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Parenteral controlled drug delivery system sushmitha

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  • 1. PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Prepared By SAI S. V M.Pharm – I st Year Dept. of Pharmaceutics KLE University, Belgaum.
  • 2.
    • Introduction
    • Objective
    • Additives used in formulation
    • Routes of administration
    • Approaches for formulation
    • Type of formulation
    • Classification
    • Approaches for formulations of Implants
    • Infusion Devices
    • References
    CONTENTS
  • 3. Objectives
    • Site-specific delivery
    • Reduced side effects
    • Increased bio-availability
    • Increased therapeutic effectiveness
  • 4.  
  • 5.
    • 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
    Advantages over conventional drug delivery system
  • 6.
    • 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.
    Disadvantages of controlled release dosage forms
  • 7.
    • Intravascular
    • Intramuscular
    • Subcutaneous
    • Intradermal
    • Intraarticular
    • Intraspinal
    • Intrathecal
    • Intracardiac
    • Intrasynovial
    • Intravaginal
    • Intraarterial
    Routes of administration
  • 8. 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
  • 9. ADDITIVES USED DURING FORMULATION OF PARENTRALS
    • Vehicles
    • Stabilizers
    • Buffering agents
    • Tonicity factors
    • Solubilizers
    • Wetting, suspending, emulsifying agents
    • Antimicrobial compounds
  • 10. APPROACHES FOR FORMUALATION
  • 11. PARAMETERS MANIPULATED IN THE DESIGN OF PARENTRAL CONTROLLED FORMS
    • Route of administration
    • Vehicles
    • Vaso-constriction
    • Particle size
    • Chemical modification of drug
  • 12. 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.
  • 13.
    • 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.
    Contd..,
  • 14. TYPE OF FORMULATION
    • Dissolution-controlled Depot formulations
    • Adsorption-type Depot preparations
    • Encapsulation-type Depot preparations
    • Esterification-type Depot preparations
  • 15. Dissolution type depot formulations
    • Drug absorption is controlled by slow dissolution of drug particles.
    • Rate of dissolution is given by ;
    • where,
    • S a – surface area of drug particles
    • D s – diffusion coefficient of drug
    • C s – saturation solubility of drug
    • h d – thickness of hydrodynamic diffusion
    ( Q t ) d = S a D s C s h d
  • 16.
    • Release of drug molecules is not of zero order kinetics as expected from the theoretical model.
      • Surface area S a of drug particles diminishes with time.
      • The saturation solubility C s of the drug at the injection site cannot be easily maintained.
    Drawbacks
  • 17.
    • Formation of salts or Complexes with Low solubility.
      • E.g., Aqueous suspensions of benzathine penicillin G.
    • Suspension of macro crystals.
      • E.g., aqueous suspension of testosterone isobutyrate for I.M. administration.
    • Exception
      • Penicillin G procaine suspension in gelled peanut oil for I.M. injection.
    Approaches
  • 18.
    • 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.
    • E.g., - Vaccine preparations
    Adsorption-type Depot Preparation 1 a(C) b.m (C) f (C) b = + (C) f (C) b,m
  • 19.
    • Prepared by encapsulating drug solids within a permeation barrier or dispersing drug particles in a diffusion matrix.
    • Membrane – biodegradable or bioabsorbable macromolecules
      • gelatin, Dextran, polylactate, lactide-glycolide copolymers, phospholipids, and long chain fatty acids and glycerides.
    Encapsulation-type Depot Preparations
  • 20. Contd..,
    • 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.
  • 21.
    • 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, and testosterone 17B-cyprionate in oleaginous solution.
    Esterification-type Depot Preparation
  • 22. CLASSIFICATION INJECTABLES IMPLANTS INFUSION DEVICES Solutions Suspensions and Emulsions Microspheres and Microcapsules Nanoparticles and Niosomes Liposomes . Resealed Erythrocytes Osmotic Pumps Vapor Pressure Powered Pumps Intraspinal Infusion Pumps Intrathecal Infusion Pumps
  • 23.
    • 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
    Solutions
  • 24. 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
  • 25. 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 μ m
  • 26. Contd..,
      • 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
  • 27. 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
  • 28.
    • 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.
    Emulsions
  • 29. Emulsions
    • Release of water soluble drugs can be retarded by presenting it as oil suspension and vice versa.
    Aqueous phase Oil phase Water soluble drug e.g., 5-Fluorouracil Oil soluble drug e.g., lipidol
  • 30.
    • 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.
    Microsphere
  • 31. 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.
  • 32.
    • 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.
    Microcapsules
  • 33.
    • 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.
    Nanoparticles and Niosomes
  • 34.
    • Spherule/vesicle of lipid bilayers enclosing an aqueous compartment.
    • Lipid most commonly used are phospholipids, sphingolipids, glycolipids and sterols.
    Liposomes GUV liposomes MLV OLV ULV MUV LUV
  • 35. 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.
  • 36. Liposomes
  • 37.
    • 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.
    Resealed Erythrocytes
  • 38.
    • Envionmentally stable
    • Biostable
    • Biocompatible
    • Nontoxic and noncarcinogenic
    • Nonirritant
    • Removable
    • Provide constant release
    Ideal Characteristics
  • 39.
    • Advantages
      • More effective and more prolonged action
      • Small dose is sufficient
    • Disadvantages
      • Microsurgery is required
    Advantages and Disadvantages
  • 40. Approaches to implantable drug delivery CDD by diffusion Activation process Feedback regulated Osmotic pressure Vapour pressure Magnetically activated Phonophoresis Hydration activated Hydrolysis activated Bioerosion Bioresponsive Polymer membrane Matrix diffusion Microreservoir
  • 41.
    • 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.
    • Usually polymer used is nondegradable.
    Polymer membrane permeation controlled DDS Polymeric membrane nonporous microporous semipermeable
  • 42.
    • Encapsulation of drug in reservoir can be done by encapsulation, microencapsulation, extrusion, molding or any other technique.
    • E.g., Norplant Subdermal Implant.
    Contd..,
  • 43.
    • Drug is homogeneously dispersed throughout polymer matrix.
    • Polymers used are :
      • Lipophilic polymers
      • Hydrophilipic polymers
      • Porous
    • Decreasing release with time
    • E.g., Compudose implant
    Polymer Matrix diffusion controlled DDS
  • 44.
    • 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
    Membrane-Matrix Hybrid type Drug Delivery Device
  • 45. Microreservoir Partition Drug Delivery Device
    • 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
  • 46. Microreservoir Partition Drug Delivery Device
  • 47.
    • Osmotic pressure activated
    • Vapor pressure activated
    • Magnetically activated
    Controlled drug delivery by activation process
  • 48. Osmotic pressure activated
    • Osmotic pressure is used as energy source
    • Drug reservoir is either a solution or semisolid formulation
    • Cellulosic outer membrane
    • Polyester internal membrane
  • 49. 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.
  • 50. Vapor pressure activated
  • 51.
    • 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.
    Magnetically activated
  • 52. 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.
  • 53. Magnetically activated 1mm Magnet ring Coated Polymer Magnet inside polymer matrix
  • 54.
    • Hydration activated
    • Hydrolysis activated
    Feedback Regulated DDS
  • 55.
    • 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
    Hydration activated
  • 56.
    • 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.
    Hydrolysis activated
  • 57. INFUSION DEVICES
  • 58.
    • 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.
    Infusion devices
  • 59. Intraspinal infusion device
  • 60. RECENT DEVELOPMENTS
    • Table 1: Main applications of modern drug delivery technology
    • Drug delivery technology Main applications
    • 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
  • 61.
    • Niosomes
    • Passive tumour targeting 
    • Vaccine adjuvants 
    • Sustained release depot at point of injection
    • Nanoparticles
    • Passive tumour targeting 
    • Vaccine adjuvants
  • 62.
    • 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
  • 63.
    • 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
  • 64.
    • 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
  • 65.
    • CYCLODEXTRIN
    • Lipophilic drug solubilisation for parenteral use
    • These compounds form inclusion complexes with hydrophobic guest molecule
    • Modfied cyclodextrins such as hydroxypropyl b-cyclodextrin and sulphobutyl b-cyclodextrins are regardedas safe for parentral use
  • 66.
    • 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
  • 67. Needle free injections Decreased pain on injection  Increased bioavailability of intradermal vaccines
  • 68.
    • “ 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.
    References
  • 69.
    • “ 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
  • 70.