“FORMULATION DEVELOPMENT AND COMPARISION OF STAVUDINE CONTROLLED RELEASE TABLETS PREPARED USING DIFFERENT POLYMERS”
M. Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560 041
By
Ms. Bindu Bezawada B.Pharm
Under the Guidance of
Mrs. S. Anitha M. Pharm (Ph.D)
Asst. Professor.
Department of Pharmaceutics,
Acharya & B. M .Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post),
Hesaraghatta Main Road, Bangalore-90.
2007- 2008
RAJIVGANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1 / Name of the candidate and address /Ms. bindu bezawada
Flat no-204,Divya Enclave,Opp- to Motinagar Community Hall,
Kalyan Nagar, Phase-III,
Hyderabad 500018.
2 / Name of the Institution / Acharya & B.M. Reddy college of pharmacy, Chikkabanavara post ,
Hesaraghatta Main Road, Soldevanahalli,
Bangalore-560 090.
3 / Course of the study and subject / M. Pharmacy
(Pharmaceutics)
4 / Date of admission / June- 2007
5 / TITLE OF THE PROJECT:-
“FORMULATION DEVELOPMENT AND COMPARISION OF STAVUDINE CONTROLLED RELEASE TABLETS PREPARED USING DIFFERENT POLYMERS”
6
6.1 / BRIEF RESUME OF INTENDED WORK:-
Need for study:-
In recent years, considerable attention has been focused on the development of new drug delivery systems. A controlled release system necessitates thorough understanding of the pharmacokinetics and Pharmacodynamic of the drug. Controlled release tablets are oral dosage forms from which the active drug is released over an extended period of time with the aim of decreasing the dosing frequency and reducing the peak plasma concentration, there by increasing the patient compliance. Mostly because low manufacturing costs and ease of application, tablets continued to be preferred dosage form for control release application.1
AIDS stands for acquired immunodeficiency syndrome. It is the most advanced stages of infection with the human immunodeficiency virus (HIV). HIV is a virus that kills or damages cells of the body's immune system.
The hallmark of human immunodeficiency virus (HIV) infection is depletion of CD-4 lymphocytes, leading to cellular immuno deficiency. Since the first reports of Acquired Immuno Deficiency Syndrome appeared in 1981.The vast majority of cases world wide has been caused by HIV-1.Another Retrovirus, HIV-2 is prevalent cause of aids in West Africa. Development of AIDS is characterized by susceptibility to various infections and malignance. 2
Stavudine is an analog of thymidine. It is phosphorylated by cellular kinases into active triphosphate. Stavudine triphosphate inhibits the HIV reverse transcriptase by competing with natural substrate, thymidine triphosphate. It also causes termination of DNA synthesis by incorporating into it. The oral absorption rate of stavudine is over 80%. Approximately half of stavudine is actively secreted unchanged into the urine and the other half is eliminated through endogenic pathways.3
Stavudine is available only as conventional type of tablets in the market.4 Therefore, in the present study, it was proposed to develop stavudine controlled release tablets using various controlled release polymers like eudragits, sodium CMC, carbopol and HPMC.
6.2 / REVIEW OF LITERATURE:-
Formulation and in vitro evaluation of eudragit microspheres of stavudine have been developed using copolymers synthesized from acrylic and methacrylic acid esters (Eudragit RS 100 and RL 100) as the retardant material, by solvent evaporation method using acetone/ liquid paraffin system. The in vitro release studies were performed in pH 6.8, the drug-loaded microspheres showed 67-91% of entrapment and release was extended upto 6 to 8 hr.The release of stavudine was influenced by the drug to polymer ratio and particle size and was found to be diffusion controlled.5
Loading efficiency of stavudine, a human immunodeficiency antiretroviral agent, on the external surfaces of polybutylcyanoacrylate and methylmethacrylate-sulfopropylmethacrylate was investigated. Preservation of the two stavudine loaded nanoparticles through cold storage at 4˚C over 6 weeks leads to an increase in particle size and a decrease in loading efficiency of stavudine. Loading efficiency of stavudine on both of the two nanoparticles decreases with a variation in pH value from pH 7.2 of loading medium, stavudine loaded methylmethacrylate-sulfopropylmethacrylate nanoparticles may be more advantageous than stavudine -loaded polybutylcyanoacrylate nanoparticles, and stavudine loaded polybutylcyanoacrylate nanoparticles may be more favorable than stavudine loaded methylmethacrylate-sulfopropylmethacrylate for intravenous injection.6
Three solid state forms of stavudine designated forms I, II and III have been identified and characterized. Forms I and II are anhydrous polymorphs where as form III is hydrated and is pseudo polymorphic with forms I and II. Physico–chemical and thermodynamic properties of the three solid state forms have been characterized. Solid-state stability and potential for interconversion of the forms to aid in the selection of preferred form for development and commercialization has been studied. Conditions of recrystallization governing the formation of thermodynamically, most stable polymorphic form I devoid of other forms were identified.7
Permeability of anti-human immuno deficiency virus (HIV) agents including stavudine D4T, delavirdine (DLV) and saquinavir (SQV), across the in vitro blood–brain barrier (BBB) was studied. Here, the anti-HIV agents were incorporated with polybutylcyanoacrylate nanoparticles (NPs), methylmethacrylate-sulfopropylmethacrylate (MMA-SPM) NPs, and solid lipid nanoparticles (SLNs). For the entrapment efficiency (EE) in SLNs, this order was reversed. Also, LE of D4T on MMA-SPM was larger than that on PBCA; however, the reverse was true for DLV and SQV. As the particle size increased, LE decreased and EE increased. For a fixed drug carrier, an increase in the particle size yielded a decrease in the BBB permeability coefficient of the anti-HIV agents indicating the clinical potential of the present NP formulations for the AIDS treatment. Experimental results revealed that the drug order of the loading efficiency (LE) on PBCA and MMA-SPM was D4T >DLV> SQV.8
`
Propranolol hydrochloride oral controlled release matrix tablets have been developed using hydrophilic polymer such as hydroxypropyl methylcellulose along with electrolytes. In this work attempt was made for in-situ interactions between drug and electrolytes are devised to control the release of highly water-soluble drugs from oral hydrophilic monolithic systems. The electrolytes low concentrations were accounted for control release of the drug. The results indicated that the drug released at controlled rate which is due to differential swelling rate, matrix stiffening and provides a uniform gel layer.9
Formulation and evaluation of controlled release aspirin tablets have been developed, where aspirin is known to be effective in primary and secondary prevention of myocardial infraction. Hence controlled release tablets were prepared to meet the requirements. Both in-vitro dissolution and in-vivo urinary excretion studies were done to ensure the effectiveness of the formulations. The results of the in-vivo testing showed that this tablet had a uniform excretion rate, compared to the marketed formulation. This study thus proves the usefulness of carbopol resins for formulating aspirin tablets with minimum risk in addition to an effective therapy for the patient.10
Oral dosage form containing 300mg theophylline in matrix-type tablets, by direct compression method using glycerylbehenate (hydrophobic) and hydroxypropyl methyl cellulose (hydrophilic) have been developed. The in-vitro release kinetics of these formulations were studied at pH 6.8 using USP dissolution apparatus with the paddle assemble. The analysis of the dissolution kinetic data for the theophylline preparation in this study shows that it follows the first-order kinetics, and the release process involves erosion/ diffusion and an alteration in the surface area diameter of the matrix system as well as in the diffusion path length from the matrix drug load during the dissolution process. This releation is best described by the use of both the first-order equation and Hixson-Crowell cube root law.11
Diclofenac matrix tablets were formulated employing olibanum and its resin and carbohydrate fractions in different concentrations and the tablets were evaluated for various tablet characters including drug release kinetics and mechanism. Olibanum and its resin component exhibited excellent retarding effect on drug release from the matrix tablets even at very low concentrations, 1 and 2% w/w in the formula. Diclofenac matrix tablets formulated employing olibanum and its resin component provided slow and controlled release of Diclofenac over more than 24h. Drug release from the matrix tablets was by Fickian diffusion and followed first order kinetics.12
Different retardant polymers including Carbopol 934P, HydroxyPropyl Methyl Cellulose (HPMC) (Methocel K4M) and Eudragit NE30D, RL30D and RS30D as release controlling materials were evaluated. The drug release medium consisted of hydrochloric acid buffer, pH-1.2, for the first two hours and phosphate buffer, pH-6.8 for the remaining period of time during the experiments. From the retardant polymers investigated, Eudragit NE30D exhibited proper release characteristics. The pattern of drug release from formulation prepared from Eudragit NE30D was shown to correspond to the Higuchi equation. According to the equation, Mt/M∞ =k.tn, ISDN release mechanism from Eudragit NE30D matrix tablets (40 mg) was based on non Fickian-Diffusion process. It was also realized that, matrix preparation was a suitable method for the formulation of ISDN-CR tablets.13
A simple technique for making polymeric matrix systems for the controlled release of rifampicin using Eudragit RL 100 is described. This method consisted of mixing drug and Eudragit RL 10 powder (polymethcrylates) and compressed at room temperature. The compressed fluffy matrices were kept in acetone chamber for 1.5, 3, and 4.5 h for sintering. The sintered tablets were characterized for physical characteristics and subjected to in vitro dissolution studies. The sintering time markedly affected the drug release rate of rifampicin from Eudragit RL 100 matrices. It is notable that the release rate of rifampicin from Eudragit RL 100 matrices was inversely related to the time of sintering. This may be due to the increase in the extent and firmness of sintering which compacts the mass further so that the drug release is affected. The drug release followed first-order release kinetics with diffusive mechanism.14
6.3
[[
7
7.1
/OBJECTIVE OF THE STUDY:-
Following are the objectives of the present study :
1. To carry out pre-formulation studies for the possible drug/polymer interactions by DSC/IR and micromeritics.
2. To formulate develop and compare controlled release tablets for Stavudine, using different polymers.
3. To evaluate the formulated dosage forms based on physico-chemical characterization and in-vitro release studies.
4. To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).
MATERIALS & METHODS:-
SOURCE OF DATA:-
1) Review of literature from:a) Journal such as
i) Indian Journal of Pharmaceutical Sciences
ii) European Journal of Pharmaceutics
iii) Journal of Controlled Release
iv) International Journal of Pharmaceutics
v) Drug Development and Industrial Pharmacy
vi) Indian Drugs
vii) Tropical Journal of Pharmaceutical Research.
b) World Wide Web.
c) I.I.Sc Library, Bangalore.
d) J-Gate@Helinet
7.2
7.3
7.4 / METHOD OF COLLECTION OF DATA:-.
1) To perform pre-formulation studies for the possible drug/polymer interactions by DSC/IR.
2) To perform Micromeritics:
· Angle of repose
· Bulk density
· Tab density
· Carr’s index
3) To develop and formulate tablets by direct compression/wet granulation methods using various polymers like Sodium carboxymethyl cellulose, Hydroxy propylmethyl cellulose, Carbopol, Eudragit etc
4) Evaluation of the various properties of the formulated tablets:-
a) Physical properties:-
· Diameter and Thickness
· Hardness and Friability
· Uniformity of Weight and Content
b) In vitro dissolution studies, in pH 7.4 buffer solution.
5) To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 20C (65 ± 5 %RH) and 40 ± 20C (75 ± 5 %RH).
Does the study require any investigation or investigation to be conducted on patient or other humans or animals?
“NO”
Has ethical clearance been obtained from your institution in case of 7.3?
“NOT APPLICABLE”
8 / REFEReNCES:-1. Vincent HL, Joseph RR. Influence of drug properties and roots of drug administration on the design of sustained and controlled released system. In: Controlled Drug Delivery. (Robinson, Lee) 2005; 2: 5-9.
2. htt://www.rxlist.com/cgi/generic/stavudin.htm.
3. SunJoel G. Hardman, Lee E.Limbard, Alford Goodman Gilman, ,The pharmacological basis of therapeutics, Tenth Edition (International Edition) John A.Oates and Nancy J. Brown , Antiretroviral Agents and Treatment of HIV Infection..2006; 1286-1287.
4. CIMS India, vol: 98. July-oct. 2007. 388.
5. Sunit Kumar Sahoo1, Abdul Arif Mallick1, BB Barik1 and Prakash Ch Senapati2. Formulation and in vitro Evaluation of Eudragit Microspheres of Stavudine. Tropical J of Pharm Research, June 2005; 4 (1): 369-375.
6. Yung-Chih. Loading efficiency of Stavudine on polybutylcyanoacrylate and methylmathacrylate-sulfopropylmethacrylate copolymer nanoparticles. Int. J. Pharm (2005); 290: 161–172.
7. Gandhi R. B, Bogardus J . B, Bugay D. E 1, Perrone R. K, Kaplan M. A 2: Pharmaceutical relationship of three solid state forms of stavudine. Int. J. Pharm. 2000; 201: 221–237.
8. Yung-Chic Kuo, Fu-Lung Su. Transport of Stavudine, delavirdine, and saquinavir across the blood-brain barrier by polybutylcyanoacrylate, methylmathacrylate-sulfopropylmethacrylate, and solid liquid nanoparticles. Int. J. Pharm.2007; 340:143-152.
9. vidyadhara S, Rama Rao. P and Prasad J. A. Formulation and Evaluation of Propranolol Hydrochloride Oral Controlled Release Matrix Tablet. Ind. J. Pharm.2004; 66(2): 188-192.
10. Sumati R, Lalla J.K.,Poddar S. Formulation and Evaluation of Controlled Release Aspirin Tablets. Ind. J. Pharm. Sci. 2001; 63(2): 110-113.
11. Raslan H. K and Maswadeh H. In-vitro dissolution kinetic study of Theophylline from Mixed Controlled Release Matrix Tablets Containing Hydroxypropylmethyl Cellulose and Glycerylbehenate. Ind. J. Pharm. Sci.2006; 68(3): 308-312.
12. Chowdary K. P. R, Mohapatra P and Murali Krishna M. N. Evaluation of Olibanum and its Resin as Rate Controlling Matrix for Controlled Release of Diclofenac. Ind. J.
13. Haririan I, Ghaffari A, Mohammad M. Formulation of Controlled Release Matrix Tablets of Isosorbide Dinitrate. Ind. J. Pharm. Sci. 2001; 63(1): 24-29.
14. Sreenivasa Rao B, Prasnna Raju Y, Srinivasa L, Seshasayana A. Design and Evaluation of Eudragit RL 100 Sintered Matrix Tablets. Ind. J. Pharm. Sci. 2004; 66(2): 202-507.