INTRODUCTION:

Bicalutamide propanamide, N- [4-cyano-3-(trifluoromethyl) phenyl]-3-[(4-fluorophenyl) sulfonyl]-2-hydroxy-2-methyl-, (+-), is a non-steroidal antiandrogen used for the treatment of prostate cancer. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. This bicalutamide blocks the growth stimulating effect of androgens on prostate cancer. The aqueous solubility of bicalutamide is low 5 μg/mL, when determined invitro pH 7 at 37°C¹. Since the pK_aof bicalutamide is 12 the solubility of the drug is likely to also be low at physiological pH². Thus, it is important to enhance the solubility and dissolution rate of bicalutamide to improve its overall oral bioavailability.

Solid dispersions (SD) in hydrophilic carriers have attracted considerable interest as a means of improving the dissolution rate and hence possibly bioavailability of poorly soluble drugs.

The term ‘solid dispersion’ has been utilized to describe a family of dosage forms where by the drug is dispersed in a biologically inert matrix, usually with a view to enhancing dissolution rate³. SD techniques are very useful in pharmaceutical sciences because of the increasing number of novel drug candidates that are poorly soluble, but there is still limited information available on their ability to be processed into the final dosage forms. These are generally prepared by solvent evaporation or co precipitation technique whereby both the guest solute and the solid carrier solvent are dissolved in a common solvent such as ethanol^{4, 5, 6and7}. The liquid solvent is removed by evaporation under reduced pressure or by freeze-drying which results in an amorphous precipitation of guest in a carrier. Thus the drug is precipitated out in an amorphous form in the former as opposed to crystalline form in the latter^8and9. The amorphous form of the drug exists only when suitable concentration of the carrier is used. The solvent evaporation can be preceded by rotary evaporation, spray drying, and spray granulation¹⁰.

Fusion technique is one of the solid dispersion technique by which the dissolution rate of the drug is enhanced dramatically and this process involves technically less difficulties for preparing dispersions provided the drug and carrier are miscible in the molten state. In this method, the dispersion is a binary system comprising of a solid solute molecularly dispersed in a solid solvent thereby the two components are crystalline together in a homogeneous one phase system, thereby it exhibits greater aqueous solubility and faster dissolution than other preparations^11,12.

In the present investigation, solid dispersions of bicalutamide were prepared by solvent evaporation technique using PVP K 30 and by fusion technique using POL and Gelucire at stoichiometric ratios. Out of these techniques, best carrier was selected depending upon their efficiency to enhance the dissolution rate of the drug. The final dispersions were characterized by powder x-ray diffractometry (PXRD).

MATERIALS AND METHODS:

Materials:

Bicalutamide (BC) was a generous gift sample from Dr. Reddy’s Laboratories Ltd (Hyderabad, India). Povidone K 30 and Sodium lauryl sulphate were obtained as gift samples from Unichem Laboratories Ltd (Goa, India). Poloxamer 407 was purchased from Sigma Chemical Co (St Louis, MO). Gelucire 50/13 was provided by Orchid Health Care Ltd (Chennai, India). All other reagents and chemicals were of analytical grade.

Methods:

Preparation of Solid dispersions:

Preparation of solid dispersions with PVP K 30¹³:

The bicalutamide solid dispersions with PVP K30 in the drug: carrier ratios of 1:3, 1:4 and 1:5 were prepared by conventional solvent evaporation technique. To a solution of bicalutamide (5 gm) in acetone (35 ml), was added the appropriate amount of PVP K 30. The minimum amount of methanol was added to solubilize the carrier. The solvents were evaporated at 50°C under reduced pressure in Rota evaporator and further dried in a desiccator for 24 hrs to remove the residual solvents. the dried mass was collected, sifted through 60 # and packed in a closed container.

Physical mixtures (PM) were prepared by simple geometric mixing of the two pure solid components with a spatula, followed by sieving the mixture three times through 60 #.

Preparation of solid dispersions with POL and with Gelucire 50/13¹⁴:

Solid dispersions of bicalutamide with POL were prepared by following fusion technique. In this process, 1:1 and 1:2 ratios of Drug: POL were used for the preparation of dispersions. Required amount of POL was taken in a glass beaker and was melted by heating on a water bath, to this molten mass drug was added with continuous stirring for 5-10 min. The mixing was continued until the drug was completely dispersed in the molten mass. After completion of the mixing, the dispersion was allowed to solidify by cooling it on an ice bath. The obtained product was further dried in a desiccator for 24 hrs. the dried mass was collected, sifted through 60 # and packed in a closed container. The same procedure was repeated with Gelucire at the concentration of drug: carrier 1:1 and 1:2.

Dissolution rate studies:

Dissolution rate studies were performed separately in 900ml of 1% SLS in water maintained at 37±0.5°C using USP XXII type II dissolution rate test apparatus at a stirring speed of 50 rpm which is official in Food and Drug Administration (FDA) dissolution methods. Samples equivalent to 50 mg of bicalutamide were taken for dissolution studies.5 ml aliquots were withdrawn at different time intervals upto one hour and replaced the same volume with fresh dissolution medium. The samples were filtered and estimated for the amount of bicalutamide dissolved by measuring the absorbance at 272nm. The dissolution experiments were done in triplicate.

Powder X- ray diffractometry (PXRD):

Powder X-ray diffractometry (PXRD) was performed for the pure drug, placebo and for the final dispersions of the both carriers to identify the nature of the dispersions (Philips PW 1729).

RESULTS AND DISCUSSION:

The solid dispersions of drug: Povidone K 30 1:3, 1:4, 1:5, drug: Poloxamer 407 1:1, 1:2 and drug: Gelucire 50/13 1:1, 1:2 weight ratios were prepared and their invitro studies were performed.

Fig 1: Chemical structure of bicalutamide.

Fig 2: Dissolution profiles of Bicalutamide - PVP K 30 dispersion systems: (X) Bicalutamide, (∆) PM 1:5 ratio, (○) SD 1:3 ratio () SD 1:4 ratio, (_*) SD 1:5 ratio.

Bicalutamide alone yielded the slowest dissolution rate about 55% of the drug release was observed at the end of one hour. The dissolution rates of the solid dispersions with PVP K 30 in the drug: carrier ratios of 1:3, 1:4 and 1:5 were shown in the Fig 2. From the dissolution data, it was observed that dissolution rate was enhanced by the increased concentration of PVP K 30. At the completion of one hour the % drug release from 1:3, 1:4 and 1:5 solid dispersions was found to be 85%, 94% and 99.9% respectively. The SD at 1:5 ratio exhibited highest drug release than other ratio dispersions may be because of the more wettability of the drug and for the reduction in crystallinity. So this ratio was considered for further characterization.

POL solid dispersions with Drug: Carrier ratios of 1:1 and 1:2 were evaluated for the dissolution rate study and the results were shown in Fig 3. Results showed that the dissolution rate was dramatically enhanced by the use of POL when compared to Povidone K30 dispersions. The physical mixture with 1:2 ratio exhibited 80 % of drug release at the end of one hour whereas the solid dispersions with 1:1 and 1:2 ratio exhibited 99.9 % and 99.7 % drug release respectively. The results showed that there was no significant difference in the dissolution profiles of 1:1 and 1:2 ratios of drug: carrier dispersions at end stage (30-60 min), but the initial stage drug release was faster in higher concentration carrier dispersion (1:2) due to formation of a soluble complex of the drug and carrier. So 1:2 ratio dispersion was considered as an optimized ratio and further characterized.

Fig 3: Dissolution profiles of Bicalutamide- POL dispersion systems:(X) Bicalutamide, () PM 1:2 ratio, (+) SD 1:2 ratio, (○) SD 1:1 ratios.

In case of Gelucire 50/13 dispersions the dissolution rate was enhanced greatly than all other dispersions. The dispersion at drug: carrier ratios of 1:1, 1:2 and physical mixture (1:2) were evaluated for the invitro study and the results were shown in Fig 4. From the dissolution data observed that maximum drug released was achieved by both the ratios of solid dispersions (1:1 and 1:2), but significant results were obtained with 1:1 ratio dispersion. The initial stage drug release was slower with high concentration of carrier dispersion due to hardening of the dispersion i.e. forming of a waxy layer over the drug. The solid dispersion at 1:1 ratio exhibited more than 95% of drug release within 10min which indicates the significant improvement of the bicalutamide solubility. From the provided dissolution data, concluded that dispersion with Gelucire 50/13 at 1:1 ratio exhibited highest dissolution rate than all other preparations, so it was finalized as optimized preparation.

Fig 4: Dissolution profiles of Bicalutamide- Gelucire dispersion systems:(X) Bicalutamide, () PM 1:2 ratio, (+) SD 1:1 ratio, (○) SD 1:2 ratios.

Powder X- ray diffractometry (PXRD):

PXRD studies were carried out for the final dispersions of the three carriers along with pure drug and carrier individually, which were shown in the Fig 5, 6 and 7. The Fig 5 represents the X- ray diffraction patterns of the drug, PVP K 30 and SD, the Fig 6 represents the X- ray diffraction patterns of the drug, POL and SD and the Fig 7 represents the X- ray diffraction patterns of the drug, Gelucire and SD. The Fig 5 showed that bicalutamide (a) exhibits sharp peaks at 12.25°, 17.05°, 23.90° and 24.30 ° (2θ) which indicates drug is in crystalline nature. PVP K 30 (b) exhibited smooth curves with no sharp peaks observed whereas the dispersion with PVP K 30 1:5 ratio exhibited no sharp peaks and diffraction pattern were similar to that of PVP K 30. This indicates that crystalline form of the bicalutamide was transformed to amorphous form during the dispersion process¹⁵.

Fig 5: X-ray diffraction patterns of (a) Bicalutamide; (b) PVP K30; (c) solid dispersion of Bicalutamide- PVP K 30 (1:5).

Diffraction patterns of the POL dispersions exhibited similar peaks to that of pure bicalutamide indicating that the crystallinity of the drug was unaffected by the use of POL. (Fig 6).

Diffraction patterns of the Gelucire dispersion (1:1) exhibited almost similar peaks with that of pure bicalutamide indicating that crystallinity of the drug was unaffected by the use of Gelucire. (Fig 7).

Fig 6: X-ray diffraction patterns of (a) Bicalutamide; (b) POL; (c) solid dispersion of Bicalutamide- POL (1:2).

Fig 7: X-ray diffraction patterns of (a) Bicalutamide; (b) GEL; (c) solid dispersion of Bicalutamide- GEL (1:1).

CONCLUSIONS:

Solid dispersions possess tremendous potential to increase the dissolution rates and bioavailability of drugs whose absorption is limited by solubility or dissolution rate. In the present study dissolution was greatly enhanced by solid dispersion process with hydrophilic carriers like PVP K 30, Poloxamer 407 and Gelucire 50/13. From the experimented results concluded that Gelucire 50/13 in the ratio of 1:1 (drug: Gel) enhanced the drug release to a maximum extent when compared to all other formulations. From the results concluded that dissolution rate order with different water soluble carriers was found to be Gelucire 50/13 > Poloxamer 407 > Povidone K30 > Bicalutamide. The fusion method was selected as an alternative method for preparing solid dispersion, which involves less manufacturing steps. Major advantage of the dispersion made by fusion technique is it avoids the usage of organic solvents which are major constituents in the preparation of solid dispersions by solvent evaporation technique. So the fusion technique was selected as optimized method. In Fusion technique the Gelucire made dispersion (1:1) was exhibited higher dissolution rate than Poloxamer dispersions. And by the PXRD results concluded that there was no significant change in the crystallinity of the drug in Gelucire made dispersion. Therefore, the Bicalutamide-Gelucire 50/13 (1:1) ratio was considered as the optimum ratio for the dispersion and best candidate for further studies which increase the solubility and dissolution rate of the bicalutamide, suggesting a possible enhancement of its oral bioavailability.

ACKNOWLEDGMENTS:

The authors are thankful to Dr.Reddy’s Laboratories, Hyderabad, India, for providing necessary facilities to carry out the research work. One of the authors, M.V.Srikanth, is thankful to GS Sharma and GSV Subrhamanyam for providing valuable information to carry out the research work.

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Received on 30.12.2009 Modified on 27.02.2010

Research J. Pharm. and Tech. 3(2): April- June 2010; Page 592-595