DEVELOPMENT AND EVALUTION OF SUSTAINED RELEASE MATRICES OF TRAMADOL HYDROCHLORIDE USING
SYNTHETIC POLYMERS.
DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
DEORE RAKESH KARBHARI
M.PHARM, PART-I,
DEPARTMENT OF PHARMACEUTICS
UNDER THE GUIDENCE OF
Mr. GANESH. N.S
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA,
KARNATAKA-571422

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE-II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / NAME OF THE CANDIDATE
AND ADDRESS (IN BLOCK LETTERS) / DEORE RAKESH KARBHARI.
M.PHARM, PART-I,
DEPARTMENT OF PHARMACEUTICS,
BHARATHI COLLEGE OF PHARMACY,
BHARATHI NAGARA, MANDYA,
KARNATAKA-571422.
2. /

NAME OF THE INSTITUTION

/ BHARATHI COLLEGE OF PHARMACY,
BHARATHI NAGARA.
3. /

COURSE OF STUDY AND SUBJECT

/ MASTER OF PHARMACY IN PHARMACEUTICS.
4. / DATE OF ADMISSION OF COURSE / 04-02-2008
5. / TITLE OF TOPIC / DEVELOPMENT AND EVALUTION OF SUSTAINED RELEASE MATRICES OF TRAMADOL HYDROCHLORIDE USING
SYNTHETIC POLYMERS.
6. / BRIEF RESUME OF THE
INTENDED WORK
6.1 Need for the study
6.2 Review of the literature
6.3 Objectives of the study /
ENCLOSURE - I
ENCLOSURE - II
ENCLOSURE - III
7. /

MATERIALS AND METHODS

7.1 Source of data

7.2 Method of collection of data

7.3 Does study require any investigations or interventions to be conducted on patients or other human or animal? If so, please describe briefly.

7.4 Has ethical clearance been obtained from your institution in case of 7.3

/ ENCLOSURE - IV
ENCLOSURE - V
ENCLOSURE - VI
ENCLOSURE – VI
8. / LIST OF REFERENCES / ENCLOSURE – VII
9. / SIGNATURE OF CANDIDATE
10. / REMARKS OF GUIDE / Recommended
11. / NAME AND DESIGNATION OF
11.1 Guide
11.2 Signature
11.3 Co guide (if any)
11.4 Signature
11.5 Head of department
11.6 Signature / Mr. GANESH. N.S.
ASSISTANT PROFESSOR
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA
KARNATAKA-571422
Not applicable.
Not applicable.
Dr. T. SIVAKUMAR
PROFESSOR AND HEAD
DEPARTMENT OF PHARMACEUTICS
BHARATHI COLLEGE OF PHARMACY
BHARATHI NAGARA, MANDYA
KARNATAKA-571422
12. / 12.1 Remarks of the
Chairman and Principal
12.2 Signature
6.0
7.0
8.0 / BRIEF RESUME OF THE INTENDED WORK
ENCLOSURE - I
6.1 Need for the study
Sustained release provides the most desirable dosing regimens with effective pharmacokinetic profile and pharmacodynamic response in chronic pain management. This approach prevents the patient from experiencing pain intermittently through maintenance of consistent drug input and it may alleviate the variability involved in the administration of multiple doses per day. Thus sustained release dosage form of analgesic drug improves patient compliance and prevents the dramatic onset of analgesia seen with immediate – release dosage forms1.
Tramadol hydrochloride, a synthetic opioid of aminocyclohexanol group, centrally acting analgesic. It was approved by USFDA in 1995. It is effective centrally acting analgesic with weak opioid against properties. Tramadol hydrochloride has plasma elimination half life of 4-6 hrs. The usual oral dosage regimen is 50-100 mg every 4-6 hrs with a maximum dosage of 400 mg/day. So, to reduce the frequency of administration and to improve patient compliance, a sustained release dosage formulation of tramadol is desirable.
Tramadol hydrochloride is associated with certain side effects, like abdominal pain, anorexia and it may also induce psychic and physical dependence. Therefore properly designed Sustained Release Dosage Form of this drug will minimize the fluctuation in blood concentration, decreasing the risk of side effects and will show uniform pharmacological response2.
Melt granulation is a process, which involves the use of a substance, which melts at relatively low temperature. This substance can be added in the molten form over the substrate or in the solid form, which is then heated above its melting point. In melt granulation substance act as liquid binding agent, but the melt granulation does not require use of organic solvents. Moreover, in melt granulation the drying step is not necessary, thus the process is less consuming in terms of time and energy compared to other methods3.
ENCLOSURE - II
6.2 Review of the literature
1.  Mahaparale PR et al., studied on sustained release matrices of Metoprolol succinate using Compritol 888 ATO & Precirol ATO 05 and concluded that, matrices prepared by Melt granulation technique. Matrices prepared from combination of both waxes showed more retardation in drug release than from Compritol & Precirol alone4.
2.  Jaleh Varshosaz et al., studied on use of hydrophilic natural gums in formulation of sustained-release matrix tablets of Tramadol Hydrochloride and concluded that, Guar gum alone cannot efficiently control drug release , & X gum has higher drug retarding ability than G gum. The combination of each natural gum with HPMC leads to a greater retarding effect compared with a mixture of 2 natural gums. No synergistic effect was seen for triple mixture of polymers. All combination of guar gum & xanthan with HPMC or xanthan alone can retard tramadol HCL release. However, according to f2 pure HPMC & H8G2 are the most similar formulation to Topalgic-LP5.
3.  Singh C et al., studied on formulation and evaluation of extended release tablet of Pioglitazone by melt granulation technique and concluded that, Pioglitazone is a potent and highly selective agonist for peroxyzome proliferators-activated receptor-gamma (PPAR). Pioglitazone has short biological half life of 3-5 hrs & is eliminated rapidly. Therefore Matrix type tablets of Pioglitazone were developed by using polymer such as Precirol ATO5, Campritol 888 ATO, Carnuba wax & Hydrogenated castor oil by melt Granulation technique. The tablet were initially placed in phosphate buffer at pH 7.4 at 8 hrs used dissolution apparatus USP-26.
4.  Patel NM et al., studied on influence of release enhancer on release of Venlafaxine HCL from Glyceryl Behenate matrix tablet and concluded that, the tablet were prepared by direct compression of physical mixture as well as compression of granules prepared by melt granulation .Release enhancers were added in ratio of 1:2:1 &1:2:2 of drug :glyceryl behenate: excipient. Polyethylene glycol 6000 exhibited the fastest release &the tablet eroded within 8 hrs .Consistent & extended drug release was found in tablet containing lactose & microcrystalline cellulose. The result generated from the study showed that the dissolution profile &kinetics of drug release were dependent on concentration of glyceryl behenate, method of preparation, type &concentration of release enhancers7.
5.  Feng Qian Li et al., studied on in vitro controlled release of Sodium Ferualte from Compritol 888 ATO- based matrix tablets and concluded that, the study shows that the solid dispersion based tablets were found to be more effective than those compressed from physical mixtures retarding the release of Sodium Ferualte. Drug release from the matrix tablets containing physical mixture nearly completed within 12 hrs. While that from the solid dispersion formulation lasted for over 24 hrs8.
6.  Cayban P et al., studied on investigations on the lipophilic matrix tablets prepared with Precirol ATO 05 of Verapamil Hydrochloride (VPH) and concluded that, the poor flow properties of Verapamil Hydrochloride were improved with Precirol ATO 05 & tablets containing Precirol ATO 05 provided the slower release than that of commercial SR tablets9.
7.  Barthelemy P et al., studied on Compritol 888 ATO: an innovative hot –melt coating agent for prolonged release drug formulations and concluded that, the present study was to assess the coating of drug loaded sugar beads & lactose granules with Compritol 888 ATO. It contains the satisfactory coating potential of the Compritol 888 ATO a large spherules or granules10.
8.  Jannin V et al., studied on influence of Poloxamers on the dissolution performance & stability of controlled release formulation containing Precirol ATO 05 and concluded that, the addition of these hydrophilic polymers (Lutrol) in the lipid matrix increased the amount of theophylline released due to the swelling of the hydrophilic polymer & the creation of a porous network into inert lipid matrix11.
9.  Obaidat AA et al., studied on controlled release of Tramadol hydrochloride from matrices prepared using Glyceryl Behenate and concluded that, Glyceryl behenate is an appropriate waxy material that can be used as a matrix-forming agent to control the release of a water-soluble drug such as Tramadol hydrochloride12.
10.  Paradkar AR et al., studied on sustained release matrices of Metformin Hydrochloride and Glyceryl Behenate and concluded that, matrices of Metformin hydrochloride and Glyceryl behenate (Compritol) were prepared by direct compression and physical mixture and by compression of granules prepared by melt granulation. The effect of release enhancers such as lactose and MCC on the release of drug was investigated. The study showed that glyceryl behenate is an appropriate waxy material that can be utilized as matrix forming agent to control the release of water soluble drug13.
11.  Tiwari Sandip et al., studied on controlled release formulation of Tramadol Hydrochloride using hydrophilic & hydrophobic matrix system and concluded that, hydrophilic matrix tablets were prepared by wet granulation and hydrophobic (wax) were prepared by melt granulation technique. Hydrophobic matrix tablets resulted in sustained in vitro drug release (>20hrs.) as compared with hydrophilic (<14hrs.).Presence of ethyl cellulose prolonged release. Tablets prepared by combination of hydrophilic and hydrophobic polymers failed to prolong release beyond 12 hrs. Hydrophobic matrix tablets prepared using hydrogenated castor oil was found to be best suited for modulating the deli very of highly water-soluble drugs14.
12.  Amaral MH et al., studied on effect of concentration of hydrophilic and hydrophobic Hydrogenated castor oil, fillers (lactose and Dicalcium phosphate) on Naproxen release and concluded that, matrix tablet prepared using HPMC and hydrogenated castor oil shows with increase in their concentration decrease the rate of drug release. Drug release modulated by adding suitable diluents. Lipid matrices forming material is suitable for sustained release dosage formulation or modulating the delivery of highly water soluble drug15.
13.  Kamble Ravindra et al., studied on melt solidification technique: Incorporation of higher wax content in Ibuprofen beads and concluded that, purpose of study was to achieve incorporation of higher amount of wax during preparation of ibuprofen beads by melt solidification technique for better integrity and prolonged drug release by using combination of waxes. Mixture of cetyl alcohol and palmitic acid used to improve matrix integrity and drug release. In vitro dissolution test did not show any significant improvement in drug release. DSC shows that different solidification and erosion properties of waxes are responsible for inability of waxes to retard drug release even at higher concentration16.
ENCLOSURE – III
6.3 Objectives of the study
1) To design a sustained release matrix tablet of Tramadol Hydrochloride with different polymers using melt granulation technique.
2) To study the effect of concentration of polymer on in vitro drug release behavior from the prepared matrix tablets.
3) To study the effect of different polymers on in vitro drug release behavior from the prepared matrix tablets.
4) Comparative study of prepared Tramadol Hydrochloride tablets with marketed formulation.
MATERIALS AND METHODS
Drug : Non Steroidal Anti-Inflammatory Drug (NSAIDs),
like Tramadol Hydrochloride.
Polymers : Compritol 888ATO (Glyceryl Behenate),
Precirol ATO 5 (Glyceryl Palmitostearate),
Ethylcellulose, etc.
Methods : Melt Granulation Technique,
Direct Compression Method.
ENCLOSURE – IV
7.1. Source of data
  1. Library: Bharathi College of Pharmacy.
  1. E-library: Bharathi College of Pharmacy.

ENCLOSURE - V
7.2. Method of collection of data
Data on drugs will be collected through literature survey and from physiochemical database. Extensive prefomulation trials would provide the basis of selection the excipients and system for final formulation development.
I.  Preformulation studies
  1. Solubility
  2. Compatibility
c.  Calibration
II. Preparations studies
Preparations of Matrix tablet by using the polymers like Compritol 888ATO (Glyceryl Behenate), Precirol ATO 5 (Glyceryl Palmitostearate), Ethylcellulose, etc. for optimum delivery of matrix drug.
III. Evaluation studies
A.  Evaluation of Granules
  1. Bulk density
  2. Angle of repose
  3. Compressibility Index
  4. Void volume
  5. Total Porosity
B. Evaluation of Tablets
a. Thickness
b. Weight variation Test
c. Drug content
d. Hardness
e. Friability
f. In vitro dissolution studies
g. In Vitro Release Studies
IV. Comparative study of prepared matrix tablets
with marketed formulation.
ENCLOSURE – VI
7.3. Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so, please mention briefly.
-NO-
7.4. Has ethical clearance been obtained from your institution in case of 7.3?
-NOT APPLICABLE-
ENCLOSURE - VII
LIST OF REFERENCES
  1. Hite AM, Turner S, Fassihi R. Novel design of a self-correcting monolithic controlled-release delivery system for Tramadol. Drug Delivery Technique 2003; 3 (2): 22-28.
  2. Http:// www.rxlist.com /tramadol hydrochloride-drug html.
  3. Http: // www. pharmainfo.net./ exclusive/ reviews/Chaudhari PD. Melt Granulation Technique: A Review, Jan. (2006).
  4. Mahaparale PR, Kasture PV, Deshmukh SS, Kuchekar BS. Sustained release matrices of Metoprolol Succinate using Compritol 888 ATO & Precirol ATO 05. J Pharm Res 2006; 5(1): 10-14.
  5. Jaleh V, Naser T, Fatemah K. Use of Hydrophilic natural gums in formulation of sustained-release matrix tablets of Tramadol Hydrochloride.AAPS Pharm Sci Tech 2006;7(1) ;Article 24:E1-E6.
  6. Singh C, Jain AK, Agarwal K. Formulation and evaluation of extended release tablet of Pioglitazone by melt granulation technique. Indian Drugs 2008 June; 45(6):461- 468.
  7. Patel NM, Soniwala MM. Influence of release enhancer on release of Venlafaxine HCL from Glyceryl Behenate matrix tablet. Indian Drugs 2008 Feb; 45(2): 98-104.
  8. Feng-Qian Li, Jin-Hong Hu, Jia-Xin Deng, Hua Su, Shu Xu, Ji-Yong Liu. In vitro controlled release of Sodium Ferualte from Compritol 888 ATO- based matrix tablets. Int J Pharm 2006; 30:1-6.
  9. Cayban P. Investigations on the lipophilic matrix tablets prepared with Precirol ATO 05 of Verapamil Hydrochloride. Inst. Physics Conference series 2004; 143: 271-274.
  10. Barthelemy P, Laforet JP, Farah N, Joachim J.Compritol 888 ATO: an innovative hot melt coating agent for prolonged release drug formulations. Eur J Biopharm Pharmacokin 1999; 47: 87-90.
  11. Jannin V, Pochard E, Chambin O. Influence of Poloxamers on the dissolution performance & stability of controlled release formulation containing Precirol ATO 05. Int J Pharm 2006; 309:6-15.
  1. Obaidat AA, Obaidat RM. Controlled release of Tramadol Hydrochloride from matrices prepared using Glyceryl Behenate. Eur J Biopharm Pharmacokin 2001; 52(2): 231-235.
  2. Paradkar AR, Maheshwari M, Chauhan MB. Sustained release matrices of Metformin Hydrochloride and Glyceryl Behenate. Indian Drugs 2004; 41 (6): 350 – 353.
  3. Tiwari SB, Murthy TK, Pai MR, Mehta PR, Chowdary PB. Controlled release formulation of Tramadol Hydrochloride using hydrophilic & hydrophobic matrix system. AAPS Pharm Sci Tech 2003; 4 (3): Article 31:110-116.
  4. Amaral MH, Sousa Lobo JM, Ferreira DC. Effect of hydroxypropyl methylcellulose& hydrogenated castor oil on Naproxen release from sustained release tablets. AAPS Pharm Sci Tech 2001; 2 (2): Article 6: 42-49.
  5. Kamble R, Maheshwari M, Paradkar AR, Kadam S. Melt solidification technique: Incorporation of higher wax content in Ibuprofen Beads. AAPS Pharm Sci Tech 2004; 5 (4): Article 61: 151-157.