REVIEW ON MICROSPHERES by gunjachaturvedi

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									                                     A
                                   Review
                                     On

Microspheres technology and its application

                                     By


                           Gunja Chaturvedi
                            (I.D no- 2008H146101)



                Submitted in partial fulfilment of the course
                    PHA G632: Dosage Form Design




                     Date of Submission 01/04/2009
                               Submitted to


                               Dr. R. N Saha
                           (Instructor In-charge)




BIRLA INSTITUTE OF TECHNOLOGY AND SCIENCE, PILANI, RAJASTHAN – 333 031
                                April 2009
                         REVIEW ON MICROSPHERES

                     Chaturvedi Gunja , Bhagav Prakash, Prof. R.N Saha
              Birla Institute of Technology and Science, Pilani, Rajasthan (India)
      3
        Faculty of Pharmacy, Birla Institute of Technology & Science, Pilani, Rajasthan
4
  Dean, Faculty Division-3, Birla Institute of Technology & Science, Pilani, Rajasthan (India)

Abstract :-
Nonideal pharmaceutical, pharmacokinetic, and therapeutic properties often combine to
reduce the effectiveness of certain compounds. For the vectoring of such compounds to target
areas, liposomes, nanoparticles, and microspheres have been suggested. Since organ
distribution of the latter is dependent upon their size and shape, it is reasonable to attempt
second-order targeting of microspheres on this basis.
The range of techniques for the preparation of microspheres offers a variety of opportunities
to control aspects of drug administration.This approach facilitates accurate delivery of small
quantities of potent drugs ,reduce drug concentrations at sites other than the target organ or
tissue and protection of labile compounds before and after administration and prior to
appearance at the site of action.

Keywords: microspheres, formulation parameters, biodegradable polymers,matrix and
reservoir type microspheres, particle size, ,colonic drug delivery, ,nasal delivery.


Contents:-
    Introduction
    Definition and description
    History
    Potential use of microspheres
    Microspheres manufacture by different methods
    Approaches related to formulation and process parameters in microsphere
      manufacturing
            Effect of process and formulation parameters on inernal morphology of
             microspheres loaded with hydrophobic drug
            Proteins encapsulated in microspheres and its stability
            Preparation of Biodegradable Microspheres and Matrix Devices Containing
             Naltrexone
   ● Approaches towards drug targeting using microspheres
            Nasal delivery
            Colonic drug delivery
   ● References


Introduction                                       drugs in vivo can be manipulated by
The range of techniques for the                    coupling the drug to a carrier particle. The
preparation of microspheres offers a               clearance kinetics,tissue distribution,
variety of opportunities to control aspects        metabolism and cellular interaction of the
of drug administration.This approach               drug are strongly influenced by the
facilitates the accurate delivery of small         behaviour of the carrier. The exploitation
quantity of the potent drugs ,reduced drug         of these changes in pharmacodynamics
concentration at the site other than the           behaviour may lead to enhanced
target site and the protection of the labile       therapeutic effect. However ,an intelligent
compound before and after the                      approach to therapeutics employing drug
administration and prior to appearance at          carriers technology requires a detailed
the site of action.The behaviour of the            understanding of the carrier interaction
with critical cellular and organ systems       THE    POTENTIAL           USE       OF
and of the limitations of the systems with     MCROSPHERES                           IN
respect to the formulation procedures and      PHARMACEUTICAL INDUSTRY
stability. A variety of agents have been          Conversion of oils and other
used      as drug      carrier, including          liquids to solids for ease of
immunoglobulins        serum       proteins        handling
,liposomes, microspheres ,nanoparticles           Taste and odour masking
,microcapsules and even cells such as             Increasing the stability of the drug
erythrocytes. The characteristics of               against     the       environmental
microspheres containing drug should be             conditions
correlated with the required therapeutic          To delay the volatilisation
action and are dictated by the materials          Separation      of     incompatible
and the methods employed in the                    materials
manufacture of delivery systems. [1]              Improvement of flow properties of
                                                   powders
DEFINITION            AND         GENERAL         Safe handling of toxic substances
DESCRIPTION                                       Improve the solubility of water
Microspheres can be defined as solid,
                                                   insoluble substances by aiding in
approximately spherical particles ranging
                                                   dispersion of such material in
in size from 1 to 1000 µm.They are made
                                                   aqueous media
of polymeric,waxy or other protective
materials,that is biodegradable synthetic         Production         of      sustained
polymers and modified natural products             release,controlled release       and
such as starches,gums ,proteins,fats and           targeted medications
waxes.The natural polymers include                Reduce the dose dumping
albumin and gelatine, the synthetic                potential compared to large
polymer include polylactic acid and                implantable devices. [1]
polyglycolic acid. The solvents used to
dissolve the polymeric materials chosen
according to the polymer and drug              Microspheres manufacture
solubilities and stabilities ,process safety   The most important physicochemical
and economic considerations.                   characteristics that may be controlled in
Microspheres are small and have large          microsphere manufacture are:
surface-to-volume ratio. At the lower end                  - Partical          size     and
of their size range they have colloidal                        distribution
properties. The interfacial properties of                  - Polymer molecular weight
microspheres are extremely important                       - Ratio of drug to polymer
,often indicating their activity. [1]                      - Total mass of drug and
                                                               polymer
                                               Different methods of microspheres
HISTORY
The concept of packaging microscopic           manufacturing are:
quantities   of         materials   within                     - Wax coating and hot
microspheres dates back to the 1930s and                            melt
the work of Bungenberg de Jong and                             - Spray coating and pan
coworkers on entrapment of substances                               coating
within coacervates. The first commercial                       - Coacervation
application of encapsulation was by the                        - Spray drying
National Cash Register Company for the                         - Solvent         evaporation
manufacture of carbonless copying paper.                            and precipitation
The technology and applications have                           - Freeze drying
advanced over the last several dacades. [1]                    - Chemical and thermal
                                                                    cross – linking
Wax coating and hot melt: wax may be           variables          like           pH,ionic
used to coat the core particles,               strength,macromolecule
encapsulating the drug by dissolution or       concentration,macromolecule ratio and
dispersion in molten wax. The waxy             macromolecular weight which results in a
solution or suspension is dispersed by         larger number of controllable parameters.
high speed mixing into cold solution, such     These can be manipulated to produce
as cold liquid paraffin. The mixture is        microspheres with specific properties.
agitated for at least one hour. The external
phase (liquid paraffin) is then decanted       Spray drying: It is single step,closed-
and the microspheres are suspended in a        system process applicable to wide variety
non- miscible solvent and allowed to air       of    materials,including     heat-sensitive
dry. Wax coated microspheres ,while            materials. The drug and polymer coating
inexpensive and often used,release drug        materials are       dissolved in suitable
more rapidly than polymeric microspheres.      solvent(aqueous or non-aqueous) or the
Carnauba wax and beeswax can be used as        drug may be present as a suspension in the
the coating materials and these can be         polymer solution. Alternatively, it may be
mixed in order to achieve desired              dissolved     or suspended within         an
characteristics.                               emulsion or coacervate system. For
                                               example,biodegradable           polylactide
Spray coating and pan coating: spray           microspheres can be prepared by
coating and pan coating employ heat-           dissolving the drug and the polymer in
jacketed coating pans in which the solid       methylene chloride. The microsphere size
drug core particles are rotated and into       is controlled by the rate of spraying,the
which the coating material is sprayed. The     feed rate of the polymer drug solution,the
core particles are in size range of            nozzle size ,the temperature in drying and
micrometers upto few millimetres. The          collecting chambers,and the size of the
coating material is usually sprayed at         two chambers. The quality of the spray
angle from the side into the pan. The          dried products are improved by the
process is continued until an even coating     addition of plasticizers that promote the
is completed. Coating a large number of        polymer coalescence and film formation
particles may provide a safer and more         and enhance the formation of smooth
consistent release pattern than coated         surfaced and spherical microspheres.
tablets. In addition,several batches of
microspheres cab be prepared with              Solvent evaporation: For this method the
different coating thickness and mixed to       drug and the polymer must be soluble in
achieve specific controlled release pattern.   organic solvent,frequently methylene
                                               chloride. The solution containing polymer
Coacervation : This process is a simple        and drug may be dispersed in an aqueous
separation of macromolecular solution          phase to form droplets. Continuous mixing
into two immiscible liquid phases,a dense      and elevated temperatures may be
coacervate phase,which is relatively           employed to evaporate the more volatile
concentrated in macromolecules and a           organic solvents and leave the solid
dilute equilibrium phase. In presence of       polymer-drug particles suspended in an
only one macromolecule this process is         aqueous medium. The particles are finally
referred to as simple coacervation. When       filtered from the suspension.
two or more macromolecules of opposite
charge are present ,it is referred to as       Precipitation : It is a variation on the
complex coacervation. Former one is            evaporation method. The emulsion
induced by various parameters like change      consists of polar droplets dispersed in a
in temperature, addition of non-solvent or     non-polar medium. Solvent may be
microions , which results in dehydration of    removed from the droplets by the use of a
macromolecules because they promote            cosolvent. The resulting increase in the
polymer-polymer       interactions     over    polymer concentration causes precipitation
polymer- solvent interaction. And the          forming a suspension of microspheres.
latter is induced by large number of
Freeze Drying: This technique involves
the freezing of the emulsion and the
relative freezing points of the continuous
and dispersed phases are important. The
continuous phase solvent is usually
organic and is removed by sublimation at
low temperature and pressure. Finally the
dispersed phase solvent of the droplets is
removed by sublimation,leaving polymer-
drug particles.

Chemical and thermal cross- linking:
microspheres made from natural polymers                  Fig 1. structure of ABT627
are prepared by a cross-linking process;
polymer include gelatin, albumin ,starch
and dextran. A water-oil emulsion is
prepared ,where the water phase is a              From the above studies it was found that
solution of polymer that contains drug to         for the encapsulation of the hydrophobic
be incorporated. The oil phase is a suitable      substances into PLGA matrix, CP/DP ratio
vegetable oil or oil - organic solvent            is a crucial factor. It was observed that the
mixture containing an oil soluble                 drug loading increased significantly with
emulsifier. Once the desired water-oil            increasing CP/DP ratio accompanied by
emulsion is formed ,the water soluble             decreasing the burst effect. At the CP/DP
polymer is solidified by thermal treatment        ratio 20,the microspheres with a core shell
or addition of a chemical cross-linking           structure were observed and the internal
agent such as glutaraldehyde to form a            porosity of the microspheres decreased
stable chemical cross link as in albumin. If      with increasing the CP/DP ratio.
chemical or heat cross linking is used , the      Increasing the PLGA concentration
amount of chemical and the period and             ,increased particle size but decreased drug
intensity of heating are critical in              release rate was observed. Increasing the
determining the release rates and swelling        PVA concentration in continuous phase
properties of the microspheres. [1],[2],[3],[4]   from 0.1% to 0.5% increased the drug
                                                  release rate. The maximum solubility of
Approaches related to formulation and             the drug in PLGA microspheres is
process parameters in microsphere                 approximately 30% under which it was
manufacturing                                     dispersed in PLGA matrix in a molecular
                                                  state. Its release rate was decreased with
1.Effect of process and formulation               increasing the intial         drug loading.
parameters on inernal morphology of               ABT627 was slowly released from the
microspheres loaded with a hydrophobic            PLGA microspheres over 30 days by a
drug: ABT627 is a newly synthesized               combination of pore diffusion and polymer
drug for the treatment of prostate cancer.        degradation. During the first 13 days,it
It is a lipophilic drug ,and taking it as a       was released mainly by diffusion
model drug the effect of continuous phase/        supported      by      unchanged      internal
dispersed phase ratio(CP/DP ratio),PLGA           morphology of the microspheres after 7
concentration ,continuous phase pH                days of release. Internal morphology
,polyvinyl alcohol concentration and initial      observation      after     incubating      the
drug loading on the physicochemical               microspheres for 17 days indicated that
characteristics    of    the     developed        ABT627/PLGA microspheres were mainly
microspheres was studied and internal             degraded by auto-catalyzation from
morphology of the microspheres was                inside,as revealed by core-shell structure
analyzed by stereological method to               of the microsphere at the release stage.
                                                  [5],[6],[7]
elucidate the distribution and the release
mechanism of the drug from microspheres.
2.Reversible protein precipitation to           production of various proteins has become
ensure stability during encapsulation           possible with the recent advances in
within PLGA microspheres: although the          biotechnology,their use for therapeutic
purpose has been limited due to physical        toxic PLGA solvent which could be used
and chemical instability. Due to relatively     to prepare PLGA microspheres. Moreover
high enzymatic susceptibility and short         ,it is a protic solvent containing hydrogen
half life,much attention has been paid to       attached to oxygen so that it is able to
their delivery from systems controlling         form hydrogen bonds or to donate a proton
local release. Since a solid-state protein      such as in stabilizing PEG. The presence
exhibits      restricted     conformational     of glucofurol induces a liquid –liquid
flexibility,non-aqueous       encapsulation     phase separation resulting in a protein –
approaches have emerged to ensure               rich phase and a protein –poor phase. The
protein stability upon encapsulation within     addition of salt (sodium chloride) helped
biodegradable                      polyester    in collecting the maximum amount of
microspheres.Various methods like spray-        protein precipitates by reducing the
drying or spray-freeze drying have been         electrostatic repulsive interactions between
reported for the preparation of small           charged proteins and promoting attractive
protein particles. Although these methods       hydrophobic interactions. The reason
can generate protein particles ,they present    behind selecting sodium chloride was
some drawbacks for microencapsulation           related to its possible use in parenteral
that they are technically complex and lead      pharmaceutical formulations and to its
to low protein recovery and also may            intermediate location in the lyotrophic
denature the proteins. The aim of this          series and also it decreases theprotein
study was to develop a non- denaturing          solubility very little with minimal
method to prepare protein particles. Freeze     denaturant effects. The various process
–drying has often been used to obtain           parameters discussed above were modified
protein particles without protein loss but it   to optimize the precipitation efficiency of
induce the formation of large particles. To     four model proteins : lysozyme,α-
obtain fine particles and preserve protein      chromotrypsin       ,peroxidase and β-
integrity,proteins have been freeze- dried      galactosidase. As monitored by enzymatic
with PEG which induces a two –phase             activity measurement of rehydrated
separation. This approach has been used         particles ,conditions to obtain more than
for protein        microencapsulation by        95% of the reversible precipitates were
solid/oil/water      (s/o/w)   and      s/o/o   defined for each protein. The study of the
techniques. However ,the remaining              rehydrated particles by absorbance
amount of PEG in the freeze-dried protein       spectroscopy, fluorescence spectroscopy
products leads to an important initial burst    and circular dichroism showed an absence
(20% in 1 hr) upon release from PLGA            of      structural-    perturbation     after
microspheres, and so an adaptation of the       precipitation. The protein particles were
process was necessary. So in order to           then microencapsulated within PLGA
obtain protein particles without these          microspheres using s/o/w technique. The
disadvantages,from an aqueous solution          average encapsulation yield was around
protein precipitation was induced via           80% and no loss of protein activity
isoelectric precipitation, reduction of         occurred after the encapsulaton step.
dielectric constant by addition of water-       Additionally , a lysozyme in vitro release
miscible organic solvents ,the reduction of     study showed that all of the released
the protein charge by changing the pH and       lysozyme was biologically active. So this
the addition of the polymers or salts. In       method of protein precipitation is
this study, an organic solvent ,Glycofurol      appropriate      for the encapsulation in
,was employed by preference to induce the       PLGA microspheres of various proteins
formation of fine protein particles. It was     without inactivation. [8],[9],[10]
chosen as a precipitant because it is non-
3.     Preparation     of    Biodegradable     antagonists. In this study ,poly(L-lactide)
Microspheres and Matrix Devices                (PLA) microspheres containing naltrexone
Containing Naltrexone: Naltrexone is an        prepared     by     sol-vent    evaporation
opiate antagonist used mainly as an            technique      were      compressed       at
adjunct to prevent relapse in detoxified       temperatures above the Tg of the polymer.
opioid-dependent patients. It is currently     The effect of different process parameters,
given orally as tablets or capsules in a       such as drug/polymer ratio and stirring
daily dose of 50 mg. Naltrexone is orally      rate during preparation of micro-spheres,
active with a relatively short half-life and   on the morphology, size distribution, and
subject to extensive hepatic first-pass        in vitro drug release of microspheres was
metabolism.Naltrexone       provides      no   studied.
euphoric effects, and there are no observ-
able pharmacological consequences when
a patient discontinues the drug. For
naltrexone treatment to be effective, a
sufficient level of the drug concentration
must be maintained. The minimum
effective concentra-tion of naltrexone for
the treatment of opiate addiction is
estimated to be in the range of 0.5 to 1.0
ng/mL. Detoxified patients are advised to
continue the naltrexone therapy for 4 to 8
months. This treatment typically requires
the patient to self-administer dosages of
the drug several times a week. The main
drawback in naltrexone treatment protocol
                                               Fig.2.Effect of particle size on drug release
is patient compliance. A possible means of
                                                from microspheres with 20% drug loading
improving patient compliance and
concomitant rehabilitation is the use of
controlled drug delivery systems of opioid




                                                 Fig.4. Effect of drug loading on drug release
                                                  from microspheres with the same size range

                                               By increasing the stirring speed from 400
Fig.3. Effect of particle size on drug         to 1200 rpm, the mean diameter of
release from microspheres with 40% drug        microspheres decreased from 251 μm to
loading                                        104 μm. The drug release rate from
                                               smaller microspheres was faster than from
                                               larger microspheres. However, drug
                                               release from microspheres with low drug
                                               content (20% wt/wt) was not affected by
                                               the particle size of microspheres.
Increasing       the    drug   content   of      nasal delivery has limitations which have
microspheres from 20% to 50% wt/wt led           restricted its use to the delivery of a few
to signifi-cantly faster drug release from       drug molecules. The permeability of nasal
microspheres. It was also shown that drug        mucosa is normally low for the polar
release from matrix devices pre-pared by         molecules: for small polar drugs the
compression of naltrexone microspheres is        bioavailability is generally in the region of
much slower than that of microspheres. No        10% and for the peptides such as
burst re-lease was observed with matrix          calcitonin and insulin normally not above
devices. Applying higher compression             1%. Another factor of importance for the
force, when compressing micro-spheres to         low membrane transport is the general
produce tablets, resulted in lower drug re-      rapid clearance of the administered
lease from matrix devices. The results           formulation from the nasal cavity due to
suggest that by regulating different             mucociliary clearance mechanism. It has
variables, desired release profiles of           been shown that for both liquid and
naltrexone can be achieved using a PLA           powder formulations that are not
micropar-ticulate system or matrix               mucoadhesive ,the half life of clearance
devices. [16],[17],[18]                          are in order of 15 -20 mins. So in this
                                                 study chitosan derivative MPC is used to
Approaches towards         drug targeting        produce microspheres for nasal delivery of
using microspheres                               metoclopramide. The mechanism of action
                                                 of chitosan in improving the transport of
1.Spray –dried microspheres based on             polar drugs across            the epithelial
methylpyrrolidinone chitosan as new              membrane is believed to be combination
carrier for nasal administration of              of bioadhesion and transient opening of
metoclopramide : In recent years,chitosan        tight junctions in the cell membrane to
derivatives have been studied to improve         enable the passage of the polar drugs. A
polymer solubility at different pH values        non –derivatized chitosan has been used as
and to promote the permeability of anionic       comparison         and       metoclopramide
drugs thereby avoiding the precipitation of      hydrochloride has been chosen as model
the drug –polymer complexes.5 –                  drug. The metoclopramide loaded MPC
methylpyrrolidinone chitosan (MPC) is a          microspheres were made by spray –drying
chitosan derivative in which the amino           technique. They showed similar properties
group of the glucosamine units of the            of microparticles       made by chitosan
polysaccharide backbone are partially            chosen as reference with respect to size
substituted by methylpyrrolidinone(MP) in        and in vitro release behaviour. And the
position 5. It belongs to the class of the gel   microspheres based on MPC are
–forming       reabsorbable      biopolymeric    characterized             by            better
substituted       chitosans         possessing   mucoadhesiveness,less swelling capability
documented biological significance. This         and more prolonged ex –vivo permeation
chitosan     derivative     combines       the   profile than the particles containing
biocompatibility of chitosan and the             chitosan,moreover they are able to provide
hydrophilic      characteristics     of    the   a gel (when they come in contact with
pyrroilidinone moiety ,being particularly        aqueous solutions) which shows different
susceptible to the hydrolytic action of          properties dependent upon the medium
lysozyme.                                        used. These properties make microspheres
Nasal delivery has generated interest as an      based on derivatized chitosan suitable for
alternative route for the administration of      nasal         administration,infact       the
drugs and biomolecules that are                  mucoadhesiveness might prolong the
susceptible to enzymatic or acidic               residential time of the formulation inside
degradation and first –pass hepatic              the nasal cavity while a moderate swelling
metabolism. Possible pathways for a drug         could avoid potential mucosal damages or
to permeate across the nasal mucosa are          inconveniences to the possible users.
                                                 [11],[12],[13]
passive transport ation ,carrier mediated
,transcytosis and transport through              2.Development of enteric –coated calcium
intercellular tight junctions. However ,the      pectinate microspheres intended for
colonic drug delivery: Among the various        suitable pectin type is very essential
strategies proposed to target orally            considering that increase in Ca amounts
administered drugs to the colon ,those          gave rise to a decrease in rate of drug
based on drug release triggered by colon        release. From the release test performed
microflora are generally considered the         under pH gradient and in presence of
most effective regarding target selectivity.    pectinolytic enzymes in simulated colonic
And for this purpose the natural                medium it was revealed that the Ca –
biodegradable polymers such as pectins          pectinate MS did not undergo any
are employed due to their ability to act as     selective colonic –microflora triggered
specific substrate for colonic microflora       drug release mechanism and the observed
and also combined with their high               slowing down effect of free Ca ions in the
safety,non –toxicity and biocompatibility       enzymatic degradation rate of the pectin
characteristics. Most of the colon targeted     matrix can only partially concur to explain
drug delivery system developed so far are       the almost complete lack of activity shown
single –unit systems. On contrary ,multi –      by pectinolytic enzymes. Inspite of this
particulate systems can offer several           unexpected result,the CF020 MS ,realized
advantages over single –unit formulations       with low Ca chloride concentration (2.5%
like quick spread out on their arrival to the   w/v) and coated with an appropriate
colon,with a sharp increase in the surface      thickness pf a pH –dependent polymeric
area exposed to bacterial breakdown that        film (100%w/v), demonstrated to be
produces rapid drug release and thereby         suitable to adequately modulate drug
improves the drug absorption. In this study     release through a mixed approach of pH
enteric     –coated     calcium pectinate       and transit –time control,completely
microspheres are formulated as a colon –        avoiding drug release during the first 2 h
targeted         delivery     system     and    in gastric ambient,limiting to less than
Theophylline is used as a model drug since      10% release in the following 2 h and
it is well absorbed in the large intestine in   reaching 100% release in the colonic
humans and both its anti –asthma activity       simulated medium within less than 24
and pharmacokinetic properties make it an       hours.[14],[15]
interesting candidate for such kind of          Conclusion:-
modified –release preparations. The             Drugs can be targeted to specific sites in
influence of pectine type ,calcium ion          the body using microspheres. Degree of
concentration and cross –linking time on        targeting can be achieved by localization
both drug entrapment efficiency and dug         of the drug to a specific area in the
release pattern was investigated. And the       body(for example in lungs),to a particular
effect of varying the level of the pH –         group of cells(for example, kupffer cells)
dependent coating polymer (Eudragit             and      even       to   the    intracellular
S100) was also evaluated. The Ca                structures(such as lyzosomes or cell
pectinate microsphere(MS) prepared with         nucleus). The rate of drug release from the
CF020 i.e low –methoxylated amidated            microspheres dictates their therapeutic
pectins were better than those obtained         action. Release is governed by the
with AU701 i.e low –methoxylated pectins        molecular structure of the drug and the
,for both their greater stability during        polymer,the resistance of the polymer to
storage     and     more      regular    and    degradation ,and the surface area
homogeneous morphological properties.           alongwith       the    porosity    of     the
The shape of the former MS was poorly           microspheres. The internal structure of the
influenced by the variations in Ca              microspheres can vary as a function of the
concentrations         maintaining          a   microencapsulation process employed.
homogeneous spherical form also at lower        Controlled drug release from microspheres
Ca concentration.while the latter required      occurs by diffusion of the drug through a
at least 20% w/v of Ca ion concentration        polymeric excipient, diffusion of the
for obtaining MS of satisfactory and well       entrapped drug through the pores in the
reproducible morphological properties.          polymeric microspheres. Microspheres
This finding lead to an important               with high drug content release the active
conclusion that the choice of the most          ingredient more rapidly than with a low
load. Physicochemical properties of the
drug and excipient such as permeability of
one in the other, identity of the polymer,
degree of crystallinity ,inclusion of
plasticizers and fillers and thickness of the
polymer influences the drug release rate.
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