ParenteralControlledReleaseDrugDeliverySystems.ppt

parenteral drug delivery

1. 1
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

2. 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
27th December 2012 KLE College of Pharmacy, Nipani

3. 3
Objectives
Site-specific delivery
Reduced side effects
Increased bio-availability
Increased therapeutic effectiveness
27th December 2012 KLE College of Pharmacy, Nipani

4. 27th December 2012 4KLE College of Pharmacy, Nipani

5. 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
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6. 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
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7. 7
Intravascular
Intramuscular
Subcutaneous
Intradermal
Intraarticular
Intraspinal
Intrathecal
Intracardiac
Intrasynovial
Intravaginal
Intraarterial
Routes of administration
27th December 2012 KLE College of Pharmacy, Nipani

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
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9. ADDITIVES USED DURING FORMULATION
OF PARENTRALS
Vehicles
Stabilizers
Buffering agents
Tonicity factors
Solubilizers
Wetting, suspending, emulsifying agents
Antimicrobial compounds
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10. 10
APPROACHES FOR
FORMUALATION
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11. 11
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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12. 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.
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13. 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.
27th December 2012 KLE College of Pharmacy, Nipani
Approaches

14. 14
TYPE OF FORMULATION
Dissolution-controlled Depot formulations
Adsorption-type Depot preparations
Encapsulation-type Depot preparations
Esterification-type Depot preparations
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15. 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
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16. 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
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17. 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
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18. 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
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19. 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
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20. 20

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
Encapsulation-type Depot
Preparations

21. 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
27th December 2012 KLE College of Pharmacy, Nipani

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
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23. 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
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24. 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
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25. 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 μm
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26. 26

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
Suspensions

27. 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
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28. 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
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29. 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
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30. 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
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31. 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.
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32. 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
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33. 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
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34. 34
Spherule/vesicle of lipid bilayers enclosing an
aqueous compartment.
Lipid most commonly used are phospholipids,
sphingolipids, glycolipids and sterols.
Liposomes
liposomes
MLV
OLV ULV
GUV
MUV
LUV
27th December 2012 KLE College of Pharmacy, Nipani

35. 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.
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36. 36
Liposomes
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37. 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
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38. 38
Envionmentally stable
Biostable
Biocompatible

Nontoxic and noncarcinogenic
Nonirritant
Removable
Provide constant release
Ideal Characteristics
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39. 39
Advantages

More effective and more prolonged action

Small dose is sufficient

Disadvantages

Microsurgery is required
Advantages and Disadvantages
27th December 2012 KLE College of Pharmacy, Nipani

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
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41. 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.
Polymeric
membrane
nonporous
microporous
semipermeable
Polymer membrane permeation
controlled DDS
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42. 42
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
Polymer membrane permeation
controlled DDS

43. 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
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44. 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
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45. 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
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46. 46
Microreservoir Partition Drug
Delivery Device
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47. 47
Osmotic pressure activated
Vapor pressure activated
Magnetically activated
Controlled drug delivery by activation
process
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48. 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
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49. 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.
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50. 50
Vapor pressure activated
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51. 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
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52. 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.
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53. 53
Magnetically activated
1mm
Magnet ring
Coated
Polymer
Magnet inside polymer matrix
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54. 54
Hydration activated
Hydrolysis activated
Feedback Regulated DDS
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55. 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
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56. 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
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57. 57
INFUSION DEVICES
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58. 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
27th December 2012 KLE College of Pharmacy, Nipani

59. 59
Intraspinal infusion device
27th December 2012 KLE College of Pharmacy, Nipani

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

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61. Niosomes
Passive tumour targeting
 
Vaccine adjuvants
 
Sustained release depot at point of injection

Nanoparticles
Passive tumour targeting
 
Vaccine adjuvants
27th December 2012 61KLE College of Pharmacy, Nipani
RECENT DEVELOPMENTS

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
27th December 2012 62KLE College of Pharmacy, Nipani
RECENT DEVELOPMENTS

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
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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
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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
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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
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67. Needle free injections

Decreased pain on injection
Increased bioavailability of intradermal vaccines
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68. 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
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69. 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
27th December 2012 KLE College of Pharmacy, Nipani
References

70. 27th December 2012 70KLE College of Pharmacy, Nipani
Thank You
E-mail: [email protected]
Cell No: 00919742431000