated Magnetically activated 27th December 2012 KLE College of Pharmacy, Nipani 47 Osmotic pressure activated 27th December 2012 Osmotic pressure is used as energy source Drug reservoir is either a solution or semisolid formulation Cellulosic outer membrane Polyester internal membrane KLE College of Pharmacy, Nipani 48 Vapor pressure activated Vapor pressure is used as the power source. Drug reservoir is a solution formulation. Fluid which vaporizes at body temperature is used such as fluorocarbon. E.g., Infusaid Pump for Heparin. 27th December 2012 KLE College of Pharmacy, Nipani 49 Vapor pressure activated 27th December 2012 KLE College of Pharmacy, Nipani 50 Magnetically activated Electromagnet is used as power source. Drug can be triggered to release at varying rates depending upon the magnitude and the duration of electromagnetic energy applied. A tiny donut shaped magnet at the centre of medicated polymer matrix that contains a homogeneous dispersion of drug It has low polymer permeability. 27th December 2012 KLE College of Pharmacy, Nipani 51 Magnetically activated External surface is coated with pure polymer, such as ethylene vinyl acetate copolymer or silicone copolymer. The drug is activated to release at much higher rate by applying the external magnetic field. 27th December 2012 KLE College of Pharmacy, Nipani 52 Magnetically activated Magnet ring 1mm Coated Polymer Magnet inside polymer matrix 27th December 2012 KLE College of Pharmacy, Nipani 53 Feedback Regulated DDS Hydration activated Hydrolysis activated 27th December 2012 KLE College of Pharmacy, Nipani 54 Hydration activated Releases drug upon activation by hydration of device by tissue fluid at the implantation site. Hydrohilic polymer is used for formulation which becomes swollen upon hydration. Drug gets released by diffusing through the water saturated pore channels in the swollen polymer matrix. E.g., Norgestomet releasing Hydron Implant 27th December 2012 KLE College of Pharmacy, Nipani 55 Hydrolysis activated Release drug upon hydrolysis of polymer base by tissue fluid at implantation site. Polymer used is bioerodible or biodegradable polymer. Pellet or bead shaped implant. Rate of drug release is determined by rate of biodegradation, polymer composition and mol. Wt., drug leading and drug polymer interactions. Erosion rate is controlled by using a buffering agent. 27th December 2012 KLE College of Pharmacy, Nipani 56 INFUSION DEVICES 27th December 2012 KLE College of Pharmacy, Nipani 57 Infusion devices The implantable infusion pump (IIP) is a drug delivery system that provides continuous infusion of an agent at a constant and precise rate. The purpose of an IIP is to deliver therapeutic levels of a drug directly to a target organ or compartment. It is frequently used to deliver chemotherapy directly to the hepatic artery or superior vena cava. 27th December 2012 KLE College of Pharmacy, Nipani 58 Intraspinal infusion device 27th December 2012 KLE College of Pharmacy, Nipani 59 RECENT DEVELOPMENTS LIPOSOMES Passive tumour targeting Vaccine adjuvants Passive targeting to lung endothelium in gene delivery Targeting to regional lymph nodes Targeting to cell surface ligands in various organs/areas of pathology Sustained release depot at point of injection 27th December 2012 KLE College of Pharmacy, Nipani 60 RECENT DEVELOPMENTS Niosomes Passive tumour targeting Vaccine adjuvants Sustained release depot at point of injection Nanoparticles Passive tumour targeting Vaccine adjuvants 27th December 2012 KLE College of Pharmacy, Nipani 61 RECENT DEVELOPMENTS Microparticles: Sustained release depot at point of injection. Vaccine adjuvants Implant system: Localised depot systems for the treatment of infections and cancers. Sustained drug release systemic therapies 27th December 2012 KLE College of Pharmacy, Nipani 62 ADEPT Active tumour targeting It is an Antibody Directed Enzyme Prodrug Therapy An antibody enzyme conjugate is administered intravenously , localises in tumour tissue and subsequently activates an administered prodrug predominantly within such tumours 27th December 2012 KLE College of Pharmacy, Nipani 63 EMULSION Lipophilic drug administration vehicles Targeting to cell surface antigens These are the dispersions of one liquid inside the other liquid Droplet size of 100-200nm which results in high drug liver uptake on I.V injection 27th December 2012 KLE College of Pharmacy, Nipani 64 CYCLODEXTRIN Lipophilic drug solubilisation for parenteral use These compounds form inclusion complexes with hydrophobic guest molecule Modfied cyclodextrins such as hydroxypropyl bcyclodextrin and sulphobutyl b-cyclodextrins are regardedas safe for parentral use 27th December 2012 KLE College of Pharmacy, Nipani 65 POLYMER DRUG CONJUGATES Passive tumour targeting These include soluble polymeric prodrugs of daunorudicin, doxorubicin, cisplatin and 5- flurouracil These PDC accumulate selectively within tumour tissues 27th December 2012 KLE College of Pharmacy, Nipani 66 Needle free injections Decreased pain on injection Increased bioavailability of intradermal vaccines 27th December 2012 KLE College of Pharmacy, Nipani 67 References “Parenteral Drug Delivery and Delivery Systems”, in “Controlled Drug Delivery System” by Y.W.Chein; Marcel Decker Publications Vol. 50 pg – 381 -513. “Parenteral Drug Delivery”, in “Targeted and Controlled Drug Delivery” by Vyas and Khar pg – 30-33. “Parenteral Products”, in “Controlled Drug Delivery” by Robinson and Lee; Marcel Decker Publications, Vol. 29 pg – 433 – 450. 27th December 2012 KLE College of Pharmacy, Nipani 68 References “Parenterals” in “Sterile Dosage Forms and Delivery Systems” by Ansel, pg 444-451, 488-489. “Parenteral Drug Delivery Systems” in “Encyclopedia of Controlled Drug Delivery System” pg 752-753. “Controlled Release Medication” in “Biopharmaceutics and Pharmacokinetics A Treatise” by D.M.Brahmankar, Sunil B. Jaiswal; pg 357-365. http://www.pharmainfo.net www.pharmj.com/.../education/parenteral2.html 27th December 2012 KLE College of Pharmacy, Nipani 69 Thank You E-mail: [email protected] Cell No: 00919742431000 27th December 2012 KLE College of Pharmacy, Nipani 70