7. / BRIEF RESUME OF THE INTENDED WORK:
ENCLOSURE - I
6.1 NEED FOR THE STUDY
Oral route of administration has been used the most for both conventional and novel drug delivery systems for systemic effects. Oral administration of drugs is always preferable than other routes because of its easier administration and its simplicity. Usually conventional dosage form produce wide ranging fluctuation in drug concentration in the blood stream and tissues with consequent undesirable toxicity and poor efficiency. If the drug is given in conventional dosage form, it has to be administered several times a day to produce the desired therapeutic effect. Because of the frequent dosing fluctuations in plasma drug level occurs. This factor such as repetitive dosing and unpredictable absorption led to the concept of controlled/ extended drug delivery system 1.
Extended release dosage forms are those that providesmedication over an extended time. The basic goal of therapy is to achieve a steady state blood/tissue level i.e therapeutically effective and non-toxic for an extended period of time. Extended released drug delivery systems reduce the frequency of dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery.
Extended release/controlled release dosage form can be prepared by using various techniques which includes:
- Barrier coating
- Embedding in slowly erodible matrix
- Skeleton type matrix
- Ion exchange resin
- Hydrophilic matrix
- Polymer resin beads
- Passage sponge formulation
- Chemical complexation 2
- Bilayer technique
- Microencapsulation.
Metformin hydrochloride will be taken as the model drug. Chemically, it is N,N-dimethylimidodicarbonimidic diamide hydrochloride. Metformin hydrochloride is an oral anti-hyperglycemic drug, the drug of choice to treat type II Diabetes Mellitus. It reduces glucose levels primarily by decreasing hepatic glucose production and by increasing insulin action in muscles and
fat. Metformin is absorbed mainly from the small intestine. The drug is stable, does not bind to plasma proteins and is excreted unchanged in the urine. It has a half life of 2 hours. Maximum recommended daily dose is 2.5g and taken three doses with meals 3. The short half life makes it a suitable candidate to prepare oral extended dosage form.
Alpha lipoic acid is an antioxidant, an anti-diabetic drug which helps mainly to convert glucose(blood sugar) into energy. In patients with type II Diabetes Mellitus, both acute and chronic administration of alpha lipoic acid improves insulin resistance, reduces plasma fructosamine levels 4. Lipoic acid also enhances glucose uptake, inhibits glycosylation and has been used to improve diabetic nerve damage and the pain associated with it. It acts directly on muscle cell to stimulate glucose transport 5.
Therefore Alphalipoic acid is used in the formulation to obtain a desired result i.e reduced serum glucose level or reduce the amount of medication such as Metformin hydrochloride/ insulin, the patient requires to control symptoms of Diabetes Mellitus.
The aim of this project is to formulate and evaluate extended release bilayer tablets of Metformin hydrochloride and Alpha lipoic acid.
ENCLOSURE - II
6.2 REVIEW OF LITERATURE:-
1.Tiwari SB, etal., developed controlled release Tramadol hydrochloride using hydrophilic (hydroxy propyl methyl cellulose) and hydrophobic (hydrogenated castor oil, ethyl cellulose) matrix system. It is evident from the result that a hydrophobic matrix prepared by hydrogenated castor oil is a better system for controlled delivery of a highly water-soluble drug like tramadol hydrochloride6.
2. Sandeep G, et al., formulated Metoprolol succinate extended release matrix tablets using different ratios of hydroxy Propyl methyl cellulose (HPMC K 100M), hydroxy propyl cellulose(HPC), ethyl cellulose, carbopol 934 and magnesium stearate. All batches were found to be nearly zero order release governed by diffusion through swollen matrix, showing the anamolous diffusion or non fickian transports 7.
3.Hart W, et al., reported Felodipine extended release tablet. Felodipine extended release tablet given once daily were as effective and well tolerated as plain tablets given b.i.d. in the treatment of hypertensive patients also receiving a β- blockers8.
4.Krishna VA, et al., formulated and evaluated Divalproex sodium extended release tablets using different grades of hydroxy propyl methyl cellulose (HPMC) in varying proportion. Formulation of extended release tablet of batch DERT-V( Divalproex sodium extended release tablets) containing 19.5% of HPMC K100 M and 7% of HPMC K4M can be taken as an ideal or optimized formulation of extended release tablet for 18 hr release as it fulfills all the requirements for extended release tablet9.
5.Rovner ES, et al., developed once daily, extended release formulations of anti-muscarinic agents in the treatment of overactive bladder. Oxybutynin extended release has demonstrated similar efficacy to the immediate release formulation without conclusive evidence of improvement in tolerability. Once-daily antimuscarinic therapy with Tolterodine extended release however, provides significant clinical efficacy & tolerability advantages over the current Tolterodine immediate release formulation 10.
6. Kumar BV, et al., developed and evaluated Guaifenesin bi-layer tablet using microcrystalline cellulose, sodium starch glycolate as fast release layer and metalose 90 SH, carbopol 934 as sustained release layer. Guaifenesin showed biphasic release in the first phase, the first fraction of the dose( immediate release) was released as a burst effect in less than 60 minutes, because of fast releasing components of loading layer then second phase was released from matrix layer as a controlled non fickian diffusion release fashion 11.
7. Shiyani B, et al., formulated and evaluated bilayer tablet of Metoclopramide hydrochloride and Ibuprofen. Optimized immediate release layer of metoclopramide hydrochloride and sustained release layer of ibuprofen show satisfactory pre and post compression parameters. Bilayer tablet of metoclopramide hydrochloride and ibuprofen might be suitable for treatment of migraine by sequential release of the drug 12.
8.Atram SC, et al., reported formulation and evaluation of bilayer tablet containing Metoprolol succinate and Amlodipine besylate. The increased use of fixed dose combination therapy may make it easier for patients to remember to take pills and get them to goal quicker and with less trouble. This should improve rates of blood pressure control and ultimately accelerate the reduction in cardiovascular diseases 13.
9. Gohel MC, et al., developed bilayer tablet containing conventional Paracetamol using poly ethylene glycol, microcrystalline cellulose, crosspovidone as independent variables and modified release Diclofenac sodium using hydroxyl propyl methyl cellulose as matrixing agent. Bilayer tablets showed immediate release of paracetamol and modified release(upto 12 h) of diclofenac sodium. The dosage form is patient friendly since the dosing frequency will be reduced. Moreover, the tablet will be easy to swallow, as the tablet weight was less than one gram 14.
10. Midaoui AE, et al., Studied on Alpha lipoic acid. These findings demonstrated that alpha lipoic acid supplementation prevents development of hypertension and hyperglycemia, presumably through its anti-oxidative properties, as reflected by prevention of an increase in heart mitochondrial superoxide anion production and in advanced glycation end products formation in the aorta of chronically glucose treated rats 15.
ENCLOSURE – III
6.3 OBJECTIVES OF THE STUDY:-
1. To carry out preformulation studies for possible drug- polymer interaction.
2. To prepare extended release bilayer tablets of Metformin hydrochloride andAlphalipoic acid.
3. To evaluate the tablets for properties and release profiles.
4. To carry out short term stability studies.
5. To come up with the decreased complications of diabetes induced neuropathy and fructosamine level in blood and increased insulin sensitivity.
MATERIALS AND METHODS:-
Material:
Drug: Metformin hydrochloride, Alpha lipoic acid.
Polymer: Various suitable grades of hydroxy propyl methyl cellulose (HPMC).
Excipients: by using suitable binders, granulating vehicle, lubricants, glidants etc.
Method:
Development of extended release bilayer tablets by wet granulation method/ by any suitable method.
ENCLOSURE - IV
7.1SOURCE OF DATA:-
I Review of Literature from:
- journals: such as
-International Journal of Pharmaceutical Sciences and Nanotechnology
-International journal of Biopharmaceutics
- International Journal of Research in Pharmaceutical and Biomedical Sciences
- Indian Journal of Pharmaceutical Sciences
- Journal of Pharmacy Research
B. Text book : The pharmacological basis of therapeutics
C. Martindale
D. Internet Browsing
E. J-gate@Helinet
F. East Point College Library
ENCLOSURE - V
7.2 METHOD OF COLLECTION OF DATA:
The steps that will be followed are:
1. preformulation studies for drug polymer interaction.
2. Formulation of bilayered tablets using different approaches.
3. Selection of suitable optimized formula for the above mentioned preparation
4. Evaluation of the above formulation for
- Thickness
- Hardness
- Friability
- Weight variation
- Disintegration time
- Drug content
- In-Vitro release profiles
- Short term stability studies
ENCLOSURE - VI
7.3 Does the study require any investigations or interventions to be conducted on patients or other humans or animals? If so, please describe briefly.
------NOT APLLICABLE ------
7.4 Has ethical clearance been obtained from your institution in case of 7.3.
----- NOT APPLICABLE-----
8. / ENCLOSURE - VII
LIST OF REFERENCES:
1) Kumar KK, Mahesh M, Sasikanth K. Design, development and characterization of sustained release of Metformin hydrochloride and Gliclazide bilayered tablets by wet granulation method. Int J Biopharm 2010;1(2):67-71.
2) Sangeetha S, Sakthisarvannan V, Komala M, Harish G, Sivakumar V. Design and evaluation of gastroretentive beads of Theophylline by ionotropic gelation. Int J pharm Pharm Sci 2010;2(3):99-101.
3) Goodman & Gilman. The Pharmacological basis of therapeutics. 10th ed. Joel G. Hardman: International edition; 2001. PP. 1705.
4) Evans JL, Heymann CJ, Goldfine ID, Gravin LA. Antioxicants: Do they have a role in the treatment of insulin resistance? Antioxidants and Insulin resistance: Clinical studies. The Ind J Med Res 2007;125(3):360-61.
5)Flatt K. Alpha lipoic acid & Diabetic neuropathy.( Natural cures and Natural remedies) Free radic Bio Med 1995;19:227-50.
6) Tiwari SB, Murthy TK, Pai MR, Mehta PR, chowdary PB. Controlled release formulation of Tramadol hydrochloride using hydrophilic and hydrophobic matrix system. AAPS Pharm Sci Tech 2003;4(3):1-6.
7) Sandeep G, Rangasamy M. Formulation and optimization of Metoprolol succinate extended release matrix tablets. J Pharm Res 2009;2(4):619-21.
8) Hart W, Westberg B. Felodipine extended release tablet once daily are equivalent to plain tablet twice daily in treating hypertension. J Cardiovas Pharmacol 1990;15(4):S65- 69.
9) Krishna VA, Srinath KR, Chowdary PC, Palanisamy P, Vijayasankar GR. Formulation development and evaluation of Divalproex sodium extended release tablets. Int J Res Pharm Biomed Sci 2011;2(2):809-31.
10) Rovner ES, Wein AJ. Once daily, extended release formulations of anti-muscarinic agents in the treatment of overactive bladder: A Review. Eur Uro 2002;41(1):6-14.
11) Kumar BV, Prasad G, Ganesh B, Swathi C, Rashmi A, Reddy AG. Development and evaluation of Guaifenesin bilayer tablet. Int J Pharm Sci 2010;3(3):1122-28.
12) Shiyani B, Gattani S, Surana S. Formulation and evaluation of bi-layer tablet of Metoclopramide hydrochloride and Ibuprofen. AAPS Pharm Sci Tech 2008;9(3):818-27.
13). Atram SC, Udavant YK, Salunke RJ, Neb GB, Shahi SR, Gulecha BS, Padalkar AN. Formulation and evaluation of bilayer tablet containing Metoprolol succinate and Amlodipine besylate as a model drug for anti hypertensive therapy. J Pharm Res 2009;2(8):1335-47.
14). Gohel MC, Parikh RK, Nagori SA, Jethwa BA. Fabrication and evaluation of bilayer tablet containing conventional Paracetamol and modified release Diclofenac sodium. Ind J Pharm sci 2010; 72(2):191-96.
15) Midaoui AE, Elimadi A, Wu L, Haddad PS, de Champlain J. Lipoic acid prevents hypertension, hyperglycemia and the increase in heart mitochondrial superoxide production. Am J Hypertens 2003;16(3):173-9.