MXPA01001524A - Pharmaceutical compositions containing lipase inhibitors - Google Patents

Abstract

Orally administrable pharmaceutical composition containing an inhibitor of gastrointestinal lipase, one (or more) additive(s) of the group consisting of poorly digestible, poorly fermentable, hydrophilic and/or hydrocolloidal food grade thickeners and emulsifiers, and auxiliary excipients.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING LIPASE INHIBITORS Field of the Invention The present invention relates to pharmaceutical compositions containing a gastrointestinal lipase inhibitor, one (or more) additives from the group consisting of low digestibility thickeners and emulsifiers, low fermentability, hydrophilic and / or food grade hydrocolloids. , and excipients.

Background of the Invention One example of an inhibitor of gastrointestinal lipases is orlistat, formerly known as tetrahydrol ipstat ina or THL. Orlistat reduces the absorption of fats from the diet. Its use for the control or prevention of obesity and hyperlipidemia is described in US Pat. 4 598 089. Anal oil loss (oil dripping) is an adverse effect that is occasionally observed in patients treated with lipase inhibitors. East 126673 This phenomenon reflects the physical separation of some non-absorbed liquid dietary fats from the rest of non-absorbed solids in the final part of the large intestine. The physical separation and the consequent anal loss of oil can be avoided with the pharmaceutical compositions of the present invention. In US Pat. No. 5,447,953 it has been shown that by combining a lipase inhibitor with substantial amounts of insoluble crude fibers in water, the inhibitory effect of fat absorption can be increased. This synergistic effect is probably attributable to the acceleration of the gastrointestinal transit of food by the water-insoluble fiber component. The consequent shortening of the period of time available for the digestion of fats combined with the reducing effect of the lipase activity intensifies the inhibitory effect of the absorption of fats. Surprisingly, it has now been found that the separation of unabsorbed oil from feces, and therefore anal oil loss, can be reduced or prevented, when a lipase inhibitor such as orlistat is administered in combination with small amounts of one or more of additives of the group consisting of thickeners and / or low fermentability, hydrophilic and / or food grade hydrocolloid emulsifiers. The invention also relates to the use of low digestibility thickeners and / or emulsifiers, low fermentability, hydrophilic and / or food grade hydrocolloids for simultaneous, separate or chronologically spaced use with lipase inhibitors, for example Orlistat, in the treatment of obesity and hyperlipidemia.

DESCRIPTION OF THE INVENTION The invention further relates to the use of the mentioned thickeners and / or emulsifiers to treat or prevent anal oil loss syndrome that occurs after the administration of a lipase inhibitor, such as the orlistat, or after the ingestion of foods containing fats or oils of low absorbability or non-absorbable or substitutes for non-digestible oil fats. Additional examples of lipase inhibitors that can be used in the scope of the present invention are lipstatin, panclicins, hespetidine, ebelactones, esterastine and its derivatives, and valilactone. Thickeners which may be mentioned are natural synthetic or semi-synthetic soluble polysaccharides, such as such as methylcellulose, xanthan gum, psyllium seed, ispágula rind, seeds of plántago ovata, karaya gum and mixtures of said compounds. Methyl cellulose is the cellulose methyl ether. It is slowly soluble in water, yielding a viscous colloidal solution. Xanthan gum is an exopolysaccharide of high molecular weight biosynthetic hydrocolloid produced by fermentation of pure cultures of Xanthomonas campestris. It contains D-glucose, D-mannose 15 and D-glucuronic acid as the dominant hexose units, and is manufactured as the sodium, potassium or calcium salt. The psyllium seed husk, that is, the envelope of the seed, constitutes a source of soluble fiber. It comprises cellulose that contains walls of endosperm, and mucilage containing the epidermis of small mature dry seeds. A clear colorless mucilage is formed in contact with water. 25 The ispagula shell consists of muciloid * ¿, S - *! * «* - & ^^^^? | ig3 | ^ i ^^^^^^^ w ^^^^^^^^^^^^^^^. hydrophilic of psyllium. It comprises the epidermis and the adjacent collapsed layer of Plantago species, for example Pl. psyllium. Rapidly swells on contact with water to form a mucilage consistent. The seeds of Plantago ovata (seed husk and seed coat) are a source of soluble fiber. They comprise cellulose that contains walls of endosperm and mucilage that contains epidermis of small, mature, dry seeds. A clear colorless mucilage is formed in contact with water. Karaya gum is an exudate or hydrocolloid gum of Sterculia species. It forms a homogenous adhesive gelatinous mass in contact with water. Examples of these types of thickeners are contained in OTC products and / or food additives, such as: 20 METHOCEL A4M, a registered trademark of Dow Chemical Co., for a high viscosity methyl cellulose, KELTROL TF, a registered trademark of Merck & Co. , Inc., 15 Rahway NJ, for xanthan gum, 25 MUCILAR, psyllium seed (Psyllii seminis - - ** "^ ~ --- '* _! ____ testa), a product" of Spirig AG, CH-4622 Egerkingen, METAMUCIL, ispagula shell (Ispaghulae testae pulvis), a product of Procter & Gamble, CH-- 1211 Geneva 2, 5 AGIOCUR, seeds of Plantago ovata, a product of Madaus AG, D-5000, Cologne 91, NORMACOL MITE, a registered trademark of Norgine Ltd., Great Britain, for karaya gum, POLI-KARAYA, a registered trademark of 1 10 Delalande for karaya gum from Interdelta SA, CH-1701, Freiburg. A further example of a thickener is FIBERCON (polycarboflio), a registered trademark of Lederle Laboratories Division, American Cyanamid Co., 15 Pearl River, NY, for the calcium salt of a lacquered synthetic resin of the polycarboxylate type. As emulsifiers which can be used in the compositions of the invention, mention may be made of sucrose polyesters, such as Ryoto Sugar Esters, for example Ryoto Sugar Ester S-170. Ryoto Sugar Esters are a trademark of Mitsubishi- Kasi Foods Corp., Chuo-Ku, Tokyo 104, for fatty acid esters of sucrose. The Ryoto Sugar 25 Ester S-170 contains polyesters of stearic acid and Sucrose Examples of excipients that can be used in the pharmaceutical compositions of the invention are binders, diluents and lubricants, such as AVICEL, polyvinyl pyrrolidone (povidone), talc, stearic acid and sodium stearyl fumarate; sweeteners such as sorbitol, glucose, sucrose, sodium saccharin salt and sodium cyclamate; flavoring agents, such as passion fruit, orange and Lima; aroma stimulators, such as citric acid, monosodium citrate, sodium chloride and quinine sulfate; effervescence agents, such as sodium bicarbonate and tartaric acid, disintegrants such as sodium starch glycolate; agents antimicrobials, such as methyl or propyl ester of p-hydroxybenzoic acid; detergents, such as sodium lauryl sulfate, and coloring agents, such as β-carotene AVICEL comprises essentially cellulose microcrystalline. It is available from the FMC Corporation, Pharmaceutical Division, 1735 Market Street, Philadelphia, PA 19103, for example as AVICEL RC-591 or CL-611, which are mixtures of microcrystalline cellulose (approximately 92%) and sodium carboxymethylcellulose (approximately 8%), - ^, * .. j? M. ~. - '- ^ ** - sil AVICEL PH 101 or PH 105, which is microcrystalline cellulose with an average particle size of 50 or 20 μ, respectively, AVICEL CE-15 is a mixture of microcrystalline cellulose and guar gum. and as indicated above, anal oil loss, occasionally observed with the therapeutic use of tated lipase inhibitors such as orlistat, can be reduced or avoided with the pharmaceutical compositions of the invention. illustrates with the following in vivo experiments: Rats maintained on a high fat diet were used as a model. The inhibition of the absorption of fats by orlistat mixed in the diet caused the anal loss of liquid oil. Without However, the amount of oil loss could not be determined easily. Due to the coprophagia and the intense grooming activity, the rats dispersed the oil in all their hair. Additionally, the state of stress caused by no Being able to complete the grooming caused a considerable excitement of the animals. The greasy hair area increased in proportion to the amount of fat not absorbed and was reduced by the administration in the diet of selected examples of the additives food products defined above. Nevertheless, ? ^ á ^^! y ^^^^ íj | ¡__¿_ ^^ | g,, ^, ^^^^ ..

For reasons of animal care for the comparative evaluation of the additives, a subrogated parameter was used to evaluate the effects of oil loss. After a meal containing orlistat, the unabsorbed fat is temporarily stored in the caecum of the rat before its excretion. The fat is partially present as a floating liquid oil, partially associated with nonabsorbable solids. In the validation studies it was possible to demonstrate that the effect of the food additives for agglutinating and sequestering liquid oil not absorbed in the solid phase of the cecum constitutes a reliable surrogate parameter predictor of a corresponding reduction in the subsequent loss of oil. The basal diet with a high content of fat used contained 56% of laboratory weight, 12% glucose and 32% olive oil. The food additives were supplemented in three concentrations, meaning 12.4, 4.5 and 1.2% of the diet composed by weight. The control diets were supplemented with a corresponding amount of starch. All diets were moistened with water to a similar consistency to facilitate acceptability by the animals. Groups of 6-7 female rats were assigned to each diet (body weight: 120-140) After adapting to the diet for a week, the rats were fed for 24 hours and on the subsequent experimental day the diets were administered as a single food (basal diet: 4.25 g, additives or starch: 0.6, 0.2 and 0.05 g) In order to completely block the absorption of oil and thus produce a defined amount of non-absorbed fats, a high dose of orlistat was dissolved (45 mg) in the fraction of olive oil (1.5 ml) of the food. The animals were sacrificed three hours after the meal was administered. At this time, the blind contained the greatest traction of oil in the diet. To determine the relative amounts of bound and free oil in the cecum, the content of the cecum was centrifuged (2000 g, 30 min) and the lipid content of the oil / water phase and solid phase was quantified gravimetrically after extraction with solvent . The food additives tested in the first experimental series were methylcellulose (MC), Ryoto Sugar Ester S-170 (RS) and xanthan gum (XG). The fat content of the liquid and solid phases in the cecum was expressed as a percentage of the amount aaA ^^ ^ fcaa of oil administered with food. The average values for the experimental groups fed with the additives, as compared to the controls (in which the thickener or emulsifier additive was replaced by the corresponding weight of starch (ST)) are shown in the following table. For the statistical evaluation of the effect of the additives the Student t test was used: n.s. = p > 0.05, * = p < 0.05, ** = p < 0.01, *** = p < 0.001. 10 Fat content in the cecum in% of the amount of oil supplied: fifteen twenty ^ ~ TiL ^ s¡ á & + a ^ * ¿£ -. ». ^ Rtf- '? - hM ****** - * ^ Additive Oil phase Solid phase MC 0.05 g 24.8ns- 16.8 * ST 0.05g 25.4 13.4 MC 0.20 g 17.0 ** 29.2 *** ST 0.20 g 24.6 13.2 MC 0.60 g 5.0 ** * 32.9 *** ST 0.60 g 37.9 9.6 RS 0.05 g 18.3ns- 13.6 * 10 ST 0.05 g 23.6 9.0 RS 0.20 g 22.4n "s- 23.3 *** ST 0.20 g 24.2 11.0 RS 0.60 g 3.1 *** 37.1 * ** ST 0.60 g 15.8 11.9 15 XG 0.05 g 12.7 *** 20.3 *** ST 0.05 g 23.6 9.0 XG 0.20 g 1.1 *** 23.2 *** ST 0.20 g 24.2 11.0 XG 0.60 g 0.7 *** 18.9 ** * 20 ST 0.60 g 23.6 10.9 As mentioned above, 0.6, 0.2 and 0.05 g of food additives provided with the test meal correspond to 12.4, 4.5 and 1.2% by weight in the diet alffeompues ta without water.

The results shown above clearly demonstrate that in animals given orlistat in combination with an additive according to the invention, the fraction of unabsorbed fat sequestered in the solid phase of the caecum increased significantly (and the liquid oil was reduced) compared to control animals to which a corresponding amount of starch was supplied. In this sense, the additives are effective in reducing or preventing the anal loss of liquid oil. Using the same procedure In an experimental experiment, several OTC products containing additives according to the invention were evaluated in a second series, as well as crude water insoluble fiber products. To ensure a relevant comparison of the products the variable content in fiber or in active additive was taken into account. In this sense, the amount of each product added to the diet was chosen so that all the meals tested contained the same amount of active additive or fiber (0.2 g, 4.5% in weight). The results of these experiments are _4iß_l_¿_l_tt = _ show in the following table: * • Fat content in the cecum in% of The amount of oil supplied: OTC product solid phase AGIOCUR 0.30 g 20 *** FIBERCON 0.35 g 18 *** Control of starch 0.20 g 12 NORMACOL MITE 0.32 g 19 ** METAMUCIL 0.41 g 17 ** Control of starch 0.20 g 13 POLY-KARAYA 0.50 g 20 *** Wheat bran 0.42 g 15 n.s Oat bran 1.60 g 11 n.s Starch control 0.20 g 12 As mentioned above, the weight of the OTC products indicated in the table is g ^ ¿ü ^^^^^ n ^ corresponds to 0.2 of thickener additive - • * »'" - emulsifier or of water-soluble fibrA The data demonstrate the agglutination and sequestration of oil in the cecum, and thus the effectiveness in the prevention of anal oil loss by the OTC AGIOCUR, FIBERCON, METAMUCIL, NORMACOL MITE and POLI-KARAYA compounds. Additionally, the results also show the superiority of the additives according to the invention, taking as an example POLI-KARAYA, on raw water-insoluble fiber, such as, for example, oat and wheat bran (non-significant effect), which has been proposed in US Pat. No. 5,447,953 as an enhancer of the inhibitory effect on the absorption of fats.

The compositions of the invention conveniently contain from 1 to 300, preferably from 3 to 30 parts by weight of an emulsifier or thickener per one part by weight of orlistat or another lipase inhibitor. Conveniently additionally contain from 1 to 500, preferably from 3 to 200 parts by weight of auxiliary excipients per one part by weight of L lipase inhibitor.

The compositions of the invention can be presented in the form of tablets, capsules or liquid formulations, which can be reconstituted from powders, granules, lozenges and tablets. standard or effervescent. They can also be formulated in the form of chewable tablets or pills. Additionally, the compositions can also be incorporated into food preparations, such as biscuits, cakes or biscuits.

The composition of the invention may also be presented in the form of a commercial pack containing a lipase inhibitor, such as orlistat, and one or more of the thickeners and emulsifiers mentioned above, together with instructions for use for simultaneous use, separated or chronologically spaced in the treatment of obesity or hyperlipidemia.

For the treatment or prevention of obesity or hyperlipidemia, a composition of the invention containing 50 to 500 mg of orlistat or another lipase inhibitor and 150 mg to 15 g of an emulsifier or thickener can be administered orally at one time per day, or two or three times per day.

A preferred composition of the invention consists of a chewable tablet for the treatment of obesity consisting essentially of orlistat as an active ingredient and of karaya gum as a thickener, in which the dosage is in the range of 50 to 150 mg of orlistat and from 3 to 30 parts by weight of karaya gum or xanthan gum or one part by weight of orlistat, more preferably in which the dose is about 60 mg of orlistat and about 1.5 g of karaya gum or gum of xanthan.

A method for avoiding anal oil loss syndrome that occasionally occurs after oral administration of orlistat, comprises oral administration of 1 to 3 chewable tablets per main meal containing fats, or the dosage being in each tablet of 50. to 150 mg of; orlistat and from 3 to 30 parts by weight of karaya gum or xanthan gum per 1 part by weight of orlistat. Preferably, this method comprises the oral administration of orlistat and karaya gum c > 5 xanthan gum in a dose of approximately 100 f ^ ~ TT TTÉlTfj ^^^^^ in * - * - mg of orlistat and approximately 2 g of karaya gum or xanthan gum per main meal containing fats.

The following non-limiting examples illustrate the pharmaceutical preparations that can be produced in a manner known per se: Example 1 Powder for reconstitution Orlistat 0.12 Xanthan gum 1.20 Sorbitol 9.91 AVICEL CL 611 1.20 ß-carotene 1% C S 0.06 Citric acid 0.10 P-hydroxybenzoic acid methyl ester 0.15 P-hydroxybenzoic acid propyl ester 0.03 Flavoring agent (passion fruit) 0.13 c AVICEL PH 105 4.00 Monosodium Citrate 1.00 c Sodium salt of saccharin 0.10 Total 18.00 c fr *? * vrifl¡rm ™ * -? a? * An oral suspension can be obtained by adding tap water to the above powder to a volume of approximately 50 ml.

Example 2 Chewable pills Orlistat 0.060 g Karaya rubber 1,500 g Polyvinyl pyrrolidone 0.750 g Sorbitol 0.970 g AVICEL CE-15 1,000 g Talc 0.480 g Stearic acid (0.240 g microfmo powder) Total 5,000 g The indicated amounts of orlistat, karaya gum, polyvinyl pyrrolidone, sorbitol and AVICEL CE 15 are mixed and sieved. Talc and stearic acid are screened and mixed with the mixture obtained above. The material is compressed below HH ^ Ü H ¡^ = ^! up to 2-cm diameter masticatory tablets and a weight of 5 g.

Example 3 Formulation in tablets containing an emulsifier: 1. Orlistat tablets: finely ground orlistat 120 mg microcrystalline cellulose 93.6 g sodium starch glycolate 7.2 mg Sodium lauryl sulfate 7.2 mg Povidone 12 mg Total 240 mg For a batch size of 4 kg of tablets, the following procedure is applied: Sodium lauryl sulfate (120 g) and povidone (200 g) are dissolved in q.s. of water. The solution is cooled to 10-15 ° C - > A. Orlistat is premixed (2000 ^^^. ^. ^^^^ - ^. ^ ,. ~ g¡fjM j¿ * ¥ '*. g), microcrystalline cellulose (1560 g) and glycol: or sodium starch (120 g) - > B. Solution A is added to premixed B and kneaded. The resulting material is subjected to extrusion to spaghetti. This extrusion is spheronized at 700 rpm. The obtained cylindrical wet pellets are dried in a fluid bed dryer and sieved. Fractions of 0.5 - 1.25 mm in size are collected as orlistat tablets in closed containers.

Emulsifier part Sugar ester Ryoto S-170 600 mg Microcrystalline cellulose 312 mg Sodium starch glycolate 15 mg Povidone 15 mg Talc 18 mg Total 960 mg For a lot size of 16 kg of pellets the following procedure is applied: fes * r ^ m.v ~ * «afa¡ = ¿fej iai fi * ^^^^ * j The liquid is liquefied: sugar (10 kg) by heating to 60 ° C. Micro cellulose such as ma (5.2 g), sodium starch glycolate (0.4 kg) and povidone (0.4 kg) are added. The dough is kneaded cold at room temperature, and then subjected to extrusion through an extrusion plate with a nominal mesh size of 0.7 mm. The greased extrudate is cut into pieces of 1 mm length, and the resulting mass is sprinkled with talcum powder in a mixer. The orlistat tablets (2. kg) and the emulsifier tablets (9.6 kg) are mixed. The mixture is filled into sachets with a filling weight of 1.2 kg, corresponding to 120 mg of orlistat and 600 mg of sugar ester.

It is noted that in relation to this date, the best method known to the applicant, to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.

Claims (13)

1. Orally administrable pharmaceutical composition, characterized in that it contains a gastrointestinal lipase inhibitor, one (or more) additive (s) of the group consisting of thickeners and emulsifiers of low digestibility, low fermentability, hydrophilic and / or food grade hydrocolloids, and auxiliary excipients.

2. A composition as in claim 1, characterized in that the additive is a thickener of low digestibility, low fermentability, hydrophilic and food grade hydrocolloid.

3. A composition as in claim 2, characterized in that the food grade thickener contains methyl cellulose, xanthan gum, psyllium seed, ispaghula husk, plantago ovata seeds, karaya gum or mixtures thereof.

4. A composition as in claim 1, characterized in that the additive is an emulsifier.

5. A composition as in claim 4, characterized in that the emulsifier is a sucrose polyester.

6. A composition as in claim 2 or 3, characterized in that it comprises from 1 to 300 parts by weight of a thickener per 1 part by weight of a gastrointestinal lipase inhibitor.

7. A composition as in claim 4, characterized in that it comprises from 1 to 300 parts by weight of an emulsifier per 1 part by weight of a gastrointestinal lipase inhibitor.

8. A composition as in any of claims 1 to 7, characterized in that the gastrointestinal lipase inhibitor is orlistat.

* -Ji **** "" **. »9. The use of one (or more) compound (s) of the group consisting of thickeners and emulsifiers with low digestibility, low fermentability, hydrophilic and / or food-grade hydrocolloids. for the treatment or prevention of the syndrome of anal oil losses that occur occasionally after the administration of a gastrointestinal lipase inhibitor, such as orlistat, or after the ingestion of foods containing fats or oils that are not absorbable or non-absorbable or substitutes for oily fats indigestible

10. A composition as in claim 3 or 8, characterized in that it is a chewable tablet for the treatment of obesity, consisting essentially of orlistat as an active ingredient and in karaya gum or xanthan gum as a thickener, in which the dose ranges from 50 to 150 mg of orlistat and 3 to 30 parts by weight of karaya gum or xanthan gum per 1 part by weight of orlistat.

11. The chewable tablet as in claim 10, characterized in that the dose is about 60 mg of orlistat and about 1.5 g of karaya gum or xanthan gum.

12. A method for the prevention of anal oil loss syndrome that occasionally occurs after oral administration of orlistat, which comprises the oral administration of 1 to 3 chewable tablets per main meal containing fats, with the dose in each tablet being 50 150 mg of orlistat and 3 to 30 parts by weight of karaya gum or xanthan gum per 1 part by weight of orlistat.

13. A method for the prevention of anal oil loss syndrome that occasionally occurs after oral administration of orlistat, characterized in that it comprises the oral administration of orlistat and karaya gum in a dosage of approximately 100 mg of orlistat and approximately 2 g of karaya gum or xanthan gum for main meal containing ashes. f ^ y ^ ¿^ &