MX2008010082A

MX2008010082A - Pharmaceutical composition in encapsulated powders comprising orlistat, process for preparing the composition and use thereof for treating obesity.

Info

Publication number: MX2008010082A
Application number: MX2008010082A
Authority: MX
Inventors: Marcos Morales Urzua; Shu Chen Chen; Marianela Del Carmen Beltran Apablaza
Original assignee: Andromaco Lab
Priority date: 2007-08-06
Filing date: 2008-08-06
Publication date: 2009-04-17
Also published as: CL2007002287A1; SV2009002991A; CL53426B; PA8786701A1; CR10132A; DOP2008000021A; PE20091224A1

Abstract

The present invention refers to a stable pharmaceutical composition based on a powder encapsulated mixture containing orlistat, a process for preparing the composition and the use thereof for treating obesity. The pharmaceutical composition comprises the following excipients: from about 15% to about 30% of an humidity absorbent agent, such as spray dried lactose; From about 5% to about 40% of a diluting agent, such as microcrystalline cellulose and/or granular mannitol; from about 1% to about 10% of a disintegrating agent, such as sodium glycolate starch; from about 1% to about 10% of an anti-binding agent, such as polyethylene glycol 4000; from about 0.5% from about 2% of a surfactant, such as sodium sulphate lauryl; a glidant and a lubricant. The process for preparing the composition consists in mixing orlistat, the humidity absorbing agent, a first part of the glidant, the anti-binding agent, and optionally a first portion of the diluting agent; the mixture is subsequently milled as well as the remaining portion of the diluting agent, the surfactant and the disintegrating agent and then mixed with the first mixture; the second portion of the glidant and the lubricant are milled and mixed with the previous ingredients so as to be encapsulated in hard gelatin capsules.

Description

PHARMACEUTICAL COMPOSITION IN THE FORM OF ENCAPSULATED DUSTS COMPRISING ORLISTAT, COMPOSITION PREPARATION AND USE FOR THE TREATMENT OF OBESITY. The present invention relates to a stable pharmaceutical composition comprising orlistat and to a process for its preparation. Orlistat or tetrahydrolipstatin is the (S) -1- [[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl] methyl] -dodecyl ester of (S) -2-formylamino-4-methyl -pentanoic It was described for the first time in the patent US 4,589,089, where its activity is disclosed as an inhibitor of pancreatic lipase and its usefulness for the treatment of obesity and hyperlipidemia. Orlistat is preferably administered orally in doses of 60 to 720 mg per day, divided into two or three doses. More preferably, 360 mg per day divided into two or three doses are administered. Various formulations containing orlistat have been described. US Patent 4,598,089 discloses the compound orlistat and only relates to pharmaceutical compositions in general comprising the compounds defined in said patent. In this North American patent no specific pharmaceutical compositions comprising orlistat are mentioned, but only one is exemplified composition containing lipstatin and Neobee-M5 in soft capsules. US patent 6,004,996 describes a pharmaceutical composition comprising a plurality of particles having an average diameter of about 0.25 mm to 2 mm, where each particle contains orlistat. In this patent it is noted that with the formulation of his invention it is possible to obtain a stable product, since orlistat has a very low melting point, approximately 44 ° C, for which it undergoes hydrolytic and thermal degradation, particularly when stored in a humid atmosphere or above 35 ° C in a dry atmosphere. In US Pat. No. 6,004,996 it is mentioned that conventional dosage forms, such as tablets or hard gelatin capsules, can not be easily formulated from a powder mixture or by a conventional wet granulation process, due to adhesion and stickiness phenomena. that occur during tablet pressing or encapsulation. The international patent application WO 01/19340 describes a pharmaceutical composition comprising orlistat, at least one surfactant and a dispersant. All the examples described in this patent consist of compositions that are formulated from a hot mix of the excipients, at 45 ° C or 60 ° C, melting the mixture. Orlistat is added together with the excipients at the indicated temperatures, condition in which it is also melted, or is added after cooling the mixture. Subsequently, in both cases the temperature is lowered to 25 ° C, the other excipients are added as appropriate, and the formulation is encapsulated in hydroxypropylmethylcellulose capsules. In the application WO 01/19340 does not refer to a formulation consisting of a mixture of powders of the ingredients. US Patent 5,643,874 discloses pharmaceutical compositions comprising, as active ingredients, a combination of orlistat together with a glucoxidase and / or amylase inhibitor. The only formulation exemplified in the form of capsules comprises excipients for wet granulation. In this patent it does not refer to compositions comprising orlistat as the sole active ingredient and in the form of a mixture of encapsulated powders. US patent 6,703,369 relates to a pharmaceutical composition comprising orlistat and at least one fatty acid ester of polyols, which has a melting point above body temperature. The examples of the patent correspond to formulations that are prepared by mixing orlistat with at least one fatty acid ester of polyols, in the solid (cryo-mix) or melted state, or in a solution in glycofurol. In this patent I do not know mentions a composition comprising orlistat consisting of a mixture of powders of the ingredients. US patent 6,756,364 describes a pharmaceutical composition comprising orlistat and a bile acid sequestrant. In this patent, pharmaceutical compositions comprising orlistat without or with the bile acid sequestrant are exemplified., which are in the form of granules or pellets, and are dosed in sachets or in capsules. All the manufacturing processes of the exemplified compositions comprise wet granulation, where the final product is obtained in the form of granules or pellets. In this patent it does not refer to a pharmaceutical composition comprising orlistat in the form of powders. Patent EP 1399152 describes pharmaceutical compositions comprising orlistat together with a monoester of sucrose fatty acid. The compositions exemplified in this patent correspond to pellets dosed in sachets, in capsules and in chewable tablets. Each method of manufacturing these dosage forms includes the addition of water, granulation or extrusion and spheronization, and drying. Also exemplified are formulations of chewable tablets which are obtained by forming a homogeneous dispersion, sieving, drying, formation of a foam structure, formation of a flowing powder and formation of the tablets. In this patent it does not refer to a pharmaceutical composition comprising orlistat in the form of encapsulated powders. On the other hand, products comprising orlistat are commercialized, where the active ingredient is in the form of encapsulated pellets or pellets formulated with the excipients microcrystalline cellulose, sodium starch glycolate, sodium lauryl sulfate, povidone and talc. There are also products where the active ingredient is encapsulated in a visible form of powder, where the excipients polysorbate 80, soy polysaccharides, maltose, colloidal silicon dioxide are used. This formulation requires the addition of a solvent for the dissolution of the surfactant. Consequently, the products in commercialization are elaborated by procedures that include stages of addition of solvent, and subsequent drying, with all the time and cost that this implies. Various formulations have been described in order to overcome the instability obstacles that the active ingredient osrlistat presents, such as formulations in the form of particles or spheres, described in the patent US 6,004,996 and cited in the present invention as reference. The inventors of this US patent state that the discovered particles containing orlistat, do not exhibit the phenomena of tackiness and adhesion, and that orlistat has an excellent stability. They also point out that conventional dosage forms, such as tablets or hard gelatin capsules, can not be easily formulated from a powder mix or by a conventional wet granulation process, due to the adhesion and tack phenomena that occur during the pressing of tablets or encapsulation. It is evident that the formulations described in the state of the art involve high production costs, due to at least the following factors: the greater time required for their elaboration; manufacturing processes involving extrusion, spheronization, drying; and the equipment necessary for its production. There is a need for a formulation comprising orlistat, which overcomes the problems of instability of the active ingredient due to its low melting point, and which in turn is inexpensive and easy to prepare. To date there is no formulation of orlistat in the form of powders encapsulated with the excipients described in the present application, since the condition of inherent instability of the active principle makes it very difficult, and thought impossible, to formulate orlistat in the form of powders on an industrial scale and from a manufacturing process as described in the present invention. With the invention described here it has been possible to overcome all the obstacles of instability of orlistat proper to its low melting point, around 44 ° C, and its tendency to both hydrolytic and thermal degradation; added to the problems of stickiness and adherence in the process of preparation of the composition when mixing conventional powders or granulation methods; difficulties that have been described in previous documents and cited herein as reference. Surprisingly, the inventors of the present invention have found that it is possible to formulate orlistat in the form of powders encapsulated on an industrial scale, as long as certain excipients in defined concentrations are included in the formulation. Additionally, the inventors have found that this pharmaceutical composition is possible to be manufactured by a direct mixing process of all its ingredients.

Surprisingly, the pharmaceutical composition of orlistat of the present invention is stable throughout the entire manufacturing process of the product and during the entire storage period, maintaining the stability requirements required for its commercialization as a medicine for human use. Even more, it has been found that the active ingredient orlistat present in the formulation of the invention, surprisingly maintains its inhibitory activity of the pancreatic lipase enzyme, mechanism of action by which it exerts its therapeutic effect for the treatment of obesity. To this is added that both the formulation and the procedure for its preparation are inexpensive and therefore are of great interest to the pharmaceutical industry and to people who need treatment. The present invention, in one of its main aspects, relates to a pharmaceutical formulation comprising orlistat as active ingredient, suitable pharmaceutically acceptable excipients in determined amounts and to a process for its manufacture. The term "pharmaceutically acceptable" as used in the present invention means that they are acceptable from the point of view of toxicity.

In the present invention, it has surprisingly been found that by formulating orlistat as a mixture of powders with the appropriate pharmaceutically acceptable excipients and encapsulating in hard gelatin capsules, it is possible to obtain a stable formulation throughout the manufacturing process and its storage, resulting in a pharmaceutical composition containing orlistat with an enzymatic inhibitory activity comparable to encapsulated products containing orlistat in the form of granules. According to a first aspect, the present invention relates to a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 15 to 30% by weight of a moisture absorbing agent, 5 to 40% by weight of an agent of dilution, 1 to 10% by weight of a disintegrant, 1 to 10% by weight of an anti-caking agent, 0.5 to 2% by weight of a surfactant or surfactant, 0.5 to 2% by weight of a glidant, 0.5 to 2% by weight of a lubricant. The "by weight" is referred to the total weight of the pharmaceutical composition.

The term "active ingredient" refers to a substance that has a therapeutic effect. The amount of the active ingredient present in the pharmaceutical composition may vary depending on the mammal to which the composition is administered and the condition of the disease to be treated. The term "moisture absorbing agent" as used herein refers to an agent that absorbs moisture at a rate greater than the moisture absorption rate of the active ingredient. The moisture absorbing agent may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of moisture absorbers are magnesium carbonate, lactose, granular mannitol, calcium salts or mixtures thereof. Preferably the pharmaceutical composition according to the present invention comprises 15 to 30% by weight of a moisture absorbing agent, more preferably 20 to 30% by weight of a moisture absorbing agent, more preferably 28% by weight of a moisture absorbing agent. humidity, with respect to the total weight of the pharmaceutical composition. The term "diluting agent" as used herein refers to an agent that increases the volume of the formulation to achieve the content weight of the form pharmaceutical, according to pharmacotechnical requirements. The diluting agent may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of diluting agents are microcrystalline cellulose, granular mannitol or mixtures thereof. Preferably the pharmaceutical composition according to the present invention comprises 5 to 40% by weight of a diluting agent, more preferably 7 to 35% by weight of a diluting agent, more preferably 8 to 20% by weight of a diluting agent , with respect to the total weight of the pharmaceutical composition. The term "disintegrant" as used herein is defined as an agent that accelerates the disintegration of the contents of the capsule and the dispersion of the active ingredient in water or in gastrointestinal fluids. The disintegrant may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of disintegrants are sodium starch glycolate, cornstarch or derivatives thereof, or mixtures thereof.

Preferably the pharmaceutical composition according to the present invention comprises 1 to 10% by weight of a disintegrant, more preferably 3 to 7% by weight of a disintegrant, more preferably 6% by weight of a disintegrant, with respect to the total weight of the pharmaceutical composition. The term "anti-caking agent" as used herein is defined as an agent that prevents or diminishes the agglomeration of the powder in the formulation. The anti-caking agent may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of anticaking agents are polyethylene glycol 4000, colloidal silicon dioxide, or mixtures thereof. Preferably the pharmaceutical composition according to the present invention comprises 1 to 10% by weight of an anti-caking agent, more preferably 1 to 5% by weight of an anti-caking agent, more preferably 2.5% by weight of an anti-caking agent, with respect to the total weight of the pharmaceutical composition. The term "surfactant or surfactant" as used herein is defined as an agent that possesses surface activity and that forms aggregates with solubilizing capacity, specifically refers to an anionic surfactant. The anionic surfactant may be present in the pharmaceutical composition as a single compound or as a mixture of compounds.

Examples of anionic surfactants are sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or mixtures thereof. Preferably the pharmaceutical composition according to the present invention comprises 0.5 to 2% by weight of a surfactant, more preferably 0.5 to 1.5% by weight of a surfactant, more preferably 1% by weight of a surfactant, with with respect to the total weight of the pharmaceutical composition. The term "glidant" as used herein is defined as an agent that improves the fluidity of the powder and thus the filling of the capsules by the encapsulating machine. The glidant may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of glidants are colloidal silicon dioxide, talc, starches, stearic acid, or mixtures thereof.

Preferably the pharmaceutical composition according to the present invention comprises 0.5 to 2% by weight of a glidant, more preferably 0.5 to 1.5% by weight of a glidant, more preferably 1% by weight of a glidant, with with respect to the total weight of the pharmaceutical composition. The term "lubricant" as used herein is defined as an agent capable of decreasing the adhesion of the powder to the dosers of the encapsulated machine and the friction between the particles. The lubricant may be present in the pharmaceutical composition as a single compound or as a mixture of compounds. Examples of lubricants are talc, magnesium stearate, calcium stearate, or mixtures thereof. Preferably the pharmaceutical composition according to the present invention comprises 0.5 to 2% by weight of a lubricant, more preferably 0.5 to 1.5% by weight of a lubricant, more preferably 1% by weight of a lubricant, with with respect to the total weight of the pharmaceutical composition. In a particular environment, the present invention relates to a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 15 to 30% by weight of spray dried lactose, 5 to 10% by weight of microcrystalline cellulose, 1 to 10 % by weight of sodium starch glycolate, 1 to 10% by weight of polyethylene glycol 4000, 0.5-2% by weight of sodium lauryl sulfate, 0.5 to 2% by weight of colloidal silicon dioxide, 0.5 to 2% by weight of talc.

Preferably, the present invention relates to a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 20 to 30% by weight of spray dried lactose, 7 to 9% by weight of microcrystalline cellulose, 3 to 7% by weight of sodium starch glycolate, 1 to 5% by weight of polyethylene glycol 4000, 0.5-1.5% by weight of sodium lauryl sulfate, 0.5 to 1.5% by weight of colloidal silicon dioxide, 0, 5 to 1.5% by weight of talc. More preferably, the present invention relates to a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 25 to 29% by weight of spray dried lactose, 7.5 to 8.5% by weight of microcrystalline cellulose, , 5 to 6.5% by weight of sodium starch glycolate, 2 to 3% by weight of polyethylene glycol 4000, 0.8 to 1.3% by weight of sodium lauryl sulfate, 0.8 to 1.3% by weight of colloidal silicon dioxide, 0.8 to 1.3% by weight of talc. Even more preferably, the present invention relates to a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: to 29% by weight of spray dried lactose, 7.5 to 8.5% by weight of microcrystalline cellulose, 0 to 30% by weight of granular mannitol, 5.5 to 6.5% by weight of sodium starch glycolate , 2 to 3% by weight of polyethylene glycol 4000, 0.8 to 1.3% by weight of sodium lauryl sulfate, 0.8 to 1.3% by weight of colloidal silicon dioxide, 0.8 to 1.3 % by weight of talc. In a particular environment, the present invention relates to a pharmaceutical composition comprising: 25 to 75% by weight of orlistat, 15 to 30% by weight of lactose spray dried, 5 to 10% by weight of microcrystalline cellulose, 0 to 30% by weight of granular mannitol, 1 to 10% by weight of sodium starch glycolate, 1 to 10% by weight of polyethylene glycol 4000, 0.5-2% by weight of sodium lauryl sulfate, 0.5 to 2% by weight of colloidal silicon dioxide, 0.5 to 2% by weight of talc. Preferably, the present invention relates to a pharmaceutical composition comprising: 25 to 60% by weight of orlistat 20 to 30% by weight of lactose spray dried, 7 to 9% by weight of microcrystalline cellulose, 0 to 30% by weight of granular mannitol, 3 to 7% by weight of sodium starch glycolate, 1 to 5% by weight of polyethylene glycol 4000, 0.5 to 1.5% by weight of sodium lauryl sulfate, 0.5 to 1.5% by weight of dioxide of colloidal silicon, 0.5 to 1.5% by weight of talc. More preferably, the present invention relates to a pharmaceutical composition comprising: 45 to 55% by weight of orlistat 25 to 29% by weight of lactose spray dried. 7, 5 to 8, 5% by weight of microcrystalline cellulose. 5.5 to 6.5% by weight of sodium starch glycolate. 2 to 3% by weight of polyethylene glycol 4000. 0.8 to 1.3% by weight of sodium lauryl sulfate. 0.8 to 1.3% by weight of colloidal silicon dioxide. 0.8 to 1.3% by weight of talc. Existing pharmaceutical compositions comprising orlistat in the form of capsules are prepared by addition steps of water or other solvents, wet granulation or by spheres. Such processes require a drying stage involving a heat source, even some processes include extrusion and spheronization stages that consume time and require additional equipment, increasing production costs.

Therefore, in another aspect, the invention relates to a method of preparing a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 15 to 30% by weight of a moisture absorbing agent, 5 to 40% in weight of a diluting agent, 1 to 10% by weight of a disintegrant, 1 to 10% by weight of an anti-caking agent, 0.5 to 2% by weight of a surfactant or surfactant, 0.5 to 2% by weight of a glidant, 0.5 to 2% by weight of a lubricant, with respect to the total weight of the pharmaceutical composition; wherein the process comprises the steps of: a) mixing the orlistat, the moisture absorbing agent, a first part of the glidant, the anti-caking agent, and optionally a first part of the dilution agent. b) grind the mixture from step a), c) grind the remaining dilution agent, the surfactant and the disintegrant, d) mix the ingredients of steps b) and e) e) grind the second part of the glidant and the lubricant, f) mixing the ingredients of steps d) and e) g) encapsulating in hard gelatin capsules The term "milling" as used in the present invention is defined as the reduction of the particle size by screening. Preferably the milling step is performed with a screen less than 2.36 mm, preferably less than 2.0 mm, and more preferably less than 1.7 mm. In a preferred environment, the present invention relates to a method of preparing a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 15 to 30% by weight of a moisture absorbing agent, 5 to 40% by weight of a diluting agent, 1 to 10% by weight of a disintegrant, 1 to 10% by weight of an anti-caking agent, 0.5 to 2% by weight of a surfactant or surfactant, 0.5 to 2% by weight of a Glidant, 0.5 to 2% by weight of a lubricant, with respect to the total weight of the pharmaceutical composition; where the process comprises the stages of: a) mix the orlistat, the moisture absorbing agent, a first part of the glidant and the anti-caking agent. b) grind the mixture from step a), c) grind the dilution agent, the surfactant and the disintegrant, d) mix the ingredients of steps b) and e) e) grind the second part of the glidant and the lubricant, f ) mixing the ingredients of steps d) and e) g) encapsulating in hard gelatin capsules In a particular environment, the present invention relates to a method of preparing a pharmaceutical composition comprising orlistat as the active ingredient and the following excipients: 15 to 30% by weight of lactose spray dried, 5 to 10% by weight of microcrystalline cellulose, 1 to 10% by weight of sodium starch glycolate, 1 to 10% by weight of polyethylene glycol 4000, 0.5 to 2% by weight weight of sodium lauryl sulphate, 0.5 to 2% by weight of silicon dioxide, 0.5 to 2% by weight of talc, based on the total weight of the pharmaceutical composition; where the process comprises the stages of: a) mix orlistat, lactose spray dried, a first part of colloidal silicon dioxide and polyethylene glycol 4000, b) grind the mixture from stage a), c) grind micro-crystalline cellulose, sodium lauryl sulfate and starch sodium glycolate, d) mix the ingredients of steps b) and c) e) grind the second part of the colloidal silicon dioxide and talc, f) mix the ingredients of steps d) and e) g) encapsulate in gelatin capsules In another aspect, the invention relates to the use of a pharmaceutical composition, as defined above, for the preparation of a medicament for the treatment and prevention of obesity. Description of the Figures: Figure 1 shows kinetics of dissolution of three series of a formulation according to the invention. Figure 2 shows dissolution kinetics for pharmaceutical compositions of Formulation A of the invention and of a known pharmaceutical composition, Xenical®. Below are examples for illustrative purposes and do not correspond in any way, nor should they be considered, as limiting the invention.

Those skilled in the art will appreciate that variations and routine modifications can be made to the following examples, without exceeding the scope of the invention. Examples Pharmaceutical composition in the form of capsules: Formulation A: 120 mg of orlistat, 67.6 mg of lactose spray dried, 20 mg of microcrystalline cellulose, 14.4 mg of sodium starch glycolate, 6.0 mg of polyethylene glycol 4000, 2.4 mg of sodium lauryl sulfate, 1.2 mg of colloidal silicon dioxide, 2.4 mg of talc. Encapsulate in hard gelatin capsules. Method of manufacturing Formulation A Mix orlistat, lactose, 50% colloidal silicon dioxide and polyethylene glycol 4000. Sieve the mixture. In parallel, sift microcrystalline cellulose, sodium lauryl sulfate and sodium starch glycolate and mix these ingredients with the first mixture. Sift the remaining 50% of the colloidal silicon dioxide and talc, and mix with the above ingredients. Finally encapsulate the formulation thus obtained in capsules of hard gelatin The temperature during the entire manufacturing process should be maintained between 18-22 ° C with a humidity of 20%. Formulation B: 60 mg of orlistat, 33.8 mg of lactose spray dried, 10 mg of microcrystalline cellulose, 7.2 mg of sodium starch glycolate, 3.0 mg of polyethylene glycol 4000, 1.2 mg of sodium lauryl sulfate , 0.6 mg of colloidal silicon dioxide, 1.2 mg of talc. Encapsulate in hard gelatin capsules. Formulation B is prepared according to the procedure described for Formulation A. Stability Studies: Accelerated Stability Study Conditions: The amount of the active ingredient dissolved for Formulation A was quantified in three different series, with a size of 5,000 capsules in each series. The amount released was measured immediately after the manufacture (T0) of the composition, at month (T30), at two months (T60), at three months (T90) and at six months (T180) after its manufacture. During the entire storage time, the pharmaceutical compositions encapsulated were maintained at 30 ° C and at a relative humidity of 65%. The dissolution tests were carried out in a USP 2 apparatus, paddles, in a medium of sodium lauryl sulfate and sodium chloride pH 6.0 in a volume of 900 mL, at a speed of 2.75 rpm and a temperature of 37 °. C. The results are summarized in Table 1. Study conditions of Stability in Environmental Condition. The amount of the active ingredient for Formulation A was quantified in three different series, with a size of 5,000 capsules in each series. The amount released was measured immediately after the manufacture of the composition (T0) and at six months (T180) after its manufacture. During the entire storage time, the encapsulated compositions were maintained at 25 ° C and at a relative humidity of 60%. The dissolution tests were carried out in a USP 2 apparatus, paddles, in a sodium lauryl sulfate and sodium chloride pH 6.0 medium, in a volume of 900 mL, at a speed of 2.75 rpm and a temperature of 37. ° C.

The results are summarized in Table 2.

Table 1.

Table 2 DISSOLUTION TRIAL FORMULATION A Storage condition: 25 ° C, 60% Relative Humidity Dissolved% time in 30 minutes storage (days) Series 1 Series 2 Series 3 0 91, 03 90.9 90.6 90 91, 6 91.1 91, 8 The results summarized in Tables 1 and 2 show that in both conditions, Formulation A remains stable throughout the storage period. In this way a dissolved average amount of the active ingredient is greater than 89% when the Formulation of the invention is stored at a temperature of 30 ° C and 65% Relative Humidity for a period of 30, 60, 90 and 180 days; and greater than 90% when stored at 25 ° C and 60% Relative Humidity. With these results, added to the parameters of valuation, uniformity of content, identity; it is concluded that the pharmaceutical composition of the invention is stable and complies with the required parameters of storage stability. Kinetics of release of the active ingredient: Release kinetics of the active ingredient for Formulation A were measured in three different series. The dissolved amount of active ingredient was quantified in time for each of the series immediately after the manufacture of the composition (T0) and six months (T180) after its manufacture. During the storage period, the encapsulated pharmaceutical compositions were maintained at 30 ° C and at a relative humidity of 60%. The dissolution tests were carried out in a USP 2 Apparatus, paddles, in a lauryl sulfate medium of sodium and sodium chloride pH 6.0, in a volume of 900 mL, at a speed of 2.75 rpm and a temperature of 37 ° C, measuring the amount of active ingredient dissolved at 15, 30, 45 and 60 minutes . Figure 1 shows that all the series of pharmaceutical compositions prepared according to the formulation of the present invention and by the process described herein, have an equivalent dissolution kinetics. That is, in each of the series of Formulation A, the amount of active ingredient dissolved in time is practically the same. This further demonstrates the reproducibility of the manufacturing process of the composition of the invention, since all the series showed similar behavior. In this Figure 1 it is observed that already at 15 minutes approximately 95% of the active ingredient has dissolved, indicating the rapid release of orlistat from the pharmaceutical form and therefore its availability to exert the therapeutic effect at the level of the gastrointestinal tract in very short times. Comparative release kinetics: Release kinetics of the active ingredient were measured for Formulation A capsules 120 mg and for a product available on the market, Xenical® capsules 120 mg. The dissolved amount of active ingredient was quantified over time. The dissolution tests were carried out in a USP 2 Apparatus, pallets; in a volume of 900 mL, at a speed of 2.75 rpm and a temperature of 37 ° C, measuring the amount of active ingredient at 15, 30, 45 and 60 minutes. In Figure 2, differences are observed in the release kinetics of the active ingredient between the two formulations tested. Under the conditions of the study, with Formulation A, at 5 minutes 60% of the orlistat has already been dissolved; on the other hand with Xenical® only about 26% dissolution is obtained, that is to say less than half that with the composition of the invention. In the same way, at about 15 minutes approximately 90% of orlistat has been dissolved with Formulation A and less than 70% von Xenical®. At longer times, the dissolved percentages are similar between both products.

To determine if there is a similarity in the dissolution percentages of both profiles, the similarity factor f2 was calculated. In practical terms, a value of f2 > 50 is considered a good predictor of the similarity between both profiles. F2 = 50 log. { [1 + (1 / n)? (I-n) D 2] ~ 1 2x 100.}.

D: difference of% dissolved at each point n: number of points Value f2: 39.5 Since the result obtained from the similarity factor between Formulation A capsules 120 mg and the product Xenical® capsules 120 mg is less than 50, concludes that the dissolution profiles have statistically significant differences. In the graph you can see that this difference is evident in the first 15 minutes. While Formulation A is about 88% dissolved at 15 minutes, Xenical® needs at least 30 minutes to reach a similar percentage. These results indicate that Formulation A has a dissolution profile faster than Xenical®, which suggests an anticipated therapeutic effect for the formulation of the invention. In vitro measurements of the enzymatic activity of pancreatic lipase: Orlistat acts at the gastrointestinal level blocking the absorption of triglycerides by inhibiting the enzymatic activity of pancreatic lipase. In order to determine if the formulation of the invention remains active after going through all the stages of the manufacturing process and finally being formulated in the encapsulated powder form, the activity of the pancreatic enzyme was measured in vitro. In parallel, the inhibitory activity of the Xenical product was evaluated. The test consists of two stages: 1) The pancreatic lipase hydrolyses the substrate 4-methylumbelliferyl oleate (4-MUO) generating 4-methylumbelliferone in the reaction medium. This hydrolysis will decrease in the presence of a lipase inhibitor; 2) The fuorescent measurement of the metabolite 4-methylumbelliferone generated is carried out. 4-Methylumbelliferone is a fluorescent compound that emits light at 450 nm when excited at 320 nm. The assays were performed at two different incubation temperatures, at 24 ° C and 37 ° C for 30 minutes, at a concentration of the active ingredient orlistat of 100 nM and 400 nM respectively. The pancreatic enzyme (type II of porcine pancreas) was used. These concentrations of orlistat were used because it has an IC 50 of approximately 60 nM (Bisogno T, Casció MG, Saha B, Mahadevan A, Urbani P, Mináis A, Appendino G, Saturnino C, Martin B, Razdan R, Di Marzo V "Development of the first potent and specific inhibitors of endocannabinoid biosynthesis." Biochim Biophys Acta, 2006; 1761 (2): 205-212).

The results are summarized in Table 3. Table 3. 24 ° C 37 ° C 100 nM of orlistat 400 nM of orlistat u.a .: arbitrary units. The results show that the formulation of the invention inhibits the enzymatic activity of pancreatic lipase at a level comparable to that of Xenical®, both at 24 ° C and at 37 ° C. This indicates that orlistat in Formulation A remains active and therefore, formulated in the encapsulated powder form, is therapeutically effective in the treatment of obesity.

Claims

CLAIMS 1. - A stable pharmaceutical composition CHARACTERIZED because it comprises an encapsulated powder mixture of orlistat and the following excipients: 15 to 30% by weight of a moisture absorbing agent, 5 to 40% by weight of a diluting agent, 1 to 10% by weight of a disintegrant, 1 to 10% by weight of an anti-caking agent, 0.5 to 2% by weight of a surfactant or surfactant, 0.5 to 2% by weight of a glidant, 0.5 to 2% by weight of a lubricant; with respect to the total weight of the pharmaceutical composition.
2. - A stable pharmaceutical composition according to claim 1 characterized in that the moisture absorbing agent is selected from magnesium carbonate, lactose, granular mannitol, calcium salts or mixtures thereof.
3. - A stable pharmaceutical composition according to claim 2 characterized in that the moisture absorbing agent is lactose spried dried.
4. - A stable pharmaceutical composition according to claim 1 CHARACTERIZED because the dilution agent is selected from microcrystalline cellulose, granular mannitol or mixtures thereof.
5. - A stable pharmaceutical composition according to claim 1 characterized in that the disintegrant is selected from sodium starch glycolate, corn starch or derivatives thereof, or mixtures thereof.
6. - A stable pharmaceutical composition according to claim 1 CHARACTERIZED because the anti-caking agent is selected from polyethylene glycol 4000, colloidal silicon dioxide, or mixtures thereof.
7. A stable pharmaceutical composition according to claim 1 characterized in that the surfactant or surfactant is selected from an anionic surfactant.
8. - A stable pharmaceutical composition according to claim 7 characterized in that the surfactant or surfactant is selected from sodium lauryl sulfate, sodium dioctyl sulfosuccinate, or mixtures thereof.
9. - A stable pharmaceutical composition according to claim 1 characterized in that the glidant is selected from colloidal silicon dioxide, talc, starches, stearic acid, or mixtures thereof.
10. - A stable pharmaceutical composition according to claim 1 CHARACTERIZED because the lubricant is selected from talc, magnesium stearate, calcium stearate, or mixtures thereof.
11. - A stable pharmaceutical composition according to claim 1 characterized in that it comprises an encapsulated powder mixture of orlistat and the following excipients: 15 to 30% by weight of spray dried lactose, 5 to 40% by weight of microcrystalline cellulose, 1 to 10 % by weight of sodium starch glycolate, 1 to 10% by weight of polyethylene glycol 4000, 0.5 to 2% by weight of sodium lauryl sulfate, 0.5 to 2% by weight of colloidal silicon dioxide, 0.5 to 2% by weight of talc, where% by weight is defined with respect to the total weight of the composition.
12. - A stable pharmaceutical composition according to claim 11 characterized in that it comprises an encapsulated powder mixture of orlistat and the following excipients: 20 to 30% by weight of spray dried lactose, 7 to 35% by weight of microcrystalline cellulose, 3 to 7% by weight of sodium starch glycolate, 1 to 5% by weight of polyethylene glycol 4000, 0.5 to 5% by weight of sodium lauryl sulfate, 0.5 to 1.5% by weight of silicon dioxide colloidal 0.5 to 1.5% by weight of talc. where% by weight is defined with respect to the total weight of the composition.
13. - A stable pharmaceutical composition according to claim 12 characterized in that it comprises an encapsulated powder mixture of orlistat and the following excipients: 25 to 29% by weight of lactose spray dried. 7.5 to 8.5% by weight of microcrystalline cellulose. 5.5 to 6.5% by weight of sodium starch glycolate. 2 to 3% by weight of polyethylene glycol 4000. 0.8 to 1.3% by weight of sodium lauryl sulfate. 0.8 to 1.3% by weight of colloidal silicon dioxide, 0.8 to 1.3% by weight of talc, where% by weight is defined with respect to the total weight of the composition.
14. - A stable pharmaceutical composition according to claim 1 CHARACTERIZED because it comprises an encapsulated powder mixture of: 25-75% by weight of orlistat, 15 to 30% by weight of lactose spray dried, 5 to 10% by weight of microcrystalline cellulose, 1 to 10% by weight of sodium starch glycolate, 1 to 10% by weight of polyethylene glycol 4000, 0.5 to 2% by weight of sodium lauryl sulfate, 0.5 to 2% by weight of colloidal silicon dioxide, O, 5 to 2% by weight of talc, where% by weight is defined with respect to the total weight of the composition.
15. - A stable pharmaceutical composition according to claim 14 CHARACTERIZED because it comprises an encapsulated powder mixture with the following ingredients: 120 mg of orlistat, 67.6 mg of lactose spray dried, 20 mg of microcrystalline cellulose, 14.4 mg of sodium starch glycolate, 6.0 mg of polyethy glycol 4000, 2.4 mg of sodium lauryl sulfate, 1.2 mg of colloidal silicon dioxide, 2.4 mg of talc.
16. - A stable pharmaceutical composition according to claim 14 CHARACTERIZED because it comprises an encapsulated powder mixture with the following ingredients: 60 mg orlistat, 33.8 mg lactose spray dried, 10 mg microcrystalline cellulose, 7.2 mg of sodium starch glycolate, 3.0 mg of polyethy glycol 4000, 1.2 mg of sodium lauryl sulfate, 0.6 mg of colloidal silicon dioxide, 1.2 mg of talc.
17. - A method of preparing a stable pharmaceutical composition comprising an encapsulated powder mixture of orlistat as the active ingredient and the following excipients: 15 to 30% by weight of a moisture absorbing agent, 5 to 40% by weight of a diluting agent, 1 to 10% by weight of a disintegrant, 1 to 10% by weight of an anti-caking agent, 0.5 to 2% by weight of a surfactant or surfactant, 0.5 to 2% by weight of a glidant, 0.5 to 2% by weight of a lubricant, where% by weight is defined relative to the total weight of the composition, CHARACTERIZED because it comprises the steps of: a) mixing the orlistat, the agent moisture absorber, a first part of the glidant, the anti-caking agent, and optionally a first part of the dilution agent, b) grinding the mixture from step a), c) grinding the remaining dilution agent, the surfactant and the disintegrant, ) mix the ingredients of steps b) and c) e) grind the second part of the glidant and the lubricant, f) mix the ingredients of steps d) and e) g) encapsulate in hard gelatin capsules.
18. A process for the preparation of a stable pharmaceutical composition according to claim 17, characterized in that it comprises the steps of: a) mixing the orlistat, the moisture absorbing agent, a first part of the glidant and the anti-caking agent, b) grinding the mixture from step a), c) grind the dilution agent, the surfactant and the disintegrant, d) mix the ingredients of steps b) and c) e) grind the second part of the glidant and the lubricant, f) mix the ingredients of steps d) and e) g) encapsulate in hard gelatin capsules.
19. A process for the preparation of a stable pharmaceutical composition according to claim 18, characterized in that it comprises the steps of: a) mix orlistat, lactose spray dried, a first part of colloidal silicon dioxide and polyethy glycol 4000, b) grind the mixture from stage a), c) grind micro-crystalline cellulose, sodium lauryl sulfate and starch sodium glycolate, d) mix the ingredients of steps b) and c) e) grind the second part of the colloidal silicon dioxide and talc, f) mix the ingredients of steps d) and e) g) encapsulate in gelatin capsules hard. 20. - A method of preparing a stable pharmaceutical composition according to claim 17 CHARACTERIZED because it is carried out at a temperature between 18-22 ° C and a humidity of 20%. 21. - Use of a pharmaceutical composition according to claim 1 characterized in that it serves to prepare a drug for the treatment of obesity.