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ORIGINAL ARTICLE
Year : 2011  |  Volume : 1  |  Issue : 2  |  Page : 48-51
Evaluation of orlistat solid dispersion using poloxomer 188 as hydrophilic carrier


Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam, India

Date of Web Publication11-Aug-2012

Correspondence Address:
Akhilesh Vikram Singh
C/O Prof. L K Nath, Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam - 786 004
India
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DOI: 10.4103/2249-5975.99652

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   Abstract 

Objective: The objective of the present investigation was to improve the dissolution rate of Orlistat (ORL), a poor water-soluble anti-obesity drug by solid dispersion technique. Materials and Methods: To improve the solubility and dissolution, ORL solid dispersion was formulated using a hydrophilic polymeric carrier poloxomer 188. Solid dispersion was formulated by kneading method and physicochemical characterization and in vitro release study was carried out. Results: Fourier transform infrared spectral (FT-IR) and Differential scanning calorimetry (DSC) study showed a change in the crystalline nature of the drug, and its conversion into amorphous form. The in vitro dissolution study of physical mixture and solid dispersion both showed enhanced solubility as compared to the pure active drug. Conclusion: This study suggests that ORL solid dispersion having drug: Carrier (1:5) could be a promising approach to improve the solubility and dissolution.


Keywords: DSC, FT-IR, Orlistat, Poloxomer, solid dispersion


How to cite this article:
Singh AV. Evaluation of orlistat solid dispersion using poloxomer 188 as hydrophilic carrier. Scho Res J 2011;1:48-51

How to cite this URL:
Singh AV. Evaluation of orlistat solid dispersion using poloxomer 188 as hydrophilic carrier. Scho Res J [serial online] 2011 [cited 2014 Apr 17];1:48-51. Available from: http://www.scholarsjournal.in/text.asp?2011/1/2/48/99652



   Introduction Top


The technique of solid dispersion has been widely used to enhance the solubility, dissolution rate, and bioavailability of poorly soluble drugs. The enhancement of oral bioavailability of poor water-soluble drugs remains one of the most challenging aspects of drug development. Salt formation, solubilization, and particle size reduction have commonly been used to increase dissolution rate, and thereby oral absorption and bioavailability of such drugs. [1],[2] Among numerous ways of enhancing drug dissolution, solid dispersion of drug in a hydrophilic carrier is one of the most promising techniques. Poloxamer 188, is a nonionic polyoxyethylene-polyoxypropylene block copolymer (HO (C 2 H 4 O) a (C 3 H 6 O) b (C 2 H 4 O) a H, where a=80 and b=27), is widely used as wetting and solubilizing agent, hydrophilic binder in the melt granulation. The polyoxyethylene segment of the poloxomer is relatively hydrophilic, while the polyoxypropylene segment is relatively hydrophobic. [3] It melts at approximately 55°C and has a hydrophilic-lipophilic balance (HLB) value of 29.

Orlistat is a lipase inhibitor for management of obesity, which acts by inhibiting the absorption of dietary fat. Orlistat is a reversible inhibitor of gastric and pancreatic lipase. [4] The chemical structure of orlistat is given in [Figure 1]. The orlistat comes under class II as per biopharmaceutical classification system meaning that its shows poor oral bioavailability due to low solubility.
Figure 1: Chemical structure of Orlistat

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In this study, the solid dispersion technique was applied to enhance the dissolution and oral bioavailability of orlistat using poloxomer 188 as a carrier. The feasibility assessment of this approach, the physicochemical characterization and in vitro dissolution are presented in this report.


   Materials and Methods Top


Orlistat was donated by Ranbaxy Pharma Ltd., Gurgaon, India. Poloxomer 188 was obtained as a gift sample from BASF, Germany. All the chemicals used were of analytical grade. Double distilled water was used throughout the study.

Preparation of Binary Physical Mixture

Physical mixtures of orlistat with poloxomer 188 were prepared by mixing the required amount of orlistat and poloxomer 188 in a glass mortar for 5 min at 1:1,1:3 and 1:5 (drug:carrier) ratio.

Preparation of Solid Dispersion by Kneading Method

The physical mixture was triturated using a small volume of ethanol:water (1:1) solution to give a thick paste, which was kneaded in different proportions, that is, 1:1, 1:3 and 1:5 (drug:carrier) and then dried at 45°C in an oven. The dried mass was pulverized, and passed through sieve to get particles in the range of 50-250 μm, and finally stored in a desiccator till further use.

Drug Content

Solid dispersions equivalent to 10 mg of orlistat were weighed accurately and dissolved in suitable quantity of methanol. The drug content was analyzed at 210 nm by UV spectrophotometer (Pharmaspec-1700, Shimadzu, Japan). Each sample was analyzed in triplicate.

Fourier Transform Infrared Spectra Study

FT-IRs were obtained using FT-IR spectrophotometer (Bruker, Germany). The samples (orlistat, poloxomer-188 and solid dispersion formulation) were previously grounded and mixed thoroughly with potassium bromide at 1:5 (sample: KBr). The potassium bromide discs were prepared by compressing the powders with hydraulic press. The samples were scanned from 4000 to 500 cm−1 .

Differential Scanning Calorimetry Study

The differential scanning calorimetry (DSC) measurements were performed on a DSC (Perkin Elmer, USA). Samples were scanned under nitrogen environment (20 mL/min), approximately 10 mg of orlistat, poloxomer 188 and solid dispersion formulation (1:5) was placed in a sealed aluminum pan, and heated at a scanning rate of 10°C/min. An empty aluminum pan was used as reference.

Dissolution Study

Dissolution rate was studied separately in 3% SLS containing 0.1 N HCl, maintained at 37±0.5°C using USP type II dissolution rate test apparatus at a stirring speed of 75 rpm. Samples were taken for dissolution studies and the aliquots were withdrawn at different time intervals up to 1 h and replaced same volume with fresh dissolution medium. Samples were filtered and dissolution was estimated by measuring absorption maxima at 210 nm (UV-Vis spectrophotometer).


   Results and Discussion Top


Drug Content

Drug content for all the formulations were in the range of 98.05%-101.03%, which is acceptable value as per the official monograph.

Physicochemical Characterization

FT-IR spectroscopy was used to study the possible interaction between orlistat and poloxomer. There is no significant interaction in the FT-IR spectra of pure drug, and its solid dispersion product was observed [Figure 2]. All major peaks of ORL were observed at wave number 3416 cm−1 (OH stretch), 1163 cm−1 (C-C stretch), and 1102 cm−1 (C-O stretch). The characteristic peaks of poloxomer were observed at wave number 2882.27 cm−1 (OH stretching), 1467 cm−1 (C-H stretching), and 1114 cm−1 (C-O stretching). The peaks in the Orlistat solid dispersions were observed similar to the pure drug but some extra peaks at 2860.03 cm−1 (OH stretch) and 1114.2 cm−1 (C-O stretching) found which proved that there is a formation of strong intermolecular hydrogen bonding in the solid dispersion. All other peaks of orlistat was smoothed, indicating no physical interaction but presence of one extra peak at 2860 cm−1 indicating chemical interaction.
Figure 2: FT-IR spectra of (a) Orlistat, (b) poloxomer 188, (c) orlistat solid dispersion

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DSC analysis was employed to evaluate the phase of transformation during the formation of solid dispersion. As reported in [Figure 3], the orlistat was characterized by a melting peak at 46°C. DSC thermogram of poloxomer showed an endothermic peak at 56°C. The orlistat solid dispersion hardly showed the endothermic peak of drug this could be due to melting of drug in the molten polymer and transformation of crystalline to amorphous form.
Figure 3: DSC thermogram of orlistat, poloxomer 188, and solid dispersion

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Dissolution Study

The increase in dissolution of hydrophobic drug using different hydrophilic polymer was probably due to the wetting and solubilizing effect of the hydrophilic carrier, which could reduce the interfacial tension between the drug and the dissolution medium, thus leading to a higher dissolution rate. When a eutectic mixture, consisting of a slightly soluble drug and a highly water-soluble carrier, was dissolved in an aqueous medium, the carrier would dissolve rapidly, leaving the insoluble drug in an extremely fine state of subdivision. The large surface area of the resulting suspension should result in an enhanced dissolution rate, and thereby improve the bioavailability. The dissolution data curve of pure orlistat and its physical mixture in 3% SLS containing 0.1 N HCl are shown in [Figure 4]. It is evident from results that the dissolution rate of orlistat has improved in all the physical mixture preparation (1:1, 1:3, and 1:5). The dissolution rate was maximum achieved for PM-2 (1:3), it might be possible due to hydrophilic and wetting nature of poloxomer. [5],[6]
Figure 4: Dissolution release study of drug and its physical mixture with poloxomer 188

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The dissolution was rapid in case of solid dispersion as compared with physical mixture and drug alone [Figure 5]. This might be due to decrease in drug crystallinity and solubilizing nature of poloxomer copolymer. The poloxomer copolymer exists as micelle in the solution form at critical micelle concentration point. [7],[8] There was a significant difference in the drug release behavior between the solid dispersion and physical mixture of orlistat; this could be due to higher wetting and more hydrogen bonding in solid dispersion formulation as compared with physical mixture.
Figure 5: Dissolution release study of drug and its solid dispersion formulation with varying proportion of drug and polymer

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   Conclusion Top


From the foregoing results it can be concluded that the dissolution rate of Orlistat can be enhanced by the use of solid dispersion technique. Using poloxomer 188 increases the wetting and hydrophilicity of the hydrophobic drug orlistat. The orlistat solid dispersion with poloxomer showed no intense physicochemical interaction. The enhancement in dissolution rate of orlistat might also be possible due to reduction of drug particle, alteration of surface property and due to decrease in crystallinity of the drug.


   Acknowledgment Top


The author is thankful to Indian Institute of Integrative Medicine, Jammu, India, for doing FT-IR characterization.

 
   References Top

1.Serajuddin AT. Solid dispersions of poorly water soluble drugs: Early promises, subsequent problems and recent breakthrough. J Pharm Sci 1999;88:1058-66.  Back to cited text no. 1
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2.Ford JL. The current status of solid dispersions. Pharm Acta Helv 1986;61:69-88.  Back to cited text no. 2
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3.Singhare, DS, Khan S, Yeole PG. Poloxamers: Promising block co-polymers in drug delivery. Indian J Pharm Sci 2005;67:523-31.  Back to cited text no. 3
    
4.Henness S, Caroline MP. Orlistat: A review of its use in the management of the obesity. Drugs 2006;66:1625-56.  Back to cited text no. 4
    
5.Dumortier G, Grossiord JL, Agnely F, Chaumeil JC. A review of poloxamer 407 pharmaceutical and pharmacological characteristics. Pharm Res 2006;23:2709-28.  Back to cited text no. 5
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6.Dallberg C, Millqvist-Fureby A, Schuleit M, Furo I. Polymer drug interactions and wetting of solid dispersions. Eur J Pharm Sci 2010;39:125-33.  Back to cited text no. 6
    
7.Passerini N, Albertini B, Gonzalez-Rodriguez ML, Cavallari C, Rodriguez L. Preparation and characterization of ibuprofen-poloxamer 188 granules obtained by melt granulation. Eur J Pharm Sci 2002;15:71-8.  Back to cited text no. 7
    
8.Vyas V, Sancheti P, Karekar P, Shah M, Pore Y. Physicochemical characterization of solid dispersion systems of tadalafil with poloxomer 407. Acta Pharm 2009;59:453-61.  Back to cited text no. 8
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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    Abstract
   Introduction
    Materials and Me...
    Results and Disc...
   Conclusion
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