WO2003097714A1

WO2003097714A1 - Fat binding using inter-polymer complex of glucosamine and polyacrylic acid

Info

Publication number: WO2003097714A1
Application number: PCT/IB2003/000845
Authority: WO
Inventors: Gour Mukherji; Clive Wilson; Ashok Rampal; Ravikumar Nithiyanandam; Mahendra R. Joshi
Original assignee: Ranbaxy Laboratories Limited
Priority date: 2002-05-20
Filing date: 2003-03-07
Publication date: 2003-11-27
Also published as: EP1507813A4; EP1507813A1; AU2003269702A1

Abstract

A method of reducing fat absorption in mammals includes orally administering to the mammals an effective amount of an inter-polymer complex formed between a polymeric glucosamine or its derivative and a polyacrylic acid or its derivative. The inter-polymeric composition can be in the form of a pharmaceutical composition that is capable of binding fat. The inter-polymer complex may be co-administering with one or more compounds selected from statins, IBAT inhibitors, MTP inhibitors, cholesterol absorption antagonists, phytosterols, stanols, CETP inhibitors, fibric acid derivatives, and antihypertensive agents.

Description

FAT BINDING USING INTER-POLYMER COMPLEX OF GLUCOSAMINE

AND POLYACRYLIC ACID

RELATED APPLICATIONS

This application is a continuation-in-part of application number PCT/--B02/01708.

TECHNICAL FIELD

The present invention relates to the use of glucosamine polyacrylate inter-polymer complexes described in co-pending application PCT/IB02/01708 for absorbing dietary fat or fatty acids in the small and/or large intestine, or the dietary fat that has not been metabolized due to treatment of the subjects with drugs that inhibit the enzymatic conversion of the fats. Such drugs include, for example, lipase inhibitors such as orlistat or bile acid sequestrants such as cholestyramine

BACKGROUND

In recent years, people have become less physically active and tend to consume food with a high fat (i.e., lipid) content. Such sedentary life styles and ingestion of food with high fat content cause obesity and, potentially, a variety of complications, including heart and circulatory diseases, respiratory disease, diabetes, etc.

It is known that the fat content of food is a major factor in causing obesity. The body tends to store fat for future use rather than utilize it immediately, which leads to weight gain. Furthermore, it has been shown that there is a relationship between the amount of fat stored in the body and the level of serum cholesterol, with a diet high in fat likely to lead to high serum cholesterol levels. As cholesterol has been implicated as a factor in arteriosclerosis, or hardening of the arteries, the risk for heart diseases and/or heart attack is increased when practicing a high fat diet. Sometimes, it becomes necessary to decrease absorption of fats and fatty acids in certain subjects to reduce the risk level of such diseases.

Dietary fats are large molecules that must be broken down by enzymes called lipases before they can be absorbed into the body. Drug such as lipase inhibitors interfere with the activity of these enzymes and therefore some portion of the fat eaten in a meal passes through the body undigested. However, these drugs can lead to unpleasant side effects, such as fat leakage or spotting, oily stools, inability to control bowel movements and flatulence.

Chitosan (1-4-β-D-polyglucosamine), a polymeric glucosamine, contains about 0-30% N-acetylglucosamine residues, has been found to be particularly effective as a cholesterol reducing agent. Chitosan is a natural, polymeric carbohydrate made through the deacylation of chitin. It has been shown to act as a powerful fat binder, binding dietary fats in vivo and thus rendering them nutritionally unavailable. The bound fats are excreted instead of being absorbed or utilized. Currently popular as a dietary supplement, chitosan is capable of binding fat, including both triaceylglycerols (TGs) and fatty acids. Like some plant fibers, chitosan' s charged nature gives it the potential ability to bind significantly more fat than any plant fiber. Under physiologic conditions, chitosan can bind an average of four to five times its weight in fat.

In recent years, it has been found that chitosan can be used as a dietary supplement for reducing rapid fat absorption in mammals, as disclosed in U.S. Patent Nos. 4,223,023; 5,932,561; 5,453,282; 5,976,550; 5,773,427 and 5,736,532, all of which are incorporated herein by reference.

U.S. Patent No. 4,233,023 describes the use of chitosan as a food additive or as a pharmaceutical preparation to reduce the absorption of fat. U.S. Patent No. 5,453,282 discloses dietary fat digestion-absorption inhibitory agents that includes a mixture of chitosan and ascorbic acid or a salt thereof. U.S. Patent No. 5,736,532 relates to a fat absorbing and cholesterol reducing formulation that includes chitosan and nicotinic acid. This formulation may additionally contain one or more other vitamin acids, such as ascorbic acid, folic acid, pantothenic acid or biotin. U.S. Patent No. 5,773,427 discloses novel dietary fiber compositions that include an effective amount of chitosan in admixture with other dietary fiber components. These compositions produce diminished flatulence upon oral administration. U.S. Patent No. 5,932,561 discloses a dietary supplement composition having lipid-binding properties and including aloin and an amino polysaccharide such as chitosan. U.S. Patent No. 5,976,550 discloses a dietary supplement that includes chitosan, an appetite reducing substance such as sugar-based confectionary and a mild anesthetic substance to mildly anaesthetize the tongue and lips. This renders the food less favorable and less organoleptically desirable thus deterring one from ingesting more food than is necessary purely for dietary needs. In co-pending application PCT/TBO2/01708, we disclosed a solid particulate complex formed by the inter-polymer complexation of a cationic polymeric glucosamine (chitosan) and an anionic, cross-linked polyacrylic acid or its derivative. This complex has the ability to form very high swelling gels with a good cohesive structure in aqueous media.

SUMMARY

In one general aspect, a method of reducing fat absorption in mammals includes orally administering to the mammals an effective amount of an inter-polymer complex formed between a polymeric glucosamine or its derivative and a polyacrylic acid or its derivative.

Embodiments of the method may include one or more of the following features. For example, the fat may be present in the emulsified form or non-emulsified form. The complex may bind an amount of fat that is up to fifteen times its own weight. The complex may be co-administered along with a lipase-inhibitor or bile acid sequestrant. The lipase-inhibitor may be orlistat. The bile acid sequestrant may be cholestyramine.

The complex may further include at least one water-soluble vitamin acid. The water-soluble vitamin acid may be selected from the group that includes ascorbic acid, folic acid, pantothenic acid, and biotin. The complex maybe administered as one or more of a tablet, a suspension, a dispersible powder or granule, and a capsule. The polyacrylic acid may be a cross-linked polyacrylic acid.

The complex may be orally co-administered with one or more compounds selected from the group comprising statins, IBAT inhibitors, MTP inhibitors, cholesterol absorption antagonists, phytosterols, stanols, CETP inhibitors, fibric acid derivatives, and antihypertensive agents.

The statin may be one or more of rosuvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, velostatin, compactin, dalvastatin, fluindostatin, dihydorcompactin, rivastatin, SDZ-63,370, CI-981, HR-780, L-645,164, CL- 274,471, alpha-, beta-, and gammatocotrienol, (3R, 5S, 6E)-9,9-bis (4-fluorophenyl)-3,5- dihydroxy-8- H-tetrazol-5- yl)-6,8-nonadienoic acid, L-arginine salt, (S)-4- [ [2- [4- (4- fluorophenyl)-5-methyl-2- (1- methylethyl)-6-phenyl-3-pyridinyl] ethenyl]-hydroxy- phosphinyl]-3-hydroxy-butanoic acid, disodium salt, BB-476, (British Biotechnology), dihydrocompactin, [4R- [4 alpha, 6 beta (E)]]-6- [2- [5- (4-fluorophenyl)-3- (1- methylethyl)-l- (2-pyridinyl)-l H-pyrazol-4- yl] ethenyl] tetrahydro-4-hydroxy-2H-pyran- 2-one, and IH-pyrrole-1-heptanoic acid, 2- (4- fluorophenyl)-beta, delta-dihydroxy-5-(l- methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]- calcium salt [R- (R*, R*)].

The stanol maybe one or more of campestanol, cholestanol, clionastanol, coprostanol, 22,23-dihydro-brassicastanol, epicholestanol, fucostanol, and stigmastanol. The CETP inhibitor may be (-) (2R, 4S)-4-Amino-2-2-ethyl-6trifluoromethyl-3,4-dihydro- 2H-quinoline-l-carboxylic acid ethyl ester. The fibric acid derivative may be one or more of clofibrate, fenofibrate, ciprofibrate, bezafibrate and gemfibrozil. The antihypertensive agent may be one or more of an andrenergic blocker, a mixed alpha beta andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, an andrenergic stimulant, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker, a diuretic, and a vasodilator.

The antihypertensive agent may be one or more of phenoxybenzamine, guanadrel, guanethidine, reserpine, terazosin, prazosin, polythiazide, methyldopa, methyldopate, clonidine, chlorthalidone, guanfacine, guanabenz, trimethaphan, carvedilol, labetalol, propranolol, metoprolol, acebutol, alprenol, amosulal, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butiridine hydrochloride, butofilolol, carazolol, carteolol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, levobunolol, mepindolol, metipranolol, moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, perbutolol, pindolol, practolol, pronethalol, sotalol, sufmalol, talindol, tertatolol, tilisolol, timolol, toliprolol, xibenolol, doxazosin phentolamine, amosulalol, arotinolold, apiprazole, doxazosin, fenspirlde, indoramin, naftopidil, nicergoline, tamsulosin, tolazoline, trimazosin, yohimbine, quinapril, perindopril, erbumine, captopril, fosinopril, trandolapril, lisinopril, moexipril, enalapril, alacepril, benazepril, ceronapril, delapril, imadapril, moveltopril, ramipril, spirapril, temocapril, candesartan cilexetil, inbesartan, losartan, valsartan, eprosartan, nifedipine, nimodipine, delodipine, nicardipine, isradipine, amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, lacidipine, lercanidipine, manidipine, nifendipine, nilvadipine, nisoldipine, nitrendipine, cirmarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, perhexiline, chlorothiazide, furosemide, bumetanide, ethacrynic acid, amiloride, triameterene, spironolactone, eplerenone, acetazolamide, althiazide, amanozine, ambuside, arbutin, azosemide, bendroflumethiazide, benzthiazide, benzylhydro-chlorothiazide, butazolamide, buthiazide, chloraminophenamide, chlorazanil, clofenamide, clopamide, clorexolone, cyclopenthiazide, cyclothiazide, disulfamide, epithiazide, ethiazide, ethoxolamide, etozolin, fenquizone, hydracarbazine, hydrochlorothiazide, hydroflumethiazide, indapamide, isosorbide, mannitol, mefruside, methazolamide, methyclothiazide, meticrane, metochalcone, metolazone, muzolimine, paraflutizide, piretanide, quinethazone, teclothiazide, ticrynafen, torasemide, triamterene, trichlormethiazide, tripamide, urea, xipamide, hydralazine, minoxidil, diazoxide, nitroprusside, aluminum nicotinate, amotriphene, bamethan, bendazol, benfurodil hemisuccinate, benziodarone, betahistine, bradykinin, brovincamine, bufeniode, buflomedil, butalamine, cetiedil, chloracizine, chromonar, ciclonicate, cinepazide, citicoline, clobenfural, clonitrate, cloricromen, cyclandelate, diisopropylamine dichloroacetate, dilazep, dipyridamole, droprenilamine, ebumamonine, efloxate, eledoisin, erythrityl, fasudil, fenoxedil, floredil, ganglefene, hepronicate, hexestrol, hexobendine, ibudilast, ifenprodil, iloprost, inositol, isoxsuprine, itramin tosylate, kallidin, kaliikrein, khellin, lidofiazine, hexanitrate, medibazine, moxisylyte, nafronyl, nicametate, nicoflxranose, nitroglycerin, nylidrin, papaverine, pentaerythritol tetranitrate, pentifylline, pentoxifylline, pentrinitrol, perhexilline, pimefylline, piribedil, propatyl nitrate, prostaglandin El, suloctidil, tinofedrine, trapidil, tricromyl, trimetazidine, trolnitrate phosphate, vincamine, vinpocetine, viquidil, visnadine, and xanthinol niacinate.

In another general aspect, a pharmaceutical composition includes an inter-polymer complex of a polymeric glucosamine or its derivative and a polyacrylic acid or its derivative. The pharmaceutical composition is capable of binding fat.

Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the polyacrylic acid may be a cross-linked polyacrylic acid. The composition may further include a lipase-inhibitor. The lipase-inhibitor may be orlistat.

The pharmaceutical composition may further include one or more excipients. The pharmaceutical composition may further include at least one water-soluble vitamin acid. The water-soluble vitamin acid may be selected from the group that includes nicotinic acid, ascorbic acid, folic acid, pantothenic acid and biotin. The composition may be in the form of one or more of a tablet, a suspension, a dispersible powder, dispersible granules, and a capsule.

In another general aspect, a method of binding fat includes providing a pharmaceutical composition and orally administering the pharmaceutical composition. The pharmaceutical composition includes an inter-polymer complex and one or more excipients. The inter-polymer complex includes polymeric glucosamine or its derivative and a polyacrylic acid or its derivative.

Embodiments of the method may include one or more of the features described herein. For example, the method may further include co-administering a lipase-inhibitor with the inter-polymer complex. The lipase-inhibitor may include orlistat.

The inventors have developed a composition, and a safe and easy method of treatment using the composition, that advantageously facilitates a person's efforts to lose weight and to control the accumulation of harmful cholesterol. This composition and method can be capable of aiding a person in accomplishing these goals without requiring additional caloric restriction and/or interfering with the taste of food. The composition and treatment can beneficially aid the body in the rapid elimination of ingested fats prior to digestion in order to prevent the build up or accumulation of harmful cholesterol. The complex can be co-administering with effective amounts of vitamin acids, such as nicotinic acid, ascorbic acid, folic acid, pantothenic acid and biotin. Such additions can advantageously function to enhance the weight reducing, cholesterol lowering effect of the complex.

The complex can be a component of a composition that can offer benefits and advantages when administered as part of a method of use for weight loss, with or without caloric restriction, in a warm-blooded animal. The composition can be formulated as a dietary supplement or therapeutic formulation that includes the complex, and which can bind triglycerides and cholesterol and limit the availability of these dietary components without introducing harmful side effects. As a result of synergistically reducing fat and cholesterol absorption, the present composition and method may also significantly reduce the risks of cardiovascular diseases, respiratory diseases and diabetes. The solid particulate complex formed by the inter-polymer complexation of a cationic polymeric glucosamine (chitosan) and an anionic, cross-linked polyacrylic acid or its derivatives has the ability to form very high swelling gels in aqueous media of pH greater than three with a good cohesive structure. The complex even forms swellable gels in a media having a pH in the range of approximately 1.8 to 2.0. With reference to the present application, the inventors have discovered that the complex disclosed in co- pending application PCT/IB02/01708 displays surprisingly good fat binding characteristics as compared to the fat-binding capacity of the two component polymers given individually.

DETAILED DESCRIPTION

The general composition of the inter-polymer complex described herein includes glucosamine or one of its derivatives and polyacrylic acid and one of its derivatives. The composition can optionally include one or more of the following agents: vitamin acids, lipase inhibitors, sweeteners, flavoring agents, coloring agents, and preservatives. The complex, with or without these agents can be provided in the fonn of a tablet, capsule, suspension, dispersible powder or granule, and further include, as necessary, inert diluents, granulating and disintegrating agents, binding agents, lubricating agents, suspending agents, and dispersing or wetting agents. Further details of these agents are provided below.

Glucosamine, which is formed in the body as glucosamine 6-phosphate, is 2- amino-2-deoxy-alpha-D-glucose. It is one of the two-hexosamine sugars (6-carbon amino sugars) common in animal cells. A glucosamine that is of particular relevance to this application is chitosan.

Chitosan is poly- [I-4]-beta-D-glucosamine and is a partially deacetylated chitin. As referred to herein, it is acid soluble and has at least a 75% degree of deacetylation, and more particularly, in excess of 85%. Other glucosamines include, but are not limited to, carboxymethyl chitosan, hydroxypropyl chitosan and glycol chitosan.

Cross-linked polyacrylic acid or its derivatives, as referred to in this application, include water-swellable, high molecular weight, cross-linked homopolymers and copolymers, which form hydrogels in aqueous solution. The cross-linker types and levels can be modified, as can the amounts and characteristics of the hydrophobic co-monomers. Commercial grades of cross-linked acrylic acid are available from Noveon (formerly, BF Goodrich) as Carbopol®, Pemulen®, and Noveon resins. Specifically, the resins are: (i) homopolymers of acrylic acid cross-linked with allyl sucrose or allyl pentaerythritol (Carbopol homopolymers), (ii) homopolymers of acrylic acid cross-linked with divinyl glycol (Noveon polycarbophils), and (iii) copolymers of acrylic acid with minor levels of long chain alkyl acrylate co-monomers cross-linked with allylpentaerythritol (Carbopol copolymers and Pemulen polymeric emulsifiers). The molecular weight of these polymers is theoretically estimated to range from 700,000 to three to four billion. They swell in water up to 1000 times their original volume to form a gel when exposed to a pH environment above approximately pH = 4 - 6. Since the pKa of these polymers is approximately 6 ± 0.5, the carboxylate groups on the polymer backbone ionise, resulting in repulsion between the negative particles, which adds to the swelling of the polymer. Cross-linked polymers do not dissolve in water.

Non-aqueous gels are stable gels with a wide range of hardness and stability over a wide range of pH conditions. These gels utilize an anhydrous liquid component extending their usefulness into many areas not suited for the use of water-based gel systems. The gellants used are in the form of alkyl amides of di- and/or tri-basic carboxylic acids or anhydrides. Reacting the di- or tri-basic organic acid or anhydride, or the methyl ester form thereof, with the desired alkyl amine produces the gellant materials. This gel-based technology makes use of an anhydrous or semi-hydrous liquid carrier.

At a broad level, one aspect of the present invention includes a composition that includes a solid particulate inter-polymer complex that is capable of absorbing a substantially high amount of fat. The term "fat" includes lipids, oils, dietary fats, fatty acids, triglycerides, and non-metabolized oils and fats.

At another broad level, one aspect of the present invention includes methods for reducing the absorption of lipids by a mammalian body. The composition, when ingested, will thus reduce the fat absorption from the diet of lipids comprised of components such as cholesterol, steroids, triglycerides and the like.

As described above, the general composition comprises an inter-polymer complex that includes a polymeric glucosamine or its derivative and a cross-linked polyacrylic acid or its derivative. The complex can be formulated as a dietary supplement or therapeutic formulation to provide a synergistic effect of glucosamine and polyacrylic acid in binding fat (e.g., triglycerides and cholesterol) and limiting the bioavailability of these dietary components. As a result of synergistically reducing fat and cholesterol absorption, the present composition also significantly reduces the risk of cardiovascular diseases, respiratory diseases and diabetes.

As noted above, the glucosamine-polyacrylic acid inter-polymer complex can be _l co-administered with effective amounts of vitamin acids, such as nicotinic acid, ascorbic acid, folic acid, pantothenic acid and biotin. Such additions can advantageously function to enhance the weight-reducing, cholesterol-lowering effects of the complex.

As also noted above, the glucosamine-polyacrylic acid complex can be administered with a lipase inhibitor. Use of the complex can advantageously eliminate the leakage of non-metabolized dietary fats and/or those fats that have not been metabolized when these drugs are administered.

The inter-polymer complex can be incorporated in oral pharmaceutical compositions. For oral administration, the components may be provided, for example, as a tablet, capsule, suspension, dispersible powder or granule. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutically acceptable compositions. "Pharmaceutically acceptable" means that the agents in the formulation are compatible with the other ingredients and are non-injurious to a patient.

As stated above, the composition of the present invention may contain other excipients, which act in one or more capacities as diluents, binders, lubricants, glidants, disintegrants, sweeteners, flavoring agents, coloring agents, and preservatives.

Suitable diluents include microcrystalline cellulose, lactose, dibasic calcium phosphate, mannitol, starch, sucrose, dextrose, maltodextrin or mixtures thereof.

Suitable binders include polyvinyl pyrrolidone, lactose, starches, gums, waxes, gelatin, cellulosic polymers, acrylic polymers or mixtures thereof. Suitable lubricants include colloidal silicon dioxide, talc, stearic acid, magnesium stearate, magnesium silicate, polyethylene glycol, sodium benzoate, sodium lauryl sulphate, fumaric acid, zinc stearate, paraffin or mixtures thereof.

Suitable glidants include talc and colloidal silicon dioxide.

Suitable disintegrants include starch, alginic acid, sodium croscarmellose, cross- linked polyvinyl pyrrolidone, microcrystalline cellulose, modified starches, gums or mixtures thereof.

Formulations for oral use may be prepared and administered as tablets or hard gelatin capsules in which the active ingredient is mixed with inert excipients. The composition may also be administered as aqueous suspensions, which may contain the complex in admixture with excipients suitable for their manufacture. Such excipients include suspending agents, dispersing or wetting agents, one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweetening agents such as sucrose or saccharin.

Dispersible powders and granules may be prepared that are suitable for the preparation of an aqueous suspension by the addition of water to provide the active ingredients in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The inventors have conducted experiments to determine the fat-binding capacity of the inter-polymer complex of glucosamine and polyacrylic acid, the glucosamine separately, and the polyacrylic acid separately. These are compared to the fat-binding capacity of ethyl cellulose, which acts as a control. The fat binding capacity of the inter- polymer complex was measured in vitro by adding an excess amount of fat (e.g., oleic acid, corn oil) to a measured amount of an aqueous dispersion of the polymer complex. Mechanical mixing of the two components (i.e., the polymer complex and the fat) ensures a homogeneous mixture and fat absorption by the complex. The oil phase and the aqueous phase are separated and the oil phase is analyzed for quantity of free oil present. The quantity of oil/fat bound to the polymer complex may be calculated correspondingly because the amount of starting oil is known and the amount of free, unbound oil is known. The quantity of bound oil is the difference between the two. Although these experiments were conducted in vitro, as is known in the art, numerous studies have shown a correlation between the in vitro fat binding capacity of oleic acid and corn oil, and mammalian fat binding capacity.

The bulk of the dietary lipids are neutral fats or triglycerides, composed of a glycerol backbone with each carbon linked to a fatty acid. Additionally, most foodstuffs contain phospholipids, sterols, such as cholesterol, and many minor lipids, including fat- soluble vitamins. In order for the triglyceride to be absorbed two processes must occur: (a) large aggregates of dietary triglyceride, which are insoluble in an aqueous environment, must be broken down physically and held in easily digestible fonn through a process called emulsification; and (b) triglyceride molecules must be enzymatically digested to yield monoglyceride and fatty acids for absorption through the small intestine. Thus, a prerequisite for lipid absorption is its emulsification before absorption.

The inventors additionally have found, however, that the inter-polymer complex between glucosamine or its derivative and cross-linked polyacrylic acid or its derivative is able to bind the lipid irrespective of whether it is emulsified or not. It was discovered that the complex exhibited substantially similar lipid/fat binding characteristics in the presence as well as the absence of an emulsifier.

Although the mechanism of fat binding by glucosamines is known, there is less knowledge about the fat-binding mechanism of polyacrylic acid. It is theorized that the fat binding property of polyacrylic acid is explained by two possible mechanisms. In the first mechanism, the fat binding properties shown by polyacrylic acid are a result of physical entrapment. Namely, during the swelling of polyacrylic acid the fat is entrapped inside the gel.

In the second mechanism, it is theorized that a hydrophilic portion of the polyacrylic acid polymer forms an adsorbed gel layer around each oil or fat droplet while a hydrophobic portion of the polyacrylic acid polymer anchors in the oil/fat phase. As support for this mechanism, it is known that Pemulen® 1622, a cross-linked copolymer of acrylic acid and C 10-30 alkyl acrylate, acts by a similar mechanism to stabilize the oil/water or water/oil emulsions. The hydrophobic interaction between the oil phase and the alkyl acrylate chains of the polymer stabilize the oil droplets against both coalescence and creaming. The following examples further exemplify the fat-binding capabilities of the glucosamine/polyacrylic acid inter-polymer complex and are not intended to limit the scope of the invention.

EXAMPLE 1

Comparison of the in vitro fat binding capacity of polymeric glucosamine or its derivative (Polymer A), polyacrylic acid or its derivative (Polymer B), the inter-polymer complex (Polymer A-B), and ethyl cellulose (control).

Experimental details:

Amount of polymer used for the study: 2g

Oil/fat used: oleic acid

Procedure:

1. Oleic acid (20.05 g/g of polymer) and 0.01N hydrochloric acid (15 ml/g of polymer) were mixed in a flask and the polymer was added to the mixture slowly with continuous stirring. 2. The flask was shaken in a shaker bath maintained at 37+0.5°C for about two hours.

3. The pH of the mixture was adjusted to 6.8 - 7.4 using phosphate buffer solution (PBS) and the flask was again shaken in a shaker bath maintained at 37+0.5°C for three hours.

4. After three hours, the mixture was centrifuged and the oil phase and aqueous phase were separated. The quantity of free oil present in the oil phase was measured.

5. The relative amount of oil in the polymer phase was calculated.

The results are shown in Table 1.

Table 1

These results show that the inter-polymer complex of glucosamine and polyacrylic acid has a proportionally greater fat binding capacity than its components taken separately or the control, ethyl cellulose.

EXAMPLE 2

Comparison of in vitro fat binding capacity of polymeric glucosamine or its derivative (Polymer A), cross-linked polyacrylic acid or its derivative (Polymer B), the inter-polymer complex (Polymer A-B), and ethyl cellulose (control).

Experimental details:

Amount of polymer used for the study: 2 g

Oil used: Corn Oil

Density of the oil: 0.913 g/ml at 20°C

Procedure:

1. Corn oil (20.05 g/g of polymer) and 0.01N hydrochloric acid (15 ml/g of polymer) were mixed in a flask and the polymer was added to the mixture slowly with continuous stirring.

2. The flask was shaken in a shaker bath maintained at 37±0.5°C for about two hours.

3. The pH of the mixture was adjusted to 6.8 - 7.4 using phosphate buffer solution and the flask was again shaken in a shaker bath maintained at 37±0.5°C for three hours.

5. The relative amount of the oil in the polymer phase was calculated.

The results are shown in Table 2.

Table 2

These results show that the inter-polymer complex of glucosamine and cross-linked polyacrylic acid has a proportionally greater fat binding capacity than either its components taken separately or the control, ethyl cellulose.

EXAMPLE 3

EMULSION STUDIES (Corn Oif)

Experimental details:

Amount of polymer used for the study: 3 g

Oil used: Corn Oil

Type of Emulsion: Oil/Water

Procedure:

1. 0.01 N HC1 (15 ml/g of polymer) was added to a suitable vessel.

2. To the above, Polysorbate 80 (130 mg/10 ml of Oil) was added and mixed.

3. Corn Oil (15 ml/g of polymer) was added to the above under stirring. 4. Stirring was continued until a homogenous emulsion was obtained.

5. Polymer was added gradually under stirring and stirring was continued for five minutes.

6. The pH was adjusted to 6.8 - 7.4 using phosphate buffer solution.

7. The resultant mixture was filtered using a suitable filter. 8. The oil and aqueous phases were separated using a separating funnel/centrifugation.

9. The quantity of the free oil was measured.

10. The quantity of oil entrapped in the aqueous phase was determined by subtracting the free oil from the total quantity of the oil added. The results are shown in Table 3.

Table 3

These results show that the inter-polymer complex exhibited substantially similar lipid/fat binding characteristics in the presence or absence of an emulsifier.

EXAMPLE 4

EMULSION STUDIES (Oleic Acid)

Experimental details:

Amount of sample used for the study: 3 g Oil used: Oleic Acid (C_l7H₃₃COOH) Type of emulsion: Oil/Water

Procedure:

1. 0.01N HC1 (15 ml/g of polymer) was taken in a suitable vessel.

2. To the above, Polysorbate 80 (130 mg/10 ml of Oil) was added and mixed.

3. Oleic Acid (15 ml/g of polymer) was added to the above under stirring.

4. Stirring was continued till a homogenous emulsion was obtained. 5. Polymer was added gradually under stirring and stirring was continued for five minutes.

6. The pH was adjusted to 6.8 - 7.4 using phosphate buffer solution.

7. The resultant mixture was filtered using a suitable filter.

8. The oil and aqueous phases were separated using a separating funnel/centrifugation.

9. The quantity of the free oil was measured.

10. The quantity of oil entrapped was determined by subtracting the free oil from the total quantity of the oil taken. The results are shown in Table 4.

Table 4

These results show that the inter-polymer complex exhibited substantially similar lipidVfat binding characteristics with or without the presence of an emulsifier.

The inter-polymer complex may be administered with (e.g., simultaneously or within a short time) other drugs and drug products to treat conditions related to consumption of too much fat, such as heart and circulatory diseases, diabetes, hyperlipidemia, and hypertension. Such drugs that may be co-administered with the inter- polymer complex generally include one or more of statins, ileal bile acid transporter (IB AT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesterol absorption antagonists, phytosterols, stanols, cholesteryl ester transport protein (CETP) inhibitors, fibric acid derivatives and antihypertensive agents.

The statins decrease liver cholesterol biosynthesis, which increases the production of LDL receptors thereby decreasing total plasma and LDL cholesterol (Grundy, S. M. New England Journal of Medicine, 319, 24 (1988); Endo, A., J. Lipid Res. 33, 1569 (1992)). Depending on the agent and the dose used, statins may decrease plasma triglyceride levels and some may increase HDLc. The statins currently marketed include atorvastatin (Pfizer), lovastatin (Merck), simvastatin (Merck), pravastatin (Sankyo and Squibb) and fluvastatin (Sandoz). Statins have become the standard therapy for LDL cholesterol lowering. The following list discloses exemplary statins and suitable dosage ranges. The patents referenced are incorporated herein in their entirety by reference.

IB AT inhibitors frequently lower LDL lipoprotein, but also may lower HDL lipoprotein. Examples of IBAT inhibitors are disclosed in patent application no. PCT/US95/10863, PCT/US97/04076, WO 98/40375, WO 00/38725, and U. S. Application Serial No. 08/816,065, each of which is incorporated herein in its entirety by reference.

Examples of MTP inhibitors include some alkylpiperidine compounds, isoindole compounds, and fluorene compounds. Further examples of MTP inhibitors are disclosed in WO/0038725, which is incorporated herein in its entirety by reference.

Cholesteryl ester transfer protein (CETP) helps shuttle excess cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglycerides. The last step of the reverse cholesterol transport involves the movement of cholesterol in its esterified form from HDL to the liver and from there into the bile, either directly or after conversion to bile acids, for ultimate elimination. Examples of CETP inhibitors are disclosed in WO/0038725, which is incorporated herein in its entirety by reference. One specific example of a CETP inhibitor is (-)(2R, 4S)-4-Amino-2-2-ethyl-6trifluoromethyl-3,4- dihydro-2H-quinoline-l-carboxylic acid ethyl ester.

Fibric acid derivatives include bezafibrate, fenofibrate, gemfibrozil and clofibrate, and are known to lower plasma triglyceride levels and elevate HDLc. Related compounds include gemfibrozil, which is a member of a class of drugs known as fibrates that act on the liver. Fibrates are fibric acid derivatives. The typical clinical use of fibrates is in patients with hypertriglyceridemia, low HDLc and combined hyperlipidemia.

Examples of stanols include campestanol, cholestanol, clionastanol, coprostanol, 22,23-dihydro-brassicastanol, epicholestanol, fucostanol, and stigmastanol.

Anti-hypertensive agents include andrenergic blockers, mixed alpha/beta andrenergic blockers, alpha andrenergic blockers, beta andrenergic blockers, andrenergic stimulants, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, calcium channel blockers, diuretics, and vasodilators.

Examples of andrenergic blockers include phenoxybenzamine, gua adrel, guanethidine, reserpine, terazosin, prazosin, and polythiazide.

Examples of alpha/beta andrenergic blockers include carvedilol and labetalol.

Examples of alpha andrenergic blocker include doxazosin and phentolamine amosulalol, arotinolold, apiprazole, doxazosin, fenspirlde, indoramin, labetalol, naftopidil, nicergoline, prazosin, tamsulosin, tolazoline, trimazosin, and yohimbine

Examples of beta andrenergic blockers include propranolol, metoprolol, acebutol, alprenol, amosulal ; arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butiridine hydrochlorid, ebutofilolol, carazolol, carteolol, carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, labetalol, levobxmolol, mepindolol, metipranolol, metoprolol, moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, perbutolol, pindolol, practolol, pronethalol, propranolol, sotalol, sufmalol, talindol, tertatolol, tilisolol, timolol, toliprolol, and xibenolol.

Examples of angiotensin converting enzyme inhibitors include quinapril, perindopril, erbumine, ramipril, captopril, fosinopril, trandolapril, lisinopril, moexipril, enalapril, benazepril, alacepril, benazepril, captopril, ceronapril, delapril, enalapril, fosinopril, imadapril, lisinopril, moveltopril, perindopril, quinapril, ramipril, spirapril, temocapril, and trandolapril.

Examples of angiotensin II receptor antagonists include candesartan cilexetil, inbesartan, losartan, valsartan, and eprosartan.

Examples of calcium channel blockers include verapamil, diltiazem, nifedipine, nimodipine, delodipine, nicardipine, isradipine, amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, isradipine, lacidipine, lercanidipine, manidipine, nicardipine, nifendipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, cinnarizine, flxmarizine, lidoflazine, lomerizine, bencyclane, etafenone, and perhexiline.

Examples of diuretics include hydrochlorothiazide, chlorotliiazide, furosemide, bumetanide, ethacrynic acid, amiloride, triameterene, spironolactone, eplerenone, acetazolamide, althiazide, amanozine, ambuside, amiloride, arbutin, azosemide, bendroflumethiazide, benzthiazide, benzylhydro-chlorotl iazide, bumetanide, butazolamide, buthiazide, chloraminophenamide, chlorazanil, chlorothiazide, chlorthalidone, clofenamide, clopamide, clorexolone, cyclopenthiazide, cyclothiazide, disulfamide, epithiazide, ethacrynic acid, ethiazide, ethoxolamide, etozolin, fenquizone, furosemide, hydracarbazine, hydrochlorothiazide, hydro flumethiazide, indapamide, isosorbide, mannitol, mefruside, methazolamide, methyclothiazide, meticrane, metochalcone, metolazone, muzolimine, paraflutizide, perhexiline, piretanide, polythiazide, quinethazone, teclothiazide, ticrynafen, torasemide, triamterene, trichlormethiazide, tripamide, urea, and xipamide.

Examples of vasodilators include hydralazine, minoxidil, diazoxide, nixroprusside, aluminum nicotinate, amotriphene, bamethan, bencyclane, bendazol, benfurodil hemisuccinate, benziodarone, betahistine, bradykinin, brovincamine, bufeniode, buflomedil, butalamine, cetiedil, chloracizine, chromonar, ciclonicate, cinepazide, cinnarizine, citicoline, clobenfural, clonitrate, cloricromen, cyclandelate, diisopropylamine dichloroacetate, diisopropylamine dichloroacetate, dilazep, dipyridarnole, droprenilamine, ebumamonine, efloxate, eledoisin, erythrityl, etafenone, fasudil, fendiline, fenoxedil, floredil, flunarizine, flunarizine, ganglefene, hepronicate, hexestrol, hexobendine, ibudilast, ifenprodil, iloprost, inositol, isoxsuprine, itramin tosylate, kallidin, kallikrein, khellin, lidoflazine, lomerizine, mannitol hexanitrate, medibazine, moxisylyte, nafronyl, nicametate, nicergoline, mcofuranose, nimodipine, nitroglycerin, nylidrin, papaverine, pentaerythritol tetranitrate, pentifylline, pentoxifylline, pentrinitrol, perhexilline, pimefylline, piribedil, prenylamine, propatyl nitrate, prostaglandin El, suloctidil, tinofedrine, tolazoline, trapidil, tricromyl, trimetazidine, trolnitrate phosphate, vincamine, vinpocetine, viquidil, visnadine, and xanthinol niacinate.

While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention. It is contemplated that any single feature or any combination of optional features of the inventive variations described herein may be specifically excluded from the claimed invention and be so described as a negative limitation. Accordingly, it is not intended that the invention be limited, except as by the appended claims.

Claims

WE CLAIM:

I . A method of reducing fat absorption in mammals comprising orally administering to the mammals an effective amount of an inter-polymer complex formed between a polymeric glucosamine or its derivative and a polyacrylic acid or its derivative.

2. The method of claim 1, wherein the fat is present in the emulsified form.

3. The method of claim 1, wherein the fat is present in non-emulsified form.

4. The method of claim 1, wherein the complex can bind an amount of fat that is up to fifteen times the weight of the complex.

5. The method of claim 1, wherein the complex is co-administered with a lipase- inhibitor or bile acid sequestrant.

6. The method of claim 5, wherein the lipase-inhibitor comprises orlistat.

7. The method of claim 5, wherein the bile acid sequestrant comprises cholestyramine.

8. The method of claim 1, wherein the complex further comprises at least one water- soluble vitamin acid.

9. The method of claim 8, wherein the water-soluble vitamin acid is selected from the group comprising nicotinic acid, ascorbic acid, folic acid, pantothenic acid, and biotin.

10. The method of claim 1, wherein the complex is administered as one or more of a tablet, a suspension, a dispersible powder or granule, or a capsule.

I I . The method of claim 1, wherein the polyacrylic acid comprises a cross-linked polyacrylic acid.

12. The method of claim 1, further comprising orally co-administering one or more compounds selected from the group comprising statins, IBAT inhibitors, MTP inhibitors, cholesterol absorption antagonists, phytosterols, stanols, CETP inhibitors, fibric acid derivatives, and antihypertensive agents.

13. The method of claim 12, wherein the statin comprises one or more of rosuvastatin, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, mevastatin, velostatin, compactin, dalvastatin, fluindostatin, dihydorcompactin, rivastatin, SDZ-63,370, CI-981, HR-780, L-645,164, CL-274,471, alpha-, beta-, and gammatocotrienol, (3R, 5S, 6E)-9,9-bis (4-fluorophenyl)-3,5-dihydroxy-8- H- tetrazol-5- yl)-6,8-nonadienoic acid, L-arginine salt, (S)-4- [ [2- [4- (4- fluorophenyl)-5-methyl-2- (1- methylethyl)-6-phenyl-3-pyridinyl] ethenyl]- hydroxy-phosphinyl]-3-hydroxy-butanoic acid, disodium salt, BB-476, (British Biotechnology), dihydrocompactin, [4R- [4 alpha, 6 beta (E)]]-6- [2- [5- (4- fluorophenyl)-3- (l-methylethyl)-l- (2-pyridinyl)-l H-pyrazol-4- yl] ethenyl] tetrahydro-4-hydroxy-2H-pyran-2-one, and IH-pyrrole-1-heptanoic acid, 2- (4- fluorophenyl)-beta, delta-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino) carbonyl]- calcium salt [R- (R*, R*)].

14. The method of claim 12, wherein the stanol comprises one or more of campestanol, cholestanol, clionastanol, coprostanol, 22,23-dihydro-brassicastanol, epicholestanol, fucostanol, and stigmastanol.

15. The method of claim 12, wherein the CETP inhibitor comprises (-) (2R, 4S)-4- Amino-2-2-ethyl-6trifluoromethyl-3 ,4-dihydro-2H-quinoline- 1 -carboxylic acid ethyl ester.

16. The method of claim 12, wherein the fibric acid derivative comprises one or more of clofibrate, fenofibrate, ciprofibrate, bezafibrate and gemfibrozil.

17. The method of claim 12, wherein the antihypertensive agent comprises one or more of an andrenergic blocker, a mixed alpha/beta andrenergic blocker, an alpha andrenergic blocker, a beta andrenergic blocker, an andrenergic stimulant, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin II receptor antagonist, a calcium channel blocker, a diuretic, and a vasodilator.

18. The method of claim 17, wherein the antihypertensive agent comprises one or more of phenoxybenzamine, guanadrel, guanethidine, reserpine, terazosin, prazosin, polythiazide, methyldopa, methyldopate, clonidine, chlorthalidone, guanfacine, guanabenz, trimethaphan, carvedilol, labetalol, propranolol, metoprolol, acebutol, alprenol, amosulal, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bufuralol, bunitrolol, buprandolol, butiridine hydrochloride, butofilolol, carazolol, carteolol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol, indenolol, levobunolol, mepindolol, metipranolol, moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol, perbutolol, pindolol, practolol, pronethalol, sotalol, sufmalol, talindol, tertatolol, tilisolol, timolol, toliprolol, xibenolol, doxazosin phentolamine, amosulalol, arotinolold, apiprazole, doxazosin, fenspirlde, indoramin, naftopidil, nicergoline, tamsulosin, tolazoline, trimazosin, yohimbine, quinapril, perindopril, erbumine, captopril, fosinopril, trandolapril, lisinopril, moexipril, enalapril, alacepril, benazepril, ceronapril, delapril, imadapril, moveltopril, ramipril, spirapril, temocapril, candesartan cilexetil, inbesartan, losartan, valsartan, eprosartan, nifedipine, nimodipine, delodipine, nicardipine, isradipine, amlodipine, bepridil, clentiazem, diltiazem, fendiline, gallopamil, mibefradil, prenylamine, semotiadil, terodiline, verapamil, aranipine, bamidipine, benidipine, cilnidipine, efonidipine, elgodipine, felodipine, lacidipine, lercanidipine, manidipine, nifendipine, nilvadipine, nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine, lomerizine, bencyclane, etafenone, perhexiline, chlorothiazide, furosemide, bumetanide, ethacrynic acid, amiloride, triameterene, spironolactone, eplerenone, acetazolamide, althiazide, amanozine, ambuside, arbutin, azosemide, bendroflumethiazide, benzthiazide, benzylhydro-chlorothiazide, butazolamide, buthiazide, chloraminophenamide, chlorazanil, clofenamide, clopamide, clorexolone, cyclopenthiazide, cyclothiazide, disulfamide, epithiazide, ethiazide, ethoxolamide, etozolin, fenquizone, hydracarbazine, hydrochlorothiazide, hydroflumethiazide, indapamide, isosorbide, mannitol, mefruside, methazolamide, methyclothiazide, meticrane, metochalcone, metolazone, muzolimine, paraflutizide, piretanide, quinethazone, teclothiazide, ticrynafen, torasemide, triamterene, trichlormethiazide, tripamide, urea, xipamide, hydralazine, minoxidil, diazoxide, nitroprusside, aluminum nicotinate, amotriphene, bamethan, bendazol, benfurodil hemisuccinate, benziodarone, betahistine, bradykinin, brovincamine, bufeniode, buflomedil, butalamine, cetiedil, chloracizine, chromonar, ciclonicate, cinepazide, citicoline, clobenfural, clonitrate, cloricromen, cyclandelate, diisopropylamine dichloroacetate, dilazep, dipyridamole, droprenilamine, ebumamonine, efloxate, eledoisin, erythrityl, fasudil, fenoxedil, floredil, ganglefene, hepronicate, hexestrol, hexobendine, ibudilast, ifenprodil, iloprost, inositol, isoxsuprine, itramin tosylate, kallidin, kallikrein, Miellin, lidoflazine, hexanitrate, medibazine, moxisylyte, nafronyl, nicametate, nicofixranose, nitroglycerin, nylidrin, papaverine, pentaerythritol tetranitrate, pentifylline, pentoxifylline, pentrinitrol, perhexilline, pimefylline, piribedil, propatyl nitrate, prostaglandin El, suloctidil, tinofedrine, trapidil, tricromyl, trimetazidine, trolnitrate phosphate, vincamine, vinpocetine, viquidil, visnadine, and xanthinol niacinate.

19. A pharmaceutical composition comprising an inter-polymer complex formed between a polymeric glucosamine or its derivative and a polyacrylic acid or its derivative, wherein the pharmaceutical composition is capable of binding fat.

20. The pharmaceutical composition of claim 19, wherein the polyacrylic acid comprises a cross-linked polyacrylic acid.

21. The pharmaceutical composition of claim 19, further comprising a lipase-inhibitor.

22. The pharmaceutical composition of claim 21, wherein the lipase-inhibitor comprises orlistat.

23. The pharmaceutical composition of claim 19, further comprising one or more excipients.

24. The pharmaceutical composition of claim 19, further comprising at least one water-soluble vitamin acid.

25. The pharmaceutical composition of claim 24, wherein the water-soluble vitamin acid is selected from the group consisting of ascorbic acid, folic acid, pantothenic acid, and biotin.

26. The pharmaceutical composition of claim 19, wherein the composition comprises one or more of a tablet, a suspension, a dispersible powder, granules, and a capsule.

27. A method of binding fat, the method comprising: providing a pharmaceutical composition comprising an inter-polymer complex and one or more excipients, wherein the inter-polymer complex comprises polymeric glucosamine or its derivative and a polyacrylic acid or its derivative; and orally administering the pharmaceutical composition.

28. The method of binding fat of claim 27, further comprising co-administering a lipase-inhibitor with the inter-polymer complex, wherein the lipase-inhibitor comprises orlistat.