Design and Evalution of Sustained Release Matrix Tablet of Tranexamic Acid

“DESIGN AND EVALUTION OF SUSTAINED RELEASE MATRIX TABLET OF TRANEXAMIC ACID”

M. PHARM DISSERTATION PROTOCOL

SUBMITTED TO THE

RAJIV GANDHI UNIVERSITY OF HEALTH

SCIENCES, BANGALURU, KARNATAKA

BY

ROHIT PATIL

B. Pharm.

UNDER THE GUIDANCE OF

Mr. VENKATESH.J.S

B. Sc, M. Pharm.

PROFESSOR

P. G. DEPARTMENT OF PHARMACEUTICS

S. C. S. COLLEGE OF PHARMACY,

HARAPANAHALLI-583131

2010-11

Rajiv Gandhi University of Health Sciences,

Karnataka, Bangalore

ANNEXURE – II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

01 / Name and Address of the Candidate / ROHIT EKNATH PATIL.
54, ROSHAN BHUVAN ,GOVIND NAGAR, SHAHADA. 425409 ,DIST-NADURBAR, MAHARASHTRA.
02 / Name of the Institution / T. M. A. E. Society’s
S. C. S. College of Pharmacy,
Harapanahalli – 583 131
(Davangere dist.) Karnataka.
03 / Course of the Study
Branch / M. Pharm ( Pharmaceutics)
04 / Date of Admission to course / 28, May 2010
05 / Title of the Topic / DESINGN AND EVALUTION OF SUSTAINED RELEASE MATRIX TABLET OF TRANEXAMIC ACID.
06 /

Brief resume of the intended work

6.1. Need for the Study /

Enclosure – I

6.2. Review of the Literature / Enclosure – II

6.3. Objective of the Study

/ Enclosure – III
07 /

Materials and Methods

7.1. Source of data /

Enclosure – IV

7.2. Methods of collection of data

/ Enclosure – V
7.3. Does the study require any
Investigations on animals?
If yes give details / NO
7.4. Has ethical clearance been
obtained from your institution
In case of 7.3. / NOT APPLICABLE
08 /

List of References

/ Enclosure – VI
09 /

Signature of the candidate

/ (ROHIT PATIL)
10 / Remarks of the Guide / The present research work is well designed with best of my knowledge upon extensive literature review. This work will be carried out in the Pharmaceutics laboratory by the above said student under my supervision.
11 / Name and Designation of
(In Block Letters)
11.1. Guide
(ACA/CDC/PGT-M.Ph/SCS/02/2005-06.
Dated on 19-01-2009)
11.2.Signature
11.3.Co-Guide (if any)
(ACA/CDC/PGT-M.Ph/SCS/02/2010-11.
Dated on 01-01-2010.)
11.4.Signature
11.5. Head of the Department
11.6.Signature / Mr. VENKATESH. J.S.
B.Sc., M. Pharm.
PROFESSOR,
P.G. Department of Pharmaceutics
S.C.S. College of Pharmacy,
Harapanahalli-583131, Karnataka.
......
Mr. SHANKRAIAH. M
M. Pharm.
ASST PROFESSOR,
P.G. Department of Pharmaceutics.
………………….
Dr. C. NAGESH
M. Pharm. Ph.D.
PROFESSOR AND HEAD,
P.G. Department of Pharmaceutics,
S.C.S. College of Pharmacy,
Harapanahalli-583131, Karnataka.
......
12 / Remarks of the Principal
12.1. Signature / The present study is permitted to perform in the Pharmaceutics laboratory of our institution by the above said student.
(………………..……………….)
(K.PRABHU)

ENCLOSURE-I

06. Brief resume of Intended Work

6.1 Need for the study.

When a blood vessel is damaged, a mechanism called clotting is triggered. The stimulus for clotting is a rough surface within a vessel, or a break in the vessel, which also creates a rough surface. The more damage there is the faster clotting begins, usually within 15 to 120 seconds. The clotting mechanism is a series of reactions involving chemicals that normally circulate in the blood and others that are released when a vessel is damaged. The chemicals involved in clotting include platelet factors, chemicals released by damaged tissues, calcium ions, and the plasma proteins prothrombin, fibrinogen, Factor 8, and others synthesized by the liver. The clot itself is made of fibrin. Fibrin is a thread-like protein. Many strands of fibrin form a mesh that traps RBCs and platelets, and creates a wall across the break in the vessel. There are a number of abnormalities of the blood or blood flow that make the blood prone to clotting. The normally smooth line of a blood vessel can become damaged. When this happens, chemicals called tissue factors are released from the injured vessel. Tissue factors will trigger the beginning of a complex chain of cellular and molecular reactions, called the clotting cascade, which leads to clot formation. Once the clot has formed and bleeding has stopped, clot retraction and fibrinolysis occur.1

Antifibrinolytic is a relating to a substance, such as aminocaproic acid, tranexamic acid that decreases the breakdown of fibrin. Antifibrinolytic act by competitively inhibiting the activation of plasminogen to plasmin. Tranexamic Acid help blood to clot. They are used for the treatment of haemorrhage (bleeding) or the risk of bleeding when there is increased risk that blood will not clot properly. It is also a weak non-competitive inhibitor of plasmin. These properties make possible its clinical use as an antifibrinolytic in the treatment of both general and local fibrinolytic haemorrhages.

Tranexamic acid binds considerably more strongly than Epsilon aminocaproic acid to both the strong and weak sites in the plasminogen molecule in a ratio corresponding to the difference in potency between the compounds. The pharmacological significance of

the binding to these different sites has not yet been evaluated. Tranexamic acid does not bind to serum albumin. The plasma protein binding seems to be fully accounted for its binding to plasminogen and appears to be negligible at therapeutic plasma The functional interaction between plasminogen and tissue activator, located mainly on fibrin, is prevented by dissociation of the complex between fibrin and specific substrate binding sites on plasminogen. A potentiating effect on natural inhibitors also appears to contribute to the clinical effect during antifibrinolytic therapy. Tranexamic acid is eliminated by glomerular filtration, excretion being about 30% after one hour, 55% after three hours and 90% after 24 hours after intravenous administration of 10 mg per kg body weight. After oral administration of 10-15 mg per kg body weight, excretion was 1% after one hour, 7% after three hours and 39% after 24 hours.2

Tranexamic acid formulated in an oral dosage form with at least one agent that decreases tranexamic acid release in the stomach. Such formulations minimize nausea, vomiting, and other adverse gastric effects that may accompany tranexamic acid therapy, for example, to treat heavy menstrual bleeding. One embodiment is an extended release formulation with waxes, polymers, etc. that prevent a bolus release of tranexamic acid in the stomach. An alternative embodiment is a delayed release formulation with polymers that prevent release of tranexamic acid in the acid environment of the stomach and delay its release until the formulation reaches the less acid environment of the intestines. Such formulations enhance patient compliance with therapy because adverse effects of tranexamic acid therapy are reduced.3

Hence, in the present work an attempt will be made to formulate and evaluate tranexamic acid sustained release tablets.

ENCLOSURE-II

6.2 Review of Literature:

Tranexamic Acid (help blood to clot) is used for the treatment of haemorrhage (bleeding) or the risk of bleeding when there is increased risk that blood will not clot properly. Gastrointestinal symptoms (nausea, vomiting, and diarrhoea) occur but disappear when the dose is reduced and the biological half-life in the joint fluid was about 3 hours. Hence, in the present work an attempt has been made to formulate and evaluate Tranexamic acid sustained release tablets.

Ø  Jabalameli M. et al.4 Tranexamic acid (TA) is an antifibrinolytic agent which reduces bleeding following certain surgical procedures. The present study was performed on 56 patients, scheduled for elective endoscopic sinus surgery under general anesthesia, to examine the effects of topical TA on providing a bloodless surgical field and evaluate the bleeding volume. The study comprised 26 patients who received topical TA and 30 patients used placebo. The hemodynamic endpoints were to maintain the mean arterial blood pressure at 30% below its preoperative level.

Ø  Hosam Fawzy et al.5 Systemic use of antifibrinolytic reduces the postoperative blood loss. The purpose of this study was to examine the effectiveness of local application of tranexamic acid to reduce blood loss after coronary artery bypass grafting (CABG). Thirty eight patients scheduled for primary isolated coronary artery bypass grafting were included in this double blind, prospective, randomized, placebo controlled study. Tranexamic acid (TA) group (19 patients) received 1 gram of TA diluted in 100 ml normal saline. Placebo group (19 patients) received 100 ml of normal saline only. The solution was poured in the pericardial and mediastinal cavities. Both groups were comparable in their baseline demographic and surgical characteristics. During the first 24 hours post-operatively, cumulative blood loss was significantly less in TA group (median of 626 ml) compared to Placebo group (median of 1040 ml) (P = 0.04). There was no significant difference in the post-op packed RBCs

transfusion between both groups (median of one unit in each) (P = 0.82). Significant less platelets transfusion required in TA group (median zero unit) than in placebo group (median 2 units) (P = 0.03). Apart from re-exploration for excessive surgical bleeding in one patient in TA group, no difference was found in morbidity or mortality between both groups. Topical application of tranexamic acid in patients undergoing primary coronary artery bypass grafting led to a significant reduction in postoperative blood loss without adding extra risk to the patient.

Ø  Biggs J. C. et al.6 The efficacy of antifibrinolytic therapy in the management of acute upper gastrointestinal haemorrhage has been investigated in a double-blind clinical trial. Two-hundred patients were studied using tranexamic acid, a potent antifibrinolytic agent. Of these, 103 were in the treatment group and 97 in the control group. Patients were analysed to determine severity of initial blood loss, transfusion requirements, together with the incidence of recurrent bleeding, surgical intervention, and death. Final diagnosis as to the site of bleeding was arrived at using endoscopy, barium studies and the findings at operation and necropsy. The groups were well matched as regards severity of initial haemorrhage, age, sex, aetiological diagnosis and precipitating factors. A significant difference was observed in the requirement for surgical intervention to control continuing or recurrent haemorrhage. Twenty-three of 97 in the control group and seven of 103 in the treatment group required surgery. There appeared to be a reduction in the transfusion rate after the first three days of hospitalization in the treatment group. There were no significant differences in mortality or in side-effects between the two groups.

Ø  Manosroi A. et al.7 Tranexamic acid has been claimed to have whitening effects. The effects of TA contents(5 % and 10%) and charges on the stability and release of TA entrapped in hydrogenated soya phosphatidylcholine/ cholesterol/charged lipid {dicetyl phosphate(-) or stearylamin(e+ )} liposomes at molar ratios of 7:2:1(-) and 7:2:1 (+) were investigated. The TA contents were determined spectrophotometrically at 415 nm, following derivatization with

2,4,6-trinitrobenzosulfonic acid. Stability and leakage of TA from liposomes were characterised at 40, 300 and 450 C for 90 days. The leakage rates of TA in negative liposome were lower than those in positive liposomes. The TA in all liposome formulation was relatively stable as> 90% of total drug remained after up to two months. The release of TA from liposomes was examined using vertical Franz diffusion cells at 370 C for 24 h. The release rates of TA from all liposome formulations were 3 times lower than those from solutions. Charges appeared to affect the physical stability, leakage and shelf life of TA in liposomes whereas TA concentrations seemed to affect the release of TA. The: 2:1 (10% TA,) liposome was the best formulation due to its small size, low leakage high stability, and prolonged and sustained release profile.

Ø  Mitra Jabalameli et al.8 Tranexamic acid(TA) is an antifibrinolytic agent to reduce bleeding following some surgical procedures(1,2,3) . It applied topically to achieve homeostasis(4) . We observed the effect of topical tranexamic acid for providing a bloodless surgical field in patients undergoing endoscopic sinus surgery. We also evaluated the bleeding volume and grading under controlled hypotension.

Ø  Michele De Bonis et al.9 Topical application of tranexamic acid into the pericardial cavity after cardiopulmonary bypass in patients undergoing primary coronary bypass operations significantly reduces postoperative bleeding. Further studies must be carried out to clarify whether a more pronounced effect on both bleeding and blood products requirement might be seen in procedures with a higher risk of bleeding

Ø  Akhtar Rasul et.al.10 Sustained release matrix tablets of metoprolol tartrate were prepared by using different ratios of drug, xanthan gum and tragacanth. Microcrystalline cellulose (MCC) was used as diluents. The polymer was incorporated into a matrix system using direct compression technique.. The polymer was incorporated into a matrix system using direct compression technique. Increasing the amount of polymer (xanthan gum) in the formulation led to slow release of drug and decreasing the amount of polymer gave enhanced release of metoprolol tartrate.

Ø  Gohel MC, Parikh RK. et.al.11 Modified release tablets of isoniazid were prepared using low, medium and high viscosity grade hydroxyl propyl methyl cellulose as release controlling agent. The tablets prepared by direct compression were subjected to physical characterization and in-vitro drug release studies. The polymer type did not affect the flow of powder blend and crushing strength of isoniazid tablets. The viscosity grade of HPMC and the drug release was inversely correlated.

Ø  Deshmukh VN et.al.12 Sustained release matrix tablet of metoprolol succinate was prepared by using karaya gum and xanthan gum as release modifier. Matrix tablets were prepared by wet granulation method and were evaluated for weight variation, content uniformity, friability, hardness, thickness, swelling index, in vitro dissolution, and stereo photography. The results showed sustained release of drug for 12hrs with cumulative percentage release of 99.24%. No chemical interaction between drug and gums was seen as confirmed by IR studies.

ENCLOSURE -III

6.3 Objectives of the study:

The steps which are intended to be carried out are as follows.

Step-1: Selection of various polymers for preparation of Tranexamic acid

sustained release tablets.

Step-2: Preparation of Tranexamic acid granules by different methods.

Step-3: Physico-chemical evaluation of Tranexamic acid granules.

Step-4: Preparation of Tranexamic acid sustained release tablets.

Step-5: Evaluation of Tranexamic acid sustained release tablets by standard