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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. CONTENTS. Introduction Objective Additives used in formulation - PowerPoint PPT Presentation
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PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM
Dr. Basavaraj K. Nanjwade M.Pharm., PhD
KLE University College of PharmacyBELGAUM-590010, Karnataka, India.
E-mail: [email protected] No: 00919742431000
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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
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Objectives Site-specific delivery Reduced side effects Increased bio-availability Increased therapeutic effectiveness
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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
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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
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Intravascular Intramuscular Subcutaneous Intradermal Intraarticular Intraspinal Intrathecal Intracardiac Intrasynovial Intravaginal Intraarterial
Routes of administration
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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
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ADDITIVES USED DURING FORMULATION OF PARENTRALS
Vehicles Stabilizers Buffering agents Tonicity factors Solubilizers Wetting, suspending, emulsifying agents Antimicrobial compounds
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APPROACHES FOR FORMUALATION
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PARAMETERS MANIPULATED IN THE DESIGN OF PARENTRAL
CONTROLLED FORMS Route of administration Vehicles Vaso-constriction Particle size Chemical modification of drug
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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.
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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.
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Approaches
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TYPE OF FORMULATION Dissolution-controlled Depot formulations
Adsorption-type Depot preparations
Encapsulation-type Depot preparations
Esterification-type Depot preparations
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Dissolution type depot formulations
Drug absorption is controlled by slow dissolution of drug particles.
Rate of dissolution is given by ;
where,Sa – Surface area of drug particlesDs – Diffusion coefficient of drug Cs – Saturation solubility of drughd – Thickness of hydrodynamic diffusion
( Q
t )d=
SaDsCs
hd
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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.
Drawbacks
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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
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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
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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
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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.
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Encapsulation-type Depot Preparations
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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
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CLASSIFICATION
INJECTABLES IMPLANTS INFUSION DEVICES
SolutionsSuspensions and
EmulsionsMicrospheres and
MicrocapsulesNanoparticles and
NiosomesLiposomes
. Resealed Erythrocytes
Osmotic PumpsVapor Pressure
Powered PumpsIntraspinal Infusion
Pumps Intrathecal Infusion Pumps
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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
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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
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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
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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
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Suspensions
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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
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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
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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
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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
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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.
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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
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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
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Spherule/vesicle of lipid bilayers enclosing an aqueous compartment.
Lipid most commonly used are phospholipids, sphingolipids, glycolipids and sterols.
Liposomes
liposomes
MLV OLV ULV
GUVMUV LUV
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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.
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Liposomes
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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
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Envionmentally stable Biostable Biocompatible Nontoxic and noncarcinogenic Nonirritant Removable Provide constant release
Ideal Characteristics
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Advantages More effective and more prolonged action Small dose is sufficient
Disadvantages Microsurgery is required
Advantages and Disadvantages
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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
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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.
Polymeric membrane
nonporous
microporous
semipermeable
Polymer membrane permeation controlled
DDS
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Encapsulation of drug in reservoir can be done by encapsulation, microencapsulation, extrusion, molding or any other technique.
E.g., Norplant Subdermal Implant.
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Polymer membrane permeation controlled
DDS
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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
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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
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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
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Microreservoir Partition Drug Delivery Device
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Osmotic pressure activated
Vapor pressure activated
Magnetically activated
Controlled drug delivery by activation process
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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
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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.
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Vapor pressure activated
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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
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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.
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Magnetically activated
1mm
Magnet ring
Coated Polymer
Magnet inside polymer matrix
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Hydration activated
Hydrolysis activated
Feedback Regulated DDS
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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
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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
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INFUSION DEVICES
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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
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Intraspinal infusion device
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RECENT DEVELOPMENTSLIPOSOMES 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
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Niosomes Passive tumour targeting Vaccine adjuvants Sustained release depot at point of injection
Nanoparticles Passive tumour targeting Vaccine adjuvants
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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
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RECENT DEVELOPMENTS
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
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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
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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
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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
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Needle free injections
Decreased pain on injectionIncreased bioavailability of intradermal vaccines
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“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
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“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
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References
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Thank YouE-mail: [email protected]
Cell No: 00919742431000