“DESIGN AND IN–VITRO CHARACTERIZATION of SUSTAINED release oral SOLID DOSAGE FORMS OF immunosuppressive drug”
DISSERTATION PROTOCOL
SUBMITTED TO THE
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
BANGALORE, KARNATAKA.
BY
shaik parveen begum
m.pharm, part-i
DEPARTMENT OF PHARMACEUTICS,
NARGUND COLLEGE OF PHARMACY,
BANGALORE- 85, KARNATAKA
(2009-2011)
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,
BANGALORE, KARNATAKA.
ANNEXURE – II
PROFORMA FOR REGISTRATION OF SUBJECTS FOR pg DISSERTATION
1. / Name of the Candidate & Address (In block letters) / SHAIK PARVEEN BEGUMNARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR,2nd main,
100ft ring road,BSK 3rd stage
BANGALORE-560085
2. / Name of the Institution / NARGUND COLLEGE OF PHARMACY,
DATTATREYA NAGAR,2nd main,
100ft ring road,BSK 3RD stage
BANGALORE-560085
3. / Course of Study and Subject / Master of pharmacy in
pharmaceutics
4. / Date of Admission to Course / 15TH JUNE 2009
5. / Title of the Topic / “DESIGN AND IN–VITRO CHARACTERIZATION of SUSTAINED release oral SOLID DOSAGE FORMS OF immunosuppressive drug”
6.
7.
8. / BRIEF RESUME OF THE INTENDED WORK
6.1 NEED FOR THE STUDY
The purpose of this research project is to design sustained release (SR) Oral Solid Dosage Forms of immunosuppressive drug (Tacrolimus), with different polymers by the suitable methods and evaluated their SR properties. Tacrolimus (TC) is an immunosuppressant drug used in liver and kidney transplants, and it is also under study for bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation.
Among all routes of administration, the oral route has been most popular and successful. This is, in part, because of the inherent simplicity of both the oral route and oral delivery systems. The SR drug delivery systems are the one which deliver the drug at predetermined rate, locally or systemically for a specific period of time. These systems help in continuously releasing the drug at specific releasing rate, thus ensuring optimal bioavailability. Polymer materials have been used for the administration of pharmaceuticals, and they are now playing an increasingly important role in the fabrication of various SR and drug-targeting systems.
Today most time release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance so that the dissolving drug has to find its way out through the holes in the matrix. In some SR formulations the matrix physically swells up to form a gel, so that the drug has first to dissolve in matrix, and then exit through the outer surface.
The drug which is planning to use for this project is TC, this is an immunosuppressant (ISP) drugs, which are also called anti-rejection drugs, are used to prevent the body from rejecting a transplanted organ. When an organ, such as a liver, heart or kidney, is transplanted from one person (the donor) into another (the recipient), the immune system of the recipient triggers the same response against the new organ that it would have against any foreign material, setting off a chain of events that can damage the transplanted organ. This process is called rejection. It can occur rapidly (acute rejection), or over a long period of time (chronic rejection). Rejection can occur despite close matching of the donated organ and the transplant patient. ISP drugs greatly decrease the risks of rejection, protecting the new organ and preserving its function. These drugs act by blocking the recipient's immune system so that it is less likely to react against the transplanted organ. A wide variety of drugs are available to achieve this aim but work in different ways to reduce the risk of rejection.
TC belongs to a group of medicines known as immunosuppressive agents. It is used primarily to lower the body's natural immunity in order to prevent the rejection of organ transplants and to prevent graft-versus-host disease. In the fight against leukemia, grafts of stem cells from donors are sometimes given to the patient to encourage the blood of a recipient to begin production of normal cells. TC may be given during the graft process because it seems to make the patient more receptive to the donated stem cells.TC should be taken without food and long after a meal. If there is food in the stomach it will interfere with the way the drug makes its way into the body. Grapefruit juice can increase the activity of TC and should be avoided.
6.2 REVIEW OF LITERATURE
For the present research project, we have done a peer reviewed of the literature of SR dosage forms for the particular drug (TC), and In detail about TC as ISP drug. Recently several technical advancement has been made; they have resulted in the development of new technique for drug delivery system. These techniques are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery to tissue. Although this advancement has leads to development of several novels drug delivery systems that could revolutionalize the method of medication and provide a number of therapeutic benefits.1
The first SR tablets were made by Howard Press in Hoboken, New Jersey in the early 1950s. The first tablets released under his process patent were called "Nitroglyn" and made under license by Key Corp. in Florida. The term SR is known to have existed as the medical and pharmaceutical literature for many decades. It has been constantly used to describe a pharmaceutical dosage form formulated to retard the release of therapeutic agent such that its appearance in systemic circulation is delayed or prolonged and its plasma profile is sustained in duration. The onset of its pharmacological action is often delayed, and the duration of its therapeutic effect is sustained.2
Polymers are uniquely suited as materials of construction for oral delivery systems. They offer a wide range of properties such as diffusivity, permeability, and solubility that are important to achieving controlled delivery. They can be processed relatively easily into tablets and membranes by a variety of methods. Active ingredient and property modifiers can be incorporated either by physical and chemical means. Drugs can be dispersed or dissolved into the polymers to manufacture SR oral solid dosage forms. And the Polymers used in oral SR technology are hydrophilic carriers, hydrophobic carriers, soluble carriers, insoluble carriers.3
Immunosuppressive drugs or immunosuppressant’s (ISP) are drugs that are used in immunosuppressive therapy to inhibit or prevent activity of the immune system. Clinically they are used to prevent the rejection of transplanted organs and tissues (e.g. bone marrow, heart, kidney, liver and the treatment of autoimmune diseases or diseases that are most likely of autoimmune origin (e.g. rheumatoid arthritis, myasthenia gravis, ulcerative colitis).4
ISP drugs can be classified according to their specific molecular mode of action, in which ISP drug TC is classified according to the specific organ that is transplanted: TC is used in liver and kidney transplants. It is under study for bone marrow, heart, pancreas, pancreatic island cell, and small bowel transplantation. Transplantation is the most appropriate therapy for several conditions of end-stage organ failure, such as renal, hepatic or cardiac failure. Hepatic and cardiac transplantation are life-saving measures and are undertaken when conservative therapies have failed.5
McCauley, jerry states that TC has similar ISP properties to cyclosporin, but is much more potent in equal volumes. Also like cyclosporin it has a wide range of adverse interactions, including that with grapefruit which increases plasma-TC concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increases drug levels by competing for degradative enzymes. ISP with TC was associated with a significantly lower rate of acute rejection compared with cyclosporin-based ISP (30.7% vs 46.4%) in one study. Clinical outcome is better with TC than with emulsified cyclosporin during the first year of liver transplantation.6
TC was discovered in 1984 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was among the first macrolide ISP discovered, preceded by the discovery of rapamycin in 1975. Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis.7
The name Tacrolimus is derived from 'Tsukuba macrolide ISP. The drug TC is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506. It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.8
The drug which is used for the present research work is TC. It is a drug that suppresses the immune system and is used to prevent rejection of transplanted organs.TC is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by TC use over cyclosporin. Although short-term ISP concerning patient and graft survival is found to be similar between the two drugs, TC results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.9
6.3 OBJECTIVE OF STUDY :
It is an object of this project to provide a pharmaceutical composition of TC in the form of Oral Solid Dosage Form which constitutes an oral sustained drug delivery system. To develop suitable formulations the following studies are conducted.
§ Study of drug profile.
§ Analytical methods for the estimation of the drugs
§ Pre-compression studies, drug-excipient compatibility studies for selection of excipients.
§ To evaluate the powder mix for pre-compression characteristic and tableting characteristics.
§ To compress the formulation according to compatibility study.
§ Study of interactions between pure drug and different polymers by FTIR.
§ Formulation of dosage forms by suitable methods.
§ Evaluation of selected formulations as per IP standards.
§ Study of kinetics release mechanisms of formulations.
§ Study of pure drug and formulations by thermal methods of analysis like DSC and PXRD
§ Evaluation of the prepared formulation by different physicochemical characterization studies.
§ Best formulation will be subjected for stability studies as per ICH guidelines.
MATERIALS AND METHODS:
Materials:
Polymers: like
a. Hydrophilic carrier’s polymer used methyl cellulose, sodium CMC, HPMC (36, 37), sodium alginate polyacrylic acid, hydroxyl ethyl cellulose etc.
b. Hydrophobic carriers
1. Soluble carriers (digestible base): glycerides, waxes, fatty alcohols, fatty acids.
2. Insoluble carriers (nondigestible base): PVC, PVA, calcium sulphate.
Drug: like. Tacrolimus.
Excipients: like, MCC, Talc, Mag stearate, etc.
Methods:
1. Dissolution controlled release
a. Encapsulation dissolution control
b. Matrix dissolution control
2. Diffusion controlled release
a. Reservoir devices
b. Matrix devices. etc
7.1 SOURCE OF DATA:
1. Library and e-library of Nargund college of pharmacy.
2. RGUHS Library, Bangalore.
3. International Pharmaceutical abstracts.
A. Journals & articles :
Ø Advanced drug delivery reviews.
Ø Journal of Cardiology.
Ø Asian journal of pharmaceutics.
Ø Journal of Lipidology.
Ø Journal of Pharmaceutical Sciences.
Ø AAPS PharmSciTech.(American Association of Pharmaceutical Scientists).
Ø Journal of Controlled Release.
B. Internet Browsing.
Ø www.sciencedirect.com
Ø www.google.com
Ø www.pubmed.com
Ø www.pharmainfo.net
C. Text books:
1. Abbas, AK, and Lichtman AH. Basic Immunology: Functions and Disorders of the Immune System. Philadelphia: W. B. Saunders Co., 2001.
2. Sompayrac LM. How the Immune System Works. Boston: Blackwell Science, 1999.
3. Travers P. Immunobiology: The Immune System in Health and Disease, 5th ed. New York: Garland Publishers, 2001.
4. Chien YW. Novel Drug Delivery System. 2nd ed. New York: Marcel Dekker INC; 2005. p.1- 42.
5. Good & Gilman’s The Pharmacological Basis of Therapeutics 10th edition, international edition.
7.2 Methods of collection of data:
· The formulation evaluated for the compatibility studies using DSC techniques and thermal analysis.
· Formulation development and evaluation.
· Pre & Post-compression and in-vitro dissolution studies for the developed formulation.
· HPLC, UV/VIS Spectrophotometeric method for the estimation of drug and for analysis of in-vitro dissolution samples.
· Statistical analysis of all the results.
· Stability studies.
7.3 Does the study require any investigation or intervention to be conducted on patients or other humans or animals? If so please describe briefly.
No.
7.4 Has ethical clearance been obtained from your institution in case of 7.3?
Not applicable.
LIST OF REFERENCES:-
1) Chien YW. Novel Drug Delivery System: Fundamentals, Developmental Concepts Biomedical Assessments. New York: Dekker 1982.
2) Chien YW. Rate-control drug delivery system: Controlled release vs. sustained Release. Medical Progress through Technology 1989; 15. p. 21-46.
3) Vansavage G, Rhodes CT. The sustained-release coating of solid dosage forms a historical
Review. Drug Dev. Ind. Pharm 1995; 21:93-118.
4) Roy S and Loh HH. Effects of opioids on the immune system. Neurochem Res 1996; 21 (11): 1375–86.
5) Gillett NA and Chan C .Applications of immunohistochemistry in the evaluation of immunosuppressive agents. Human & Experimental Toxicology 2000 ; 19 (4): 251–4
6) O'Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus emulsified cyclosporin in liver transplantation the TMC randomized controlled trial. The UK and Ireland Liver Transplant Study Group 2002; 360: 1119-25.
7) Pritchard D Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today 2005; 10 10: 688–91.
8) Ponner, B, Cvach, Fujisawa B. Pharmaceutical Co.: Protopic Update 2005.
9) Abou-Jaoude MM, Naim R, Shaheen J, Naufal N, Abboud S, AlHabash M, et al. Tacrolimus (FK506) versus cyclosporin microemulsion (Neoral) as maintenance immunosuppresion therapy in kidney transplant recipients. Transplantation Proceedings 2005; 37: 3025–3028.
9. / Signature of the candidate / (SHAIK PARVEEN BEGUM)
10. / REMARKS OF THE GUIDE / RECOMMENDED FOR DISSERTATION WORK.
11. / NAME AND DESIGNATION OF
11.1 GUIDE
11.2 SIGNATURE / Mr. R.K.MOHAMED MUATAHAR
ASSISTANT PROFESSOR
DEPT. OF PHARMACEUTICS
NARGUND COLLEGE OF PHARMACY
11.3 CO-GUIDE
11.4 SIGNATURE / Mr. ANIL KUMAR R.
GROUP LEADER(F&D)
ARCOLAB LIMITED.
BANGALORE
11.5 HEAD OF THE DEPT.
11.6 SIGNATURE / Dr. C.S.R. LAKSHMI
PROFESSOR AND HEAD
DEPT. OF PHARMACEUTICS
NARGUND COLLEGE OF PHARMACY.
12. / 12.1 REMARKS OF THE PRINCIPAL
12.2 SIGNATURE / FORWARDED AND RECOMMENDED FOR FAVORABLE CONSIDERATION.
Prof. M.S. HARISH