International Journal of Drug Development and Research

References

1. 1) Kahkeshan KF, Nikghlab LA, Singh G, Singh G. Solid Dispersion: Methods and Polymers to increase the solubility of poorly soluble drugs. J Applied Pharm Sci 2012.2 (10):170-175.
2. 2) Ratnaparkhi M, Dhomse R. Formulation development and evaluation of fast dissolving aceclofenac tablets prepared by solid dispersion by using mannitol. Int J Pharm Chem Bio Sci. 2012; 2(3):325-334.
3. 3) Chiou WL and Riegelman S. A review on Pharmaceutical Application of Solid Dispersion.J Pharm Sci. 1971; 60:1281-1302.
4. 4) PanigrahiR ,Behera S , Panda C . A Review On Fast Dissolving Tablets. WebmedCentral Pharmaceutical Sciences 2010;1(11):WMC001107
5. 5) Sweetman SC. In Martindale: The Complete Drug Reference. Pharmaceutical press. London. 2002; 33:322.
6. 6) Kumar AR et al. Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques. Int J Drug Del.2010;2:49-57
7.  
8. 7) Kuchekar BS, Badhan AC, Mahajan HS. Mouth dissolving tablets of salbutamol sulphate: A novel drug delivery system. Indian Drugs.2004.41.592- 598.
9. 8) Subrahmanyam CVS. A textbook of Physical Pharmaceutics.Vallabhprakashan Delhi.2000: 214-229
10. 9) Sreenivas SA, Gadad AP “Formulation and evaluation of OndancetronHCl directly compressed mouth disintegrating tablets.” Indian Drugs, 2006; 43(1):35-38.
11. 10) Xiao L, Zhang Y, Jin X, Zhao Z. Optimization of extended zero order release gliclazide tablet using d-optimal mixture design. Pharm Society Japan.2008; 128(10):1475-1483.
12. 11) Yunxia B et al. Preparation and evaluation of compressed tablet rapidly disintegrating in the oral cavity. Chem. Pharm. Bull. 1996; 44(11):2121-2127.
13. 12) United States Pharmacopeia 30, National Formulary 25. Rockville MD. The United States Pharmacopeial Convention Inc.2007:276-286.
14. 13) Rowe RC, Sheskey PJ, Owen SC. In Handbook of Pharmaceutical Excipients.PhP Pharmaceutical Press. 2006; 5:181.
15. 14) Shetty CM, Prasad DV, Gupta VR, Sa B. Development of fast dispersible aceclofenac tablets: effect of functionality of superdisintegrants. Ind J Pharm Sci. 2008;2:180-185.

Key words

Gliclazide; Solid dispersion (SD); PVP K30; Mouth dissolving tablets (MDT)

INTRODUCTION

Solubility is a significant physicochemical factor affecting absorption of drug and its therapeutic effectiveness. The rate and extent of dissolution of the drug from any solid dosage form determines the rate and extent of absorption of the drug. In the case of poorly water-soluble drugs, dissolution is the rate limiting step in the process of drug absorption [1]. Potential bioavaibility problems are prevalent with extremely hydrophobic drugs (aqueous solubility less than 0.1 mg/ml at 37o C) due to erratic or incomplete absorption from gastrointestinal tract [2]. Solid dispersion (SD) is such a methods that involves a dispersion of one or more active ingredients in an inert carrier or matrix in solid state prepared by melting, dissolution in solvent or melting-solvent method. The formulation of drugs having low aqueous solubility using solid dispersion technology has been an active area of research since 1960. Among the various approaches to improve solubility, the solid dispersion (SD) technique has often proved to be the most successful in improving the dissolution and bioavailability of poorly soluble drugs because it is simple, economic, and advantageous. Most commonly used carriers for the preparation of SDs are different grade of polyethylene glycols (PEGs) and polyvinylpyrrolidone (PVPs), Gelucire 44/14, Labrasol, sugars, and urea [3].

Mouth dissolving tablets is the fast growing and highly accepted drug delivery system, because of economic, convenience of self administration, compactness, stability and easy of manufacturing. The concept of Mouth Dissolving Drug Delivery System emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets and hard gelatin capsules. Hence they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy. In some cases such as motion sickness, sudden episodes of allergic attacks or coughing and unavailability of water, swallowing conventional tablets may be difficult. Particularly the difficulty is experienced by pediatric and geriatric patients. Such problems can be resolved by means of fast dissolving tablet [4].

Gliclazide is a second generation anti-diabetic drug used for the treatment of type II diabetes. Chemically it is (1-(3-azabicyclo-[3, 3, 0]-Oct-3-yl)-3-(p-tolyl sulfonyl) urea) [5]. The drawback of the drug is, it is practically insoluble in water and so possesses poor solubility, GI abruption and bioavailability. Hence the objective of the present work was to obtained faster onset of action and successfully enhanced the bioavailability by developing mouth dissolving tablets of gliclazide by solid dispersion.

MATERIALS AND METHODS:

Materials: Gliclazide was a kind gift from Indoco Remdies Ltd Baddi. Microcrystalline cellulose, PVP K30, aspartame, talc was purchased from Loba chemicals, Mumbai. Crospovidone and Sodium starch glycolate were purchased from Colorcon Asia Pvt Ltd, Goa. All other reagents used were of analytical grade.

Methods:

Solvent Evaporation Method [6]

The solid dispersions of gliclazide were prepared by dissolving the mixture of gliclazide and the PVP K 30 at the weight ratios of 1:0.5, 1:0.75 and 1:1 w/w, with the aid of a minimal volume of mixture of methanol and acetone solvent system (1:1 v/v). The solvent was removed by evaporation under reduced pressure at 37oC (Osworld Vacuum oven, Mumbai). Solid mass obtained was passed through the # 60 and stored in vacuum desiccator until use.

Fourier Transform Infrared spectroscopy:

The drug-polymer interactions were studied by FT- IR, Spectrum RX1, Perkin Elmer Ltd Switzerland by scanning the sample in potassium bromide discs. The samples of pure drug and mixture containing drugs with pvp k 30 polymer were scanned individually.

Differential scanning calorimetry (DSC):

Differential scanning calorimetry analysis was performed for optimum SDs, plain gliclazide (GZ), PVP K 30, and drug-polymer physical mixture using DSC-60 (Shimadzu, Japan) on 2 mg sample. Samples were heated in a hermetically sealed aluminum pans in the temperature range of 30-250°C at heating rate of 10°C/min under nitrogen flow of 30 ml/min.

In vitro dissolution studies of SDs:

The dissolution studies was accomplished using USP type-I method using an Electrolab Dissolution apparatus (Mumbai). The dissolution medium was 900 ml of phosphate buffer pH 6.8 maintained at 37 ± 0.5°C and 50 rpm stirring rate. A weighed amount of sample (equivalent to 40 mg SD) was filled in hard gelatin capsule. The capsule was then placed in to basket that is immersed in to the medium. The sample (5 ml) was withdrawn, filtered, and concentration of SD was determined spectrophotometrically at 226 nm.

Preparation of mouth dissolving tablets of Gliclazide [7]:

MDT of gliclazide was prepared by direct compression method and compositions of all batches are represented in table-2. The solid dispersion containing 40 mg of drug and microcrystalline cellulose were mixed with superdisintegrant for 15 min in porcelain mortar, this blend was mixed with aspartame and talc for 5 min. Finally, mixture was blended with magnesium stearate and processed for direct compression by using 8 mm round concave- faced punch at 10 station tablet press. Compression force was maintained at constant level and magnesium stearate as lubricant was fixed at 2% w/w for all formulations. Disintegrants are used at 2, 4 and 6% in tablets.

Preformulation studies [8]: Prior to compression, granules were evaluated for their characteristic precompression parameters, such as bulk density, tapped density, hausner ratio, Car’s compressibility index and angle of repose.

Evaluation of tablets:

Thickness [9]: Six tablets were selected at random from each batch and thickness was measured by using Vernier caliper.

Hardness [9]: Tablets require a certain amount of hardness to withstand mechanical shocks of handling in manufacturing, packaging and shipping. Hardness was measured using Pfizer hardness tester. For each batch six tablets are tested.

Friability [9]: Friability is the measure of tablet strength. Roche type friabilator was used for this purpose. Twenty tablets were weighed accurately and placed in the tumbling apparatus that revolves at 25 rpm dropping the tablets through a distance of 6 inches with each revolution. After 4 min, the tablets were weighed and the percentage loss was determined.

Weight variation: The weight variation test was performed as per procedure of IP. The weight (mg) of each of 20 individual tablets, selected randomly from each formulation was determined by dusting each tablet off and placing it in an electronic balance. The individual weight was compared with average weight for determination of percent deviation.

Drug content uniformity [10]: The tablets were assayed for the drug content using methanol as the extracting solvent. Four tablets weighted and crushed in a mortar then weighed powder contain equivalent to 100mg of drug transferred in 100ml methanol. The solution was diluted appropriately and gliclazide was estimated spectrophotometrically at 226 nm.

Wetting time and water absorption ratio [11]: The method reported by Yunixia et.al. was followed to measure tablet wetting time. A piece of tissue paper folded twice was placed in a small petri dish (ID 6.5 cm) containing 6ml pH 6.8 phosphate buffer. A tablet was put on the paper, and the time for complete wetting was measured. The wetted tablet was then weighed. The water absorption ratio (R) was determined using formula as,

R=100×Wa-Wb/Wb

Where, Wa = weight of a tablet after absorption

Wb = weight of a tablet before absorption

Three trials for each were performed.

In vitro disintegration time [12]: The disintegration test was performed using Electrolab disintegrating apparatus. Placed one tablet in each of the six tubes of the basket and operate the apparatus using pH 6.8 phosphate buffer maintained at 37±0.5ºC as the immersion fluid. Than noted down the time to complete disintegration of tablets.

In vitro dissolution study [12]: In vitro drug release studies of all the formulations were carried out using USP XXII type II dissolution test apparatus (Electro Lab, Mumbai) at 50 rpm and phosphate buffer pH 6.8 was used as the dissolution media with temperature maintained at 37±1ºC. Samples were withdrawn at 5 min intervals, diluted suitably and analyzed at 226nm for cumulative drug release using an UV- spectrophotometer (Shimadzu-1700, Shimadzu Corporation, Japan). The study was performed in triplicate.

RESULT AND DISCUSSION:

FTIR peaks of the solid dispersions compared to the pure drug indicates the lack of significant interaction between the drug and the polymer components in the solid dispersion at the molecular level (fig-1). Differential scanning calorimetry scan of pure gliclazide, PVP K 30 and SD are depicted in fig- 2.Gliclazide showed an endothermic peak at 168.93°C and PVP K30 shows the endothermic peak at 92.85°C corresponding to their melting point. Intensity of peak sharpness was reduced in solid dispersion compared to pure drug, because PVP K30 inhibits crystillanity of drugs and resulting in amorphous nature of drug in the solid dispersions. Crystallization inhibition was may be due to hydrogen bonding interactions between the drug and polymer or the entrapment of the drug molecules in the polymer matrix during solvent evaporation or a combination of both.

Solid dispersion of gliclazide was prepared with PVP K30 polymer in 1:0.5, 1:0.75 and 1:1 w/w, drug:carrier ratio using solvent evaporation methods. Dissolution profiles of plain drug and all solid dispersion is shown in table-1 & fig-3 which indicated that the SD ratio 1:1 of drug: PVP K 30 gives fast dissolution of drug as compared to other ratios and plain drug. An increase in the dissolution rate of gliclazide has been attributed to the hydrophilic nature of the polymer, which increased the wettability of the drug and also due to decrease in its crystallinity when prepared as a solid dispersion. Based on in vitro dissolution performance, the SD drug: pvp k 30(1:1) was selected as optimized ratio for formulation of mouth dissolving tablet (MDTs). Six formulation of MDT were prepared by varying the concentration of superdisintegrants (table-2). The precompression parameters are tabulated in table-3. The bulk density and tapped density was found in range of 0.26 to 0.28g/cm3 and 0.28 to 0.31 gm/cm3 respectively which indicated good packing characteristics. The Carr’s compressibility index was found to be below 15% which suggested good compressibility of blend. The values of hausner ratio where found in the range of 1.01 to 1.10 suggested good flowability of powder blend. The angle of repose of all the blend was within range of 21.05 to 24.00o indicated excellent flow property of powder blend. The hardness was in the range of 3.40 to 3.80 kg/cm2 respectively which was within the acceptable range of pharmacopeial specification. The thickness was from 2.50 to 2.53 cm suggested uniformity in thickness of all batches. The friability was less than 1% indicated good handling properties. The weight variation results suggested uniformity in weight of all batches. The drug content uniformity was in range of 90.21 to 98.65% indicated uniform dispersion of gliclazide. Water absorption ratio and wetting time which are important criteria for understanding the capacity of disintegrants to swell in presence of little amount of water were also found within limit. The in vitro disintegration time for the MDT containing sodium starch glycolate was 38.42 to 52.33 sec, and the MDT containing crospovidone showed 35.66 to 39.82 sec (table-4). The in vitro release data of gliclazide MDT is tabulated in table-5 and the percent drug release versus time was plotted as depicted in fig-4. The in vitro release of gliclazide was rapid from all the formulations. The formulation MD-3 prepared by using sodium starch glycolate showed 98.60% within 25 mins which was due to enormous swelling followed by rapid disintegration[13]. The rapid and highest in vitro release of gliclazide in the range 99.73% in 15 mins was observed from the formulation MD-6 containing crospovidone which was attributed to high capillary activity with pronounced hydration capacity of the superdisintegrants when it comes in contact with aqueous fluids [14]. The in vitro release of gliclazide followed the rank order of crospovidone>sodium starch glycolate. As the concentration of superdisintegrants increased in all the formulated layers, the release was more and rapid which was due to rapid disintegration in shortest time.

CONCLUSIONS:

The present investigations showed that solubility of gliclazide was markedly increased by its solid dispersion using pvp k30 as carrier. The formulation MD-6 containing croscarmellose sodium (6%) shows highest dissolution rate 99.73% in 15 mins. Hence the solid dispersion and superdisintegrants addition way is useful technique in providing fastest onset of action of gliclazide as well as enhanced dissolution rate as compared to plain gliclazide.

Acknowledgement:

The Author is thankful to Indoco Remedies Ltd, Baddi for providing gliclazide as a gift sample for this work.

Tables at a glance

Table 1 Table 2 Table 3 Table 4 Table 5

Figures at a glance

Figure 1 Figure 2 Figure 3 Figure 4

References

1. 1) Kahkeshan KF, Nikghlab LA, Singh G, Singh G. Solid Dispersion: Methods and Polymers to increase the solubility of poorly soluble drugs. J Applied Pharm Sci 2012.2 (10):170-175.
2. 2) Ratnaparkhi M, Dhomse R. Formulation development and evaluation of fast dissolving aceclofenac tablets prepared by solid dispersion by using mannitol. Int J Pharm Chem Bio Sci. 2012; 2(3):325-334.
3. 3) Chiou WL and Riegelman S. A review on Pharmaceutical Application of Solid Dispersion.J Pharm Sci. 1971; 60:1281-1302.
4. 4) PanigrahiR ,Behera S , Panda C . A Review On Fast Dissolving Tablets. WebmedCentral Pharmaceutical Sciences 2010;1(11):WMC001107
5. 5) Sweetman SC. In Martindale: The Complete Drug Reference. Pharmaceutical press. London. 2002; 33:322.
6. 6) Kumar AR et al. Enhanced dissolution and bioavailability of gliclazide using solid dispersion techniques. Int J Drug Del.2010;2:49-57
7. 7) Kuchekar BS, Badhan AC, Mahajan HS. Mouth dissolving tablets of salbutamol sulphate: A novel drug delivery system. Indian Drugs.2004.41.592- 598.
8. 8) Subrahmanyam CVS. A textbook of Physical Pharmaceutics.Vallabhprakashan Delhi.2000: 214-229
9. 9) Sreenivas SA, Gadad AP “Formulation and evaluation of OndancetronHCl directly compressed mouth disintegrating tablets.” Indian Drugs, 2006; 43(1):35-38.
10. 10) Xiao L, Zhang Y, Jin X, Zhao Z. Optimization of extended zero order release gliclazide tablet using d-optimal mixture design. Pharm Society Japan.2008; 128(10):1475-1483.
11. 11) Yunxia B et al. Preparation and evaluation of compressed tablet rapidly disintegrating in the oral cavity. Chem. Pharm. Bull. 1996; 44(11):2121-2127.
12. 12) United States Pharmacopeia 30, National Formulary 25. Rockville MD. The United States Pharmacopeial Convention Inc.2007:276-286.
13. 13) Rowe RC, Sheskey PJ, Owen SC. In Handbook of Pharmaceutical Excipients.PhP Pharmaceutical Press. 2006; 5:181.
14. 14) Shetty CM, Prasad DV, Gupta VR, Sa B. Development of fast dispersible aceclofenac tablets: effect of functionality of superdisintegrants. Ind J Pharm Sci. 2008;2:180-185.