FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF NATEGLINIDE
M.Pharm Dissertation Protocol Submitted to
Rajiv Gandhi University of Health Sciences, Karnataka
Bangalore – 560 041.
By
Mr. SYED NAMATH ULLA B.Pharm
Under the Guidance of
Mr. ANUP KUMAR ROY M.Pharm
Asst. Professor
Department of Industrial Pharmacy,
Acharya & B. M. Reddy College of Pharmacy,
Soldevanahalli, Chikkabanavara (Post)
Hesaraghatta Main Road, Bangalore – 560 090
2008-2009
RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES
KARNATAKA, BANGALORE.
ANNEXURE II
PROFORMA FOR REGISTRATION OF SUBJECT FOR DISSERTATION
1/ Name of the candidate and address /
Mr. SYED NAMATH ULLA
# 7/3, 5TH CROSS,MAGADI ROAD,
BANGALORE - 560023
KARNATAKA.
2 / Name of the Institution / Acharya and B.M. Reddy college of pharmacy,
SOLDEVANAHALLI,
CHIKKABANAVARA POST,
HESARAGHATTA MAIN ROAD,
BANGALORE - 560 090.
3 / Course of the study and subject / M. Pharmacy
(Industrial Pharmacy)
4 / Date of admission / June- 2008
5 / TITLE OF THE PROJECT:-
FORMULATION AND EVALUATION OF SUSTAINED RELEASE MATRIX TABLETS OF NATEGLINIDE
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6.1
6.2 / BRIEF RESUME OF INTENDED WORK:-
NEED FOR THE STUDY :-
SUSTAINED RELEASE DOSAGE FORM:-
It is defined as the term used to identify drug delivery systems that are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of a single dose.
The frequency of drug administration is reduced, patient compliance can be improved and drug administration can be made more convenient as well. A less obvious advantage implicit in the design of sustained release forms is that the total amount of drug administered can be reduced, thus maximizing availability with a minimum dose. The safety margin of high potency drugs can be increased and the incidence of both local and systemic adverse side effects can be reduced in sensitive patients. Overall, administration of sustained release forms enables increased reliability of therapy.1
DIABETES MELLITUS:-
It is a metabolic disorder characterized by hyperglycaemia, glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia. A wide spread pathological change is thickening of capillary basement membrane, increase in vessel wall matrix and cellular proliferation resulting in vascular complications like lumen narrowing, early atherosclerosis, sclerosis of glomerular capillaries, and peripheral vascular insufficiency.
There are two types of diabetes mellitus:
1) Type 1 Diabetes mellitus/ insulin dependent Diabetes mellitus is an autoimmune disorder and is managed by insulin administration.
2) Type 2 Diabetes mellitus/ non insulin dependent diabetes mellitus, treatment is initially dietary although oral hypo-glycaemic drugs usually become necessary.
There are many classes of oral anti-diabetic agents. The objective of the treatment is to achieve euglycaemia, by using an ideal dosage regimen. An ideal dosage regimen in the drug therapy of any disease is the one, which immediately attains the desired therapeutic concentration of drug in plasma and maintains it constant for the entire duration of treatment.
Nateglinide is a meglitinide analogues, another nonsulfonylurea derivatives which principally stimulates 1st phase insulin secretion resulting in rapid onset and shorter duration of hypoglycaemic action than Repaglinide. The drug is widely used for the management of type-2 diabetes. It has short biological half life (1.5±0.7 hrs) and bioavailability is 73%. Moreover, site of absorption of Nateglinide is in the intestine. Therefore, the objective of the present work is to develop a sustained release matrix drug delivery system for the drug Nateglinide for the better management of the disease to minimize side effect as well as to improve patient compliance.2
REVIEW OF LITERATURE :-
This study examined the release of acetaminophen (APAP) from hydroxypropyl methylcellulose (HPMC) and hydroxypropyl cellulose (HPC) matrices. The effect of pseudoephedrine (PE) as a co-active, HPMC:HPC ratio, polymer loading, pH of the dissolution media, and compression force on APAP release were studied. Granules formulated with APAP or both APAP and PE, and various blends of HPMC and HPC were compressed into tablets at different compression forces.3
The monolithic matrix tablets of ambroxol hydrochloride were formulated as sustained release tablets employing hydroxypropyl methylcellulose polymer (HPMC) and sustained release behaviour of the fabricated tablets was investigated. Sustained release matrix tablets containing 75mg ambroxol hydrochloride were developed using different drug polymer ratios of HPMC. Tablets were prepared by direct compression.4
The purpose of this study was to examine a level A in vitro–in vivo correlation (IVIVC) for glipizide hydrophilic sustained release matrices, with an acceptable internal predictability, in the presence of a range of formulation/ manufacturing changes. The effect of polymeric blends of ethylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, xanthan gum, guar gum, Starch 1500 and lactose on in vitro release profiles was studied and fitted to various release kinetics models.5
The low bioavailability and short half-life of metformin hydrochloride (MH) have made the development of sustained-release forms desirable. However, drug absorption is limited to the upper gastrointestinal (GI) tract, thus requiring suitable delivery systems providing complete release during stomach-to-jejunum transit. In this study directly compressed matrix tablets of metformin with the hydrophobic triacetyl-b-cyclodextrin (TAbCD) was dispersed in a polymeric material.6
The evaluation of natural gum copal and gum damar as novel sustained release matrix forming materials was formulated in tablet form. Along with the physicochemical properties, gum copal and gum damar were characterized for molecular weight, poly dispersity index and glass transition temperature. Matrix tablets were prepared by wet granulation technique using isopropyl alcohol as a granulating agent. Diclofenac sodium was used as a model drug. Tablet weight (250 mg) and diameter (9 mm) was kept constant. Tablets were evaluated for pharmaco technical properties, drug content uniformity and in vitro drug release kinetics.7
The effects of formulation variables on the release profile of diclofenac sodium (DS) from hydroxypropylmethyl cellulose (HPMC) and chitosan matrix tablets were studied. DS tablets were prepared by wet granulation and direct compression methods and different ratios of HPMC and chitosan were used. Physical properties of the prepared tablets and targeted commercial sustained release (SR) tablet and the drug release were studied in tablets that were placed in 0.1M HCl for 1 h and phosphate buffer solution was added to reach pH 7.5.8
The release of acetyl salicylic acid from directly compressed alginate tablets was investigated. The effect of the amount and type of alginate on the drug release rate was evaluated in different formulations. Four different grades of alginate were used. The in vitro release studies were carried out using the apparatus II (paddle) equipment as described in the USP XXIII. Dissolution medium was 0.1M HCl for 2 h followed by phosphate buffer pH 6.8; both at 370C. Sustained drug release upto 16 h was achieved using sodium alginate in combination with dibasic calcium phosphate.9
Mefenamic acid (MA) having analgesic, anti-inflammatory and antipyretic properties were studied. The usual oral dose is 250 or 500 mg and reported half-life is 2 h. Sodium alginate (NaAL) is the sodium salt of alginic acid. It has the ability to form a water-insoluble gel with a bivalent metal ion as calcium. In this study, tablet formulations containing different ratios of NaAL and calcium gluconate (CaGL) were prepared by direct compression method. In vitro release studies were carried out using USP XXIII basket method and release data were kinetically evaluated. According to release studies, it can be emphasized that NaAL and CaGL can be used for design of sustained release preparation of MA.10
Didanosine, a nucleoside analog used in the treatment of acquired immuno deficiency syndrome (AIDS), was incorporated into directly compressed monolythic matrices using excipients mixtures of a methacrylic resin (Eudragit RSPM) and an ethylcellulose (Ethocel 100). Technological characterization (drug particle morphology, mean weight, diameter, thickness and hardness of tablets) was carried out and in vitro drug release behaviour was measured using the USP basket apparatus. The effect of varying the Eudragit–Ethocel ratio, as well as the drug–polymeric matrix ratio, was evaluated. The results showed the suitability of Eudragit–Ethocel mixtures as matrix-forming material for Didanosine sustained release formulations. 11
The mechanism of sustained release (SR) from tablet matrices prepared with hydroxypropyl methylcellulose (HPMC) 2910 polymers were investigated to define the conditions for selection of appropriate polymers for SR formulation development. It was well known that the two important parameters for the release of drug from tablet matrices are the infiltration rate of medium into the matrix, for those drugs with reasonable aqueous solubility, and the erosion rate of the matrix system, for those drugs with poor aqueous solubility. In addition, the amount of drug loaded into the tablet also influences the release rate of the drug.12
A bilayer tablet of propranolol hydrochloride was developed using super disintegrant sodium starch glycolate for the fast release layer and water immiscible polymers such as ethylcellulose, Eudragit RLPO and Eudragit RSPO for the sustaining layer. In vitro dissolution studies were carried out in a USP XXIII apparatus I. The formulations gave an initial burst effect to provide the loading dose of the drug followed by sustained release for 12 h from the sustaining layer of matrix embedded tablets.13
The study of the oral sustained release gastro-retentive dosage forms offers many advantages for drugs having absorption from upper gastrointestinal tract and improve the bioavailability of medications were characterized by a narrow absorption window. A new gastro-retentive sustained release delivery system was developed with floating, swellable and bioadhesive properties. All these properties were optimized and evaluated. Various release retarding polymers like psyllium husk, HPMC K100M and a swelling agent, crosspovidone in combinations were tried and optimized to get the release profile for 24 h.14
The tablets containing theophylline (66.67%) based on a Eudragit matrices containing 10% to 30% of either of the polymer were produced by compression method. The influence of the different proportions of methacrylic esters, the use of lactose and tribasic calcium phosphate as diluents and also the effects of the addition of magnesium stearate as a hydrophobic agent lubricant on the theophylline release, were studied. In vitro drug release studies were carried out in simulated gastric fluid without pepsin (pH1.2) and simulated intestinal fluid without pancreatin (pH7.5). A relatively prolonged release of theophylline from the polymer matrices for a 7 h release period was detected.15
6.3 / OBJECTIVE OF THE STUDY :-
The objectives of the present study is to formulate sustained release matrix tablets of Nateglinide, with an aim to improve patient compliance, better therapeutic efficacy, less side effect and reduce doses of regimen with less toxicity for treatment of chronic disease like diabetes which require long term therapy. Keeping this in view the present investigation will be aimed to design suitable sustained release matrix tablet using different polymers.
The major objectives of the present work are:
1. To carry out preformulation studies for possible drug/polymer/excipients interactions by FTIR.
2. To develop and formulate Sustained release matrix tablet of Nateglinide for the treatment of Type 2 Diabetes by direct compression/ wet granulation method.
3. To evaluate the core and the compression coated tablets for the following parameters:
a. Diameter and Thickness.
b. Hardness and Friability.
c. Weight uniformity.
d. Content uniformity.
e. In- vitro drug release studies.
4. To carry out short term stability studies on the most satisfactory formulation as per ICH guidelines.
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7.1 / MATERIALS AND METHOD :-
SOURCE OF DATA:-
1) Review of literature from:a) Journals such as
i) Indian Journal of Pharmaceutical Sciences
ii) European Journal of Pharmaceutical Sciences
iii) Journal of Controlled Release
iv) International Journal of Pharmaceutics
v) Drug Development and Industrial Pharmacy
vi) Indian Drugs
vii) Brazilian journal of Pharmaceutical Sciences
b) World Wide Web
c) I.I.Sc Library, Bangalore
d) J-Gate@Helinet
7.2 /
METHOD OF COLLECTION OF DATA :-
1. To carry out preformulation study
a) Drug polymer interaction by FTIR.
b) Micromeritics study
v Angle of repose
v Bulk density
v Percentage compressibility.
2. To develop and formulate Sustained Release Matrix tablets by direct compression/ wet granulation methods using various polymers.
3. Evaluation of the various properties of the formulated Sustained Release tablets.
a) Physico-chemical properties:-
v General appearance
v Diameter and thickness
v Hardness and friability
v Weight variation
v Content uniformity
b) In vitro dissolution studies will be carried out in a USP Type-II dissolution apparatus.
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).
7.3 / Does the study require any investigation or investigation to be conducted on patient or other humans or animals?
“NO”
7.4 / Has ethical clearance been obtained from your
institution in case of 7.3?
“NOT APPLICABLE”
8 / REFERENCES :-
1. Lachman L, Lieberman A, Kanig J. The theory and practice of Industrial Pharmacy. Mumbai: Varghese publishing house 1990; 3: 430-431.
2. Tripathi KD. Essentials of Medical Pharmacology. New Delhi: Jaypee Brothers, Medical publishers (P) LTD 2003; 5: 235-249.
3. Nkere K, Alan B. Sustained release of acetaminophen from a heterogeneous mixture of two hydrophilic non-ionic cellulose ether polymers. Int J Pharm 2004; 272: 19–27.
4. Basak S, Jayakumar R, Lucas Mani. Formulation and release behavior of sustained release ambroxol hydrochloride HPMC matrix tablet. Ind J Pharm Sci 2008; 594-596.
5. Sankalia M, Sankalia G, Rajashree C. Drug release and swelling kinetics of directly compressed glipizide sustained-release matrices: Establishment of level A IVIVC. J Control Release 2008; 129: 49–58.
6. Giovanna C, Marzia C, Francesca M, Natascia M, Paola M. Sustained-release matrix tablets of metformin hydrochloride in combination with triacetyl-b-cyclodextrin. Eur J Pharm Biopharm 2008; 68: 303–309.
7. Morkhade D, Fulzele S, Satturwar P, Joshi S. Gum copal and gum damar: novel matrix forming materials for sustained drug delivery. Ind J Pharm Sci 2006; 68(1): 53-58.
8. Ayhan S¸ Yalcin O, Askin I. Preparation and in vitro evaluation of sustained release tablet formulations of diclofenac sodium. Farmaco 2005; 60: 171–177.
9. Oyvind H, Edvar O, Rolf M, Karlsen J. Sustained release of water-soluble drug from directly compressed alginate tablets. Eur J Pharm Sci 2003; 20: 403–407.
10. Gungo S, Yildiz A, Zsoy Y, Cevher E, Araman A. Investigations on mefenamic acid sustained release tablets with water-insoluble gel. Farmaco 2003; 58: 397-401.
11. Carla L, Teresa Faucci M, Mercedes Fernandez A, Josefa A, Antonio M, Paola M. Development of sustained release matrix tablets of didanosine containing methacrylic and ethylcellulose polymers. Int J Pharm 2002; 234: 213–221.
12. Koichiro T, Ken Y, Toshiaki N. Overall mechanism behind matrix sustained release (SR) tablets prepared with hydroxypropyl methylcellulose 2910. J Control Release 1995; 35: 59-66.
13. Chinam P, Arethi B, Hemant P, Satya prakash S, Meduri V. Design and evaluation of sustained release bilayer tablets of propranolol hydrochloride. Acta Pharm 2007; 57: 479–489.
14. Mahesh D, Paras J, Sachin C, Rajesh S, Pradeep R. Novel sustained release, swellable and bioadhesive gastroretentive drug delivery system for ofloxacin. Int J Pharm 2006; 316: 86–92.
15. Evelyn O, Edna Mitie M, Tais Cobo V, Vladi Olga C. Formulation and in vitro evaluation of theophylline-Eudragit sustained-release tablets. Brazilian Journal of Pharmaceutical Sciences 2005; 41(3): 377-384.
9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:
11.1 / Institutional Guide: / Mr. Anup Kumar Roy
Asst. Professor
Dept. ofIndustrial
Pharmacy
11.2 /
Signature:
11.3 / Co-Guide: / Mr. Venkatesh D.P
Lecturer
11.4 / Signature:
11.5 / Head of the Department: /
Dr. Roopa Karki
Professor & HODDept. of Industrial Pharmacy
11.6 / Signature
12 / 12.1 / Remarks of the Principal
12.2 / Signature /
Dr. Goli Divakar
Prinicipal
ACHARYA B.M.REDDY
COLLEGE OF PHARMACY,
SOLDEVANAHALLI,
HESARAGHATTA MAINROAD,
BANGALORE-90
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