JPH04503962A - Microbeaded colestipol hydrochloride - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Microbeaded colestipol hydrochloride The present invention is an emulsion polymerization method for producing microbeaded colestipol hydrochloride (FBCH). Concerning improved methods. The improved method improves the weight ratio of water to polyethylene polyamine and Utilizing the ratio of surfactant or surfactant to polyethylene polyamine It becomes more. The resulting FBCH is a new substance and can be used in new formulations and methods. I can be there. In particular, the present invention provides substantially uniformly small amounts of colestibol hydrochloride. pharmaceutically effective particles, pharmaceutical compositions containing them, and human use. and methods of using them to treat hypercholesterolemia. this The pharmaceutical compositions of Oral suspensions or powders without Includes pharmaceutical foods.

Cholesterol is a diprotonate compound in which approximately one out of five amine nitrogens is protonated. Ethylenetriamine and 1-chloro-2,3-epoxypropane (epichlorohydride) A basic anion exchange resin described as a high molecular weight copolymer with be. It is a pale yellow color that is hygroscopic and swells when placed in water or aqueous fluids. It is colored resin. See Metal Indenons (10th edition) No. 2440, 2438 pages. Light. Colestipol hydrochloride is available from COLESTID (registered trademark). It is commercially available in granular form as granules. Fishermen's Desk L/F Physician Desk Reference (PDR) No. See 42nd edition, p. 2119 (1988).

COLESTID granules are commercially available as an oral hyperlipidemia agent. C0L-E STID granules have a pronounced sandy texture when suspended in orally consumed liquids. Although it has a char, it is tasteless and odorless.

Cholesterol is the major, and perhaps only, bile acid precursor. normal erase During oxidation, acid is secreted from the liver and gallbladder into the intestinal tract via bile. bile acids emulsifies fatty substances present in foods, thus making them easier to absorb. secreted Most of the bile acids are chewed through the intestines, reabsorbed, and returned to the liver via the portal circulation, thus Completes the enterohepatic cycle. Only very small amounts of bile acids are found in normal serum. Ru. Physicians' Desk Reference Reference) 42nd edition, 1988.21] p. 5.

Colestipol hydrochloride, such as COLESTID granules, is a primary Plasma cholesterol levels in patients with hypercholestyolemia (elevated low-density lipoproteins) It is indicated as an adjunctive treatment to a diet that suppresses roll elevation.

Hitherto, the only known form of colestibol hydrochloride has been the granular form, especially the 75% by weight or volume of particles are greater than 100 microns in diameter and at least 30% by weight or volume Spherical beads of colestibol hydrochloride in which % of particles exceed 8o microns in diameter It was COLESTID. These granules should not be consumed orally. Must be mixed with a vehicle that provides a pleasant taste upon oral consumption. Requires. COLESTID (COLEST ID) granules are colestipol salt The acid salt exceeds 99.5% by weight. Colestide (used for anticholesterolemia) Typical daily dose of CQLESTID) granules is 15 to 30 grams per day. It changes with Patients taking this drug usually experience a decrease in serum cholesterol levels. Anticholesterolemic drugs must be taken continuously throughout life to maintain Must be.

The conventionally known form of colestibol hydrochloride, namely colestide (COLESTI) D) Granules were not well accepted by patients. This means that the product The taste texture is unpleasant and seriously compromises pharmaceutical elegance and patient tolerability. Because it will ruin it.

Additionally, the use of granule formulations requires that the drug be mixed with a liquid vehicle at the time of consumption. This means inconvenience for many patients. For example, if you take this drug To take, the patient weighs the powder, disperses it in the liquid vehicle, and pours out the entire contents. I have to drink it. Pharmaceutically, the most convenient dosage form for Nilegant is tablets or capsules. It's probably a capsule agent.

Previously, the known bead form of colestipol hydrochloride had sufficient pharmaceutical elegance and None had the efficacy to provide patients with a sufficiently convenient and effective drug. .

159 disclosure Small particles (with 75% by weight or volume of particles exceeding 100 microns in diameter and 30% by weight) or large particles in which % by volume of the particles are in the form of spherical beads with a diameter exceeding 80 microns. The size of colestibol hydrochloride is known. See PDR1, supra, page 2115. high Oral locholestipol hydrochloride in spherical bead form to treat cholesterolemia The use of salt formulations is also known. See, eg, US Pat. No. 3,892,895.

US Pat. No. 3,692,895 reduces hypercholesterolemia in humans. The patent claims a method of using colestipol hydrochloride to treat cancer. It is a diseased movement (tablets and capsules) for reducing hypercholesterolemia in animals and birds. Discloses >m compositions including capsules and methods of making the same. The composition and manufacture The law requires oral effective doses of polyethylene polyamides such as tetraethylenepentamine. A non-toxic polymer prepared from 1.2:3.4 and epichlorohydrin or - Utilize bifunctional materials such as jepoxybutane.

U.S. Patent No. 4,439,419 neutralizes gastric acidity and treats humans with excess stomach acidity. How to use colestibol hydrochloride to treat hyperacidity and gastric ulcers Discloses the treatment of

U.S. Pat. No. 4,631,305 discloses that polymeric materials such as colestipol hydrochloride It claims compressed tablets containing it as a tablet disintegrant. That's 74 microns Discloses tablets containing colestipol hydrochloride with a particle size of less than or equal to: death However, it is important to note that the present invention in which most of the particles are less than about 50 microns in size It does not disclose colestipol hydrochloride, such as colestipol hydrochloride.

Co-pending PCT application filed May 24, 1989, PCT/U 589102 No. 187 discloses colestipol hydrochloride in micronized non-spherical form.

Preference for colestipol hydrochloride for medical use disclosed in U.S. Pat. No. 3,803,237 A preferred manufacturing method is known as the “bead process”. Ru. The process consists of (a) introducing a polymer such as ethylenetriamine by mechanical agitation; polyethylenepolyamine and (the alkyl moiety has 10 to 18 carbon atoms) ) Surfactants or surfactants such as sodium alkylbenzene sulfonates. Dispersed in a hydrophobic solvent such as toluene; (b) such as epichlorohydrin; adding the bifunctional substance to the dispersion of (a); (C) the mixture obtained from (b); for about 1 to 5 hours; (d) and the reaction mixture from (c) are diluted with sodium hydroxide. (e) by conventional distillation methods; It therefore consists of recovering the copolymer from the reaction mixture in (d).

In the bead process disclosed in U.S. Pat. No. 3,803,237, polyethylene The ratio of water to polyamine should vary from about 1.5:1 to 6.0:1. and preferably about 4.0:1.

The amount of surfactant or surfactant is 1 kg of polyethylene polyamine used in the reaction. Approximately 13 grams to 12 grams per O. o grams range.

The process of U.S. Pat. No. 3,803,237 provides at least 75% by weight or volume of Particles are greater than 100 microns in diameter, and 30% by weight or volume of particles are 80 microns in diameter. It is used to collect COLESTID granules in the form of spherical bead particles exceeding the It is known that it has the size characteristics described above. Until this invention, commercial production During production, colestibol hydrochloride granules of less than 63 microns were prepared by chance. However, they were classified and discarded. Practical homogeneity of colestipol hydrochloride Materials consisting of small beads have never been prepared before.

Summary of the invention °　The present invention particularly provides: (1) colestipol hydrochloride, (A) containing about 2 to about 10 ethylene units; and a polyethylene polyamide having an average molecular weight of about 103 to 450. and (B) 1-chloro-2,3-epoxypropane (epichlorohydrin). ), comprising about 10% to about 47% of the epichlorohydrin 1. A process for producing a product containing (+) Polyethylene polyamine (A) and alkyl groups inclusively 10 to 1 Alkali metal salts of alkylbenzenesulfonic acids having 8 carbon atoms (i.e. Aqueous solutions of surfactants or surfactants) are mixed with aromatic hydrocarbon water by mechanical stirring. dispersed in a hydrophobic solvent selected from the group consisting of carbon atoms and chlorinated carbon atoms. , where the weight ratio of water to the polyethylene polyamine is from 1.5:1 to 6. 0:1, and the volume ratio of hydrophobic solvent to water is 3.0:1 to 13.0: 1; (II) Adding the component (B) to the dispersion, and adding the polyethylene to the component. The molar ratio of polyamine is 1:6.0 to 1:1.3; (II[) The resulting mixture is heated at a temperature of 40°C to 10.0°C for 1 to 5 hours. Heat; (IV) treating the heated mixture with an aqueous solution of an alkali metal hydroxide; (V) collecting the crosslinked copolymerization product in the form of beads; i) 1.8 to 3.6 grams/gram of water to polyethylene polyamine using weight ratio; and 1i) for 1.0 to 3.0 g/kg polyethylene polyamine an improvement characterized by using a surfactant or a weight ratio of surfactants; (2) The weight ratio of water to the polyethylene polyamine is 2.2 g/g. and the weight of the surfactant or surfactant relative to the polyethylene polyamine. said improvement in which the ratio is 2.5 grams/kilogram; (3) Composition consisting essentially of microbeaded Frestibol hydrochloride (FBCH) : (4) More than 95% of the particles are spherical, non-agglomerated, and 75% (weight or more than 35% (by weight or FBCH in which more than % by volume of the particles are less than about 45 microns in diameter.

(5) FBCH in the form of pharmaceutical dosage units; (6) in the form of tablets or capsules; (7) FBCH containing about 500 mg of drug.

(8) Patients by administering a pharmaceutical composition containing colestibol hydrochloride in a method of treating hypercholesterolemia in which the composition comprises microbeads. An improvement characterized in that it uses colestipol hydrochloride (FBCH); (9) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibition As for the drug gemfibrozil (LOP ID) (10) consuming a predetermined amount of food; Concentrations of FBCH that are effective in treating hypercholesterolemia when The present invention provides a food containing:

Thus, the present invention provides a method for producing finely beaded colestipol hydrochloride (FBCH). Provides improvements in emulsion polymerization processes. Surprisingly and unexpectedly, here By selecting a range of water and surfactant levels to claim A small amount of colestibol hydrochloride that is uniform in size is obtained. The obtained FBCH is new It is a novel substance and can be used in new pharmaceutical formulations and methods. In particular, the present invention Frestipol hydrochloride in substantially uniform, pharmaceutically inert particles; and for treating hypercholesterolemia in humans. Provide instructions on how to use them. These pharmaceutical compositions may be tablets, (flavored or non-flavored) Oral suspensions or powders with good or unpalatable taste, and improvements It includes various drug-containing foods with a pleasant mouthfeel.

““Fine beading” means that particles exceeding approximately 75% by weight or volume are 50 mm in diameter. 4.5 mm in diameter or less, with more than about 35% (by total weight or volume) of the particles having a diameter of about 45 mm. Colestibol hydrochloride in submicron, substantially spherical form (more than 95% spherical, non-agglomerated particles, most preferably greater than about 99% spherical) Ru. These particle sizes were determined by standard light scattering assays.

``Pharmaceutical unit volume'' means a classified pharmaceutical unit that is in a form suitable for administration for medical purposes. FBCH. Thus, ideally a unit dose would be one unit or That total! ! (e.g. one or more each containing a predetermined amount of FBCH) packet) contains a safe and effective dose to lower serum cholesterol It must be something.

As will be apparent to those skilled in the art of formulation, the microbeaded colestibo of the present invention If desired, known tablet ingredients such as binders, fillers, etc. etc., it can be formulated into ordinary tablets for oral administration.

"Surfactant or surfactant" means an alkali of alkylaryl sulfonic acid. Jinxing salts, i.e. sodium, lithium, or potassium salts or mixtures thereof wherein the alkyl group of the nucleic acid has 10 to 18 carbon atoms inclusively. have a child Examples of surfactants or surfactants that can be used include decyl Sodium benzenesulfonate, sodium dodecylbenzenesulfonate, tri Potassium benzenesulfonate, sodium octadecylbenzenesulfonate, etc. be.

The microbeaded colestibol hydrochloride (FBCH) of the present invention most preferably comprises: An improved method includes the following process from the scope disclosed in U.S. Pat. No. 3,803,237. Processing conditions: i) 1.8 of 1.5:1 to 6.0:1 g/g 3.6 grams/gram, most preferably 2.2 grams/gram polyethylene Utilizing the weight ratio of water to polyamine and 1i) from 0.3 to 12,0 grams 1.0 to 3.0 g/kg, most preferably is 2.5 g/kg of surfactant or is the use of the weight ratio of surfactants; It is prepared by an emulsion polymerization "bead process" consisting of:

Surprisingly and unexpectedly, FBCs produced by the improved method of the present invention H is more than essentially or substantially uniformly small spherical particles of colestibol hydrochloride. It is a free-flowing powder.

By microscopic observation of FBCH produced by the improved production method of the present invention, It is shown that all particles are spherical and a few aggregated particles are dumbbell shaped.

Essentially all particles are in the 30-65 micron range. FBCH powder is Ideally, it is suitable for incorporation into a number of pharmaceutical dosage forms and food products.

Surprisingly and unexpectedly, the novel forms of cholesterol hydrochloride of the present invention are superior to the conventional large size beads of the prior art and convenient for oral administration. and benefit from reduced frequency/dose of medication. FBCH in quail The potency was found to be increased by an average of 3 times compared to regular colestibol hydrochloride granules. Ta. Furthermore, since this increased capacity combines with that occurring with oral tablets, the present invention Surprisingly and unexpectedly, a fairly elegant and convenient pharmaceutical product provide.

Thus, hyperlipidemia with a serum cholesterol level exceeding 200 mg/l 00 mf2 In patients with FBCH, the compositions of the present invention may provide a daily dose of about 3 to about 12 gm of FBCH. - effectively lowers cholesterol levels when administered 1 to 3 times a day lower. Therefore, unexpectedly, the present invention provides a method for administering high-potency tablets to patients before each meal. This provides patients with the opportunity to conveniently administer the drug.

Check serum cholesterol, triglyceride and LDL cholesterol levels. Combining FBCH with other known cholesterol-lowering agents to lower be able to. Such agents include, for example, \IEVAcOR®, Niatin (niacin), LOPID (registered trademark) or LORELCO (registered trademark) ).

The FBCH can be added to flavored dry mixes in flavored beverages by simply adding water. Suitable for coming. Typically these flavoring mixes are gums or low molecular weight compounds. Viscosity inducers such as synthetic polymers; sucrose, aspartame or saccharin Flavoring agents such as sodium; colorants sodium nidioctyl sulfosuccinate; humectants such as sodium lauryl sulfate; citric acid, ascorbic acid, Add acidity and control acidity, such as potassium citrate or sodium citrate. flavoring agents such as lemon or orange; and preservatives such as BHA. Contains. Similarly, it is used in pudding and pie filling mixes, gelatin, cakes, Kimix, powdered eggs and powdered potatoes, instant breakfast drinks, gravy and and sauces (e.g. Holandaise), prepared Cereal products (oatmeal, cream of wheat, corn groats), and and drink mixes (powdered fruit punches, powdered flora drinks). It can be used as an additive. Similarly, the FBCH is a For example, it can be used in cakes, pasta products, candies. , kutskis, confectionery, yogurt products including frozen yogurt products, ice cream and ice cream products, and during preparation (hamburgers, sausages, etc.) It can be used as an additive in

Description of preferred specific examples Example 1 Preparation of finely beaded colestibol hydrochloride The reaction vessel had four sidewall bags. has a full heating mantle, cooling water reflux condenser-1 distillation condenser, and a 5-liter, three-neck round-bottom flask equipped with a 4.5-inch stirring blade. .

At room temperature, 1237 milliliters of toluene, 283 milliliters of deionized water (by reverse osmosis) Milliliter (Witconate 60B 2.9:1 Yitconate (prepared by diluting with 0　B stock solution overnight 1.70ml, and diethylenetriamine 13 5.7 millilisotol is introduced into the reaction vessel.

This initial charge was stirred at 350 rpm with the reflux condenser running. , to a temperature range of 78°C to 82°C. Once this temperature range is achieved , remove the heating mantle and add 186ml of epichlorohydrin for 45 minutes. Add over a period of time. Addition of epichlorohydrin initiates polymerization and reaction mixture The substance becomes milky white and then slowly changes to form a water-swelled polymeric resin in toluene. This results in a clearer slurry. Heating of the reactants produces an exotherm, which causes The temperature of the reaction mixture rises to its boiling point. Once the boiling has subsided, turn on the heating mantle. Return to maintain reflux temperature of 85°C. Once the epichlorohydrin addition is complete, The mixture is stirred at reflux temperature for 3 hours (cook-down). ).

After tuck down, add 50 milliliters of 50 percent sodium hydroxide solution. Add over 10 minutes. Start the distillation condenser. resume heating to remove water produced by the reaction mixture and ripen the polymer. Volume in reactor The water removed by distillation should be replaced with an equal volume of toluene to maintain the be. This distillation process takes up to 4 hours. Reflux to ripen the polymer Continue for another 5 hours. The reaction mixture was then cooled to below 9o''C and deionized. Add 842 ml of hot water.

The toluene added during the water distillation is also removed by distillation. First, the collected vapor A constant volume in the reactor is maintained by adding the same volume of water as the distillate. Heat the reaction vessel to maintain a reflux temperature of 85°C, which takes approximately 5 hours. After toluene distillation, The reaction mixture is first cooled with cold water; then the mixture is cooled to room temperature on a water bath.

Passed through a polyester cloth ceramic filter with a diameter of 20 cm and a height of 7 cm. Filter the reaction mixture. Add filter cake to 500ml of deionized water. Wash. The cake was then slurried with 1250 milliliters of deionized water, Filter again as above. Finally, refill with 1250 ml of deionized water. Make a slurry, but this time rinse with two 500ml portions of deionized water. profit From the wet cake obtained, 1160 grams of pumpkin were obtained.

Dry the wet cake in a vacuum oven at 50'C to constant weight and bake it on FB. Obtain 8260 grams of C.

Submission of translation of written amendment (Article 184-8 of the Patent Act) February 16, 1991゛

Claims (12)

[Claims] 1. colestipol hydrochloride, (A) containing from about 2 to about 10 ethylene units; and a polyethylene polyamine having an average molecular weight of about 103 to 450. , and (B) 1-chloro-2,3-epoxypropane (epichlorohydrin) a crosslinked copolymerization product of from about 10% to about 47% of said epichlorohydrin. A method for producing a product containing: (1) The polyethylene polyamine (A) and the alkyl group are inclusively 10 to 1 Alkali metal salts of alkylbenzenesulfonic acids having 8 carbon atoms (i.e. Aqueous solutions of surfactants or surfactants) are mixed with aromatic hydrocarbon water by mechanical stirring. dispersed in a hydrophobic solvent selected from the group consisting of , where the weight ratio of water to the polyethylene polyamine is from 1.5:1 to 6. 0:1, and the volume ratio of hydrophobic solvent to water is 3.0:1 to 13.0: 1; (II) Adding the component (B) to the dispersion, and adding the polyethylene to the component. The molar ratio of polyamine is 1:6.0 to 1:1.3; (III) Heating the resulting mixture at a temperature of 40°C to 100°C for 1 to 5 hours death; (IV) treating the nuclear heating mixture with an aqueous solution of an alkali metal hydroxide; then (V) collecting the crosslinked copolymerization product in the form of beads; i) 1.8 to 3.6 grams/gram of water to polyethylene polyamine using weight ratio; and ii) for 1.0 to 3.0 grams/kg of polyethylene polyamine; An improvement characterized by using a surfactant or a weight ratio of surfactants. 2. The weight ratio of water to the polyethylene polyamine is 2.2 grams/gram. Therefore, the weight ratio of the surfactant or surfactant to the polyethylene polyamine 2.5 grams per kilogram. 3. A composition consisting essentially of finely beaded colestipol hydrochloride (FBCH). More than 4.95% of the particles are spherical, non-agglomerated particles, where 75% (by weight or more than 35% (by weight or by volume) of particles less than approximately 50 microns in diameter; Claim 3, wherein more than % (by volume) of the particles are less than about 45 microns in diameter. FBCH. 5. Claim 4, wherein more than about 99% of the particles are spherical, non-agglomerated particles. F.B.C.H. 6. Antihypercholesterolemia consisting essentially of colestipol hydrochloride in unit dosage form microbeaded colestipol hydrochloride (FBCH). Improvement characterized by its use as an active ingredient. 7. Claim 6, wherein the composition is in the form of a tablet, packet, or capsule. Improvements described in section. 8. The improvement according to claim 7, wherein the composition is a 500 mg tablet. 9. Hypercholesterolemia in patients by administering colestipol hydrochloride microbeaded colestipol hydrochloride (FBCH) is used in a method to treat An improvement characterized by its use as a sexual component. 10. Claim 9, wherein FBCH is co-administered with another cholesterol-lowering agent. Improvements described in section. 11. Claim that the cholesterol-lowering agent is an HMG-CoA reductase inhibitor Improvements described in item 10. 12. Effective in treating hypercholesterolemia when consuming certain amounts of food The food containing finely beaded colestipol hydrochloride (FBCH) at a concentration of .