SUSTAINED RELAEASE MULTIPARTICULATE DRUG DELIVERY SYSTEMS OF

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					 SUSTAINED RELAEASE MULTIPARTICULATE DRUG
 DELIVERY SYSTEMS OF HIGHLY WATER SOLUBLE
                      DRUGS




              SYNOPSIS FOR
          M.PHARM. DISSERTATION




               SUBMITTED TO
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
               KARNATAKA



                    BY

    PATEL DHAVALKUMAR RAJENDRABHAI
                I M.PHARM.




      DEPARTMENT OF PHARMACEUTICS
 DAYANANDA SAGAR COLLEGE OF PHARMACY
                   2008
        RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
                         BANGALORE, KARNATAKA
                                     ANNEXURE-II

     PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1.     Name of the candidate and        PATEL DHAVALKUMAR
       address (in block letters)       RAJENDRABHAI
                                        I M.Pharm.,
                                        Department of Pharmaceutics,
                                        Dayananda Sagar College of Pharmacy,
                                        Kumaraswamy Layout,
                                        Bangalore-560078.
                                        PERMANENT ADDRESS
                                        To:Sundarpura, Ta:Bayad,
                                        Post:Ranechi, Dist:Sabarkantha,
                                        State:Gujarat (383325)




2.     Name of the Instuition           Dayananda Sagar College of Pharmacy,
                                        Shavige Malleswara Hills,
                                        Kumaraswamy Layout,
                                        Bangalore-560078,
                                        Karnataka.


3.     Course of study and subject      Master of Pharmacy in Pharmaceutics
4.     Date of admission to course      21 February 2008
5.     Title of the project:
       SUSTAINED RELAEASE MULTIPARTICULATE DRUG DELIVERY
       SYSTEMS OF HIGHLY WATER SOLUBLE DRUGS
6.   Brief resume of the intended work:


     6.1 Need of the study:
     Ideally, a drug should arrive rapidly at the site of action in the optimum
     concentration, remain for the desired time, be excluded from other sites, and be
     rapidly removed when the goal is achieved.
     However, where highly water-soluble drugs are concerned, formulation into a
     dosage form is tricky and complicated due to its high solubility. If the release of
     drug is rapid from a single dosage form, it may be beneficial for therapies where
     immediate onset of action is desired. But mostly drug dumping is seen with highly
     water soluble drugs which in turn is associated with side effects like nausea and
     vomiting, not to mention the aggravation of the potential side effects seen. This
     problem is particularly noticed with drugs having a short half-life, requiring
     frequent dosing of the drug to maintain steady state concentrations.
     The goal of designing sustained or controlled release multiparticulate delivery
     systems of such highly water soluble drugs is to reduce frequency of dosing
     thereby minimizing the occurrence of side effects and to increase the effectiveness
     of the drug since multiparticulates are known to disperse freely in the gastric fluids
     covering greater surface of absorption. In addition they also offer benefits of
     reducing the dose required, and providing uniform drug delivery.
     So in the present study, attempts will be made to establish a optimum method and
     polymer system of a sustained release multiparticulate delivery system for the
     delivery of some model highly water soluble drugs like Venlafaxine HCl and
     Tramadol HCl.
     The aforementioned drugs have been selected basically due to their high water
     solubility along with their attributes of short half lives, frequent dosing
     requirements and reported side effects seen on oral dosing.
6.2 Review of literature

A study1 was conducted to develop a microspherical dosage form for Fenoterol
HBr, a highly water-soluble drug by using the ethyl cellulose. The oil-in-oil
solvent evaporation method efficiently encapsulated Fenoterol HBr in these ethyl
cellulose microspheres. A significant increase in the encapsulation efficiency of
fenoterol was observed when the drug/polymer ratio was decreased from 15% to
5% (p < 0.05). The diffusion-controlled release followed by a constant release
was exhibited in these microspheres.

Pseudoephedrine HCl, another highly water-soluble drug, was entrapped within
poly (methyl methacrylate) microspheres by a water/oil/water emulsification-
solvent evaporation method2. Microspheres were formed after solvent evaporation
and polymer precipitation. The drug content of the microspheres increased with
increasing theoretical drug loading, increasing amounts of organic solvent,
polymer and polymeric stabilizer, and decreased with increasing stirring time,
increasing pH of the continuous phase and increased volume of the internal and
external aqueous phase.

Microencapsulation of highly water-soluble pharmaceuticals especially of those
requiring high drug loading (more than 50%) was carried out3. Biodegradable poly
(lactic acid) (PLLA) as coating material and polyvinyl alcohol as surfactant was
found suitable for this purpose. Active drug substance was microencapsulated by
water-in-oil-in-water technique using biodegradable poly (lactic acid) (PLLA) as
coating material and polyvinyl alcohol as surfactant. To evaluate the drug physical
state in microcapsules powder, DSC analysis confirmed absence of any drug-
polymer interaction, X-ray diffraction patterns showed the changes of polymer
crystallinity during the encapsulation procedure as well as decrease of crystallinity
of the drug; SEM investigations showed the morphology of obtained product and
demonstrated the drug location inside the capsule.
An oral controlled release formulation matrix for highly water-soluble Ranitidine
HCl was developed4 using, sodium alginate- xanthan gum- zinc acetate matrix and
prepared by direct compression so as to achieve a 24 hours release profile. The in
vitro release tests were carried out in simulated intestinal fluid (SIF, pH7.5) and
simulated gastric fluid (SGF, pH1.2). The release of the drug in the sodium
alginate formulation containing only xanthan gum completed within 12 hours in
the SIF, while the drug release in the sodium alginate formulation containing only
zinc acetate finished almost within 2 hours in the same medium. Only the sodium
alginate formulation containing both xanthan gum and zinc acetate achieved a 24-
hour release profile. Evaluation of the release data showed the release mechanism
for the novel formulation might be attributed to the diffusion of the drug.

Poly(ethylene glycol)-terephthalate / poly (butylene terephalate) multiblock
copolymer was investigated5 as possible matrix for controlled delivery of small
water soluble drugs like leuprorelin acetate and vitamin B12 for sustained release.
It was first prepared using a double emulsion method and addition of surfactant in
this preparation led to increase microsphere entrapment efficiency, where as
decrease of the PEGT copolymer content allowed the release rates from
microspheres to be decreased. Leuprorelin acetate - loaded microspheres did not
show same characteristics. This study shows the suitability of PEGT/PBT
microspheres as controlled release system for vitamin B12, but not for leuprorelin
acetate.

The effect of Microcrystalline Cellulose (MCC) and Waxy cornstarch and Lactose
as a cofiller, cellulose acetate phthalate (CAP) as enteric film coat used in
riboflavine sodium phophate pellet on diffusion and dissolution was studies6 .The
in vitro release Diffusion of drug from core to film coat containing Lactose was
greater than with waxy cornstarch. Dissolution of enteric-coated waxy cornstarch
had good acidic resistance in 0.1N HCl solution for at least 1 hr, others failed the
test. Waxy cornstarch containing enteric pellets dissolved at SIF in 10 min, and
film coated pellets had less drug dissolved than lactose containing pellets because
Waxy cornstarch minimizes premature drug diffusion from core in to the film coat
layer.

The aim of one other study7 was to obtain a good drug incorporation and
controlled release of drug from poly (glycerol adipate) backbone (PGA)
nanoparticles. They were prepared by the interfacial deposition technique and the
simultaneous emulsification method. Dexamethasone phosphate(DXMP) and
Cytosine arabinoside (CYT-ARA) were incprporated in PGA polymer. Polymers
with acyl group chain lengths containing 8 carbon atoms (C8) showed both good
drug incorporation and a controlled release for DXMP while for CYT-ARA it was
the unsubstituted polymer backbone that had maximum drug loading and slower
release. It was concluded from the study that drug loading and release from
nanoparticles are primarily influenced by the nature of interactions between the
drug and polymers.
6.3 Objective of the study:
The objective of the study is to develop a sustained release multiparticulate delivery
system for highly water soluble drugs which are expected to
       1. Maintain the therapeutic drug concentration in the blood for a prolonged
           period of time
       2. Reduce the frequencies of drug administration
       3. Reduce the dose related side effects
       4. Improve patient compliance


Plan of work
The work will be executed as follows


          Preformulation studies
          Optimisation of Process parameters for method of preparation of the
           multiparticulate delivery system
          Formulation of different batches of the multiparticulate delivery system
          Evaluation of the formulations for size analysis, density, angle of repose,
           surface topography, encapsulation efficiency, in vitro release.
          Statistical evaluation of the obtained data.
          To perform the stability studies for selected formulations as per ICH
           guidelines.
7.   Materials and methods


     7.1 Source of data:
     Official Pharmacopoeia, Standard books, Pharmaceutics databases, internet, etc.


     7.2 Method of collection of the data (including sampling procedure, if any):


     The pharmacological details of the drug will be collected from various standard
     books, peer reviewed national and international journals and other sources like
     research literature databases such as Medline, Science direct, etc.


     Experimental data will be collected from the evaluation of designed formulation
                1. Preformulation studies like solubility, melting point, compatiblity
                      of the drug with polymers will be carried out by IR, XRD and DSC
                      instruments.
                2. Multiparticulates of the highly water soluble drugs will be prepared
                      by the appropriate methods like solvent evaporation method or
                      multiple emulsion-solvent evaporation method etc. using natural,
                      synthetic or combination of both type of polymers.
                3. The multiparticulates will be evaluated for size analysis, surface
                      characteristics, flow properties and encapsulation efficiency.
                4. In-vitro release studies will be carried out by using dissolution test
                      apparatus USP-XXIV and the data of the drug release will be
                      subjected to statistical analysis for significance and evaluation of
                      kinetics and mechanisms of drug release.
                5. Stability studies will be carried out as per ICH guidelines.


     7.3. Does the study require any investigation or interventions to be conducted
     or patients or other humans or animals? If so please describe briefly:


     No
     7.4. Has ethical clearance been obtained from your institute in case of 7.3?


     Not applicable


8.   References:
     1. Lin WJ, Wu TL. Modifacation of the initial release of a highly water soluble
     drug from ethyl cellulose microspheres. J Microencapsul.1999; 16(5): 639-646(8).
     2. Alex R, Bodmeier R. Encapsulation of water-soluble drug by a modified solvent
     evaporation method. 1. Effect of process and formulation variables on drug
     entrapment. J Microencapsul. 1990; 7(3): 347 -55.


     3. Dagnija Loca, Pugovics O and Berzina-Cimdina L. Evaluation of Highly-Water
     Soluble Drug Physical State in Biodegradable microcapsules.14th Nordic-Baltic
     conference on biomedicals engineering and medical physics.2008; 20(1680-0737):
     619-622.

     4. Zeng W.M. Oral controlled release formulation for highly water-soluble drugs:
     Drug-sodium alginate-xanthan gum-zinc acetate matrix. Drug Dev Ind Pharm.
     2004; 30(5): 491-95.

     5. Sohier JR, Van Dijkhuizen-radersma, De Groot K and Bezemer JM. Release of
     small water-soluble drug from multiblock copolymer microspheres; a feasibility
     study. Eur J Pharm Biopharm. 2003: 62(2): 221-28.

     6. Guo HX, Heinamaki and Yliruusi J. Diffusion of a Freely Water Soluble Drug
     in Aqueous Enteric coated Pellets. AAPS Pharm SciTech. 2002; 3(2): 1-8.


     7. Sanuogita P, Paraskevi K, Sean H, Gillian A, Hutcheon and Martin CG. Drug
     Incorporation and release of Water-soluble drugs from novel functionalised poly
     (glycerol adipate) nanoparticles. J Control Release. 2008; 125(1): 59-67.




9.   Signature of the candidate


                                                    (PATEL DHAVALKUMAR
                                                         RAJENDRABHAI)
10. Remarks of the guide:                   The proposed work is of significance in the
                                            formulation and delivery of highly water-
                                     soluble drugs. Hence it is recommended for
                                     registration.
11. Name and Designation (in block
     letters)
     11.1. Guide                     DR.ARSHIA SHARIFF
                                     PROFESSOR AND HEAD,
                                     Department of Pharmaceutics,
                                     Dayananda Sagar College of Pharmacy,
                                     Kumaraswamy Layout,
                                     Bangalore-560078.


     11.2. Signature
     11.3. Co-guide if any           No
     11.4. Signature                 Not applicable
     11.5. Head of the department    DR.ARSHIA SHARIFF
                                     HEAD,
                                     Department of Pharmaceutics,
                                     Dayananda Sagar College of Pharmacy,
                                     Kumaraswamy Layout,
                                     Bangalore-560078.


     11.6. Signature


12. 12.1. Remarks of the principal
                 Dr. V. Murugan,
12.2 Signature   Principal,
                 Dayananda Sagar College of Pharmacy,
                 Kumaraswamy Layout,
                 Bangalore-560078
                 09343824404
                 murugan62@yahoo.com




                      (Dr. V. Murugan)

				
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