Download 3. Objective of study

A. Brief Resume Of Intended Work
1. Need for Study
During the past few decades, sustained release formulations have been one of the major focuses in
pharmaceutical research. Among the various sustained release formulations, matrix systems have been found to
be convenient to make, cost effective and patient friendly. Various materials of synthetic, semi synthetic and
natural origins are used as release retardants in the development of sustained release tablets. Of the various
matrix forming materials, wax/ hydrophobic materials are popular and are widely used because of their low-cost,
non-toxic, inertness and ease of availability.
The drug release rate from the matrix system depends upon the type of matrix forming material, amount
of drug incorporated in matrix, solubility of drug used and solvent system used1. Wax materials being lipophilic
are popular in sustained release single or multiple-unit solid dosage form. Wax matrix drug delivery systems
include wax granules, beads, tablets and wax filled hard gelatin capsule. Wax matrix controlled drug release
formulations are prepared either by melt granulation or by direct compression of dry blend 2, 3.
Waxes have been used by the pharmaceutical industry for many years. Their application in semisolid
preparations, including ointments, creams, or lotions, and in suppositories are well known
2, 3
. Various
researchers have used thermal treatment as a mode for modulating drug release from the wax matrix tablets.
However, until now, researchers have used Compritol and Precirol as the primary wax materials for the study.
The use of other wax materials in sustained release matrix tablets have been less explored. Therefore, in the
present investigation it is hypothesized that hydrogenated vegetable oils, which have melting temperature of 5060° C, if subjected to thermal treatment would modulate drug release similar to that reported for Compritol 4 and
Precirol 5.
Hydrogenated vegetable oil serves as a lubricant in tablet and capsule formulations at concentration of
0.5-4% w/w 6. It may also be applied to dry granulated formulation during the slugging/ rollen compaction
process. Additionally it is also used as the matrix forming material in lipophilic based modified release
formulations 7. It melts and re-solidifies during the compaction process, enhancing the bounding capacity of the
tablet matrix resulting in a more robust tablet.
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Tramadol HCl is a synthetic opioid of the aminocyclohexanol group. It is a centrally acting analgesic with
weak opioid agonist properties. Tramadol has been proven to be effective in both experimental and clinical pain
without causing serious cardiovascular and respiratory side effects 8. The half life of the drug is ~ 5.5 h and the
usual oral dosage regimen is 50-100 mg every 4-6 h 9.
To reduce the frequency of administration and to improve patient compliance, a sustained release formulation of
tramadol hydrochloride is desirable. The drug is freely soluble in water and it is desirable to include it in a
hydrophobic matrix system to achieve sustained release 10.
2. Review of literature
Ghaly and workers used direct compression and melt granulation (solid dispersion) to prepare wax
matrix-controlled drug release formulations. Their results revealed that at 30-50% wax levels, the drug release
from the tablets made by melt granulation yielded slower drug release than by direct compression 11.
Matrix tablets containing ephedrine HCl and hydrogenated castor oil were prepared either by
compression of a physical mixture or by compression of a congealed melt 2, 3.
Compritol 888 ATO used as wax matrix material for sustained release tablets of theophylline and
phenylpropanolamine hydrochloride made by melt granulation and dry blending 12.
A combination of ethyl cellulose and paraffin wax or hydrogenated castor oil was used as carrier material
in sustained-release aminophylline tablets 13. Hydrophobic wax matrix sustained release tablets of tramadol HCl
were prepared by melt granulation technique 14.
Sustained release nitrofurantoin granules containing stearic acid and glycerol monostearate as matrix
materials were prepared by fusion, solvent evaporation or melt granulation technique 15.
Diclofenac sodium-carnauba wax matrix granules containing various release-controlling agents such as
hydroxy propyl cellulose, Eudragit L-100 or NaCl were prepared with a twin screw extruder 16, 17.
In a recent study, Tiwari et al
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evaluated the effect of concentration of hydrophilic and hydrophobic
polymers on the release rate of tramadol. The release of tramadol was sustained for over 20 h with hydrophobic
matrix in comparison to hydrophilic matrix (<14 h).
3. Objective of study
The objectives of the proposed study are to evaluate:
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1. The effect of compositions of matrix tablet on tablet properties.
2. The effect of thermal treatment on tablet properties.
3. The influence of tablet storage condition on its properties.
B. Material and Method
1. Source of data
Preliminary data required for the experimental study would be obtained from
1. Pubmed, Science direct, medline, US patent office website, other internet facilities
2. Books available in National college of Pharmacy Library
3. Preformulation Work done in Pharmaceutics PG laboratory, NCP Shimoga.
4. Scientific Journals.
2. Method of collection of data
Data on drug and excipients will be collected from drug information center, standard books, catalogs etc.
On the basis of extensive preformulation trials the drug and excipient will be fixed for final formulation so as to
develop a stable system.
Drug, wax ingredient and other excipients will be homogeneously mixed and the powder blend will be
granulated by either wet granulation or melt solidification techniques. Granules will be then compressed on a
single station tabletting machine. Prepared tablets will be evaluated for various physical properties like drug
content, weight variation, content uniformity and in vitro drug release properties.
Based on the data obtained from the in vitro evaluation of the prepared batches, selected batch will be
subjected to thermal treatment at various temperatures for pre-identified durations. The thermally treated batches
will be evaluated for the changes in physical properties and in vitro drug release.
The effect of long term storage at different temperature and humidity will be evaluated by storing
selected batches at various temperature and humidity for 6 months. After the storage period, the batches will be
evaluated for various physical properties like drug content, weight variation, content uniformity and in vitro drug
release properties.
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3. Does this study require any investigation or interventation to be conducted on patients or other humans
or animals? If so, please describe briefly.
NO
4. Has ethical clearance been obtained from your institution in case of B(3)
Not Applicable
C. References:
1. Desai SJ, Simonelli AP, Higuchi WI. Investigation of factors influencing release of solid drug dispersed in
inert matrices. J. Pharm. Sci.1965;54:1459-64.
2. Foster TP, Parrott EL. Effect of processing on release from an inert heterogeneous matrix. Drug Dev. Ind.
Pharm.1990;16:1309-24.
3. Foster TP, Parrot EL. Release of highly water-soluble medicinal compounds from inert heterogeneous
matrixes II: Melt. J. Pharm. Sci. 1990;79:938-42.
4. Zhang YE, Schwartz JB. Melt granulation and heat treatment for wax matrix controlled drug release. Drug
Dev.Ind.Pharm.2003;29:131-38.
5. Ghali ES, Klinger GH, Schwartz JB. Thermal treatment of beads with wax for controlled release. Drug Dev.
Ind.Pharm.1989;15:1311-28.
6. Stainforth JN. Use of hydrogenated vegetable oil as a tablet lubricant. Drug Dev. Ind.Pharm.1987;13:114158.
7. Ciftci K, Capan Y, Ozturk O, Hincal AA. Formulation and in vitro-in vivo evaluation of sustained release
lithium carbonate tablets.Pharm.Res.1990;7:357-63
8. Lehmann KA. Tramadol in acute pain. Drugs.1997;53:25-33.
9. Scott LJ, Perry CM. Tramadol: a review of its use in preoperative pain. Drugs. 2000;60:139-76.
10. Salsa T, Veiga F, Pina ME. Oral controlled-release dosage forms I. Cellulose ether polymers in hydrophilic
matrix. Drug Dev.Ind.Pharm.1997;23:929-38.
11. Perez MA, Ghaly ES, Marti A. Sustained release phenylpropanolamine hydrochloride from ATO 888 matrix.
Puerto. Rico. Health. Sci. J. 1993;12 :263-67.
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12. Zhang YE, Joseph BS. Melt granulation and heat treatment for wax matrix- controlled drug release. Drug
Dev. Ind.Pharm.2003;29:131-38.
13. Boles MG, Desay PB, Donnellan MF. Design and evaluation of sustained release aminohpylline tablet. Drug
Dev.Ind.Pharm.1993;19:349-70.
14. Foster TP, Parrot EL. Constant release rate from inert heterogeneous matrixes by means of position
dependent loading. Drug Dev.Ind.Pharm.1990;16:1633-48.
15. Shanawany S. Sustained Release of nitrofurantoin from inert wax matrixes. J.contro.Rel.1993;36:11-19
16. Miyagawa Y, Sato H, Okabe T, Nishiyama T, Miyajimi M, Sunada H. In Vivo performance of wax matrix
granules prepared by a twin-screw compounding Extruder. Drug Dev.Ind.Pharm.1999;25:429-35.
17. Miyagawa Y, Okabe T, Yamaguchi Y, Miyagima M, Sato H, Sunada H. Controlled-release of diclofenac
sodium from wax matrix granule. Int.J.Pharm.1996;138:215-24.
18. Tiwari SB, Murthy TK, Pai MR, Mehta PR, Chowdary PB. Controlled release formulation of tramadol
hydrochloride using hydrophilic and hydrophobic matrix system. AAPS Pharm.Sci.Tech.2003;4:Article 31
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