biodegradable polymers in controlled drug delivery
TRANSCRIPT
CONTROLLED DRUG DELIVERY BY BIODEGRADABLE
POLYMERSBY- Ch.R.Naveen , P.Venkat Rao
Ch.R.Naveen,
3rd year, B.Pharmacy,
Raghu College of Pharmacy,
Dakamarri,
Bheemili,
Visakhapatnam – 531 162. [email protected]
URL :http://www.pharmainfo.net/raghanaveen
P.Venkat Rao,Assoc.Professor,
Raghu College of Pharmacy,
Dakamarri,
Bheemili,
Visakhapatnam – 531 162.
URL :http://www.pharmainfo.net/venkatpasupuleti
CONTENTS
Introduction Biomaterials For Delivery Systems Factors Affecting Biodegradation of Polymers Controlled-Release Mechanisms Factors Influencing Drug Release from Polymers Uses of biodegradable polymers in Parenteral Depot Systems Biodegradable polymeric microspheres Miscellaneous Recent advances Future opportunities in controlled drug delivery Conclusion
Biodegradable polymeric drug delivery systems (DDS) have been widely studied for several drug delivery systems for human health purpose. During the last two decades, advances in biodegradable materials have been made significantly for the development in biomedical applications, and in this category there are industrial applications as well. Controlled and sustained drug delivery take place when a polymer (natural or synthetic) will prudently combined with a drug or other active substance in such a way that the active substance is released from the material in a tailored manner. The release of the active substance may be stable over a long period, it may be repeated over a long period, or it may be activated by the environment or other external actions. In any situation, the purpose behind controlling the drug delivery is to achieve more effective therapies while eliminating the adverse effects of both under- and overdosing.
INTRODUCTION
Poly(2-hydroxy ethyl methacrylate). Poly(N-vinyl pyrrolidone). Poly(methyl methacrylate). Poly(vinyl alcohol). Poly(acrylic acid). Poly(ethylene-co-vinyl acetate). Poly(ethylene glycol). Poly(methacrylic acid).
In recent years additional polymers designed primarily for medical applications have entered the arena of controlled release .There are:-
Polylactides (PLA). Polyglycolides (PGA). Poly(lactide-co-glycolides) (PLGA). Polyanhydrides. Polyorthoesters.
BIOMATERIAL FOR DELIVERY SYSTEMS
CLASSIFICATION OF BIODEGRADABLE POLYMER
Biodegradable polymer may be classified based on the mechanism of release of the drug entrapped in it:
Natural - albumin starch, dextran, gelatin, fibrinogen, hemoglobin.
Synthetic - -cynoacrylates), poly ethylpoly (alkyl cynoacrylates, poly amides. Nylon 6-10 nylon-cynoacrylates, poly butyl - 6-6, poly acryl amides, poly amino acid, poly urethane.
Chemical structure , Chemical composition. Distribution of repeat units in multimers. Presents of ionic groups. Presence of unexpected units or chain defects. Configuration structure. Molecular weight, Molecular-weight distribution. Morphology (amorphous/semi crystalline, microstructures, residual stresses). Presence of low-molecular-weight compounds. Processing conditions. Annealing. Sterilization process. Storage history, Shape , Site of implantation. Adsorbed and absorbed compounds (water, lipids, ions, etc.). Physicochemical factors (ion exchange, ionic strength, pH). Physical factors (shape and size changes, variations of diffusion coefficients,
mechanical stresses, stress- and solvent-induced cracking, etc.). Mechanism of hydrolysis (enzymes versus water).
FACTORS AFFECTING BIODEGRADATION OF POLYMERS
CONTROLLED-RELEASE MECHANISMSThere are three primary mechanisms by which active agents
can be released from a delivery system: diffusion, degradation, and swelling followed by diffusion. Any or all of these mechanisms may occur in a given release system. Diffusion occurs when a drug or other active agent passes through the polymer that forms the controlled-release device. The diffusion can occur on a macroscopic scale—as through pores in the polymer matrix—or on a molecular level, by passing between polymer chains. The mechanisms are classified into two types i.e. Chemical and Physical types.
Classification based on Chemical mechanisms includes :•Type-I•Type-II•Type-III
xx x
x x
C
O OR
C
O OH
C
O OR
C
O O-
x
x x
x
x x
x
x x
x
Type I
Type II
Type III
Biodegradable PolymersBiodegradable Polymers
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xx x
x x
C
O OR
C
O OH
C
O OR
C
O O-
x
x x
x
x x
x
x x
x
Type I
Type II
Type III
xx x
x x
xx x
x x
xx x
x x
C
O OR
C
O OH
C
O OR
C
O O-
C
O OR
C
O OH
C
O OR
C
O OR
C
O OH
C
O OH
C
O OR
C
O O-
C
O OR
C
O OR
C
O O-
C
O O-
x
x x
x
x x
x
x x
xx
x x
x
x x
x
x x
x
x x
x
x x
xx
x x
x
Type I
Type II
Type III
Biodegradable PolymersBiodegradable Polymers
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H2O solubleSwellingDimensional stability
H2O insolubleChemical changeNo backbone cleavage
H2O insolubleChemical cleavageMW↓
.Classification based on Physical mechanisms includes :
Drug delivery from a typical matrix drug delivery system
Drug delivery from typical reservoir devices
Delivery from release Environmentally Responsive systems
Drug delivery from bulk-eroding and surface-eroding biodegradable systems
DRUG DELIVERY FROM A TYPICAL MATRIX DRUG DELIVERY SYSTEM
In Figure , a polymer and active agent have been mixed to form a homogeneous system, also referred to as a matrix system. Diffusion occurs when the drug passes from the polymer matrix into the external environment. As the release continues, its rate normally decreases with this type of system, since the active agent has a progressively longer distance to travel and therefore requires a longer diffusion time to release.
DRUG DELIVERY FROM TYPICAL RESERVOIR DEVICES
In this design, a reservoir is surrounded by a film or membrane of a rate-controlling material whether solid drug, dilute solution, or highly concentrated drug solution within a polymer matrix. The only structure effectively limiting the release of the drug is the polymer layer surrounding the reservoir. Since this polymer coating is essentially uniform and of a non changing thickness, the diffusion rate of the active agent can be kept fairly stable throughout the lifetime of the delivery system.
Figure a is representative of an implantable or oral reservoir delivery system
Figure b illustrates a transdermal drug delivery system, in which only one side of the device will actually be delivering the drug.
ENVIRONMENTALLY RESPONSIVE SYSTEMS
It is also possible for a drug delivery system to be designed so that it is incapable of releasing its agent or agents until it is placed in an appropriate biological environment.
Swelling-controlled release systems are initially dry and, when placed in the body, will absorb water or other body fluids and swell.
The swelling increases the aqueous solvent content within the formulation as well as the polymer mesh size, enabling the drug to diffuse through the swollen network into the external environment.
DELIVERY FROM ENVIRONMENTALLY SENSITIVE RELEASE SYSTEMS
This picture illustrate the basic changes in structure of these sensitive systems. Once again, for this type of system, the drug release is accomplished only when the polymer swells. Because many of the potentially most useful pH-sensitive polymers swell at high pH values and collapse at low pH values, the triggered drug delivery occurs upon an increase in the pH of the environment. Such materials are ideal for systems such as oral delivery, in which the drug is not released at low pH values in the stomach but rather at high pH values in the upper small intestine.
DRUG DELIVERY FROM BULK-ERODING AND SURFACE-ERODING BIODEGRADABLE SYSTEMS.
Previously described systems are based on polymers that do not change their chemical structure beyond what occurs during swelling.
However it is the not case happens in biodegradable polymers.
These materials degrade within the body as a result of natural biological processes, eliminating the need to remove a drug delivery system after release of the active agent has been completed.
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Most biodegradable polymers are designed to degrade as a result of hydrolysis of the polymer chains into biologically acceptable, and progressively smaller, compounds.
Degradation may take place through bulk hydrolysis, in which the polymer degrades in a fairly uniform manner throughout the matrix, as shown in Figure a.
For some degradable polymers, most notably the polyanhydrides and polyorthoesters, the degradation occurs only at the surface of the polymer, resulting in a release rate that is proportional to the surface area of the drug delivery system as shown in Figure b.
USES OF BIODEGRADABLE POLYMERS IN PARENTERAL DEPOT SYSTEM (PDS)
Parenteral depot systems [PDS] ,these new drug delivery systems are injected or implanted into the muscle or subcutaneous tissue and release the incorporated drug in a controlled manner, allowing the adjustment of release rates over extended periods of time, ranging from several days up to one year.
Parenteral products with a prolonged action have been known for some time. In contrast to these formulations, PDS allow the control and modulation of drug release using biodegradable polymers.
The major advantage of the use of biodegradable polymers is that, it does not required surgical removal even after complete drug exhaustion. In addition the breakdown products are natural biocompatible which overcome the problem of toxicity associated with non-biodegradable implants .
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Another advantage of the biodegradable polymers in implants or drug delivery devices is that it releases drug by diffusion controlled mechanism hence predetermined drug delivery rate can be achieved easily.
Most of PDS developed so far are designed to deliver drugs to the systemic compartment. Also local drug delivery is a possibility in this case one attempts to achieve high drug concentration at the site of implantation without exposing non affected tissue to the drug.
Biodegradable materials, such as polylactic acid co-glycolic acid, are of course preferred as this removes the need for surgical removal of the implant after treatment has ended. However, non-biodegradable materials do provide therapeutic levels of drug for up to one year in vivo
Factors Influencing Drug Release from Factors Influencing Drug Release from PolymersPolymers
Diffusingmolecule
polymerchains
polymerchains
(a) Symmetrical model
(b) Unsymmetrical model
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Factors Influencing Drug ReleaseFactors Influencing Drug Release1. Molecular Weight
20
40
60
80
100
Avg
. cum
ulat
ive
%ag
e W
R-7
557
rele
ase
in v
itro
0 10 30 40 50 60 70 80 9020
Time (days)
150 000 Molecualr Weight
210 000 Molecular Weight
450 000 Molecular Weight
10
2. 2. CrystallinityCrystallinity
Change in the Crystallinity of Poly(-Caprolactone) as a
Function of Molecular Weight
MolecularWeight (Mw)
59,30053,00046,40037,10030,60026,80023,40021,700
Crystallinity(%)
47.550.650.552.557.058.658.459.5
11
2. 2. CrystallinityCrystallinity
Change in the Crystallinity of Poly(-Caprolactone) as a
Function of Molecular Weight
MolecularWeight (Mw)
59,30053,00046,40037,10030,60026,80023,40021,700
Crystallinity(%)
47.550.650.552.557.058.658.459.5
11
%CrystallinityPolymer
Poly(L-lactic acid)Poly(DL-lactic acid)Poly(Glycolic acid)
37%0%
50%
12
0.83
0.84
0.85V
/(10
-3 m
3 k
g-1)
-25 0 25 50T/°C
Tg(0.02)
Tg(100)
0.02h
100h
Polymer Tg (°C) SS Flux(1011 g/cm/s)
Poly(-caprolactone)Poly(DL-lactic acid)1:1 copolymer
-655727
6.10.00033
5.8
33. . Glass Transition TemperatureGlass Transition Temperature
13
4. Cross4. Cross--Links DensityLinks Density
Dependence of in vitro and in vivo Release Profiles of Norgestomet and Polymer Diffusivities on Extent of Cross-Linkage (XL) in Hydrogel Implants
XL(%)
1.24.89.6
12.014.416.819.2
Dp x 103
(cm2/day
97.224.212.19.78.16.96.1
Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa
0.6050.3960.1850.1330.1010.0740.058
0.6400.504--------------------
0.129
aResults from the subcutaneous implantation of Norgestomet-releasing Hydrogen implants in 39 cows for 16 days
14
4. Cross4. Cross--Links DensityLinks Density
Dependence of in vitro and in vivo Release Profiles of Norgestomet and Polymer Diffusivities on Extent of Cross-Linkage (XL) in Hydrogel Implants
XL(%)
1.24.89.6
12.014.416.819.2
Dp x 103
(cm2/day
97.224.212.19.78.16.96.1
Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa
Q/t1/2 (mg cm-2 day -1/2)In vitro In vivoa
0.6050.3960.1850.1330.1010.0740.058
0.6400.504--------------------
0.129
aResults from the subcutaneous implantation of Norgestomet-releasing Hydrogen implants in 39 cows for 16 days
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TIME
INT
EN
SIT
Y5.5. BiocompatibilityBiocompatibility
Acute Chronic
Healing
PMN’sFibroblasts
Fibrosis
Mononuclear Leukocytes
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BIODEGRADABLE POLYMERIC MICROSPHERES Biodegradable polymeric microspheres have been used to deliver a
variety of therapeutic substances such as proteins, peptides, NSAIDs, antibiotics and anticancer drugs in recent years because of their biocompatibility and degradation in vivo , to toxicologically acceptable lactic and glycolic acids which are further eliminated by the normal metabolic pathways and approved by US FDA
Biodegradable polymeric drug delivery systems based on aliphatic polyesters, polylactic acid (PLA), polyglycolic acid (PGA) and poly(D,L-lactide-co-glycolide) (PLGA) microspheres have been studied to protect encapsulated drugs from degradation, enhance bioavailability and sustain drug release
The objective of the present study was to prepare and characterize protein loaded biodegradable polymeric microspheres
EXAMPLES OF BIODEGRADABLE POLYMERIC MICROSPHERES
Biodegradable polymeric microspheres fabricated by conventional technology (50 - 100 μm)
Monodisperse PLGA microspheres with encapsulated fluorescent protein
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Hollow biodegradable capsules after core-liquid removal
MISCELLANEOUS
Sustained release medicationsEthyl cellulose and methyl stearate mixturesHydrated hydroxy alkyl celluloseSalts of polymeric carboxylatesChelated hydrogelsWater-insoluble hydrophilic copolymersCellulose ether compositionsPartial esters o facrylate-unsaturated anhydride
copolymer
RECENT ADVANCES Medisorb
Microencapsulation (50 m) by PLA, PGA, PLGA Drug release : week to one year
Polymeric prodrugsCellulose and polyarabogalactants as drug carrierNaproxen with polyphosphazene : bioerodable implantConjugate of poly(glutamic acid) and p-
phenylenediamine using immunoglobulin as a homing device
Immunogenicity, hemolytic activity, pyrogenicity, osmotic property, interaction with plasma components
AlzamerBioerodible polymer : release at a controlled rateChronic disease, contraception, topical therapy
Sustained release tabletCompressed plastic matrixDiffuse through a network of channelsRelease controlled by altering the porosity or surface area of
the matrix, changing the solubility of drug, adding other compounds that either speed up or delay the release
Mixture of two or more substances : Polycaprolactone and cellulose propionate
Aqueous polymeric dispersionSafety hazards associated with use of organic solventWater-based coating formulation
Latex or pseudo-latexTo coat pellets or tablets, film deposition on the substrateTackiness or film rupturing
HydrogelSwelling and biocompatibilityMultiblock copolymers
FUTURE OPPORTUNITIES IN CONTROLLED DRUG DELIVERY
Exciting opportunities in controlled drug delivery lie in the field of responsive delivery systems
By this it will be possible to deliver drugs through implantable devices in response to a measured blood level or to deliver a drug precisely to a targeted site
Much of the development of novel materials in controlled drug delivery is focusing on the preparation and use of these responsive polymers with specifically designed macroscopic and microscopic structural and chemical features.
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Such systems include:
Copolymers with desirable hydrophilic/hydrophobic interactions.
Block or graft copolymers.
Complexation networks responding via hydrogen or ionic bonding.
Dendrimers or star polymers as nanoparticles for immobilization of enzymes, drugs, peptides, or other biological agents.
New biodegradable polymers.
New blends of hydrocolloids and carbohydrate-based polymers.
CONCLUSION• The main advantages in using biodegradable polymeric
substances are there is no possibility of toxicity problems, their release rates can be customized and they degraded to form biocompatible or non-toxic products in biological fluids, which are removed from the body through normal metabolic pathways and physiological mechanisms.
• However, biodegradable polymeric substances do produce ‘degradation by-products’ that must be tolerated with little or no adverse reactions within the biological environment.
• Control and modulation of drug release is enhanced using Parenteral Depot Systems [PDS] and microspheres.
ACKNOWLEDGMENT
Firstly I want to thank several colleagues who shared their knowledge with me. I was lucky once again to have all of my professors with me especially our professor Venkat Rao garu for giving his valuable suggestions and prodigious support for us.
I also thank pharmainfo.net for giving me an opportunity to participate in this contest.
THANK YOU
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