1 PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India

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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

27th December 2012 KLE College of Pharmacy, Nipani

mailto:[email protected]

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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


27th December 2012 4KLE College of Pharmacy, Nipani

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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


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


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.


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

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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.


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


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


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


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.


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


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 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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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.



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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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1mm

Magnet ring

Coated Polymer

Magnet inside polymer matrix


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Hydration 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.



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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


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


Niosomes

Passive tumour targeting

Vaccine adjuvants

Sustained release depot at point of injection

Nanoparticles

Passive tumour targeting

Vaccine adjuvants


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


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


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


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


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


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 27th December 2012 KLE College of Pharmacy, Nipani

References

http://www.pharmainfo.net/

http://www.pharmj.com/.../education/parenteral2.html


Thank YouE-mail: [email protected]

Cell No: 00919742431000

mailto:[email protected]

Documents

1 PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE University College of Pharmacy BELGAUM-590010, Karnataka, India