A NOVEL FORMULATION OF ORLISTAT SOLID DISPERSIONS USING SOLVENT EVAPORATION TECHNIQUE

Solubility is an important physicochemical factor affecting absorption of drug and there by its therapeutic effect. About 40% of newly discovered drugs are lipophilic and failed to reach market due to their poor water solubility. Solid dispersions proved to have tremendous potential for improving drug solubility. Orlistat is a poor water soluble substance possessing anti-obesity property; in the present study an attempt was made to increase the solubility of orlistat by preparing solid dispersions using solvent evaporation technique. Three different formulations were prepared using Hydroxy propyl methyl cellulose (HPMC), Polyethylene glycol (PEG) and Eudragit with varying ratios of drug and carrier viz. 1:1, 1:2, 1:3 and the corresponding physical mixtures were also prepared. These solid dispersions were evaluated for flowability, solubility characteristics and in-vitro drug release. The in-vitro release of the formulation OP-SD3 was found to be best among all the 9 formulations with a release of 87.2% at the end of 2 hours. Release was best fitted with Korsmeyer-peppas kinetics and it shows that the drug release may follow diffusion mechanism. In-vitro dissolution studies showed that the dispersion system containing orlistat, dissolution of orlistat was retarded which attributed to ionic interaction and gel forming respectively but the solid dispersion containing PEG as carrier gave faster dissolution rate than physical mixture. Thus the solid dispersion technique found to be effective in increasing aqueous solubility of orlistat.


Introduction
Orlistat is also known as tetrahydrolipstatin, is a drug designed to treat obesity. 1 Its primary function is preventing the absorption of fats from the human diet, thereby reducing caloric intake. It is intended for use in conjunction with a physician-supervised reducedcalorie diet. Orlistat is the saturated derivative of lipstatin, a potent natural inhibitor of pancreatic lipases isolated from the bacterium Streptomyces toxytricini. 2 However, due to simplicity and stability, orlistat rather than lipstatin was developed into an anti-obesity drug. 3 It works by inhibiting gastric and pancreatic lipases, the enzymes that break down triglycerides in the intestine. When lipase activity is blocked, triglycerides from the diet are not hydrolyzed into absorbable free fatty acids, and are excreted undigested instead. Only trace amounts of orlistat are absorbed systemically; the primary effect is local lipase inhibition within the GI tract after an oral dose. The solubility issues complicating the delivery of these new drugs also affect the delivery of many existing drugs. Many technological methods of enhancing dissolution characteristics of slightly soluble drugs have been reported in literature such as micronisation, formation of solvates, absorbates, complexes, microspheres and more often solid dispersion. Thus the present study aimed to investigate solubility enhancement of orlistat using various polymers by using solvent evaporation technique.

Materials and Methods:
Orlistat is a gift sample obtained from Glukem Pharmaceuticals.pvt.ltd, Hyderabad. HPMC, Polyethylene Glycol, eudragit were also procured from the same company. Dichloromethane obtained from SD fine chem. Ltd, Mumbai. All chemicals are of analytical grade.

Method of preparation: 2.1.1. Preparation of physical mixture:
Drug and carrier were weighed in the ratio of 1:1, 1:2 and 1:3. The physical mixture was prepared by mixing drug and carrier in a mortar. Solid mass was pulverized and passed through sieve no.80 to get uniform sized particles.

Preparation of solid dispersions: 9 formulations
of solid dispersions containing orlistat with HPMC, PEG and Eudragit L 100 as a carrier in the ratios of 1; 1, 1; 2, 1:3 were prepared by dispersion method in a mortar and pestle. Then to that powder add suitable solvent in which the powder was completely soluble. Heat the solution till all the solvent gets evaporated leaving a clear solvent free film of residue at the bottom of the china dish. The film was further dried to get the constant weight and then subjected to evaluation tests. In this present study nine formulations of orlistat dispersions were prepared using varying proportions of HPMC, PEG and Eudragit L100 as shown in Table 1.

Pre-formulation studies: 3.1. Solubility Studies 4 :
Weighed accurately about 10gm of pure drug and dissolved each in 5ml of the solvent system i.e. water, chloroform, toluene, hexane, ethanol, n-butane, methanol, acetone in a well closed air tight containers. Then add the successive amount of the drug in to the containers containing solvent until the solution became saturated solution. Then the containers were placed in a thermostat shaker for 24hrs and then calculate the percentage solubility in each container.

Melting Point 5 :
Push the open end of a capillary tube into the powdered drug. Move the powder to the closed end of the capillary tube by tapping it on the table. Repeat until the powdered drug occupies 1-2 mm of the capillary tube end. Then attach the capillary tube to a thermometer and align the bulb of the thermometer with the closed end of the capillary tube. Make a glycerin bath as before by half filling a 100 ml beaker with glycerin. Place the thermometer/capillary tube assembly in the glycerin bath so that the surface level of the powdered drug is beneath the surface level of the water bath. Place the beaker on the burner stand and, stirring frequently to insure even heating, carefully heat the glycerin bath with heat source. Note the temperature at which the powder melts. Remove heat source. Let the powder cool and recrystallize. Repeat the procedure two more times and average the results. 6 : 500mg of powder drug was weighed accurately and subjected to flow tests such as bulk density, true density, angle of repose etc.Repeated the procedure three times and average the results. 3.3.1. Bulk Density 6 : 500mg of powder drug was weighed accurately and was transferred to a measuring cylinder and its bulk volume was measured out. The same procedure was repeated as triplicate and the average bulk density was calculated out. The bulk density was calculated by using the formula.    The percentage Solubility of the drug in different solvents after 24hrs was tabulated in Table no2. Results revealed that the pure drug Orlistat was freely soluble in chloroform and insoluble in water. Melting point of the pure drug was found to be 40-48 0 C. It shows that the pure drug unstable at higher temperatures. Derived properties were performed for pure drug. Results show that the drug compiles with the IP specifications as shown in Table 3.FT-IR spectra was taken for solid dispersion containing HPMC, PEG and eudragit as shown in figure 5, 6, 7 and compared with pure drug FTIR data as shown in fig.4 which reveals that there were no interaction between the pure drug and excipients. The data obtained for in-vitro release were fitted into equations for the zero order and first order, Higuchi, Korsmeyer, and Hixson release models; the interpretation of the data was based on the value of the resulting regression co-efficient. The invitro drug release showed the highest regression value for the Korsmeyer-peppas as tabulated in Table 7 indicating diffusion to be the predominant mechanism of drug release.

Conclusion:
Orlistat solid dispersions were prepared using HPMC, PEG, and Eudragit L100 as carriers to improve physicochemical characteristics of orlistat. Solid dispersion technique found to be effective in increasing the aqueous solubility of orlistat. In -vitro dissolution studies showed that in dispersion systems containing HPMC, Eudragit L100, and dissolution were retarded, which attributed to ionic interaction and gel forming respectively but solid dispersion containing PEG, as a carrier, gave faster dissolution rates than the physical mixture. Finally, solid dispersions of orlistat: PEG (OP-SD3) prepared in ratio 1:3 showed excellent physicochemical characteristics and was found to be described by the zero order kinetic, and was selected as the best formulation in this study. Thus the solid dispersion technique found to be effective in increasing aqueous solubility of orlistat.