PREPARATION DESIGN AND EVALUATION OF SUSTAINED …"Sustained release, sustained action, prolong...

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RESEARCH ARTICLEDepartment of Pharmaceutics

Mantry et.al / UJPSR / 2 (1), 2016, 13-20e ISSN: 2454-3764

Print ISSN: 2454-3756

PREPARATION DESIGN AND IN-VITRO EVALUATION OF SUSTAINED RELEASE TABLET OF GLIBENCLAMIDE

*Meera Sharma, Richa Kashyap, Shubhrajit Mantry

Department of Pharmaceutics, Himalayan Pharmacy Institute, Majhitar, Rangpo, E. Sikkim – 737136, INDIA

Abstract

Key words

The conventional dosage forms used in the treatment of diabetes mellitus is not much effective because in such dosage form the drugs do not reach the site of action in required concentration & therefore frequent dosing is required. To overcome such problems, various pharmaceutical technologies have been adopted. One of such technologies is matrix dosage form that tends to release drug in a sustained release pattern. The purpose of the performed study was to develop hydrophilic polymer based Glibenclamide tablet. After performing In-vitro drug release study, it was observed that the formulation F6 containing HPMC K4M & HPMC E15 in the ratio 1:1 showed good release pattern for 12 hours compared to other formulations. Short term stability study was also performed for the prepared formulations & no change in the physical parameters were observed.

Glibenclamide, Matrix dosage form, Sustained release,

HPMC K4M, HPMC E15, HPMC K100.

ARTICLE INFO: Article history: Received:05 January 2016Received in revised form:09 January 2016Accepted: 02 February 2016Available online: 10 May 2016

Corresponding Author:

Mr. Shubhrajit MantryDepartment of PharmaceuticsHimalayan Pharmacy Institute Majhitar, E. Sikkim, INDIAEmail: [email protected]: +91-7384205300

INTRODUCTION

The oral route for drug delivery is the most popular, desirable and most preferred method for administrating therapeutic agents because it is natural, convenient and cost effective to manufacturing processes [1]. A drug is delivered to the patient using various pharmaceutical forms such as tablets, capsules, pills, suppositories, creams, ointments, injectables. To achieve better therapeutic action, various types of drug delivery systems are available, out of which sustained release systems are gaining much more importance because of their wide advantages over others like ease of administration, convenience and non-invasiveness [1]. "Sustained release, sustained action, prolong action, controlled release, extended action, depot are terms used to identify drug delivery systems that are designed to achieve prolong therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose". In the case of orally

administered dosage form, this period is measured in hours while in the case of injectables this period varies from days to months [2].

The design of oral sustained drug delivery system (DDS) should be primarily aimed to achieve more predictability and reproducibility to control the drug release, drug concentration in the target tissue and optimization of the therapeutic effect of a drug by controlling its release in the body with lower and less frequent dose. The materials most widely used in preparing matrix systems include both hydrophilic and hydrophobic polymers. Commonly available hydrophilic polymers include Hydroxy propyl methyl cellulose (HPMC), Hydroxy propyl cellulose (HPC), Hydroxy ethyl cellulose (HEC), Xanthan gum, Sodium alginate, Polyethylene oxide and cross-linked homo polymers and copolymers of Acrylic acid. These are

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usually supplied in micronized forms because small particle size is critical to the rapid formation of gelatinous layer on the tablet surface. HPMC is the dominant hydrophilic vehicle used for the preparation of oral sustained drug delivery. While HPMC could potentially control the release of a soluble drug, it could also facilitate the release of relatively insoluble drug. In the later case, insolubility of the drug molecule would be the rate limiting step in its release and HPMC's solubilizing effect would facilitate the release. The net result is controlled drug delivery for a prolonged period of time. The objective of the present study was to develop a hydrophilic polymer (HPMC) based Glibenclamide matrix sustained release tablet which can release the drug up to time of 12 hours in predetermined rate. The formulation of Glibenclamide matrix tablet was prepared by the polymer combination in order to get required theoretical release profile. The influence of hydrophilic polymer and granulation technique on Glibenclamide was studied. The formulated tablets were also characterized by physical and chemical parameters like drug content, hardness, friability, dissolution rate etc [1]. Diabetes mellitus Type 2 is a long term metabolic disorder that is characterized by high blood sugar, insulin resistance and relative lack of insulin. It primarily occurs due to obesity. Symptoms of high blood sugar include frequent urination, increased thirst and increased hunger [5]. Type 2 diabetes is a progressive condition in which the body becomes resistant to the normal effects of insulin and/or gradually loses the capacity to produce enough insulin in the pancreas. We do not know what causes type 2 diabetes. Type 2 diabetes is associated with modifiable lifestyle risk factors. Type 2 diabetes also has strong genetic and family related risk factors. Type 2 diabetes is diagnosed when the pancreas does not produce enough insulin (reduced insulin production) and/or the insulin does not work effectively and/or the cells of the body do not respond to insulin effectively known as insulin resistance [3]. Over 90% cases of diabetes are type 2 [6].

?Usually develops in adults over the age of 45 years but is increasingly occurring in younger a g e g r o u p s i n c l u d i n g c h i l d r e n , adolescents and young adults.

?Is more likely in people with a family history of type 2 diabetes or from particular ethnic backgrounds.

?For some, the first sign may be a complication of diabetes such as a heart attack, vision problems or a foot ulcer.

?Is managed with a combination of regular physical activity, healthy eating and weight reduction.

As type 2 diabetes is often progressive, most people will need oral medications and/or insulin injections in addition to lifestyle changes over time [3].

Glibenclamide, also known as glyburide, is an antidiabetic drug belonging to the class of sulfonylureas. Therapy with Glibenclamide is usually initiated with 2.5mg given once daily. The maximal recommended daily dose is 20mg. Glibenclamide is 200 times more potent than tolbutamide in evoking pancreatic secretion of insulin. It differs from other oral hypoglycemic drugs where in tolerance to this action apparently does not occur. It also upregulates insulin receptors in the periphery, which seems to be the primary action. It has a special status in the treatment of non-insulin-dependent diabetes mellitus because it is effective in many cases which are resistant to all other oral hypoglycemic drugs. It differs from other oral hypoglycemic drugs i.e. more effective during eating than during fasting [4]. It was developed in 1966. It works by binding and inhibiting the ATP-sensitive potassium channels in pancreatic beta cells.

It causes cell membrane depolarization, opening voltage-dependent calcium channels. As a result, intracellular calcium level increases in the beta cells and release of insulin is stimulated.

Fig. 1: Sustained release Drug profile Fig. 2: Structure of Glibenclamide

Formulation code

Drug (mg)

PVP (mg)

HPMC K4M (mg)

HPMC E15 (mg)

HPMC K100 (mg)

Lactose (mg)

Starch (mg)

MCC (mg)

Aerosil (mg)

Talc (mg)

Mg. Stearates

(mg) F1 5 10 30 40 50 52 -- -- 3 5 5

F2 5 10 -- 50 50 72 -- -- 3 5 5

F3 5 10 -- -- 50 122 -- -- 3 5 5

F4 5 -- -- 50 -- 125 10 -- -- 5 5

F5 5 -- 50 - -- 122 10 -- 3 5 5

F6 5 -- 50 50 -- -- 10 72 3 5 5

F7 5 -- 50 40 30 -- 10 52 3 5 5

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MATERIALS AND METHOD

Material

Glibenclamide was obtained as a gift sample product from Yarrow chemical products, Mumbai. HPMC K4M, HPMC E15, HPMC K100, Starch, PVP was procured from Yarrow chemical products, Mumbai.

Talc, magnesium & stearate, from SD Fine-Chem Limited, Mumbai. Microcrystalline cellulose & aerosil from Ozone international, Mumbai.

Accurately weighed amount of drug (Glibenclamide) & the excipients were taken into a mortar. Slowly the drug along with excipients was triturated & a wet mass was prepared using ethanol. The wet mass was then passed through a #22 mess sieve.

Method

oThe granules were dried at 60 C.The granules were lubricated with talc (2.5%) and Mg.stearate (2.5%) & compressed into tablet on a 10 station rotary punching machine using 5mm concave punches. Each tablet contains 5mg of Glibenclamide.

Accurately weighed amount of drug (Glibenclamide) & excipients were taken into a mortar (except talc & Mg.stearate) & triturated. Then the triturated mixture was lubricated with talc (2.5%) &

Formulation F4 to F7 was prepared by direct compression method (Table -1)

Preparation of sustained release tablet of Glibenclamide:

Formulation F1 to F3 was prepared by wet granulation method (Table- 1)

Procedure

Procedure

Mg.stearate(2.5%). The mixture was then compressed into tablets on a 10 stationary rotary punching machine. Each tablet contains 5mg of Glibenclamide.

Table 1: Composition of Glibenclamide sustained release tablet

RESULT AND DISCUSSIONStandard graph

Preparation of hydrochloric acid pH 1.2 buffers

8.5 ml of HCl was dissolved in little amount of ethanol in 1000 ml volumetric flask. Then the volume was made up to 1000 ml with the addition of excess C H OH. 2 5

Standard calibration curve of Glibenclamide at pH 1.2

100 mg of Glibenclamide was taken and dissolved in 1.2 pH HCl stock solution in 100 ml volumetric flask. The volume was made up to the mark and marked as A. 10 ml

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Concentration Absorbance

1 0.02

2 0.065

3 0.11

4 0.158

5 0.206




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from above solution (A) was taken into another 100 ml volumetric flask and volume was made up with stock solution and marked as B.

From the above stock solution B, 1 ml, 2 ml, 3 ml, 4 ml,

and 5 ml respectively were withdrawn into other 5 volumetric flasks of 10 ml and volume was maintained. The absorbance of above solution were scanned in UV region and found that Glibenclamide showed more absorbance at 298 nm.

Concentration Absorbance

1 0.030

2 0.072

3 0.120

4 0.165

5 0.209

Table 2: Standard Curve of Glibenclamide at pH 1.2

Fig. 3: Standard Graph of Glibenclamide at pH 1.2

About 6.8 gm of KH PO and 1.564 gm of sodium 2 4

hydroxide was dissolved in little amount of water.

Preparation of phosphate pH 7.4 buffer

100 mg of Glibenclamide was transferred to 100 ml of volumetric flask and dissolved with little quantity of above phosphate pH 7.4 buffer solution. The volume was made up by adding the buffer solution and marked as "A". 10 ml of solution from "A" was transferred to

Volume was made up to 1000 ml of volumetric flask by addition of ethanol (excess).

Standard calibration curve of Glibenclamide at pH 7.4

another 100 ml volumetric flask and diluted up to the mark adding buffer stock solution and marked as "B". From this solution "B" 1 ml, 2 ml, 3 ml, 4 ml, and 5 ml respectively transferred into other 10 ml volumetric flask. It was then diluted and absorbance was found out at 298 nm.

Table 3: Standard curve of Glibenclamide at pH 7.4

Fig. 4: Standard Graph of Glibenclamide at pH 7.4

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FTIR [8]

The pure drug, physical mixtures and optimized formulations (F6) were subjected for FTIR analysis. The samples were prepared on KBr-press. The samples were

scanned over a range of 4000-400 cm-1 using Fourier transformer infrared spectrophotometer (8600, Shimadzu Corporation, Japan). Spectra were analysed for drug polymer interactions.

Fig. 5: FTIR of Drug (Glibenclamide)

Fig.6: FTIR of HPMC K4M

Fig.7: FTIR of HPMC E15

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Fig. 8: FTIR of HPMC K100

Fig. 9: FTIR of Optimized Formulation (F6)

PRE-COMPRESSION EVALUATIONS [7]

Bulk density

Apparent bulk density was determined by pouring a weighed quantity of tablet blends into graduated cylinder and measuring the volume and weight.

Bulk Density = Mass of powder / Bulk Volume of the powder

Take 10 gm of tablet powder and transfer in a measuring cylinder. Now tap the measuring cylinder 100 times and check the volume. Repeat the tapping process till the

Tapped density

value of volume does not decrease. The final unchanged volume is called tapped volume (VT).

Tapped density = weight of powder/tapped volume (VT)

Hausner's ratio (H)

Hausner's ratio (H) = tapped density/bulk density

Carr's index

Carr's index = [1-(1/H)] ×100

The angle of repose of tablet blends was determined by the funnel method. The blends were allowed to flow through the funnel freely onto the surface. The diameter of

Angle of repose the powder cone was measured and angle of repose was calculated using the equation: Tan ? = h/r Where 'h' and 'r' are the height and radius of the powder cone, respectively.

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Formulation Code

Bulk Density

Tapped Density

Hausner’s Ratio

Carr’s Index

Angle of Repose

F1 0.36 0.44 1.22 18.04 30.3 F2 0.4 0.5 1.25 20 29.9 F3 0.36 0.46 1.30 23.1 32 F4 0.48 1 2.08 52 34.61 F5 0.44 0.75 1.7 41 36.67 F6 0.33 0.66 2 50 38.87 F7 0.36 0.44 1.23 19 36.55

Formulation Code

Hardness (kg/cm2)

Thickness (mm)

Weight (mg)

Friability (%)

Drug content (%)

F1 4.22±0.58 3.09±0.66 199±1.14 0.45 102.33±1.25 F2 4.08±0.31 3.08±0.25 200±0.11 0.50 99.83±1.87 F3 4.24±0.58 3.08±0.71 199±1.13 0.30 94.88±1.98 F4 4.42±0.60 3.07±0.89 200±0.01 0.37 94.35±1.14 F5 4.74±0.78 3.10±0.37 199±1.12 0.56 99.58±2.16 F6 4.92±0.80 3.09±0.52 200±0.06 0.47 100.11±2.31 F7 5.08±0.86 3.15±0.56 200±0.09 0.71 93.78±1.56




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Table 4: Pre-compression parameters of tablet formulation

POST-COMPRESSION EVALUATIONS [7, 8]

Thickness: The thicknesses of the tablets were determined using a Vernier caliper, 20 tablets from each batch were used and average values were calculated.

Weight variation test: Every individual tablet in a batch should be in uniform weight and weight variation within the permissible limits. The weights were determined to within ±1mg by using digital balance. Weight control is based on a sample of 20 tablets.

Hardness test: For each formulation, hardness test of 20 tablets each were determined by using the Pfizer hardness tester.

Friability test: For each formulation, friability test of 20 tablets each were determined by using the Electro lab friabilator tester.

Drug content uniformity: Ten tablets were randomly selected and allowed to equilibrate with HCl acid buffer

of pH 1.2 overnight and the solution was filtered after 24 hours. Suitable dilutions were made with HCl acid buffer of pH 1.2 to get the concentration. Absorbance of the solution was analyzed spectrophotometrically at 298nm a g a i n s t s u i t a b l e b l a n k u s i n g U V- v i s i b l e spectrophotometer and drug content per tablet was calculated.

In-vitro dissolution study: Dissolution study was carried out using USP dissolution test apparatus type II. The dissolution medium used was 900 ml of 0.1N HCl buffer at 37±0.5oC. The paddle speed was kept at 50 rpm throughout the study. Aliquot of 5 ml was withdrawn at predetermined time interval and equivalent amount of fresh medium was replaced to maintain a constant volume. After each sampling suitably diluted with 0.1N HCl buffer and analyzed spectrophotometrically at 298nm against suitable blank using UV-visible spectrophotometer.

Table 5: Post compression parameters of tablet formulation

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Table 6: In Vitro Dissolution study of Glibenclamide Tablets of all formulations

Time (hours)

F1 F2 F3 F4 F5 F6 F7

1 26.04±0.79 27.73±0.96 33.98±0.84 31.86±1.37 32.23±1.15 22.38±1.54 32.87±0.83 2 41.78±0.83 42.25±0.89 44.95±0.65 44.35±1.52 47.67±1.73 35.09±1.65 40.63±0.37 3 53.26±1.19 56.85±1.16 59.47±0.88 59.83±1.46 64.83±1.58 51.93±1.69 53.74±0.49 4 65.82±1.28 67.38±1.32 68.86±0.59 70.82±1.04 75.38±1.01 62.15±1.99 65.09±0.43 6 79.72±1.59 83.25±1.63 81.87±0.83 87.43±1.96 89.25±1.90 73.88±2.01 77.26±0.82 8 87.26±1.68 90.12±1.82 98.97±0.64 95.64±1.09 97.63±0.97 81.09±2.92 88.57±0.64 10 96.16±2.28 95.88±2.05 -- 98.25±1.89 -- 90.04±2.48 90.93±0.89 12 -- 96.54±2.09 -- -- -- 98.22±2.60 93.24±0.79

Fig. 10: Dissolution Profile of All Formulations (F1- F7)

Stability studies of the optimized formulation did not reveal any degradation of the drug and there was no significant change in the physical properties,

Stability studies

drug content, and in vitro release profiles of the optimized formulation after storage for 3 months

Optimized formulation F6 (Polymer ratio 1:1) which includes both HPMC K4M and HPMC E15 (1:1) has successfully sustained the drug release for 12 hours and the drug release pattern was similar to theoretical release profile. There was an alteration in the surface area and

CONCLUSIONdiameter of the tablets with the progressive dissolution of the matrix as a function of time, as indicated in Hixson-Crowell plot. FTIR studies combined with stability studies proved the integrity of the developed matrix tablets.

REFERENCES1. Shree Ram Jayaswal et.al. international journal

of pharmacy & technology, Volume 6 Issue 2, Page No. 6527-6586.

2. http://www.pharmatutor.org/articles/review-sustained-release-dosage-forms

3. https://www.diabetesaustralia.com.au/type-2-diabetes

4. Marikanti Rajkumar et.al. J.Chem.Pharm.Res., 2010,2(4):291-303

5. https://en.wikipedia.org/wiki/diabetes_mellitus

6. Tripathi K.D, Essential's of Pharmacology 7th edition, Page. No.258.

7. Venkateswara Rao. S, Alekhya. Golla and Padmalatha. K/ World Journal Of Pharmacy And Pharmaceutical Sciences; Volume 3, Issue 12, 975.

8. Shubhrajit Mantry et al. Indo American Journal of Pharmaceutical Research, Vol 3, Issue 5, 2013, Page No.4031-4041.

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