Pharmaceutical composition comprising a lipase inhibitor and glucomannan

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DESCRIPTION

Pharmaceutical composition comprising a lipase and glucomannan inhibitor.

The present invention relates to pharmaceutical compositions and their use for the preparation of a medicament for preventing and treating obesity. More particularly, the invention relates to a composition comprising a lipase inhibitor, preferably a compound of the formula (orlistat),

<img file="ES2335876T3_D0001.tif" />

and glucomannan, optionally containing one or more pharmaceutically acceptable excipients,

Unfavorable effects occasionally seen in patients treated with lipase inhibitors are anal oil leakage (oily spotting) and fecal incontinence. The oily staining appears as a result of the physical separation of some ingested but not absorbed dietary fats, from the volume of the fecal mass found in the colon.

In US Pat. No. 5,447,953, it has been shown that by combining a lipase inhibitor with substantial amounts of water-insoluble crude fibers, the inhibitory effect of fat absorption can be increased. International patent application WO 00/09123 shows that, by combining a lipase inhibitor such as orlistat with small amounts of cytosan, or a derivative or a salt thereof, the phenomenon of anal oil leakage can be strongly reduced. .

Several studies have been conducted to address the problem, focused on controlling the leak, and these have been discussed. Such strategies include i) the use of a surfactant to stabilize the oil / water interface, in order to prevent coalescence of the oil emulsion in the colon, ii) intensify the viscosity of the water in the colon, in order to reduce both the intensity and the frequency of droplet-droplet interactions and thereby reduce the probability of coalescence, iii) the physical absorption of oil by a lipophilic compound, or (iv) increase in natural volumetric mass, facilitating bacterial growth in the colon. The last study leading to solving the problem can be carried out, both by administering a prebiotic material (for example, a lactobacillus), and by ingesting fermentable fibers that act as substances for bacterial growth.

Surprisingly, konjac, for example konjac flour, and especially glucomannan, has now been found to be active in reducing gastrointestinal adverse events (GI-AE). ]) commonly observed after administration of a lipase inhibitor, such as orlistat, or after ingestion of artificial fat substituents.

Konjac (Amorphophallus konjac), is a plant whose tuber is a source of a well-known first food material in China and Japan, namely the so-called konjac flour. This flour comprises a highly viscous glucomannan sol and soluble starches, when reconstituted in water. The main constituent is glucomannan (formula II), a polysaccharide composed of D-glucose and D-mannose, which is useful as an ingredient in various food raw materials, as well as in industrial applications, such as films, drilling fluids, and paints.

<img file="ES2335876T3_D0002.tif" />

In accordance with the foregoing, the present invention refers to a composition comprising a lipase inhibitor and glucomannan, as defined in the claims.

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Unless otherwise indicated, the definitions given below are set forth to illustrate and define the meanings and scopes of the various terms used to describe the invention presented herein.

The term "lipase inhibitor" refers to compounds which are capable of inhibiting the action of lipases, for example gastric and pancratic lipases. Thus, for example, orlistat and lipstatin, as described in US Patent No. 4,589,089, are potent lipase inhibitors. Lisptatin is a natural product of microbial origin and orlistat is the result of a hydrogenation of lipstatin. Other lipase inhibitors include a class of compounds commonly referred to as panclicins. Panclycins are orlistat analogs (Mutoh et al., J. Antibiot. 47 (12): 1369-1375 (1994)). The term "lipase inhibitor" also refers to polymer-bound lipase inhibitors, such as those described in international patent application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized by the fact that they have been substituted with one or more groups that inhibit lipases. The term "lipase inhibitor" also encompasses pharmaceutically acceptable salts of these compounds. The term "lipase inhibitor" also refers to 2-oxy4H-3,1-benzoxacin-4-ones, which have been described in international patent application WO 00/40569 (Alizyme Therapeutics Ltd.), for example , 2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one, 6-methyl-2-tetradecyloxy-4H-3,1-benzoxazin-4-one, and 2-hexadecyloxy-6-methyl -4H-3,1-bezoxazin-4-one and other oxetanones described for example in international patent applications WO 01/32616, WO 01/32669 and WO 01/32670. Most preferably, the term "lipase inhibitor" refers to orlistat.

Orlistat is a known compound that is useful for the control or prevention of obesity and hyperlipidemia. See, for this purpose, US Patent No. 4,598,089, published on July 1, 1986, which also discloses processes for the manufacture of orlistat, and also US Patent No. 6,004,996, which discloses appropriate pharmaceutical compositions. Additional suitable pharmaceutical compositions are described, for example, in international patent applications WO 00/09122 and WO 00/09123. Additional procedures for the preparation of orlistat are disclosed in European Patent Application Publication Nos. 185,359, 189,577, 443,449 and 524,495.

Orlistat is preferably administered orally, in dosages ranging from 60 to 720 mg per day, in divided doses corresponding to two or three times per day. Dosages where 180 to 360 mg per day, preferably 360 mg per day, of a lipase inhibitor, are administered to an individual, preferably in divided doses, twice or, in a particular way, are preferred. , three times a day. The individual is preferably an overweight or obese human, eg, a human, with a body mass index of 25 or higher. Generally, it is preferred that the lipase inhibitor is administered within about an hour to two hours of ingestion of a fat-containing meal.

Orlistat can be administered to humans in conventional oral compositions, such as, for example, tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers that can be used for tablets, coated tablets, lozenges, and hard gelatin capsules are lactose, other sugars, and sugar alcohols, such as sorbitol, mannitol, maltodextrin, or other fillers; surfactants, such as sodium lauryl sulfate, Brij 96, or Twenn 80; disintegrants, such as sodium starch glycolate; corn starch, or derivatives thereof; polymers, such as providone and crosspovidone, talc, stearic acid or their salts, and the like. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-liquid and liquid polyols, and the like. In addition, the pharmaceutical preparations can contain preserving agents, solubilizers, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents, salts for varying the osmotic pressure, buffers, coating agents and antioxidants. These can also contain other therapeutically acceptable substances. The formulations may be conveniently presented in dosage unit form and may be prepared by any procedures known in the art of pharmaceutical art. Orlistat is preferably administered according to the formulations shown in the examples and in US Patent No. 6,004,996, respectively.

The term "konjac flour" refers to a hydrocolloidal polysaccharide obtained from tubers of Amorphophallus konjac species. The perennial tuber is unique in Asia and is grown especially in Japan. Konjac flour is a high molecular weight, nonionic glucomannan consisting primarily of glucose and mannose molecules, combined in a 1.6: 1.0 molar ratio. This is a slightly branched polysaccharide, connected with 1-4 beta links, and has an average molecular weight in the range of 200,000 to 2,000,000 daltons. Acetyl groups arranged along the glucomannan chain contribute to its solubility and are located, on average, in every 9 to 19 sugar units. Refined konjac flour is easily soluble in cold water and forms a highly viscous solution with a pH value between 4.0 and 7.0. The addition of a mild alkaline solution results in the formation of a heat stable gel that resists melting, even under extended heat conditions. The purification process for konjac flour is carried out in large-scale plant extraction. Konjac tubers are first pulverized, and then the collected glucomanan particles are cleaned to dislodge and remove harmful materials adhering to them. This process provides a refined konjac flour, with a high degree of purity, which improves the solubility, stability and functionality of the product as a whole. The particles are tasteless, odorless and white in color.

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Konjac flour and glucomannan (PROPOL®, RHEOLEX®) are commercially available products (Kyoei Konnyaku, Inc., Behr. Wunderlich &amp; Co. Provisco, FMC Biopolimers, Naturland, SiberHegner and Co. Ltd.). The preparation and use has been described, for example, in US Patent Nos. 3,767,424, 3,973,007, 4,588,589, 5,486,364, 5,486,364, 5,733,593, 5,536,521, 6,126,906.

The term "pharmaceutically acceptable" as used herein means that the corresponding compounds are acceptable from a toxicity standpoint.

In greater detail, the present invention relates to a pharmaceutical composition comprising a lipase inhibitor and glucomannan. Optionally, this composition may contain one or more pharmaceutically acceptable excipients. Glucomannan can be provided in the form of konjac. Konjac preferably contains at least 80% glucomannan, preferably at least 90% glucomannan. The glucomannan, or konjac, may be provided in the form of konjac powder, for example, in the form of konjac flour. Preferably, the lipase inhibitor is orlistat.

Pharmaceutically acceptable compositions incorporating both a lipase inhibitor and glucomannan compound correspond to important presentation forms in accordance with the present invention. Such types of pharmaceutical compositions comprise a pharmaceutically acceptable amount of each of the compounds. Each dosage unit may contain the daily doses of both compounds, or it may contain a fraction of the daily dose, such as one third of the doses. Alternatively, each dosage unit may contain the entire dose of one of the compounds, and a fraction of the dose of the other compound. In such a case, the patient would ingest one of the combination dosage units daily, and one or more units containing only the compound.

In a preferred presentation form of the present invention, the composition comprises, a) 0.1 to 20% (weight / weight) of lipase inhibitor, b) 10 to 75% (weight / weight) of konjac, and c) 0.1 to 90% (weight / weight), of one or more pharmaceutically acceptable excipients. More preferably, a composition may comprise a) 0.1 to 10% (w / w) lipase inhibitor, b) 20 to 75% (w / w) konjac , and c) from 0.1 to 90% (weight / weight), of one or more pharmaceutically acceptable excipients. Preferably , the amount of one or more pharmaceutically acceptable excipients is 5 to 50%, more preferably 5 to 20%. In more detail, the composition may contain a) from about 5 to about 1000 mg of lipase inhibitor, for example orlistat, in an amount of for example about 10 to about 500 mg of lipase inhibitor, preferably, from about 20 to about 100 mg of lipase inhibitor, for example, from about 10 to about 360 mg of orlistat, more preferably, from about 30 to about 120 mg of orlistat much more preferably, from about 40 to about 80 mg of orlistat, and b) from about 0.5 to about 10 g of glucomannan, preferably from about 0.5 to about 8 g of glucomannan and more preferably about 0.5 to about 6 g of glucomannan.

Pharmaceutically acceptable excipients can be selected from the group consisting of fillers, surfactants, disintegrants, binders, lubricants, flow improvers, sweeteners, and colorants, for example, a composition may contain a) from about 5 to about 1000 mg of lipase inhibitor; b) from about 0.5 to about 10 g of glucomannan; and optionally, pharmaceutically acceptable excipients selected from the group and amounts corresponding to, from about 0.1 g to about 10 g of fillers, from about 0.05 to about 5.0 g of surfactants (surfactants), from about 0.05 to about 2.0 g of disintegrants, from about 0.02 to about 5.0 g of binder, from about 0.001 to about 1.0 g of lubricants, from about 0.1 to about 5.0 g of flow improvers, from about 0.01 to about 4.0 g of sweeteners, and from about 0.001 to about 0.5 g of colorants.

The pharmaceutically acceptable excipients may be selected from the group consisting of fillers, for example, sugars and / or sugar alcohols, for example, lactose, sorbitol, mannitol, maltodextrin, etc .; surfactants, eg, sodium lauryl sulfate, TPGS, Brij 96 or Tween 80; disintegrants, for example sodium starch glycolate, cornstarch or derivatives thereof; binders, eg, povidone, crosspovidone, (cross povidone), polyvinyl alcohols, hydroxypropylmethylcellulose; lubricants, for example stearic acid or its salts; flow improvers, for example silicon dioxide; sweeteners, for example aspartame; and / or colorants; for example β-carotene.

In a preferred embodiment of the present invention, the composition comprises, a) from about 0.1 to about 20% (w / w) lipase inhibitor; b) from about 10 to about 75% (w / w) glucomannan, and optionally, pharmaceutically acceptable excipients, selected from the group and amounts consisting of about 0.1 to about 20% (w / w) fillers, from about 0.1 to about 10% (w / w) surfactants, from about 0.1 to about 10% (w / w) disintegrants, from about 0.1 to about 10% (w / w) binder, from about 0.1 to about 10% (w / w) lubricants, from about 0.1 to about 10% ( weight / weight) of flow improvers, from about 0.1 to about 10% (weight / weight) of sweeteners, and from about 0.1 to about 5% (weight / weight) of colorants.

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In greater detail, the composition may contain a) from about 5 to about 1000 mg of lipase inhibitor, for example, orlistat, in an amount comprised, for example, within ranges of from about 10 to about 500 mg of lipase inhibitor, preferably about 20 to about 100 mg of lipase inhibitor, for example, about 10 to about 360 mg orlistat, more preferably, from about 30 to about 120 mg of orlistat, much more preferably from about 40 to about 80 mg of orlistat and, b) from about 0.5 to about 10 g of glucomannan, preferably from 0.5 to about 8 mg glucomannan, and more preferably about 0.5 to about 6 g glucomannan.

Oral dosage forms are the preferred compositions for use in the present invention, and these are the known pharmaceutical forms for such type of administration, for example, tablets, capsules, bars, sachets, granules, syrups and aqueous suspensions and oily. Pharmaceutically acceptable excipients (diluents and carriers) are known in the art of the pharmaceutical art. Tablets can be formed from a mixture of charged active compounds, eg, calcium phosphate; disintegrating agents, for example cornstarch, lubricating agents, for example magnesium stearate; binders, for example, microcrystalline cellulose, or polyvinylpyrrolidone and other optional ingredients known in this specialized art of the art, which allow the formation of tablets with the mixture, by known procedures. In a similar way, capsules, for example hard and soft gelatin capsules, containing the active compound with or without added excipients can be prepared by known procedures. The contents of the capsule can be formulated using known procedures in such a way that a sustained release of the active compound is obtained. Thus, for example, tablets and capsules may conveniently each contain the amounts of lipase inhibitor and glucomannan as described above.

Other forms for oral administration include, for example, aqueous suspensions containing the active compounds in an aqueous medium, in the presence of a non-toxic suspending agent, such as sodium carboxymethylcellulose, and oil suspensions containing the compounds. active ingredients in a suitable vegetable oil, for example, peanut oil, olive oil, or miristol 318. The active compounds can be formulated in granules (granules), with additional excipients, or without them. The granules can be ingested directly by the patient, or they can be added in an appropriate liquid carrier (eg water), prior to ingestion. The granules can contain disintegrants, for example, an effervescent couple, formed by an acid and a carbonate or bicarbonate salt, to facilitate dispersion in the liquid medium.

In the compositions of the present invention, the active compounds can be combined, if desired, with other pharmacologically compatible active ingredients. Optionally, with the compounds according to the present invention, vitamin supplements can be administered.

Both compounds, the lipase inhibitor and glucomannan, can be administered simultaneously, separately, or sequentially (eg, orlistat, as described above, and glucomannan at night). Preferably, the compounds or compositions are administered during a meal or 1-2 hours before or after a meal. The amount of glucomannan to be administered will depend on a large number of factors, including the age of the patient, the severity of the condition, and the patient's prior medical history, and will be at the discretion of the prescribing physician.

The invention also relates to compositions, as described above, for use in the treatment and prevention of obesity and to a process for the preparation of a composition as described above, comprising mixing of a glucomannan lipase inhibitor and optionally one or more pharmaceutically acceptable excipients.

The invention also relates to a kit, by way of a "kit", for the treatment of obesity, said kit comprising a) a first component that is a lipase inhibitor and b) a second component, which is glucomannan , as defined above, for example, in oral unit dosage form, preferably comprising a) from 1 to 100 dose units of orlistat, and b) from 1 to 100 units dose of a glucomannan.

Another form of presentation of the present invention refers to a kit-like kit for the treatment of obesity, said kit-like kit comprising a) a first component which is a lipase inhibitor, and b) a second component, which is a glucomannan in oral unit dose form.

The present invention also relates to the use of the composition, as defined above, in the manufacture of drugs useful for the treatment and prevention of obesity and to the use of a lipase inhibitor, such as defined above, in the manufacture of a medicament for the treatment and prevention of obesity, in a patient, who is also receiving glucomannan treatment, as defined above, up. This use of glucomannan and lipase inhibitor refers to the simultaneous, separate or sequential use for the treatment and prevention of obesity. Additionally, the invention relates to a method for the treatment of obesity in a human who is in need of said treatment, which comprises the administration, to the human, of a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of glucomannan, as defined above,

ES 2 335 876 ​​T3 above. The procedure refers to the simultaneous, separate or sequential administration of the compounds. A further presentation form of the present invention is a lipase and glucomannan or kojac inhibitor, as defined above, as a combination prepared for simultaneous, separate or sequential use for the treatment and prevention of obesity. . The invention also relates to the use of glucomannan or konjac, as defined above, in the manufacture of useful drugs for the treatment and prevention of gastrointestinal side effects, selected from the group of oily staining, volumetric masses greasy / oily, fecal urgency, increased defecation and fecal incontinence, and a procedure for the treatment or prevention of gastrointestinal side effects, selected from the group of oily staining, greasy / oily volumetric masses, fecal urgency, increased defecation and fecal incontinence, in a human who is in need of such type of treatment, which comprises, the administration to the human, of a therapeutically effective amount of konjac or glucomannan, as defined above. Additionally, the invention relates to a lipase and glucomannan or konjac inhibitor, as defined above, for simultaneous, separate or sequential use for the treatment and prevention of obesity.

The invention will be better understood by reference to the examples below, which illustrate the invention described herein.

Figures (edit)

Figure 1 shows konjac test emulsions, after centrifugation at 3100 g, for time courses t = 1 minute (a), and t = 300 minutes (b), respectively. After a centrifugation time of t = 300 minutes, only a weak stabilization of the emulsion is observed, in emulsions containing konjac in concentrations greater than 1.5% (weight / weight).

Figure 2 shows konjac test emulsions after centrifugation at 3100 g, for time courses t = 1 minute (a), and t = 300 minutes (b), respectively. The emulsions contained 1.0% (weight / weight) of konjac, at different pH values. After a centrifugation time of t = 300 minutes, less stabilization was observed, at pH 6 and pH 7, respectively. For all other emulsions, extensive coalescence was observed.

Figure 3: shows the free oil reduction effect of different types of glucomannan, in% relative to controls (data as means ± SE).

Examples

Example 1

In vitro studies

It has now been observed, surprisingly, that glucomannan is active in the reduction of gastrointestinal adverse effects (GI-AE), commonly observed after the administration of a lipase inhibitor, such as orlistat. .

The interaction of konjac (glucomannan source) with water and oil was examined by means of an absorption test. Samples of the compound were contacted with either soybean oil or simulated intestinal fluid (SIF - phosphate buffer without pancreatin) and incubated for a period of 24 hours. hours, at a temperature of 37 ° C. The remaining liquid was separated from the solid material, by means of centrifugation (3x5 minutes at 3100 g). While significant swelling was observed in the polymer SIF, no swelling occurred in the soybean oil. The absorption capacity of SIF and soybean oil of konjac was calculated at 4.8 g / g and 0.5 g / g, respectively. The reduced amount of oil binding demonstrates its poor lipophilicity.

The coalescence behavior of the konjac-stabilized emulsions was tested using a centrifugal procedure. With this in vitro procedure, both parameters consisting of the stability of the emulsions, dependent on the concentration and the pH value, were examined. The results of these stability studies are compiled in tables 1 and 2. The use of konjac, in a percentage less than 0.5% (w / w), revealed very unstable emulsions that resulted in a rapid oil / water phase separation (table 1). Even at konjac concentrations of 1.0% (w / w), the emulsions remained somewhat unstable and a clear phase separation was obtained after 10 minutes of centrifugation. Only the emulsions containing more than 1.0% (weight / weight), showed, after centrifugation times of up to t = 300 minutes, a medium stability, with the emulsion practically broken (figure 1).

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TABLE 1

Stability of test emulsions, at various concentrations c and centrifugation times t

<td>c (% w / w)¹⁾</td><td colspan="9">Stability of the emulsions, with Konjac t / minute</td>

<td></td><td> 1</td><td> 10</td><td> 40</td><td> 70</td><td> 100</td><td> 130</td><td> 160</td><td> 220</td><td> 300</td>

<td> 0.01</td><td> 1 *</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>L</td><td> 1</td><td> 1</td><td> 1</td>

<td> 0.1</td><td>L</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>L</td><td> 1</td><td> 1</td><td> 1</td>

<td> 0.5</td><td>L</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>L</td><td> 1</td><td> 1</td><td> 1</td>

<td> 1.0</td><td>M</td><td>m</td><td> 1</td><td> 1</td><td> 1</td><td>L</td><td> 1</td><td> 1</td><td> 1</td>

<td> 1.5</td><td>H</td><td>m</td><td>m</td><td>m</td><td>m</td><td>M</td><td>m</td><td>m</td><td>m</td>

<td> 2.0</td><td>H</td><td>m</td><td>m</td><td>m</td><td>m</td><td>M</td><td>m</td><td>m</td><td>m</td>

1) = (% w / w) * 1 = low stability: oil and water form two clearly separated distinct phases, m = medium stability: partially broken emulsion;

h = high stability: no indications of coalescence, optionally stable non-transparent emulsion.

Figure 1 shows konjac test emulsions, after centrifugation at 3100 g, for time courses t = 1 minute (a), and t = 300 minutes (b), respectively. After centrifugation times of t = 300 minutes, only a weak stabilization of the emulsion is observed, in emulsions containing konjac, at concentrations greater than 1.5% (weight / weight).

In order to investigate the stability of the emulsions at different pH values, emulsions were prepared with constant concentrations of c = 1.0% (weight / weight), which covered the range between 4 to 9 (table 2). A very poor emulsion of the test emulsions was observed at both extremes of pH values ​​of 4 and 9, resulting in an instantaneous lamination of the oil phase. While, at pH values ​​of 8, short centrifugation times of less than 30 minutes also led to a complete breakdown of the emulsion, emulsions at pH = 5 revealed slightly higher stability. Here, the coalescence occurred at centrifugation times greater than 60 minutes. The optimum pH, in terms of stability of the emulsion, was observed to correspond to one acidic to neutral pH values ​​(pH values ​​of 6-7).

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TABLE 2

Stability of konjac test test emulsions, at various pH values ​​and centrifugation times t

<td>pH</td><td colspan="5">Stability of emulsions with Konjac t / minutes</td>

<td></td><td> 1</td><td> 30</td><td> 60</td><td> 120</td><td> 300</td>

<td> 4</td><td> 1 *</td><td>L</td><td> 1</td><td>L</td><td>L</td>

<td> 5</td><td>m</td><td>M</td><td>m</td><td>L</td><td>L</td>

<td> 6</td><td>m</td><td>M</td><td>m</td><td>M</td><td>M</td>

<td> 7</td><td>m</td><td>M</td><td>m</td><td>M</td><td>M</td>

<td> 8</td><td>m</td><td>L</td><td> 1</td><td>L</td><td>L</td>

<td> 9</td><td> 1</td><td>L</td><td> 1</td><td>L</td><td>L</td>

* 1 = low stability: oil and water form two distinct phases clearly separated, m = medium stability: partially broken emulsion;

h = high stability: no indications of coalescence, optionally stable non-transparent emulsion.

Figure 2 shows konjac test emulsions after centrifugation at 3100 g, for time courses t = 1 minute (a), and t = 300 minutes (b), respectively. The emulsions contained 1.0% (weight / weight) of konjac, at different pH values. After a centrifugation time of t = 300 minutes, a lower stabilization of the emulsions was observed, at pH 6 and pH 7, respectively. For all other emulsions, extensive coalescence was observed.

Konjac solutions were prepared with concentrations of 0.01%, 0.1%, 0.5%, 1.0%, 1.5% and 2.0% (weight / weight), in simulated intestinal fluid ( SIF), without pancreatin, according to USP XXII, page 1789 (pH = 7.5, potassium dihydrogen phosphate buffer). To 18 g of this solution, 2 g of soybean oil (FLUKA, 85471) were added, which gave a final concentration of oil with respect to the aqueous phase of 10% w / w. The soybean oil was not purified and was used as received. Emulsions were then prepared using a Miccra homogenization apparatus, at an angular speed of 28,000 revolutions per minute, (level E) and a homogenization time of 1 minute. As a reference, mixtures of soybean oil and phosphate buffer were used, without the addition of a surfactant. Staining of the emulsion with nile red and subsequent analysis under an optical microscope revealed the fact that the emulsions were of the oil-in-water type. Performing a mean size droplet analysis, after preparation using a Galai CIS-1 apparatus, provided values ​​of typically 20-30 pm. Glass capillaries with a height of approximately 95 mm and a diameter of approximately 1.7 mm (glass thickness, approximately 0.8 mm), up to approximately 6.5 cm, were filled with the prepared emulsions, by means of a syringe, and centrifuged at a maximum speed of 5000 revolutions per minute (Eppendor, Centrifuge 5403, Rotor No. 16A4-44), which corresponds to a centrifugal force of 3100 g (bottom of the glass capillary). In order to record the demulsion process, the centrifugation process was interrupted at defined time intervals (t = 1, 10.40, 70, 100, 130, 160, 220, 300 minutes) and the capillaries were placed in an optical scanner, operating in transition mode (Image Densimeter of the type Bio-Rad GS-700 Imaging Densiometer). The distance between the capillaries was kept constant by means of a sample holder made at home. All measurements were carried out at room temperature.

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Example 2

In vitro studies I

To test substances that ameliorate the oil-related side effects associated with orlistat treatment, an acute human model was developed.

Healthy volunteers received orlistat alone, or in combination with the test substance, for 3 consecutive meals (3-meal test). The modified orlistat formulations were given to the volunteers in order to record side effects. The most severe oil-related side effect is oily staining (uncontrolled oil loss). This side effect is difficult to quantify in an appropriate way in an acute model, however, in some volunteers, a simultaneous separation of fat from formed volumes was observed. This amount of fat, called free oil (containing mainly triglycerides), was isolated and weighed.

The amount of free oil was used as a surrogate marker for oily staining, since this is considered necessary for the appearance of oily staining.

Two clinical studies were conducted to investigate the adverse gastrointestinal event modifying effects of numerous substances. It appears that volunteers show individual sensitivity to gastrointestinal side effects related to orlistat. Thus, therefore, each volunteer was used as their own control (orlistat treatment only). Volunteers showing weak sensitivity to orlistat side effects were excluded from the trial test evaluations. For a given volunteer, a substance is considered positive when the amount of free oil is reduced to less than 50%, compared to the control value (orlistat only).

Glucomannan was tested as a konjac powder. Konjac powder is obtained from the root of a tree (Amorphophallus konjac), and this is the natural source of glucomannan. This substance was subjected to a test test in the acute side effects model, at a dosage of 4 g / flour. Among the 5 volunteers tested (2 during the BP 16191 test, 3 during the NP 16227 / arm 2 test), 4 had a decrease of at least 50% of free oil generated without GINCA (see appendix 2, table 2). The volunteers treated with glucomannan / orlistat, did not have a decrease in fat excretion, (compared to the volunteers treated with orlistat alone, data not shown), suggesting that there was no interaction of glucomannan with orlistat. No increased AEs (acute side effects) were associated with glucomannan treatment.

TABLE 3

Results with konjac (glucomanan)

<td rowspan="2">Glucomannan (Konjac; 4g / meal)</td><td colspan="2">Free oil production (g / week)</td>

<td>orlistat</td><td>Orlistat + Konjac</td>

<td>Trial test 1</td><td> 11 9</td><td> 8 0</td>

<td>Trial test 2</td><td> 39 17 40</td><td> 16 8 6</td>

<td>Positive / total (50% &lt;control)</td><td colspan="2"> 4/5</td>

Example 3

In vitro studies II

Results from in vitro experiments were further supported by studies carried out with an in vivo mouse model. The experiment is based on the observation of the fact that, the mice under the

ES 2 335 876 ​​T3 effect of a high fat diet, with treatment by orlistat or another lipase inhibitor, they distribute the free oil excreted on their skins, while they take care of themselves. Various types and formulations of glucomannan were examined for their ability to reduce or eliminate free oil production. The results obtained are shown in figure 3.

Example 4

Pharmaceutical compositions of orlistat

TO)

<td>Ingredient</td><td>Amount mg ​​/ Capsule</td>

<td>Orlistat</td><td> 120.00</td>

<td>Microcrystalline cellulose (AVICEL PH-101)</td><td> 93.60</td>

<td>Sodium starch glycolate (PRIMOJEL)</td><td> 7.20</td>

<td>Sodium lauryl sulfate</td><td> 7.20</td>

<td>Polyvinylpyrrolidone (Povidone K-30)</td><td> 12.00</td>

<td>talcum powder</td><td> 0.24</td>

<td>Total</td><td>240.24 i</td>

Process

1. Mix orlistat, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Granulate with a solution of polyvinylpyrrolidone and sodium lauryl sulfate, in purified water.

3. Pass the granulation through an extruder, and pass the extrudate through a spheronizer to form granules (pellets).

Four. Dry the granules at a temperature of 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

ES 2 335 876 ​​T3

B)

<td>Ingredient</td><td>Amount in mg / Capsule</td>

<td>Orlistat</td><td> 60</td>

<td>Cellulose microcrystalline</td><td> 46,8</td>

<td>Sodium starch glycolate</td><td> 3.6</td>

<td>Sodium lauryl sulfate</td><td> 3.6</td>

<td>Polyvinylpyrrolidone</td><td> 6.0</td>

<td>talcum powder</td><td> 0.12</td>

<td>Total</td><td>120.12 mg</td>

Process

1. Mix orlistat, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Granulate with a solution of polyvinylpyrrolidone and sodium lauryl sulfate, in purified water.

3. Pass the granulation through an extruder, and pass the extrudate through a spheronizer to form granules (pellets).

Four. Dry the granules at a temperature of 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

C)

<td>Ingredient</td><td colspan="2">Amount in mg / Capsule</td>

<td>Orlistat</td><td> 60</td><td> 120</td>

<td>Lactose</td><td> 40</td><td> 80</td>

<td>Cellulose microcrystalline</td><td> 60</td><td> 120</td>

ES 2 335 876 ​​T3

<td>Sodium lauryl sulfate</td><td> 5.7</td><td> 11.4</td>

<td>Sodium starch glycolate</td><td> 20</td><td> 40</td>

<td>Polyvinylpyrrolidone</td><td> 10</td><td> 20</td>

<td>Tale</td><td> 0.2</td><td> 0.4</td>

<td>Total</td><td>195.9 mg</td><td>391.8 mg</td>

Process

1. Mix orlistat, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Granulate with a solution of polyvinylpyrrolidone and sodium lauryl sulfate, in purified water.

3. Pass the granulation through an extruder, and pass the extrudate through a spheronizer to form granules (pellets).

Four. Dry the granules at a temperature of 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

Example 5

Glucomannan Pharmaceutical Compositions

Composition

<td>Ingredient</td><td>Amount in g / chewable tablet</td>

<td>Glucomannan</td><td>1.5 g</td>

<td>Sorbitol</td><td>1.1 g</td>

<td>anhydrous lactose</td><td>0.376 g</td>

<td>talcum powder</td><td>0.16 g</td>

<td>Sodium stearyl fumarate</td><td>0.064 g</td>

<td>Total</td><td>3.2 g</td>

Process

1. Mix the glucomannan, sorbitol and lactose in a suitable mixer.

2. Pass the mixture in powder form through a sieve.

3. Add talc and sodium stearyl fumarate and mix.

Four. Directly compress the powder mixture into a chewable tablet.

ES 2 335 876 ​​T3

Example 6

Glucomannan Pharmaceutical Compositions

Composition

<td>Ingredient</td><td>Quantity in g / sachet</td>

<td>Glucomannan</td><td>4 g</td>

<td>Aspartame</td><td>0.5 g</td>

<td>beta-caroteño</td><td>0.001 g</td>

<td>Total</td><td>4,501 g</td>

Process

1. Fill glucomannan into a suitable high shear mixer.

2. Granulate with a colloidal solution / suspension of aspartame and beta-carotene in purified water.

3. Dry the granules at a temperature of 60 ° C.

Four. Pass the dry granulate through a sieve.

5. Fill into sachets.

Example 7

Glucomannan Pharmaceutical Compositions

Composition

<td>Ingredient</td><td>Amount in g / chewable tablet</td>

<td>Glucomannan</td><td>0.5 g</td>

<td>Lactose</td><td>0.5 g</td>

<td>Cellulose microcrystalline</td><td>1.31 g</td>

<td>Sodium lauryl sulfate</td><td>0.09 g</td>

<td>Sodium starch glycolate</td><td>0.3 g</td>

<td>Polyvinylpyrrolidone</td><td>0.15 g</td>

<td>talcum powder</td><td>0.15 g</td>

<td>Total</td><td>3.0 g</td>

ES 2 335 876 ​​T3

Process

1. Mix the glucomannan, lactose, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Dissolve sodium lauryl sulfate and polyvinylpyrrolidone in purified water.

3. Pass the granulation through an extruder, and pass the extrudate through a spheronizer to form granules (pellets).

Four. Dry the granules at a temperature of 30 ° C.

5. Add talc and mix.

6. Compress the granules to form a chewable tablet.

Example 8

Orlistat / glucomanan pharmaceutical compositions

Composition

<td>Ingredient</td><td>Amount in g / chewable tablet</td>

<td>Orlistat</td><td>0.06 g</td>

<td>Glucomannan</td><td>0.75 g</td>

<td>Lactose</td><td>0.5 g</td>

<td>Microcrist cellulose.</td><td>1.31 g</td>

<td>Sodium lauryl sulfate</td><td>0.09 g</td>

<td>Sodium starch glycolate</td><td>0.3 g</td>

<td>Polyvinylpyrrolidone</td><td>0.15 g</td>

<td>talcum powder</td><td>0.15 g</td>

<td>Total</td><td>3.31 g</td>

Process

1. Mix the orlistat, glucomannan, lactose, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Dissolve sodium lauryl sulfate and polyvinylpyrrolidone in purified water.

3. Granulate with the liquid.

5. Pass the granulation through an extruder, and pass the extrudate through a spheronizer to form granules (pellets).

6. Dry the granules at a temperature of 30 ° C.

5. Add talc and mix.

10. Compress the granules to form a chewable tablet.

ES 2 335 876 ​​T3

Example 9

Orlistat / glucomanan pharmaceutical compositions

Composition

<td>Ingredient</td><td>Quantity in g / sachet</td>

<td>Orlistat</td><td>0.12 g</td>

<td>glucomannan</td><td>4 g</td>

<td>Saccharose</td><td>2.8 g</td>

<td>beta-caroteño</td><td>0.001 g</td>

<td>Silicon dioxide</td><td>0.5 g</td>

<td>Total</td><td>7,421 g</td>

Process

1. Mix the orlistat, glucomannan and sucrose in a suitable mixer.

2. Mix in several portions with the beta-carotene and silicon dioxide mixture.

3. Fill into sachets.

Example 10

Orlistat / glucomanan pharmaceutical compositions

Composition

<td>Ingredient</td><td>Amount in g / chewable tablet</td>

<td>Orlistat</td><td>0.12 g</td>

<td>Glucomannan</td><td>2.0 g</td>

<td>Sodium starch glycolate</td><td>0.1 g</td>

<td>Cellulose microcrystalline</td><td>1.2 g</td>

<td>Sodium lauryl sulfate</td><td>0.03 g</td>

<td>Crospovidone</td><td>0.1 g</td>

<td>Aspartame</td><td>0.15 g</td>

<td>talcum powder</td><td>0.15 g</td>

ES 2 335 876 ​​T3

<td>Magnesium stearate</td><td>0.03 g</td>

<td>Total</td><td>2.85 g</td>

Process

1. Mix the orlistat, glucomannan, lactose, microcrystalline cellulose and sodium starch glycolate in a suitable mixer.

2. Granulate with a colloidal solution / suspension of lauryl sulfate and aspartame, in purified water.

3. Pass the granules through a sieve.

Four. Dry the granules at a temperature of 30 ° C.

5. Pass the dry granules through a sieve.

6. Mix with talc and magnesium stearate.

7. Compress to a chewable tablet.