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PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM

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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. – PowerPoint PPT presentation

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Title: PARENTERAL CONTROLLED DRUG DELIVERY SYSTEM


1
PARENTERAL CONTROLLED DRUG
DELIVERY SYSTEM
Dr. Basavaraj K. Nanjwade M.Pharm., PhD KLE
University College of Pharmacy BELGAUM-590010,
Karnataka, India. E-mail nanjwadebk_at_gmail.com Cel
l No 00919742431000
2
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

3
Objectives
  • Site-specific delivery
  • Reduced side effects
  • Increased bio-availability
  • Increased therapeutic effectiveness

4
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5
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

6
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.

7
Routes of administration
  • Intravascular
  • Intramuscular
  • Subcutaneous
  • Intradermal
  • Intraarticular
  • Intraspinal
  • Intrathecal
  • Intracardiac
  • Intrasynovial
  • Intravaginal
  • Intraarterial

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

11
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
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.

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,
  • Sa Surface area of drug particles
  • Ds Diffusion coefficient of drug
  • Cs Saturation solubility of drug
  • hd Thickness of hydrodynamic diffusion

16
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.

17
Approaches
  • 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.

18
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.
  • E.g., - Vaccine preparations

19
Encapsulation-type Depot Preparations
  • 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.

20
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.

21
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, and testosterone 17B-cyprionate in
    oleaginous solution.

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
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

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 lt 10 µm

26
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

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
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.

29
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
30
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.

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
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.

33
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.

34
Liposomes
  • Spherule/vesicle of lipid bilayers enclosing an
    aqueous compartment.
  • Lipid most commonly used are phospholipids,
    sphingolipids, glycolipids and sterols.

GUV
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
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.

38
Ideal Characteristics
  • Envionmentally stable
  • Biostable
  • Biocompatible
  • Nontoxic and noncarcinogenic
  • Nonirritant
  • Removable
  • Provide constant release

39
Advantages and Disadvantages
  • Advantages
  • More effective and more prolonged action
  • Small dose is sufficient
  • Disadvantages
  • Microsurgery is required

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
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.

42
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.

43
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

44
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

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
Controlled drug delivery by activation process
  • Osmotic pressure activated
  • Vapor pressure activated
  • Magnetically activated

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
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.

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
Magnet ring
1mm
Coated Polymer
Magnet inside polymer matrix
54
Feedback Regulated DDS
  • Hydration activated
  • Hydrolysis activated

55
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

56
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.

57
INFUSION DEVICES
58
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.

59
Intraspinal infusion device
60
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

61
RECENT DEVELOPMENTS
  • Niosomes
  • Passive tumour targeting 
  • Vaccine adjuvants 
  • Sustained release depot at point
    of injection
  • Nanoparticles
  • Passive tumour targeting 
  • Vaccine adjuvants

62
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

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
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.

68
69
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

70
Thank You E-mail nanjwadebk_at_gmail.com Cell No
00919742431000
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