Study on Effect of Excipients in Enhancing the Solubility of Nateglinide by Solid Dispersions

M. Kranthi Kumar Reddy*, B. Narasimha Rao and K. Ravindra Reddy.

Department of Pharmaceutics P. Rami Reddy Memorial College of Pharmacy, Kadapa-516003 Andhra Pradesh, India

*Corresponding Author E-mail: m.kranthi7@gmail.com

ABSTRACT:

Nateglinide is a novel anti diabetic drug that lowers blood glucose levels by stimulating insulin secretion from the pancreas. This action is dependent upon functioning beta-cells in the pancreatic islets. One of the major problems with this drug is its low solubility in biological fluids, which results into poor bioavailability after oral administration. Therefore, solid dispersions (SDs) of nateglinide were prepared using lactose, mannitol and urea to increase its aqueous solubility. Nateglinide SDS was prepared in 1:1, 1:2, and 1:3 ratios of the drug to polymer (by weight). In vitro release profiles of all SDs (F-1 to F-9) were comparatively evaluated and also studied against pure Nateglinide. Faster dissolution was exhibited by solid dispersion containing 1:3 ratio of drug: mannitol. The increase in dissolution rate of the drug may be due to increase in wettability, hydrophilic nature of the carrier and due to reduction in drug crystallinity. The prepared solid dispersion was subjected for % practical yield, drug content and infrared (IR) spectroscopic studies. Absence of significant drug-carrier interaction was confirmed by infrared spectroscopic (IR) data.

KEYWORDS: Nateglinide, solid dispersions (SDs), mannitol, urea, lactose, kneading method

INTRODUCTION:

Oral bioavailability of drugs depends on its solubility and/or dissolution rate, therefore major problems associated with these drugs was its very low solubility in biological fluids, which results into poor bioavailability after oral administration. Many methods are available to improve dissolution rate, solubility characteristics, including salt formation, micronization, and addition of solvent or surface active agents. SDs is one of these methods, which was most widely and successfully applied to improve the solubility, dissolution rates and consequently the bioavailability of poorly soluble drugs. The concept of solid dispersions (SDs) was introduced in 1961 by Sekiguchi and Obi [1], in which the drug is dispersed in inert water - soluble carrier at solid state. Several water soluble carriers such as mannitol, urea, lactose, citric acid, polyvinyl pyrrolidone (PVP) and polyethylene glycols are used as carriers for SDs. [2-5] Nateglinide is a novel anti diabetic drug that lowers blood glucose levels by stimulating insulin secretion from the pancreas.

Nateglinide is practically insoluble in water leading to poor dissolution and variable bioavailability upon oral administration. [6-9]. The main objective of this work was to investigate the possibility of improving the solubility and dissolution rate of Nateglinide by preparing SDs with various water-soluble polymers such as mannitol, lactose and urea. The prepared SDs were evaluated for % practical yield, drug content, in vitro dissolution rate studies and interactions between the drug and polymer using IR spectral studies

MATERIALS AND METHODS:

Nateglinide having purity of 99.3 % was a generous gift from drugs India Hyderabad. Mannitol, Lactose and Urea of pharmacopoeial grade were purchased from Universal laboratories Mumbai. Methanol where purchased from SD fine-chem. Limited Mumbai. Double distilled water was used for all the experiments.

Estimation of Nateglinide:

Nateglinide contents were estimated by UV Spectrophotometric method by measuring at 209 nm. The method was validated for linearity, accuracy, precision and interference. The method obeyed Beer’s law in the concentration range of 2.5-50 μg/ml (r = 0.999).

Table 1: Formulation Plan of Aceclofenac Solid Dispersions

S.No	Polymer	Drug to polymer ratio
F1	Mannitol	1:1
F2		1:2
F3		1:3
F4	Urea	1:1
F5		1:2
F6		1:3
F7	lactose	1:1
F8		1:2
F9		1:3

Preparation of solid dispersions (SDs):

Nateglinide solid dispersions were prepared by using carriers (i.e. mannitol, lactose and urea) in proportions viz. 1:1,1:2,and1:3, (drug: carrier) and triturated. The drug and carrier was dissolved in methanol and triturated in dry mortar until the solvent evaporated by heating and a clear film of drug and carrier was obtained. The resultant solid dispersion was scraped out with a spatula. Dispersions were pulverized in a mortar and pestle and passed through a 250μm sieve before packing in an air tight container. [10]

% Practical Yield:

Percentage practical yield was calculated to know about percent yield or efficiency of any method, thus it helps in selection of appropriate method of production. SDs were collected and weighed to determine practical yield (PY).

Drug content:

Solid dispersions equivalent to 10 mg of nateglinide were weighed accurately and dissolved in the 10 ml of methanol. The solution was filtered, diluted suitably drug content was analyzed at 209 nm by UV spectrophotometer. [12].

Infrared spectroscopy:

IR spectra of pure nateglinide, mannitol, urea, lactose and nateglinide with its solid dispersions were obtained by a Perkin-Elmer Fourier transform infrared spectrophotometer. By comparing the peaks obtained for pure drug and drug polymer mixture we can make a conclusion that both drug and polymer has good compatibility.

In vitro drug release studies:

The release profile of an entrapped drug predicts how a delivery system might function and gives valuable insight into its in vivo behavior. In vitro release profile for each solid dispersion as well as pure drug were performed using USP II type 2 dissolution apparatus (TDP-06P, Electro lab, Mumbai, India). Sample equivalent to 100 mg of nateglinide was added to 900 ml phosphate buffer pH 6.8 at 37± 0.5ºC and stirred at 50 rpm. Aliquot of 5ml was withdrawn at time of 5, 10, 15, 20, 30, 45, and 60min. The withdrawn volume was replaced with the same volume of dissolution medium in order to keep the total volume constant. The absorbance of the samples was measured at λmax 209 nm after suitable dilution if necessary, using appropriate blank.

Drug release pattern from solid dispersion:

In order to understand the kinetics of drug release, the results of the in vitro drug release study were fitted with various kinetic equations like zero order (cumulative percent drug released vs. Time), first order (Log cumulative percent drug retained vs. Time), Higuchi (cumulative percent released vs. square root of T), Peppas (log of cumulative percent drug released Vs. log Time) and Hixson- Crowell’s cube root model ((Percentage Retained) 1/3 Vs. Time). The kinetic model that best fits the dissolution data was evaluated by comparing the regression coefficient (r) values obtained in various models. Peppas model used ‘n’ value to characterize different release mechanisms. The values of n = 0.5 for Fickian diffusion, between 0.5 to 1.0 for non-Fickian diffusion and n = 1 for zero order.

RESULTS AND DISCUSSION:

SDs of nateglinide was prepared by using carriers like mannitol, lactose and urea. In the present work, nine formulations were prepared and their complete composition is shown in Table 1. All the SDs prepared was found to be fine and free flowing powders. Percent practical yield for all formulations of solid dispersions found to be 80%-92 %. Maximum yield was found to be 92 % in F4 and F8. The drug content of the prepared SDs was found to be in the range of 84%- 106 %. Maximum % drug content was found in the formulation F-3.

Table 2: In Vitro Dissolution Profile of Pure Drug and Different Formulations of nateglinide Solid Dispersions

S.No	Time	% Drug Release
S.No	Time	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	10	36.94	37.77	33	39.16	37.77	38.6	35	33.61	35.83
2	20	44.72	45.27	49.72	48.8	46.1	44.16	41	41.66	42.21
3	30	50.55	53.83	64.72	55.01	53.6	53.05	46.9	47.77	48.8
4	40	63.05	72.77	76.94	61.3	61.3	65.83	56	58.61	57.77
5	50	72.502	83.61	86.94	76.6	77.2	82.7	77	78.61	78.05
6	60	87.22	96.11	98.8	83.88	92.7	95.27	81	85.83	86.38

Kinetic studies

Table No 3. Kinetics values obtained for solid dispersion (F3)

Formula code

% Drug release Vs time

Zero order equation

Log % Drug retained Vs time First order equation

Cumulative %drug release Vs square of time Higuchi’s equation

Log cumulative % drug release Vs time Korsemeyer’s equation

Slope

Regression coefficient

Slope

Regression coefficient

Slope

Regression coefficient

Slope

Regression coefficient

1.826

0.908

0.043

0.130

12.13

0.988

1.205

0.949

Figure No.1. Comparative Invitro Release Profile of nateglinide from solid dispersions

Table 2, shows the cumulative percent drug released as a function of time for all formulations. Cumulative percent drug released after 60 min was 87.22 %, 96.11 %, 98.8 %, 83.88 %, 92.7 %, 95.70 %, 81.00 %, 85.83 % and 86.38 % for F-1 to F-9 respectively and was 37.52% in 60 min for pure drug. In vitro release studies reveal that there is marked increase in the dissolution rate of nateglinide from all the solid dispersions when compared to pure nateglinide itself. From the in vitro drug release profile, it can be seen that formulation F-3 containing mannitol (1:3 ratio of drug: mannitol) shows higher dissolution rate compared with other formulations. This may be attributed to the increase in drug wettability, conversion to amorphous form and solubilization of the drug due to hydrophilic carrier. The increase in dissolution rate is in the order of Mannitol> Urea>lactose. The regression coefficient (r) values for formulations F-1 to F-9 are tabulated in Table 3. In order to elucidate the release mechanism, the data of mannitol solid dispersions of nateglinide by kneading (1:3) were fitted into the models representing zero order, first order, Higuchi and korsemeyer’s equations. When data was plotted according to zero order kinetics, a linear plot was obtained with their high regression coefficient value 0.908, suggesting that the rate of release from solid dispersions was followed as per “zero order kinetics”. The data fitted with higuchi equation yields a linear plot with their high regression coefficient values 0.988,indicating that mechanism of release from solid dispersions was diffusion controlled .To know precisely whether fickian’s or non fickian’s diffusion exists the data was plotted according to Korsemeyer’s equation . The plot showed the slope value n=1.205, this shows that mechanism of release was “super case II transport mechanism.” IR spectroscopic studies conducted for possible drug: carrier interactions IR spectra of pure drug nateglinide, mannitol, lactose, urea and nateglinide with its SDs were obtained which shows all the characteristic peaks of nateglinide and carriers were present in the solid dispersions; thus indicating no significant evidence of chemical interaction between drug and carrier, which confirms the stability of drug with its solid dispersion (Fig. 2-5). The solid dispersions of the water- insoluble drug nateglinide were successfully prepared by kneading technique using hydrophilic carriers. The in vitro dissolution test showed a significant increase in the dissolution rate of solid dispersions as compared with pure nateglinide. Mechanisms involved are solubilization and improved wetting of the drug in the hydrophilic carriers rich microenvironment formed at the surface of drug crystals after dissolution rate. The crystallinity of the drug was reduced in solid dispersion formulation with polymers i.e. urea. Results from IR spectroscopy concluded that there was no well defined interaction between nateglinide and carriers. Finally it could be concluded that solid dispersion of nateglinide using hydrophilic polymers would improved the aqueous solubility, dissolution rate and thereby enhancing its systemic availability.

Figure No.2. IR Spectra of solid dispersions of pure nateglinide

Figure No.3. IR Spectra of solid dispersions of nateglinide with lactose

Figure No.4. IR Spectra of solid dispersions of nateglinide with urea

Figure No.5. IR Spectra of solid dispersions of nateglinide with mannitol

ACKNOWLEDGEMENTS:

The authors wish to thank Drugs India, Hyderabad for providing the gift sample of nateglinide. The authors are also thankful to P. Rami Reddy College, Kadapa of Pharmacy for providing facilities to carry out the research work.

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Received on 05.09.2012 Accepted on 15.10.2012

Asian J. Pharm. Res. 2(4): Oct. - Dec. 2012; Page 144-147