FORMULATION AND EVALUATION OF VOGLIBOSE MOUTH DISSOLVING TABLETS

M. Pharm Dissertation Protocol Submitted to

RajivGandhiUniversity of Health Sciences, Karnataka

Bangalore– 560 041

By

Mr. KISHOR SB.Pharm

Under the Guidance of

Dr. KALYANI PRAKASAMM.PharmPh.D

Professor HOD

Department of Pharmaceutics,

Acharya & B.M. Reddy College of Pharmacy,

Soldevanahalli, Chikkabanavara (Post)

HesaraghattaMain Road, Bangalore – 560 090.

2010-2011

RAJIV GANDHI UNIVERSITY OF HEALTH SCIENCES,

KARNATAKA, BANGALORE.

ANNEXURE - II

PROFORMA FOR REGISTRATION OF SUBJECTS FOR DISSERTATION

1. / Name of the Candidate
and Address / Mr. KISHOR S
s/oShankarappa c.
Chowdeshwarinilaya,Bhagavathi layout,
A.M Palya,Siragate
Tumkur-572106
2. /
Name of the Institution
/ ACHARYA & B.M. REDDY COLLEGE OF PHARMACY,
Soldevanahalli,HesaraghattaMain Road,
Chikkabanavara Post.
Bangalore-560090
3. / Course of Study and Subject / M. Pharm
(Pharmaceutics)
4. /
Date of Admission
/
06-07-2010
5. TITLE OF THE PROJECT:-
FORMULATION & EVALUATION OF VOGLIBOSE MOUTH
DISSOLVING TABLETS
6
6.1
6.2
6.3
7
7.1
7.2
7.3


7.4 / BRIEF RESUME OF THE INTENDED WORK:
NEED FOR THE STUDY:
Alpha-glucosidase inhibitorsare oralanti-diabetic drugsused fordiabetes mellitus-type 2,that work by preventing the digestion of carbohydrates (such asstarchandtablet sugar). Carbohydrates are normally converted into simple sugars (monosaccharides), which can be absorbed through the intestine. Hence, alpha-glucosidase inhibitors reduce the impact of carbohydrates onblood sugar.1
There are three drugs which belong toalpha-glucosidase inhibitors.Acarbose, Miglitol and Voglibose.
Voglibose an alpha-glucosidase inhibitor that act as competitive inhibitor of enzymes needed to digest carbohydrates: specifically alpha-glucosidase enzymes in the brush border of the small intestines. The membrane-bound intestinal alpha-glucosidasehydrolyzes oligosaccharides, trisaccharides, and disaccharides to glucose and other monosaccharides in the small intestine. Inhibition of this enzyme system reduces the rate of digestion of complex carbohydrates. Less glucose is absorbed because the carbohydrates are not broken down into glucose molecules.2
Oral route is the most commonly employed route of drug administration. Although different route of administration are used for the delivery of the drugs, oral route remain the preferredmode. The popularity of the oral route is attributed patient’s acceptance, ease of administration, accurate dosing, cost effective manufacturing method and generally improved shelf life of the product.
Pediatric and geriatric patients may have difficulties in swallowing or chewing pharmaceuticaldosage forms for oral administration. Tablets that rapidly dissolve upon contact with saliva in the buckle cavity could present a solution to those problemsand so there is an increased interest in fast dissolving dosage forms for buckle, sublingual and oral administration. Mouth dissolving tablets are perfect fit for these patients as these immediately release the active drug when placed on tongue by rapid disintegration/ dispersion, followed by dissolution of drug.5
Mouth dissolving tablets are dosage form, whichdisintegrate/ disperse in patient’s mouth within a few seconds without the need of water, or chewing, providing best remedy for the patient suffering from dysphasia. Some drugs are absorbed from the mouth, pharynx and esophagus as the saliva passes down the stomach. In such cases the bioavailability is greater than those observed for conventional dosage form.5
The major advantages of mouth dissolving tablets
  • Good mouth feel property of Fast dissolving tablets helps to change the basic view of medication as "bitter pill", particularly for pediatric patients.
  • Rapid dissolution of drug and absorption which may produce rapid onset of action.
  • Some drugs are absorbed from the mouth, pharynx and oesophagus as the saliva passes down into the stomach; in such cases bioavailability of drugs is increased.
  • Ability to provide advantages of liquid medication in the form of solid preparation.
  • Ease of administration to patients who refuse to swallow a tablet, such as pediatric and geriatric patients.3
The present study is to develop mouth dissolving tablets of voglibose for better formulation in terms of bioavailability, convenience and rapid onset of action.
REVIEW OF LITERATURE :
  • Koh N et al., studiedsafety profile of voglibose oral disintegrating tablet (VODT), that is whether treatment with VODT results in improvement of medication compliance and glycemic control. Patients with diabetes received VODT 0.6 or 0.9 mg/day for 12weaks. Among 2930 eligible patients, adverse drug reactions were observedin 3.6%, with the most common being abdominal distension, flatulence, diarrhea, and increased alanineaminotransferase levels. In 1067 who received conventional voglibose tablet (CVT) prior to VODT, 53.1% reported that taking VODT was easier than taking CVT. Medication compliance was improved after switching to VODT in 28.4 % of patients who missed taking tablets more than one time a weak during CVT treatment. A significant decrease in HbA1c levels was observed in patients whose medication compliance was improved after switching to VODT, but there was nosignificant reduction in HbA1C levels in patients whose medication compliance did not change. In conclusion, the present survey suggests that the safety profile of VODT is compliance with that of CVT, and switching from CVT to VODT has positive impact on medication compliance which may lead to an improvement in glycemic control.4
  • Kumar R et al.,formulatedmouth dissolving tablets of fenofibrateusing different subliming agents like camphor, thymolammonium bicarbonate and different concentrations of menthol using direct compression method. The technique is to increase the porosity of the tablets whereby subliming material was sublimed from the granules by exposing the granules to vacuum. The porous granules were then compressed in to tablets. The blend was examined for angle of repose, bulk density, tapped density, compressibility index and hausner’s ratio. The prepared tablets were evaluated for general appearance, content uniformity, hardness, friability, taste evaluation, mouth feel, wetting time, in-vitroand in-vivodisintegration time, andin-vitrodissolution studies. Tablets with menthol at 12.5% concentration have shown quick disintegrating features i.e., within 20s, which is very characteristic of orodispersible tablets. 5
  • Kumar G et al.,formulated matrix tablets of acarbose using hydroxypropyl methyl cellulose and guar gum with the aim to study of release kinetic and to attain a near zero order release.in-vitrodissolution studies were carried out using USP type 2 dissolution test apparatus. Matrix tablets was formulated by employing hydroxypropyl methyl cellulose and guar gum shows slow release of acarbose over a period of 12 h and were found suitable for maintenance portion of oral controlled release tablets. Acarboserelease from these tablets was diffusion controlled and followed zero order kinetics after a lag time of 1h. The most successful of the study, exhibited drug release pattern is very close to theoretical release profile. A decrease in release kinetics of the drug was observed on increasing polymer ratio.6
  • Deshpandea MC et al.,formulated controlled release formulations of miglitol comprising of multilayered pellets. The formulation(CR4) containing 30% of 20cps of ethyl cellulose displayed slowest release of miglitolin-vitro in comparison to other formulations. In anex vivo experimental setup for studying the mucoadhesion of the pellets in the lumen of the intestine, the results indicated that amongst all of the adherent pellets, 5% were found to be adhering in the duodenal region, 61% in the jejunum, 32% in the ileum and 2% in the colon.7
  • Rani PAet al.,formulated oro dispersible tablets of metforminHcl usingcrosspovidone, Isphagula husk, a naturalsuperdisintegrant. The pure drug and formulation blend was examined for angle of repose, bulk density, tapped density, compressibility index and haussner’s ratio. The tablets were evaluated for hardness, tensilestrength, drug content, friability and were found satisfactory. The disintegration timein the oral cavitywas also tested and was foundto be around 10sec. Based on dissolutionrate thedisintegrants can be rated as isphagula husk > crosspovidone. Hence ishapgulahusk was recommended as suitable disintegrant for the preparation of direct compressionmelt‐in‐mouth tablets of metformin Hcl.8
  • Jokob S et al.,formulated fast dissolving effervescent tablets (FETs) of glibenclamidebased on highly plastic granules that can be compressed at low pressure to form fast-melting pharmaceutical tablets. Here citric acid was coated with plastic materials such as polyethylene glycol (PEG), which provide a physical barrier to the reaction. Sodium bicarbonate was blended with sugar alcohol like mannitol, which would give a protective coating. PEG 1000 melts at body temperature (approximately 37°C) and thereby does not delay the reaction between the acid source and base. The present formulation using citric acid-sodium bicarbonate and citric acid-sodium glycine carbonate tablet with PEG and mannitol was found to have better reaction properties and reaction stability than does the standard citric acid-sodium bicarbonate tablet.9
  • Valleri M et al.,formulatedglyburide tablets, allowing fast, reproducible, and complete drug dissolution, by using drug solid dispersion in polyethylene glycol. Phase-solubility studies were performed to investigate the drug-carrier interactions in solution, whereas differential scanning calorimetry, x-ray powder diffraction, and infrared spectroscopy were used to characterize the solid state of solid dispersions. The effects of several variables related to solid dispersion preparation (co evaporation technique, drug-to-carrier ratio, polyethylene glycol molecular weight) and tablet production (direct compression, tablet hardness, drug and solid dispersion particle size) on drug dissolution behavior were investigated. Tablets obtained by direct compression, with a hardness of 7-9 kPa, and containing larger sized solid dispersions (20-35 mesh, i.e., 850-500 micron) of micronized Glyburide in polyethylene glycol 6000 prepared by the co-fusion method gave the best results. Moreover, the Glyburide dissolution profile from the newly developed tablets was clearly better than those from various commercial tablets at the same drug dosage.10
  • Patel Bet al.,formulated fast dissolving tablets of glipizide by direct compression method with a view toenhance patient compliance. Two superdisintegrants, crospovidone and croscarmellose sodium (4%, 5%, 6%) with different binders, PVP k-30 and pregelatinized starch (3%) were used. The prepared batches of tablets were evaluated for hardness, friability, weight variation, disintegration, wetting time, drug content and in vitro dissolution studies. Based on evaluating parameters, Formulation prepared by using 5% croscarmellose sodium with 3% PVP k-30 was selected as optimized formulation. Stability studies were carried out at 25ºC / 60% RH and 40ºC / 75% RH for optimized formulation for 2 months. Stability studies on the optimized formulation indicated that there was no significant change found in physical appearance, disintegration time and wetting time of the tablets.11
  • Arjun Get al.,formulated mouth dissolving tablets of rosiglitazone by direct compression methodwith sodium starch glycolate, cross povidone & cross carmellose sodium were tableted with a view to obtain mouth dissolving tablets. Rosiglitazone mouth dissolving tablets containing cross povidone & cross carmellose sodium in the ratio 1:1 showed maximum drug release. Formulations were subjected to stability studies. Formulations are stable for 4 weeks at 40°C / 75 % RH with insignificant change in the hardness, disintegration time and in vitro drug release pattern.12
  • Satoh N et al.,studied postprandial hyperglycemia and hyperlipidemia are considered risk factors for cardiovascular disease. This study was designed to elucidate whether improving the postprandial state by voglibose- anα-glucosidase inhibitor, leads to the reduction of oxidative stress markers and soluble adhesion molecules in obese type 2 diabetic patients. A total of 30 Japanese obese type 2 diabetic patients were randomly assigned and treated for 3 weeks with either diet alone (the control group) or diet plus voglibose (0.9 mg daily) (n = 15 each). Analysis of the diurnal metabolic profiles revealed a significant reduction of postprandial hyperglycemia and hyperlipidemiawith voglibose relative to the control group.Voglibose also decreased significantly the plasma levels of soluble intercellular adhesion molecule 1 and urinary excretion `of 8-iso-prostaglandin F2α and 8-hydroxydeoxyguanosine andC-reactive protein relative to the control group. In conclusion, this study represents the first demonstration thatvoglibose reduces oxidative stress generation and soluble intercellular adhesion molecule 1 in parallel with the reduction of postprandial hyperglycemia and hyperlipidemia in obese type 2 diabetic patients.13
  • Vichayanrat Aet al.,performed open comparative study to evaluate the efficacy and safety of voglibose and acarbose in 30 patients with type 2 diabetes who were not controlled with diet therapy. In contrast to voglibose, treatment with acarbose significantly decreased the 2 h PPBG at 4 and 8 weeks and the 2 h postprandial serum insulin concentration at 8 weeks. Adverse drug events were more commonly reported in acarbose-treated patients. Increased flatulency was observed in 56.7 and 90 % of the patients taking voglibose and acarbose, respectively, while abdominal distension was noted in 10 and 16.7 %. Significantly decreased body weights of 0.9 and 0.8 kg were recorded at 8 weeks after voglibose and acarbose therapy, respectively. We conclude that both voglibose (0.2mg) and acarbose (100mg) thrice daily significantly decreased HbA, PPBG and postprandial insulin levels. At these dose levels, voglibose was associated with less gastrointestinal side effects as compared to acarbose.14
  • Negishi M et al., worked onpioglitazone, a member of the thiazolidinedionedrug family, which is widely used for the treatment of Type 2 diabetic patients.Here investigation is carried that whether it is possible to prevent pioglitazone-induced body weight gain with voglibose treatment. A total of 31 randomly chosen Japanese Type 2 diabetic patients (14 men, 17 women) was recruited into this study.Body weight was examined at the beginning and the end of the study.A final result shows that voglibose treatment prevented the increase of body weight induced by pioglitazone in Type 2 diabetes patients. Thus, voglibose may be a potentially useful drug for increasing the benefit of pioglitazone treatment by controlling body weight.15
OBJECTIVE OF THE STUDY:-
The objectives of the present study is to formulate mouth dissolving tablets of voglibose by direct compression method, with an aim to improve patient compliance, better therapeutic efficacy and rapid onset of action. Keeping this in view the present investigation is aimed to design mouth dissolving tablets of voglibose using different super disintegrants along with suitable excipients.
Evaluation parameters:
  1. To carry out pre-formulation studies such as angle of repose, bulk density, Carr’s index whichever are required.
  2. To evaluate in-vitro disintegration time of formulation.
  3. To carry out in-vitro release studies using suitable testing apparatus.
  4. To carry out stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).
MATERIALS AND METHODS:
SOURCE OF DATA:-
1)Review of literature from:
  1. Journals – such as
  2. International Journal of Pharmacy and Pharmaceutical sciences
  3. The PharmaResearch, A Journal
  4. International Journal Chem Tech Research
  5. International Journal of Pharmacy and Bio Sciences
  6. Tohuku Journal of Pharma Education
  7. Indian Journal of Pharma Education
  1. World Wide Web
  2. J-Gate@Helinet
MethodS:-
  1. To carry out preformulation studies
  2. Drug-polymer interaction studies using FTIR and DSC.
  3. Micromeritic properties:
  • Angle of repose
  • Bulk density
  • Percentage compressibility
  1. Preparation of mouth dissolving tablet by direct compression.
  2. Characterization of mouth dissolving tablets by following parameters
  3. Hardness/ Crushing strength
  4. Friability
  5. Wetting time
  6. Moisture uptake studies
  7. Weight variation
  8. Content uniformity
  9. in-vitro disintegration time
  10. In-vitro dissolution studies
  11. To carry out stability studies on the most satisfactory formulation as per ICH guidelines at 30 ± 2°C (65 ± 5 %RH) and 40 ± 2°C (75 ± 5 %RH).
DOES THE STUDY REQUIRE ANY INVESTIGATION OR INVESTIGATIONS 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. Alpha-glucosidase inhibitors [online]. [cited 2010 Nov 08]; Available from:URL:
  1. Showing drug card for voglibose [online]. [cited 2010 Nov 08]; Available from: URL:
  1. Kuchekar BS, Bhinse SB, Armugam V. Design of fast dissolving tablets. Indian J PharmEdu 2001; 35(4):150-2.
  1. Koh N, Sakamoto S, Chino F. Improvement in medication compliance and glycemic control with voglibose oral disintegrating tablet. Tohuku J Exp Med 2008;216: 249-57.
  1. Kumar R, Patil S, Patil MB, Patil SR, Paschapur MS. Formulation evaluation of mouth dissolving tablets of fenofibrate using sublimation technique. Int J Chem Tech Res 2009 Oct-Dec;1(4):840-50.
  1. Kumar G, Juyal V, Badoni PP, Rawat MSM, Semalty A. Formulation and release kinetic study of hydrogel containing acarbose using polymers as hydroxypropylmethyl cellulose and guar gum. J Pharm Res 2009 Mar;1(3):370-4.
  1. Deshpandea MC, Vobalaboina V, Babub RK, Trivedib RK. Design and evaluation of oral bioadhesive controlled release formulations of miglitol, intended for prolonged inhibition of intestinal α-glucosidases and enhancement of plasma glucagon like peptide-1 levels. Int J Pharm 2009 Oct;380(1-2):16-24.
  1. Rani PA, Archana N, Teja SP, Vikas MP, Kumar SM,Sekaran BC. Formulation and evaluation of orodispersibleMetformin tablet: A comparative study on Isphagula husk and crosspovidone as superdisintegrant. Int J ApplPharm 2010;2(3):15-21.

  1. Jokob S, Shirwaikar A, Nair A. Preparation and evaluation of fast-disintegrating effervescent tablets of glibenclamide. Drug Dev Indian pharm 2009 Mar;35(3):321-8.
  1. Valleri M, Mura P, Maestrelli F, Cirri M, Ballerini. Development and evaluation of Glyburide fast dissolving tablets using solid dispersion technique. Drug Dev Indianpharm 2004 May;30(5):525-34.
  1. Patel B, Patel D, Parmar R, Patel C, Serasiya T, Sania SD. Development and in-vitro evaluation of fast dissolving tablets of glipizide. Int J PharmPharmSci 2009 Nov-Dec;1(1):145-50.
  1. Arjun G, Prasad SM, Santhosha D, Achaiah G. Formulation and evaluation of Rosiglitazone mouth dissolving tablets. Int J Pharm Bio Sci 2010;1(1):1-9.
  1. Satoh N, Shimatsu A, Yamada K, Abe MA, Suganami T, Kuzuya H et al. An α-glucosidase inhibitor-voglibose, reduces oxidative stress markers and soluble intercellular adhesion molecule 1 in obese type 2 diabetic patients. Metab 2006 Jun;55(6):786-93.
  1. Vichayanrat A, Ploybutr S, Tunlakit M, Watanakejorn P. Efficacy and safety of voglibose in comparison with acarbose in type 2 diabetic patients. Diabetes Res Clin Practice 2002;55:99-103.
  1. Negishi M, Shimomura K, Proks P, Shimomura Y, Mori M. Alpha glucosidase inhibitor voglibose can prevent pioglitazone-induced body weight gain in type 2 diabetic patients. Br J ClinPharmacol 2008 Aug;66(2):318-9.

9 / Signature of the candidate:
10 / Remarks of the Guide:
11 / Name and Designation of:
11.1 / Institutional Guide: / Dr. KALYANI PRAKASAM M.PharmPh.D
Professor & HOD
Dept. of Pharmaceutics.
11.2 / Signature:
11.3 / Co-Guide:
11.4 / Signature:
11.5 / Head of the Department: / Dr. KALYANI PRAKASAM M.PharmPh.D
Professor
Dept. of Pharmaceutics.
11.6 / Signature
12 / 12.1 / Remarks of the Principal
12.2 / Signature /
Dr. DIVAKAR GOLI M.PharmPh.D
Professor &Principal
Acharya & B.M. Reddy College of Pharmacy
Bangalore

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