Pharmaceutical composition comprising a lipase inhibitor and glucomannan

The subject of the invention is a pharmaceutical composition, a method for its preparation and its use, a kit for the treatment of obesity, a lipase inhibitor in the form of orlistat and glucomannan or konjac, the use of a lipase inhibitor in the form of orlistat, and the use of glucomannan or konjac.

Side effects that are sometimes seen in patients treated with lipase inhibitors include leakage of oil from the anus (oil spotting) and faecal incontinence. Oil spotting is the result of the physical release of some of the ingested but unabsorbed dietary fat from the stool in the colon.

US Patent 5,447,953 shows that by combining a lipase inhibitor with a large amount of water-insoluble crude fibers, the inhibitory effect on fat absorption can be increased. The international patent application WO 00/09123 shows that by combining a lipase inhibitor such as orlistat with a small amount of chitosan or a derivative or salt thereof, the leakage of anal oil can be significantly reduced.

Various approaches to controlling rectal oil leakage are discussed. Such methods include i) the use of a surfactant to stabilize the oil / water interface, to reduce the coalescence of the oil emulsion in the colon, and ii) to increase the viscosity of the colon water to reduce the severity and frequency of drop-to-drop interactions and thereby reduce the probability of coalescence, iii) physically absorbing the oil by the lipophilic compound; or iv) increasing the natural weight of the stool by facilitating the growth of bacteria in the colon. The latter approach can be accomplished by feeding prebiotic material (e.g., lactobacilli) or by ingesting fermentable fibers to act as a substrate for bacterial growth.

It has been surprisingly observed that konjac, e.g. konjac meal, and in particular glucomannan, have the effect of reducing gastrointestinal side effects (GI-AE), often observed after administration of a lipase inhibitor such as orlistat, or after ingestion of artificial fat substitutes.

Konjac (AmorphophalIus konjac) is a plant whose tuber is the source of a well-known food product in China and Japan, that is, konjac meal. This flour, when reconstituted with water, forms a highly sticky sol of glucomannan and soluble starches. Its main soluble component is glucomannan (formula II), a polysaccharide composed of D-glucose and D-mannose which is useful as an ingredient in various food products and in industrial applications such as films, muds and paints.

<img file="PL216022B1_D0001.tif" />

M = D-Mannose, G = D-Glucose

WO 02/00201 discloses a process for the preparation of a sponge or foam composition. Orlistat was mentioned as the most preferred active ingredient. Numerous polyols, gums, polymers or pharmaceutically acceptable salts thereof are mentioned as glass matrix forming or depositing materials, including glucomannan.

However, the present invention is based on a deliberate choice resulting from the unexpected finding that glucomannan reduces gastrointestinal side effects associated with the administration of lipase inhibitors. This unexpected effect has so far not been revealed or suggested anywhere.

The invention relates to a pharmaceutical composition, characterized in that it comprises 5 - 1000 mg of a lipase inhibitor in the form of orlistat and 0.5 - 10 g of glucomannan.

Preferably the composition comprises one or more pharmaceutically acceptable excipients.

Preferably the composition comprises glucomannan as konjac.

A pharmaceutical composition wherein the konjac contains at least 80% glucomannan is preferred.

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A pharmaceutical composition is more preferred, wherein the konjac contains at least 90% glucomannan.

A pharmaceutical composition is preferred, wherein the konjac or glucomannan is konjac flour.

Preferably the composition comprises 0.5-8 g of glucomannan.

More preferably the composition comprises 0.5-6 g of glucomannan.

Preferably the composition comprises a pharmaceutically acceptable excipient selected from the group consisting of fillers, surfactants, disintegrants, binders, lubricants, flow agents, sweeteners and colorants.

Preferably the composition comprises

a) 5 - 1000 lipase inhibitor orlistat;

b) 0.5-10 g of glucomanann; and optionally pharmaceutically acceptable excipients selected from the group consisting of 0.1-10 g fillers, 0.05-5.0 g surfactants, 0.05-2.0 g disintegrants, 0.02-5.0 g binders , 0.001 - 1.0 g of lubricants, 0.1 - 5.0 g of flow agents, 0.01 - 4.0 g of sweetening agents and 0.001 - 0.5 g of coloring agents.

Preferably the composition comprises

a) 0.1 - 20 wt.% of the lipase inhibitor orlistat;

b) 10-75% by weight of glucomannann; and optionally pharmaceutically acceptable excipients selected from the group consisting of 0.1 - 20% by weight of fillers, 0.1 - 10% by weight of surfactants, 0.1 - 10% by weight of disintegrants, 0.1 - 10% by weight of binders, , 1 - 10% by weight of lubricants, 0.1 - 10% by weight of flow agents, 0.1 - 10% by weight of sweeteners and 0.1 - 5% by weight of colorants.

Preferably the composition comprises 10-500 mg of the lipase inhibitor as orlistat.

More preferably the composition contains 20-100 mg of the lipase inhibitor as orlistat.

Preferably the composition comprises 10-360 mg of orlistat.

More preferably the composition comprises 30-120 mg orlistat.

Even more preferably the composition comprises 40-80 mg of orlistat.

Preferably the composition comprises 0.5-8 g of glucomannan.

More preferably the composition comprises 0.5-6 g of glucomannan.

The invention relates to a composition as defined above for use in the treatment and prophylaxis of obesity.

The invention further relates to a process for the preparation of a composition as defined above, characterized in that the orlistat lipase inhibitor is mixed with glucoamannan and optionally with one or more pharmaceutically acceptable excipients.

The invention also relates to the use of a composition as defined above for the preparation of medicaments useful for the treatment and prevention of obesity.

The invention also relates to a kit for the treatment of obesity, characterized in that it comprises a) a first component which is an orlistat lipase inhibitor in an amount of 5-1000 mg, and b) a second component which is glucomannan in an amount of 0.5-10 g. , in oral unit dosage forms.

The invention further relates to a lipase inhibitor in the form of orlistat and glucomannan or konjac, as defined above, for simultaneous, separate or sequential use in the treatment and prophylaxis of obesity.

The invention also relates to the use of a lipase inhibitor orlistat as defined above for the manufacture of a medicament for the treatment and prophylaxis of obesity in a patient who is also administered glucomannan as defined above.

Preferably the use is for simultaneous, separate or sequential use in the treatment and prophylaxis of obesity.

The invention also relates to a lipase inhibitor in the form of orlistat and glucomannan or konjac, as defined above, in the form of a combined preparation for simultaneous, separate or sequential use for the treatment and prophylaxis of obesity.

The invention also relates to the use of glucomannan or konjac as defined above for the preparation of medicaments for the treatment or prophylaxis of gastrointestinal side effects associated with the administration of a lipase inhibitor orlistat selected from the group consisting of spotting.

Oily, greasy / oily stools, a sudden urge to defecate, severe defecation and faecal incontinence.

Unless otherwise stated, the following definitions are provided to illustrate and define the meaning and scope of the various terms used to describe the invention.

The term "lipase inhibitor" relates to compounds which are capable of inhibiting the action of a lipase, for example gastric lipase and pancreatic lipase. For example, orlistat and lipstatin, described in US Patent No. 4,598,089, are potent lipase inhibitors. Lipstatin is a natural product of microbial origin, and orlistat is produced by hydrogenation of lipstatin. Other lipase inhibitors include a group of compounds commonly called panclycins. Panclycins are analogs of orlistat (Mutoh et al., J. Antibiot., 47 (12): 1369-1375 (1994)). The term "lipase inhibitor" also refers to polymer-bound lipase inhibitors, eg as described in WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they are substituted with one or more groups that inhibit lipases. The term "lipase inhibitor" also includes the pharmaceutically acceptable salts of such compounds. The term "lipase inhibitor" also refers to 2-oxy-4H-3,1-benzoxazin-4-ones which are described in WO 00/40569 (Alizyme Therapeutics Ltd.), e.g. 2-decycloxy-6-methyl- 4H-3,1-benzoxazin-4-one, 6-methyl-2-tetradecycloxy-4H-3,1-benzoxazin-4-one and 2-hexadecycloxy-6-methyl-4H-3,1-benzoxazin- 4-one and other oxetanones described e.g. in WO 01/32616, WO 01/32669 and WO 01/32670. According to the present invention, the term "lipase inhibitor" refers to orlistat.

Orlistat, a compound of formula I.

<img file="PL216022B1_D0002.tif" />

is a known compound useful in the treatment or prevention of obesity and hyperlipidemia. See US Patent No. 4,598,089, issued Jul. 1, 1986, which also discloses methods for making orlistat, and US Patent No. 6,004,996, which discloses suitable pharmaceutical compositions. Other suitable pharmaceutical compositions are described, for example, in WO 00/09122 and WO 00/09123. Additional processes for the preparation of orlistat are disclosed in European Patent Application Publication Nos. 185359, 189577, 443449 and 524495.

Orlistat is preferably administered orally in an amount of 60-720 mg, in divided doses, two to three times a day. Preferably, the lipase inhibitor is administered to the subject in a dose of 180-360 mg, most preferably 360 mg per day, preferably in divided doses, two or in particular three times a day. The subject is preferably an obese human or an overweight human, i.e. a human having a body mass index of 25 or greater. It is generally preferred that the lipase inhibitor is administered within one or two hours of the consumption of a fatty meal.

Orlistat can be administered to humans in conventional oral compositions such as tablets, coated tablets, hard and soft gelatin capsules, emulsions or suspensions. Examples of carriers that can be used in tablets, coated tablets, dragées and hard 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 Tween 80; disintegrants such as sodium starch glycolate, corn starch or derivatives thereof; polymers such as povidone and crospovidone; talc; stearic acid or its salts, etc. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. In addition, the pharmaceutical preparations may contain preservatives, solubilizing agents, stabilizing agents, wetting agents, emulsifying agents, sweetening agents, coloring agents, flavoring agents. fragrances, salts for varying the osmotic pressure, buffers, coatings and antioxidants. They can also contain still other therapeutically valuable substances. The preparations may conveniently be presented in unit dosage form and may be prepared in any manner

By methods known in the pharmaceutical arts. Preferably, orlistat is administered in the formulation shown in the Examples below and in US Patent No. 6,004,996, respectively.

The term "konjac meal" refers to a hydrocolloidal polysaccharide obtained from tubers of the plant of the species AmorphophalIus konjac. This bulbous perennial is found only in Asia and is grown especially in Japan. Konjac flour is a high molecular weight non-ionic glucomannan, consisting mainly of mannose and glucose molecules combined in a molar ratio of 1.6: 1.0. It is a slightly branched polysaccharide, β 1-4 linked and has an average molecular weight of 200,000 - 2,000,000 Daltons. The acetyl groups located along the glucomannan skeleton contribute to its solubility and are located on average every 9-19 sugar units. Refined konjac flour is easily soluble in cold water and forms a very viscous solution with a pH of 4.0 - 7.0. The addition of a slightly basic solution leads to the formation of a thermostable gel that resists melting, even under prolonged heating conditions. The Konjac meal purification process is carried out in industrial extraction installations. Konjac tubers are first pulverized and then the collected glucomannan particles are polished to remove and extract harmful materials adhering to them. This process produces refined konjac flour with a high degree of purity which improves the solubility, stability and overall functionality of the product. The particles are tasteless, odorless and white in color.

Konjac meal and glucomannan (PROPOL®, RHEOLEX®) are commercially available products (Kyoei Konnyaku, Inc., Behr, Wunderlich &amp; Co., Provisco, FMC Biopolymers, Naturland, SiberHegner and Co. Ltd.). Their preparation and use are described e.g. in U.S. Patent Nos. 3,767,424, 3,973,007, 4,588,589, 5,486,364, 5,486,364, 5,733,593, 5536521, 6126906, etc.

The term "pharmaceutically acceptable" as used herein means that the corresponding compounds are toxicologically acceptable.

More particularly, the invention relates to a pharmaceutical composition comprising a lipase inhibitor and glucomannan. These compositions may optionally contain one or more pharmaceutically acceptable excipients. Glucomannan can be provided in the form of konjac. Preferably the konjac comprises at least 80% glucomannan, more preferably at least 90% glucomannan. The glucomannan or konjac may be provided in the form of a konjac powder, e.g. konjac meal. According to the invention, the lipase inhibitor is orlistat.

Pharmaceutical compositions containing both the lipase inhibitor compound and glucomannan are important embodiments of the invention. Such pharmaceutical compositions contain a therapeutically effective 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 dose. 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 may take one combined dosage unit and one or more units containing only the second compound per day.

In a preferred embodiment of the invention, the composition comprises a) 0.1 - 20% (w / w) of a lipase inhibitor, b) 10 - 75% (w / w) of konjac and c) 0.1 - 90% (w / w) of one or more pharmaceutically acceptable earnings. More preferably the composition may contain a) 0.1 - 10% (w / w) of a lipase inhibitor, b) 20 - 75% (w / w) of glucomannan and c) 0.1 - 90% (w / w) of one or more pharmaceutically acceptable excipients. Preferably the amount of the one or more pharmaceutically acceptable excipients is 5-50%, more preferably 5-20%. In particular, the composition may contain a) 5-1000 mg of a lipase inhibitor in the form of orlistat, in an amount of e.g. 10-500 mg of a lipase inhibitor, preferably 20-100 mg of a lipase inhibitor, e.g. 10-360 mg of orlistat, more preferably 30-120 mg of orlistat , more preferably 40-80 mg of orlistat, and b) 0.5-10 g of glucomannan, preferably 0.5-8 g of glucomannan, and more preferably 0.5-6 g of glucomannan.

The pharmaceutically acceptable excipients may be selected from the group consisting of fillers, surfactants, disintegrants, binders, lubricants, flow agents, sweeteners and colorants, e.g. the composition may contain a) 5 - 1000 mg of a lipase inhibitor; b) 0.5-10 g glucomannan and optionally pharmaceutically acceptable excipients selected from the group consisting of 0.1-10 g fillers, 0.05-5.0 g surfactants, 0.05-2.0 g disintegrants, .02 - 5.0 g of binding agent, 0.001 - 1.0 g of lubricants, 0.1 - 5.0 g of flow agents, 0.01 - 4.0 g of sweeteners and 0.001 - 0.5 g of coloring agents .

Pharmaceutically acceptable excipients may be selected from the group consisting of fillers, e.g. sugars and / or sugar alcohols, e.g. lactose, sorbitol, mannitol, maltodextrin and the like; surfactants, e.g. sodium lauryl sulfate, TPGS, Brij 96 or Tween 80; disintegrants, e.g. salt

Sodium starch glycolate, corn starch or derivatives thereof; binders, e.g., povidone, crospovidone, polyvinyl alcohols, hydroxypropyl methylcellulose; lubricants, e.g., stearic acid or its salts; flow promoters, e.g. silicon dioxide; sweetening agents, e.g. aspartame, and / or coloring agents, e.g. β-carotene.

In a preferred embodiment of the invention, the composition comprises a) 0.1 - 20% (w / w) of a lipase inhibitor; b) 10 to 75% (w / w) glucomannan and optionally pharmaceutically acceptable excipients selected from the group consisting of 0.1 - 20% (w / w) fillers, 0.1 - 10% (w / w) surfactants, 0.1 - 10% (w / w) of disintegrants, 0.1 - 10% (w / w) of binders, 0.1 - 10% (w / w) of lubricants, 0.1 - 10% (w / w) of free flowing agents, 0.1-10% (w / w) sweeteners and 0.1-5% colors.

In particular, the composition may contain a) 5-1000 mg of a lipase inhibitor in the form of orlistat, in an amount of e.g. 10-500 mg of a lipase inhibitor, preferably 20-100 mg of a lipase inhibitor, e.g. 10-360 mg of orlistat, more preferably 30-120 mg of orlistat , more preferably 40-80 mg of orlistat, and b) 0.5-10 g of glucomannan, preferably 0.5-8 g of glucomannan, and more preferably 0.5-6 g of glucomannan.

Oral dosage forms are the preferred compositions for use according to the invention and are the known pharmaceutical forms for such administration, e.g. tablets, capsules, bars, sachets, granules, syrups, and aqueous and oily suspensions. Pharmaceutically acceptable excipients (solvents and carriers) are known in the art of pharmacy. Tablets can be made from a mixture of the active compounds with fillers, for example calcium phosphate; disintegrants, e.g. corn starch, lubricants, e.g. magnesium stearate; binders, e.g. microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known to those skilled in the art, allowing the mixture to be tabletted by known methods. Likewise, capsules, e.g., hard or soft gelatin capsules, containing the active compound with or without the addition of excipients, can be prepared by known methods. The contents of the capsule can be formulated by known methods to achieve the sustained release of the active compound. For example, tablets and capsules may conveniently contain the above-mentioned amounts of the lipase inhibitor and glucomannan.

Other dosage forms intended for oral administration are, for example, aqueous suspensions containing the active compounds in an aqueous medium in the presence of a non-toxic suspending agent such as sodium carboxymethyl cellulose, and oily suspensions containing the active compounds in a suitable vegetable oil, e.g. peanut oil, olive oil or myritol. 318. The active compounds can be formulated into granules with or without additional excipients. The granules may be administered directly to the patient or may be added to a suitable liquid carrier (e.g., water) prior to administration. The granules may contain disintegrants, e.g., effervescent steam formed by acid and carbonate or bicarbonate, to facilitate dispersion in a liquid medium.

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

Both the lipase inhibitor and glucomannan compounds can be administered simultaneously, separately or sequentially (e.g. orlistat as described above and glucomannan in the evening). Preferably, the compounds or compositions are administered with a meal, within 1-2 hours before or after the meal. The amount of glucomannan administered will depend on many factors including the age of the patient, the severity of the condition being treated, and the patient's medical history, and is at the discretion of the attending physician.

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

The invention also relates to an obesity treatment kit; wherein the kit comprises a) a first component which is a lipase inhibitor, and b) a second component which is glucomannan as defined above, in an oral unit dosage form, preferably a) 1-100 orlistat dosage units, and b) 1-100 dosage units glucomannan.

Another embodiment of the invention relates to a kit for the treatment of obesity, the kit comprising a) a first component which is a lipase inhibitor and b) a second component which is glucomannan in oral unit dosage forms.

PL 216 022 B1

The invention also relates to the use of a composition as defined above for the preparation of medicaments useful for the treatment and prophylaxis of obesity, and the use of a lipase inhibitor as defined above for the manufacture of a medicament for the treatment and prevention of obesity in a patient who is also treated with glucomannan as defined above. This use of glucomannan and a lipase inhibitor relates to the simultaneous, separate or sequential use for the treatment and prophylaxis of obesity. The invention further relates to a method. According to the invention, there is thus possible a method of treating obesity in a human in need of such treatment which comprises administering to the human a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of glucomannan as defined above. The method relates to the simultaneous, separate or sequential administration of the compounds. A further embodiment of the invention is a lipase inhibitor and glucomannan or konjac as defined above as a combined preparation for simultaneous, separate or sequential use in the treatment and prophylaxis of obesity. The invention also relates to the use of glucomannan or konjac as defined above for the preparation of a medicament useful for the treatment and prevention of gastrointestinal side effects selected from the group consisting of oil spotting, greasy / oily stools, urgency to defecate, severe defecation and incontinence, and way. A method of treating or preventing gastrointestinal side effects selected from the group consisting of oily spotting, greasy / oily stools, the urge to urinate, severe defecation and fecal incontinence in a human in need of such treatment by administering a therapeutically effective amount to a human being is also possible. konjac or glucomannan as defined above. Additionally, the invention relates to a lipase inhibitor and glucomannan or konjac, as defined above, for simultaneous, separate or sequential use in the treatment and prophylaxis of obesity.

The invention will be better understood by reference to the following examples which illustrate but do not limit the invention described herein.

Drawings

Fig. 1 shows the tested Konjac emulsions after centrifugation at 3100 g for t = 1 minute (a) and t = 300 minutes (b), respectively. After centrifugation time t = 300 minutes, slight stabilization of emulsification was observed only in emulsions containing konjac at concentrations higher than 1.5% (w / w).

Fig. 2 shows the tested Konjac emulsions after centrifugation at 3100 g for t = 1 minute (a) and t = 300 minutes (b), respectively. The emulsions contained 1.0% (w / w) konjac at various pH values. After a centrifugation time t = 300 minutes, a slight stabilization of the emulsification was observed at a pH of 6 and 7, respectively. Strong coalescence was observed for all other emulsions.

Fig. 3: Effect of different types of glucomannan to reduce the free oil content in% relative to the control (data shown as mean 6 standard error).

Examples

Example 1: In vitro studies

It has been surprisingly noted that glucomannan has the effect of reducing gastrointestinal side effects (GIAE) often seen with the administration of a lipase inhibitor such as orlistat.

The interaction of konjac (a source of glucomannan) with oil and water was investigated in an absorption test. Compound samples were brought into contact with soybean oil or simulated intestinal fluid (SIF, phosphate buffer without pancreatin) and incubated for 24 hours at 37 ° C. The remaining liquid was separated from the solid material by centrifugation (3 x 5 minutes at 3100 g). While significant polymer swelling was observed in the SIF, no swelling occurred in the soybean oil. The calculated absorption capacity of konjac for SIF and soybean oil was 4.8 g / g and 0.5 g / g, respectively. Low oil binding shows its poor lipophilicity.

The coalescence of emulsions stabilized with the konjac agent was investigated by the centrifugation method. In this way, both concentration-dependent and pH-dependent emulsions were tested in vitro. The results of these stability studies are shown in Tables 1 and 2. The use of konjac at a concentration of less than 0.5% (w / w) resulted in very unstable emulsions leading to a rapid oil / water phase separation (Table 1). Even at a konjac concentration of 1.0% (w / w), the emulsions remained rather unstable and a clear phase separation was obtained after 10 minutes of centrifugation. Only emulsions containing konjac at a concentration greater than 1.0% (w / w) showed intermediate stability, with partial separation of the emulsion after a centrifugation time of t = 300 minutes maximum (Fig. 1).

PL 216 022 B1

Table 1.

Stability of tested konjac emulsions at different concentrations c and centrifugation times t.

<td>C (%, wt.)</td><td colspan="9">Durability of konjac emulsion t / min</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>n *</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 0,1</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 0,5</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 1,0</td><td>s</td><td>s</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 1,5</td><td>in</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td>

<td> 2,0</td><td>in</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td>

* n = low durability: oil and water form clearly separated phases; ś = average life; partially split emulsion; w = high durability: no signs of coalescence, optically opaque, stable emulsion.

Figure 1 shows the tested Konjac emulsions after centrifugation at 3100 g for t = 1 minute (a) and t = 300 minutes (b), respectively. After centrifugation time t = 300 minutes, only a slight stabilization of emulsification was observed for emulsions containing konjac at a concentration higher than 1.5% (w / w).

To test the emulsion stability at different pH values ​​covering the pH range 4-9 (Table 2), test emulsions were prepared having a constant konjac concentration c = 1.0% (w / w). At both extreme pH values ​​of 4 and 9, very little emulsification of the tested emulsions was observed, leading to an immediate formation of an oil phase layer. While short centrifugation times of less than 30 minutes at pH = 8 also resulted in complete separation of the emulsions, the emulsions at pH = 5 showed a slightly higher stability. In this case, the coalescence occurred at centrifugation times longer than 60 minutes. The pH optimum in terms of emulsion stability was observed at slightly acidic to neutral pH values ​​(pH 6-7).

Table 2.

Stability of the tested konjac emulsions at different pH values ​​and centrifugation times t.

<td>PH</td><td colspan="5">Durability of konjac emulsion t / min</td>

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

<td> 4</td><td>n *</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 5</td><td>s</td><td>s</td><td>s</td><td>n</td><td>n</td>

<td> 6</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td>

<td> 7</td><td>s</td><td>s</td><td>s</td><td>s</td><td>s</td>

<td> 8</td><td>s</td><td>n</td><td>n</td><td>n</td><td>n</td>

<td> 9</td><td>n</td><td>n</td><td>n</td><td>n</td><td>n</td>

* n = low durability: oil and water form clearly separated phases; ś = average life; partially split emulsion; w = high durability: no signs of coalescence, optically opaque, stable emulsion.

Figure 2 shows the tested Konjac emulsions after centrifugation at 3100 g for t = 1 minute (a) and t = 300 minutes (b), respectively. The emulsions contained 1.0% (w / w) konjac at various pH values. After centrifugation for t = 300 minutes, little stabilization of the emulsion at pH values ​​of 6 and 7, respectively, was observed. Considerable coalescence was observed for all other emulsions.

Konjac solutions were prepared at concentrations of 0.01%, 0.1%, 0.5%, 1.0%, 1.5% and 2.0% (w / w) in simulated intestinal fluid (SIF), without pancreatin, according to USP XXII, p. 1789 (pH = 7.5, potassium dihydrogen phosphate buffer). To 18 g of this solution, 2 g of soybean oil (FLUKA, 85471) was added to give a final oil concentration of 10% by weight. relative to the water phase. The soybean oil was not refined and was used as received. Emulsions were then made using a Miccra homogenizer at 28,000 rpm (level E) and a homogenization time of 1 minute. Mixtures of soybean oil and phosphate buffer without added surfactant were used as the reference mixture. Nile red staining of the emulsions followed by optical microscopic analysis confirmed that they were oil-in-water emulsions. Medium size analysis

The droplets carried out immediately after production with a Galai CIS-1 apparatus showed values ​​of typically 20-30 µm. Glass capillaries 95 mm high and 1.7 mm in diameter (glass thickness 0.8 mm) were filled to about 6.5 cm with the pre-prepared emulsion using a syringe and centrifuged at a maximum speed of 5000 rpm (Eppendorf, 5403 centrifuge, rotor no. 16A4-44), which corresponds to a centrifugal force of 3,100 g (at the bottom of the glass capillary). In order to record the demulsification process, centrifugation was interrupted at specified time intervals (t = 1, 10, 40, 70, 100, 130, 160, 220, 300 minutes) and the capillaries were placed in an optical scanner operating in the transmission mode (Bio-Rad GS-700 Imaging Densitometer). The distance between the capillaries was kept constant using a custom sample holder. All measurements were made at room temperature.

Example 2: In vivo studies I.

An ad hoc human model was developed to investigate substances that will reduce oil-related side effects associated with orlistat treatment.

Healthy volunteers received orlistat, alone or in combination with the test substance, during 3 consecutive meals (3 meal test). The modified formulations used in these 3-meal tests produced 70-80% fat excretion. Volunteers were given a questionnaire to record side effects. The most serious side effect associated with oil is oil spotting (uncontrolled oil loss). It is difficult to quantify this side effect in the acute model, however, spontaneous separation of fat from formed stool was observed in some volunteers. This amount of fat, called free oil (mainly containing triglycerides), was isolated and weighed.

The amount of free oil was used as an auxiliary oil spotting indicator as it is believed that free oil is essential for oil spotting to appear.

Two clinical trials have been conducted to investigate the effects of many substances in modifying gastrointestinal side effects. Volunteers appear to be individually sensitive to orlistat-related gastrointestinal side effects. Therefore, each volunteer served as a control for himself (treatment with orlistat alone). Volunteers showing a low sensitivity to orlistat related side effects were excluded from the study. For a given volunteer, a substance was considered to be beneficial if the amount of free oil was reduced by at least 50% compared to the control value (orlistat alone).

Glucomannan in the form of konjac powder was tested. Konjac powder is obtained from the roots of the tree (AmorphophalIus konjac) and is a natural source of glucomannan. This substance was tested in the acute side effect model at a dose of 4 g / meal. Of the 5 volunteers tested, 4 experienced a decrease of at least 50% in free oil made without glucomannan (see Table 3). There was no decrease in fat excretion in volunteers treated with glucomannan / orlistat (compared to volunteers treated with orlistat alone, data not shown) suggesting no interaction of glucomannan with orlistat. No serious adverse events related to the administration of glucomannan have been reported.

Table 3:

Konjac (Glucomannan) Results

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

<td></td><td>orlistat</td><td>orlistat + konjac</td>

<td>Study 1</td><td> 11</td><td> 8</td>

<td></td><td> 9</td><td> 0</td>

<td>Study 2</td><td> 39</td><td> 16</td>

<td></td><td> 17</td><td> 8</td>

<td></td><td> 40</td><td> 6</td>

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

Example 3: In vivo studies II

The results obtained in the in vitro experiments were further confirmed in the in vivo tests carried out in the mouse model. The experiment is based on the observation that mice on a high-fat diet and receiving orlistat or another lipase inhibitor spread the excreted free oil on their fur as they groom themselves. Several types have been studied

And glucomannan preparations for the ability to reduce or eliminate the production of free oil. The results obtained are shown in Fig. 3.

Example 4: Pharmaceutical compositions containing orlistat

AND)

<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>talc</td><td> 0,24</td>

<td>together</td><td>240.24 mg</td>

Procedure

1. Mix the 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 granulate through an extruder and pass the extrudate through a spheronizer to obtain pellets.

4. Dry the pellets at 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

B)

<td>Ingredient</td><td>Amount (mg / capsule)</td>

<td>orlistat</td><td> 60,00</td>

<td>microcrystalline cellulose</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>talc</td><td> 0,12</td>

<td>together</td><td>120.12 mg</td>

Procedure

1. Mix the 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 granulate through an extruder and pass the extrudate through a spheronizer to obtain pellets.

4. Dry the pellets at 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

C)

<td>Ingredient</td><td colspan="2">Amount (mg / capsule)</td>

<td> 1</td><td> 2</td><td> 3</td>

<td>orlistat</td><td> 60</td><td> 120</td>

<td>lactose</td><td> 40</td><td> 80</td>

To be continued

<td> 1</td><td> 2</td><td> 3</td>

<td>microcrystalline cellulose</td><td> 60</td><td> 120</td>

<td>sodium starch glycolate</td><td> 5,7</td><td> 11,4</td>

<td>sodium lauryl sulfate</td><td> 20</td><td> 40</td>

<td>polyvinylpyrrolidone</td><td> 10</td><td> 20</td>

<td>talc</td><td> 2,0</td><td> 0,4</td>

<td>together</td><td>195.9 mg</td><td>391.8 mg</td>

Procedure

1. Mix the orlistat, lactose, 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 granulate through an extruder and pass the extrudate through a spheronizer to obtain pellets.

4. Dry the pellets at 30 ° C.

5. Add talc and mix.

6. Fill into hard gelatin capsules.

Example 5 A pharmaceutical composition containing glucomannan Composition:

<td>Ingredient</td><td>Quantity (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>talc</td><td>0.16 g</td>

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

<td>together</td><td> 3,2</td>

Procedure

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

2. Pass the powder mixture through a sieve.

3. Add talc and sodium stearyl fumarate and mix.

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

Example 6. Pharmaceutical composition containing glucomannan

Composition:

<td>Ingredient</td><td>Quantity (g / sachet)</td>

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

<td>aspartame</td><td>0.5 g</td>

<td>β-carotene</td><td>0.001 g</td>

<td>together</td><td>4.501 g</td>

Procedure

1. Place the glucomannan in an appropriate high shear mixer.

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

3. Dry the granules at 60 °.

4. Pass the dry granules through a sieve.

5. Fill the sachets.

PL 216 022 B1

Example 7. A pharmaceutical composition containing glucomannan Composition:

<td>Ingredient</td><td>Quantity (g / chewable tablet)</td>

<td>glucomannan</td><td>0.5 g</td>

<td>lactose</td><td>0.5 g</td>

<td>microcrystalline 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>talc</td><td>0.15 g</td>

<td>together</td><td>3.0 g</td>

Procedure

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

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

3. Granulate with liquid.

5. Pass the granulate through an extruder and pass the extrudate through a spheronizer to obtain round pellets.

6. Dry the pellets at 65 ° C.

7. Add talc and mix.

8. Press the pellets into a chewable tablet.

Example 8 Pharmaceutical composition containing orlistat / glucomannan Composition:

<td>Ingredient</td><td>Quantity (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>microcrystalline 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>talc</td><td>0.15 g</td>

<td>together</td><td>3.31 g</td>

Procedure

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

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

3. Granulate with liquid.

5. Pass the granulate through an extruder and pass the extrudate through a spheronizer to obtain round pellets.

6. Dry the pellets at a maximum temperature of 35 ° C.

9. Add talc and mix.

10. Press the pellets into a chewable tablet.

PL 216 022 B1

Example 9. Pharmaceutical composition containing orlistat / glucomannan

Composition:

<td>Ingredient</td><td>Quantity (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>β-carotene</td><td>0.001 g</td>

<td>silicon dioxide</td><td>0.5 g</td>

<td>together</td><td>7.421 g</td>

Procedure

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

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

3. Fill the sachets.

Example 10. Pharmaceutical composition containing orlistat / glucomannan

Composition:

<td>Ingredient</td><td>Quantity (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>microcrystalline cellulose</td><td>0.2 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>talc</td><td>0.15 g</td>

<td>magnesium stearate</td><td>0.03 g</td>

<td>together</td><td>2.85 g</td>

Procedure

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

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

3. Pass the granules through a sieve.

4. Dry the granules at a maximum temperature of 30 ° C.

5. Pass the dry granules through a sieve.

6. Mix with talc and magnesium stearate.

7. Compress into a chewable tablet.