MXPA01001574A - Pharmaceutical compositions containing lipase inhibitors and chitosan - Google Patents

Abstract

Orally administrable pharmaceutical composition containing an inhibitor of gastrointestinal lipases, one (or more) additional compound(s) of the group consisting of chitosan, its derivatives and salts thereof, and auxiliary excipients.

Description

PHARMACEUTICAL COMPOSITIONS CONTAINING LIPASE AND QUITOSAN INHIBITORS FIELD OF THE INVENTION The present invention relates to pharmaceutical compositions, one (or more) additional compound (s) of the group consisting of chitosan, its derivatives and salts thereof, and auxiliary excipients. An example of an inhibitor of gastrointestinal lipases is orlistat, previously known as tetrahydro-lip tatin or THL, which reduces the absorption of dietary fat. Its use for the control or prevention of obesity and hyperlipidemia is described in US patent 4598089. Orlistat is the ester of N-formyl-L-leucine with (3S, 4 S) -3-hexyl-4- [(2S) -2-hydroxy-tridecyl] -2-oxetanone. Anal oil loss (oil drip) is an adverse effect that is occasionally observed in treated patients. This results from the physical separation of some liquid diet fats not absorbed from the volume of fecal mass in the final part of the large intestine. This effect can be avoided with the pharmaceutical compositions of the present invention.

Ref: 126765 In US patent 5447953 it has been shown that by combining a lipase inhibitor with substantial amounts of water insoluble raw fibers, the inhibitory effect of fat absorption can be increased. Surprisingly, it has now been found that by combining the lipase inhibitor with small amounts of chitosan or a derivative or a salt thereof, the phenomenon of anal oil loss can be strongly reduced. The invention also relates to the use of chitosan or a derivative or salt thereof for simultaneous combined, separate or chronologically spaced use with a gastrointestinal lipase inhibitor, for example orlistat, in the treatment of obesity and hyperlipaemia, as well such as comorbidities such as type II diabetes mellitus. Artificial non-absorbed fats, mainly sucrose polyester, are used in the food industry for the production of low-fat foods, such as low-fat potato chips, low-fat cookies, salad dressings with low content in fat and ice cream with low fat content. Ingestion of high amounts of food products containing nonabsorbable fats can induce oil loss. The invention further relates to the use of chitosan or a derivative or salt thereof to treat or prevent anal oil loss syndrome that occurs after the administration of an inhibitor of gastrointestinal lipases, such as orlistat, or after ingestion of foods containing non-absorbable or non-absorbable fats or oils of indigestible oily fat substitutes. Chitosan is derived from chitin, a polysaccharide composed of bound residues (l-> 4) of 2-acetamido-2-deoxy-β-D-glucopyranosyl isolated from natural sources, by partial or complete deacetylation and partial depolymerization . Chitosan has a molecular weight in the order of 104 to 105. Guitosan is soluble at gastric pH and insoluble or gelled at intestinal pH. Examples of chitosan derivatives are N-alkyl- or N-alkanoyl-qui tosan of medium or long chain. The term "middle chain N-alkyl- or N-alkanoyl" refers to N-alkyl or N-alkanoyl chains of C8-? 3, the term "N-alkyl or long-chain N-alkanoyl" refers to chains of N-alkyl or N-alkanoyl of C? 4_18. "Examples of chitosan salts are those formed with acetic acid, citric acid, formic acid and tartaric acid, as well as those formed with dilute mineral acids. (Merck index, lia ed., # 2052, 1989) poly-D-glucosamine, poly- [l-> 4] -β-D-glucosamine and deacetylated chitin Deacetylation of chitin with the formula to chitosan of the formula it can be carried out in hot concentrated NaOH solution (40-50%). Chitosan is commercially available from pronova Biopolymer, Inc., 135 Commerce Way, Suite 201, Portsmouth, NH03801, for example as SEACURE 142-, 242 or 342 with a viscosity lower than 20 cps, from 20 to 200 cps and from 200 to 200 cps. 800 cps, respectively.

Examples of auxiliary 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 lime; 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; antimicrobial agents, such as p-hydroxybenzoic acid methyl or propyl ester; detergents, and coloring agents, such as β-carotene. AVICEL comprises essentially microcrystalline cellulose. 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%). %), AVICEL PH 101 or PH 105, which is microcrystalline cellulose with an average particle size of 50 to 20 μ, respectively; AVICEL CE-15 is a mixture of microcrystalline cellulose and guar gum. The superiority of chitosan over microcrystalline cellulose, for example AVICEL, in the reduction of anal oil loss is shown in the following experiment. The experiment performed to measure the loss of free fecal oil is based on the observation that mice, due to the continuous grooming of their hair, distribute any free fecal oil excreted throughout their body. This results in an easily visible brown coloration of the hair (oil greasing of the hair). In mice weighing 20 to 25 g, the excretion of free oil was caused by administering an excessive dose of orlistat (300 umol / kg / day) together with a diet containing 7% fat, which resulted in a daily intake of fats of 1 g / day. The diet consisted of burgers, fried potatoes and crushed green beans. The following treatment program was followed: Days 1-5: feeding groups of 3 mice with the previous diet and food additives (increasing doses of chitosan or AVICEL) and a control group without food additives Days 3-4: addition of orlistat ( 300 umol / kg / day) Day 5: photographic record of oil greasing hair. Oil greasing of the hair was evaluated scoring daily with scores of 1 to 4: 1 represents an affectation of 0 to 25% of the skin, 2: 26-50% of skin affectation, 3: 50-75% of affectation of the skin, and 4: 75-100% of skin involvement. The involvement of the skin of the individual mice was added during the days from 3 to 5 (for example, 100% skin involvement during days 3-5 supposes that the score will be maximum, that is, 4 + 4 + 4 = 12 units). The hair greasiness score in the controls was 6.3 ± 1.6 units (mean ± SE). In the 7 groups of mice that received chitosan xx AVICEL against hair oil greasing, the extent of greasing was initially evaluated in accordance with the indicated score, and then expressed in% of the control groups, and finally averaged between the animals of each group. The results are shown in the table below: Oil lubrication (% of controls) in mice that ingest orlistat (300 μmol / kg / day) Food additive Chitosan AVICEL (glOO g food) 15 n. d. 1 1 ± 1 10 n. d. 29 ± 7 5 n. d. 53 ± 24 3 6+ 3 n. d. 1 37 + 16 n. d. 0. 3 53 ± 5 n.d. 0. 1 63 ± 9 n. d. n. d. = = not determined When the diet contained chitosan, the extent of greasing by hair oil was reduced. For example, compared to the controls, the same inhibition of 53% of the hair oil binding is obtained with a feed containing 5% by weight of AVICEL and only 0.3% by weight of chitosan. The compositions of the invention conveniently contain from 10 to 50, preferably from 20 to 40 parts by weight of chitosan or a derivative or a salt thereof, and from 10 to 200, preferably from 20 to 80 parts by weight, of auxiliary excipients per 1 part by weight of a gastrointestinal lipase inhibitor, such as orlistat. The composition of the invention can also be in the form of a commercial pack containing a gastrointestinal lipase inhibitor and chitosan or a derivative or salt thereof, with instructions for use for simultaneous, separate or chronologically spaced use in the treatment of obesity or hyperlipidemia. For the treatment or prevention of obesity or hyperlipidemia, a composition of the invention containing from 10 mg to 500 mg of a gastrointestinal lipase inhibitor, such as orlistat, and from 500 mg to 20 g, preferably from 2 to 10 g. g of an additional compound, such as chitosan, can be administered orally one, two or three times per day. The compositions of the invention can be presented in the form of drinkable formulations, such as solutions or suspensions, which can be reconstituted from powders, granules, pellets and tablets for reconstitution or effervescent. They can also be formulated in the form of chewable tablets, such as, for example, tablets, capsules or tablets. Additionally, the compositions can also be incorporated into food preparations, such as biscuits, cakes or bread, or they can be presented in the form of swallowable formulations, such as tablets or capsules. A preferred composition of the invention is a chewable tablet for the treatment of obesity, consisting essentially of orlistat as the active ingredient and in chitosan as the additional compound, in which the dose ranges from 10 to 120 mg of orlistat and from 0.5 to 5 g of chitosan. More preferably, the chewable tablet consists essentially of about 60 mg of orlistat and about 2.5 g of chitosan. A further preferred composition of the invention is a biscuit for the treatment of obesity, consisting essentially of orlistat as an active ingredient and in chitosan as the additional compound, in which the dose ranges from 10 to 200 mg of orlistat and from 1 to 10 g of chitosan. More preferably, the cookie consists essentially of about 120 mg of orlistat and about 5 g of chitosan. A preferred method for avoiding anal oil loss syndrome that occasionally occurs after oral administration of orlistat, comprises the oral administration of orlistat, comprises the oral administration of orlistat and chitosan in a dose of about 10 to 200 mg of orlistat, and 0.5 to 10 g of chitosan per main meal containing fats. Most conveniently, this method comprises the oral administration of orlistat and chitosan, the dose being from 10 to 120 mg of orlistat and from 2 to 6 g of chitosan, in particular about 60 mg of orlistat and about 2.5 g of chitosan per main meal containing fats. The following non-limiting examples illustrate the pharmaceutical preparations that can be produced by conventional procedures: EXAMPLE 1 The granules or pellets of chitosan for the simultaneous, separate or chronologically spaced administration of orlistat are prepared as follows: 50 g of chitosan (SEACURE 342) and 50 g of AVICEL RC-591 are mixed and kneaded with demineralised water until get an adequate consistency. The wet mass is sifted and then dried in a fluid bed to yield granules. Alternatively, the wet mass is extruded and spheronized and then dried in a fluid bed to obtain pellets. An amount of 5 g or 10 g of granules or pellets is filled into bags as unit doses. Alternatively, this material is filled into suitable containers. The dosage can be carried out with suitable spatulas.

Example 2 Powder for reconstitution: Orlistat 0.12 g Chitosan of low viscosity. { SEACURE 142) 5 g Sorbitol 7.11 g AVICEL CL 611 1.20 g ß-carotene 0.06 g Citric acid 0.10 g Methyl ester of p-hydroxybenzoic acid 0.15 g P-hydroxybenzoic acid propyl ester 0.03 g Flavoring agent (passion fruit) 0.13 g AVICEL PH 105 8.00 g Monosodium Citrate 1.00 g Sodium salt of saccharin 0.10 g Total 23.00 g An oral suspension is obtained by adding tap water to the above powder to a volume of about 100 ml.

Example 3 Granules or pellets: Orlistat 0.120 g Chitosan (SEACURE 242) 5.0 g AVICEL PH 101 4.88 g The above ingredients are mixed and kneaded with demineralized water until the proper consistency is obtained. The wet mass is screened and dried in a fluid bed at a temperature below 35 ° C to yield the granules. Alternatively, the wet mass is extruded and spheronized, and then dried in a fluid bed to obtain the pellets. An amount of 10 g of granules or pellets is filled into sachets as unit doses. Alternatively, this material is filled into suitable containers. The dosage can be carried out with suitable spatulas.

EXAMPLE 4 Effervescent tablets: Orlistat 0.120 g Sucrose powder 1,669 g Chitosan of low viscosity (SEACURE 142) 2.5 g Sodium cyclamate 0.115 g Sodium salt of saccharin 0.004 g Sodium bicarbonate 0.7 g Tartaric acid (crystallized ^ 1.12 g Sodium chloride (ground) 0.04 g Quinine Sulfate 0.007 g Flavoring agent 0.025 g Total 6.3 g The orlistat, the sucrose, the chitosan, the sodium cyclamate and the sodium saccharin are mixed and sieved. The mixture is kneaded with a mixture of ethanol and demineralized water, granulated and dried at a temperature below 35 ° C in a fluid bed to yield the mixture A. Sodium bicarbonate, tartaric acid, sodium bicarbonate are mixed and sieved. Sodium chloride, quinine sulfate and flavoring agent to yield a mixture B. A and B are mixed and compressed into effervescent tablets of 6 ^ 3 g and a diameter of 30 mm.

Example 5 Chewable tablets: Orlistat 0.060 g Chitosan (SEACURE 242) 2.5 g Sorbitol 1.84 g AVICEL CE-15 1.0 g Talc 0.480 g Sodium stearyl fumarate 0.120 g Total 6.0 g Orlistat, chitosan, sorbitol and AVICEL CE-15 are mixed and sieved. Sodium talc and stearyl fumarate are screened and mixed with the first mixture obtained, and then compressed as 6.0 g chewable tablets, and a diameter of 2 cm.

EXAMPLE 6 Chitosan cookies for the simultaneous, separate or chronologically spaced administration of orlistat are prepared as follows: Corn flour (5 g) and 5 g of chitosan are mixed. Soybean oil (2 g) is added and the mixture is mixed for 15 minutes. Water is added to form a wet mass which is then extruded. The wet cookies are dried in an oven at 35 ° C and then packaged.

Example 7 Cookies: Chitosan 5 g Soybean oil 2 g Cornmeal 5 g Orlistat 120 mg The process is the same as in Example 6, except that orlistat is first dissolved in soybean oil and added to the mixture. After wet kneading with water and extrusion, the cookies are dried at 35 ° C.

Example 8 Biscuits: the proportions of the ingredients and the procedure are the same as described in Example 7, except that the soybean oil is replaced by ground tripalmitin.

EXAMPLE 9 Chitosan cookies for the simultaneous, separate or chronologically spaced administration of orlistat are prepared as follows: Chitosan (5 g) and 5 g of bad todextrin are mixed.

Ground tripalmitin (2 g) is added to the mixture. The mass is then moistened with water and the wet mass is extruded. The cookies are dried at 35 ° C.

Example 10 Cookies: Chitosan 5 g Maltodextrin 5 g Tripalmitin g Orlistat 120 mg The process is the same as described in Example 9, except that orlistat is dissolved in ground tripalmitin, and then added to the mixture. The cookies are dried at 35 ° C. 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.

Claims (9)

1. Having described the invention as above, the content of the following claims is claimed as property: 1. Pharmaceutical composition for oral administration, characterized in that it contains a gastrointestinal lipase inhibitor, one (or more) additional compound (s) of the group consisting of chitosan, its derivatives and salts thereof, and auxiliary excipients.
2. 2. A composition according to claim 1, characterized in that it comprises from 500 mg to 20 g, preferably from 2 to 10 g of the additional compound (s) and from 10 mg to 500 mg of a lipase inhibitor. gastrointestinal
3. 3. A composition according to claim 1 or 2, characterized in that the inhibitor of gastrointestinal lipases is orlistat.
4. 4. A composition according to claim 1, 2 or 3, characterized in that the additional compound is chitosan.
5. 5. The use of chitosan, its derivatives or its salts for the manufacture of a medicament for the treatment or prevention of anal oil loss syndrome that occurs occasionally after oral administration of a gastrointestinal lipase inhibitor, such as orlistat, or after the ingestion of foods that contain non-absorbable or nonabsorbable fats or oils or substitutes for non-digestible oily fats.
6. 6. A composition according to claim 3 or 4 which is a chewable tablet for the treatment of obesity, characterized in that it consists essentially of orlistat as an active ingredient and in chitosan as an additional compound, in which the dose ranges from 10 to 120 mg of orlistat, and 0.5 to 5 g of chitosan.
7. 7. The chewable tablet according to claim 6, characterized in that the dose is approximately 60 mg of orlistat and approximately 2.5 g of chitosan.
8. 8. A composition according to claim 3 or 4, characterized in that it is a biscuit for the treatment of obesity, consisting essentially of orlistat as an active ingredient and chitosan as an additional compound, in which the dose is from 10 to 200 mg of orlistat and from 1 to 10 g of chitosan.
9. 9. The cookie according to claim 8, characterized in that the dose is approximately 120 mg of orlistat and approximately 5 g of chitosan.