TABLETS CONTAINING AN ANION EXCHANGE RESIN

Abstract: The present invention relates to a pharmaceutical composition comprising anion exchange resin, silicon dioxide, crystalline cellulose, and pharmaceutically acceptable carriers and more particularly to tablets containing anion exchange resin prepared by mixing anion exchange resin, silicon dioxide and crystalline cellulose without adding water and tabletting the mixture. More preferably, the present invention relates to said pharmaceutical composition or tablets wherein the anion exchange resin is non-crosslinked anion exchange resin represented by the formula (I): wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or An alkyl group having from 1-20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1-4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000.

Description: The present invention relates to tablets containing an anion exchange resin useful as a cholesterol depressant, particularly a non-crosslinked anion exchange resin represented by the formula (I): (wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or an alkyl group having from 1 to 20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1 to 4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000) and the invention relates to coating tablets using the same, and more particularly, to coating tablets with excellent stability, in which the content of the active ingredient is increased in order that they can be administered with ease and that the number of the tablets to be administered can be decreased. Cholestyramine of a crosslinked type, which is a conventional cholesterol depressant, is problematic in that its amount to be administered is large (8 to 16 g/day) and that it must be administered in the form of its suspension. Therefore, many studies have heretofore been made to produce tablets and coated tablets of anion exchange resins. For example, a method has been reported of coating tablets of a solid cholestyramine resin having a water content of from 8 to 14 % with a melt of polyethylene glycol and stearic acid in the presence of no solvent to give coated tablets, which do not swell in the mouth (see Japanese Patent Application Laid-Open No. 3-236326). Regarding tablets of an imidazole-type anion exchange resin (see Japanese Patent Application Laid-Open No. 60-209523), known are a method of producing those tablets in the presence of a predetermined amount of water (see Japanese Patent Application Laid-Open No. 2-286621); a method of producing coated tablets by coating those tablets as prepared in the presence of a predetermined amount of water, with hydroxypropyl cellulose or the like (see Japanese Patent Application No. 4-320155 (published before examination as Laid-Open No. 6-157325)); and a method of producing those tablets in the presence of a predetermined amount of water and silicon dioxide (see Japanese Patent Application Laid-Open No. 7-97330). However, the conventional methods require the addition of a predetermined amount of water to the hygroscopic anion exchange resins being tabletted. The present inventors have already reported that non-crosslinked anion exchange resin represented by the formula (I): (wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or an alkyl group having from 1 to 20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1 to 4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000) is extremely useful as a cholesterol depressant (WO 93/13781). Because this anion exchange resin is a non-crosslinked and linear polymer, it does not expand by swelling unlike cross-linked polymers such as cholestyramine etc, so there are no side effects such as feeling of distension in the abdomen or constipation accompanying swelling. Further, the effective adsorption of bile acid per unit weight is large, so the anion exchange resin is extremely useful. However, this agent is soluble in water and has strong astringency, and in addition, it is highly hygroscopic and deliquescent. Therefore, the novel, non-crosslinked cholesterol depressant comprising the compound of formula (II) is problematic in that, if tabletted in any of the conventional methods that require water in the mixing step, it is formed into tablets with poor strength and stability since its flowability and tablettability is very poor. Even if the cholesterol depressant comprising the compound of formula (II) is tabletted in the absence of water, the resulting tablets are still problematic in that they are very astringent because of the strong astringency intrinsic to the compound of formula (II) itself. The dose of the compound of formula (II), though varying depending on the case to which it is administered, is relatively large or is generally from 0.1 to 9 g/day, preferably from 0.1 to 5 g/day. Tablets comprising the compound of formula (II) and containing a large amount of vehicles in order to reduce the bitterness of the compound are problematic in that the number of the tablets to be administered at a time shall be large. In order to produce practical medicaments comprising the compound of formula (II) being extremely useful, it is desired to formulate the compound into highly-stable preparations without strong astringency while adding thereto the smallest possible amount of vehicles. As a result of further study in view of the above problem, the present inventors found that an anion exchange resin, particularly a non-crosslinked anion exchange resin represented by the formula (I): (wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or an alkyl group having from 1-20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1 to 4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000) can be used to prepare tablets industrially by tabletting a mixture without adding water comprising a non-crosslinked anion exchange resin as a cholesterol depressant, silicon dioxide and crystalline cellulose. Further, these tablets are coated as base tablets with a coating agent containing cellulose etc to solve the above problem. The present invention relates to a water-free pharmaceutical composition comprising an anion exchange resin, silicon dioxide, crystalline cellulose and pharmaceutically acceptable carriers. Further, the present invention relates to tablets containing an anion exchange resin obtainable by adding at least silicon dioxide and crystalline cellulose to the anion exchange resin and tabletting the mixture without adding water. More specifically, the present invention relates to tablets containing a non-crosslinked anion exchange resin obtainable by adding at least silicon dioxide and crystalline cellulose to the compound represented by the formula (I) and tabletting the mixture without adding water. If silicon dioxide or crystalline cellulose is not present, not only tabletting properties but also the tabletting yield is significantly worsened due to high scattering of tablet weights, cracking on the surfaces of the tablets and fracture of the edges thereof (see Comparative Examples 2 and 3). The present inventors unexpectedly found that the anion exchange resin which has been considered difficult for industrially tabletting in the absence of water, particularly the non-crosslinked anion exchange resin represented by the formula (I), can provide industrially obtainable tablets by adding suitable amounts of both silicon dioxide and crystalline cellulose. A method of producing anion exchange resin tablets having excellent stability under humidity by adding water to suppress the hygroscopicity of the anion exchange resin and lessening the rate in change of the diameters of base tablets caused by relative humidity, followed by further coating them with cellulose is disclosed in Japanese Patent Application Laid-Open Publication Nos. 97330/95 and 157325/94. However, this prior art method is intended for use in coating of base tablets as cores containing a predetermined amount of water with reduced change in the diameters of base tablets caused by humidity. The base tablets of the present invention are prepared by tabletting an anion exchange resin without adding water, particularly the non-crosslinked anion exchange resin represented by formula (I), which is not useful for preparing tablets due to its strong hygroscopicity. Said known method of tabletting base tablets containing a predetermined amount of water was difficult to apply as such to the highly hygroscopic base tablets of the present invention. The present inventors found that by coating the highly hygroscopic base tablets with a coating agent containing cellulose, it is possible to prevent not only the astringency of an anion exchange resin, particularly of the compound represented by the formula (I), but also the hygroscopicity of the water-free base tablets. Therefore, tablets having stability in long-term storage are provided. Accordingly, the present invention also relates to coating tablets containing an anion exchange resin, wherein base tablets are coated by coating agents containing celluloses and base tablets are provided by tabletting a mixture comprising the anion exchange resin, silicon dioxide and crystalline cellulose without adding water. More specifically, the present invention relates to coating tablets containing non-crosslinked anion exchange resin, which tablets are prepared by adding at least silicon dioxide and crystalline cellulose to the non-crosslinked anion exchange resin represented by formula (I): (wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or an alkyl group having from 1-20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1 to 4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1 to 4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000) without adding water and tabletting the mixture to prepare tablets, followed by coating them with a coating agent containing celluloses. The preparation of the present invention is characterized in that manufacturing of the preparation with trace fillers, i.e. with a high content of drug, is made feasible. Further, the products according to the present invention can be applied sufficiently to successive productions and to industrial productions. The anion exchange resin of the present invention is preferably a non-crosslinked anion exchange resin, more preferably the compound represented by formula (I). The substituent group R 1 in the compound of formula (I) is an aralkyl group having from 7 to 10 carbon atoms or an alkyl group having from 1 to 20 carbon atoms, and the aryl group of said aralkyl group may be substituted but is preferably not substituted. More specifically, said alkyl group may be a straight chain or branched chain alkyl group. Further more specifically, a benzyl group which may have a substituent group, phenylethyl group, methyl group, ethyl group, n-propyl group, iso-propyl group, hexyl group, dodecyl group, octadecyl group, eicosyl group etc, more preferably a benzyl group, methyl group, hexyl group, dodecyl group, and octadecyl group can be listed as examples. The substituent groups R 2 and R 3 are each independently the same or different and may be straight chain or branched chain lower alkyl groups having from 1-4 carbon atoms. More specifically, a methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group etc, more preferably a methyl group can be listed as examples. The substituent group R 4 is a hydrogen atom or a straight chain or branched chain lower alkyl group having from 1-4 carbon atoms. More specifically, a hydrogen atom, methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group etc, more preferably a hydrogen atom or methyl group can be listed as examples. The counter ion X is particularly not limited insofar as it is a physiologically acceptable counter ion, and halogens, inorganic salts such as sulfate, carbonate etc and organic acid salts such as acetate, propionate, malonate, ascorbate, glucuronate, glutamate, sulfonate, phosphate, preferably halogens, sulfate, phosphate, more preferably halogens such as chlorine ion, bromine ion and fluorine ion can be listed as examples. The compound of formula (I) of the present invention can be produced by preparing its corresponding monomer, i.e. quaternary ammonium salt, and then polymerizing it in the presence of a polymerization initiator such as a radical polymerization agent. Examples of the compound of formula (I) of the present invention are the following: poly(acryloyloxyethyl-N,N,N-trimethylammonium chloride), poly(methacryloyloxyethyl-N,N,N-trimethylammonium chloride), poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride), poly(methacryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride), poly(acryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride), poly(methacryloyloxyethyl-N,N-dimethyl-N-hexylammonium chloride), poly(acryloyloxyethyl-N,N-dimethyl-N-dodecylammonium chloride), poly(methacryloyloxyethyl-N,N-dimethyl-N-dodecylammonium chloride), poly(acryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride), and poly(methacryloyloxyethyl-N,N-dimethyl-N-octylammonium chloride). A particularly preferred compound of formula (1) is poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride). The content of the anion exchange resin of the present invention, particularly the compound of formula (I), is in the range of from 50 to 95 % by weight, preferably from 70 to 90 % by weight, more preferably from 75 to 90 % by weight, relative to the total weight of the base tablets. Silicon dioxide and crystalline cellulose used in the present invention are not particularly limited inasmuch as they are acceptable for oral administration, preferably those having been used as peroral pharmaceutical preparations are industrially suitable. Silicon dioxide is used to impart fluidity to the compositions of the invention. For example, hydrous silicon dioxide (white carbon), silicon dioxide (silica gel or silicic anhydride) etc, preferably finely divided silicon dioxide and light silicic anhydride which are not hydrous, are used. The apparent specific gravity of silicon dioxide used is 70 g/l to 20 g/l, preferably 50 g/l to 20 g/l, and light silicic anhydride with lower apparent specific gravity is preferred. The silicon dioxide is added in an amount of 0.01 to 5 % by weight, preferably 0.1 to 3 % by weight, more preferably 0.1 to 1 % by weight relative to the total weight of the base tablets. Crystalline cellulose is preferably fine crystalline cellulose, and the average particle diameter of the crystalline cellulose is 5 to 50 microns, preferably 10 to 50 microns, more preferably 10 to 30 microns. The crystalline cellulose is added in an amount of 0.1 to 30 % by weight, preferably 1 to 30 % by weight, more preferably 10 to 30 % by weight relative to the total weight of the base tablets. Silicon dioxide used in the present invention, particularly light silicic anhydride improves the powder fluidity as its content increases and as the apparent specific gravity (bulk density) of silicon dioxide decreases, whereas tabletting properties (compressibility) seem to decrease. Therefore, if silicon dioxide is added in an amount of 5 parts or more relative to the compound of formula (I), tabletting properties are deteriorated and cracks frequently occur in the resulting tablets. Crystalline cellulose used in the present invention improves tabletting properties (compressibility) as its content increases and as the average particle size of crystalline cellulose decreases, whereas powder fluidity appears to be decreased. With respect to fine crystalline cellulose, if its content exceeds 30 parts, the scattering of the weights of tablets is raised. Because there is no particular advantage in using crystalline cellulose in a content of 30 parts or more relative to the compound of formula (I), it is preferred to add inexpensive fillers such as lactose if a large amount of additional fillers is required. Accordingly, the present invention relates more specifically to tablets containing anion exchange resin prepared by tabletting a water-free mixture containing at least an anion exchange resin, preferably the non-crosslinked anion exchange resin represented by formula (I), light silicic anhydride with a low apparent specific gravity of 70 g/l to 20 g/l, preferably 50 g/l to 20 g/l, and crystalline cellulose with an average particle diameter of 50 to 10 microns, preferably 30 to 10 microns. More specifically, the present invention relates to tablets prepared by tabletting a water-free mixture containing at least the non-crosslinked anion exchange resin represented by formula (I), silicic anhydride with a low apparent specific gravity of 50 g/l to 20 g/l, preferably 40 g/l to 20 g/l, and crystalline cellulose with an average particle diameter of 50 to 10 microns, preferably 30 to 10 microns wherein the content of said anion exchange resin is 50 to 90 % by weight, preferably 70 to 90 % by weight, more preferably 75 to 90 % by weight relative to the total weight of the tablets. Further, the present invention relates to coating tablets containing non-crosslinked anion exchange resin by further coating said tablets with a coating agent containing cellulose. Besides said silicon dioxide and crystalline cellulose, ingredients conventionally used in tabletting can be added in suitable amounts. For example, the following can be added as necessary; fillers such as disaccharides or monosaccharides such as lactose (milk sugar), sucrose, glucose, mannitol, sorbitol etc, starch such as potato starch, wheat starch, corn starch, rice starch, inorganic substances such as calcium phosphate and calcium sulfate, higher fatty acids and metallic salts thereof (e.g. stearic acid, magnesium stearate etc), lubricants such as higher alcohols, talk, synthetic aluminum silicate etc, disintegrators such as starch, sodium salts or potassium salts of carboxymethyl cellulose, methyl cellulose, carboxymethyl starch, sodium alginate etc, and binders such as starch, sucrose, gelatin, gum Arabic, methyl cellulose, carboxymethyl cellulose sodium, polyvinyl pyrrolidone, polymethyl pyrrolidone etc. The base tablets of the present invention, which are subsequently coated can be produced by mixing the respective ingredients and tabletting the mixture. The order of addition of the respective ingredients is not particularly limited, but preferably crystalline cellulose and silicon dioxide are first mixed, and then the compound represented by formula (I) is preferably gradually added and mixed, and other components are added to the mixture and mixed as necessary. The mallet pressure for tabletting is not particularly limited, and is preferably 2 tons or less. The celluloses contained in the coating agent used in the coating step of the present invention are not particularly limited inasmuch as they are pH independent and water-soluble. Specific examples are hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose etc. Hydroxypropyl methyl cellulose is preferred. In the present invention, the celluloses may be used each solely. As necessary, a small amount of wax, titanium oxide, talk, low substituted hydroxypropyl cellulose, polyethylene glycol, triethyl citrate etc can also be added to the celluloses. For strength and from an economical viewpoint of the resulting coating film, polyethylene glycol (Macrogol) is preferably added. The amount of cellulose coated is too large if the concentration of cellulose in the coating solution is high, so its use at high concentrations is not preferred. Its concentration is preferably less than 20 % by weight, more preferably about 6 to 15 % by weight. If polyethylene glycol (Macrogol) is to be added, its concentration is preferably about 1 to 50 % by weight, more preferably about 5 to 40 % by weight. As other coating agents, acid-soluble coating agents can be used. For example, it is possible to use coating agents dissolving in gastric acid, such as diethyl aminomethacrylate, polyvinyl acetal diethyl aminoacetate (AEA), dimethyl aminoethyl methacrylate-methyl methacrylate copolymer (trade name: Eudragit E (methyl methacrylate-butyl methacrylate-dimethyl aminoethyl methacrylate copolymer)), cellulose acetate N,N-di-n-butylhydroxypropyl ether (CABP) etc. The method of coating is not particularly limited, but spray coating is preferred. Preferably, the coating is such that the coating film itself is coated in an amount of 1 to 10 % by weight relative to the tablets (base tablets). For the purpose of masking of astringency, a coating in an amount of 1 % by weight or more is sufficient, but it is not particular useful even if 10 % by weight or more coating is applied, and about 3 % by weight coating is most preferable. For coating, the water content of base tablets is measured and the coating is continued until there is no increase in water content. Hereinafter, the present invention is described in more detail with reference to Examples, but it is evident that the invention is not limited to the following examples insofar as the scope of the invention lies in the gist thereof. Example 1 (1) Mixing step For mixing the ingredients, a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 1000 g of crystalline cellulose and 50 g of light silicic anhydride shown in the mixture formulation below were introduced into the mixing machine and mixed for 5 minutes. The total amount of poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride) (the compound (referred to hereinafter as "Compound 1") of formula (I) wherein R 1 is a benzyl group, R 2 and R 3 are methyl groups, R 4 is a hydrogen atom, n is 2, and X is a chlorine ion) was divided into 4 portions and each portion was added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate were introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 8900 g crystalline cellulose (trade name: Abicel PH-F20 (average particle diameter: 17 microns)) 1000 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 30 g/l) 50 g (2) Tabletting step In the tabletting step a Rotary type tabletting machine HT-AP15SS (Hata Tekkosho Co.) has been used. (2-1) Tabletting conditions Rotation 35 rpm Thickness 5 mm Hardness 7 or more Upper and lower mallet pressure 2 tons or less Forced feeder used (3) Coating step In the coating step a Doria coater 650 (POWREX) has been used. (3-1) Coating method 7 kg of the tablets obtained in (2) above are introduced into a pan, and the coating pan is set at a 0 rpm at a suction air temperature of 80 °C, and it is left until its exhaust temperature becomes constant. At this time, it is confirmed that the exhaust temperature is 50 °C or more. 20 tablets are taken and weighed, and then divided into powder, and its water content is determined. The number of revolutions is set at 7 rpm, and it is initiated to spray a coating liquid having the formulation shown below at 12 g/min. 30 minutes later, the number of revolutions is set at 15 rpm and spraying is conducted at about 18 g/min. 20 tablets are sampled and measured for the weight and water content of the tablets at suitable intervals. When the water content does not increase any more and the weight of tablets becomes 3 % relative to the base tablets, spraying is terminated and the number of revolutions is set at 5 rpm and the tablets are dried for about 60 minutes. (3-2) Formulation of the coating liquid Hydroxypropyl methyl cellulose 2910 400 g Macrogol 6000 120 g Ion-exchanged water 4600 g Example 2 (1) Mixing step For mixing the ingredients a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 2000 g of crystalline cellulose and 50 g of light silicic anhydride shown in the mixture formulation below are introduced into the mixing machine and mixed for 5 minutes. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 7900 g crystalline cellulose (trade name: Abicel PH-301 (average particle diameter: 40 microns)) 2000 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 50 g/l) 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Example 3 (1) Mixing step For mixing the ingredients, a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 1000 g of crystalline cellulose, 550 g of milk sugar, and 50 g of light silicic anhydride shown in the mixture formulation below are introduced into the mixing machine and mixed for 5 minutes. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 8350 g crystalline cellulose (trade name: Abicel PH-F20 (average particle diameter: 17 microns)) 1000 g milk sugar 550 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 50 g/l) 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Example 4 (1) Mixing step, tabletting step The mixing step and tabletting step were carried out in the same manner as in Example 1. (2) Coating step (2-1) Coating method The coating method is carried out in the same manner as in Example 1 until the step of drying, 5 g of carnauba wax is further added, the number of revolutions is set at 5 rpm and the machine is operated for 5 minutes. (2-2) Formulation of the coating liquid Hydroxypropyl methyl cellulose 2910 400 g Macrogol 6000 120 g Titanium oxide 28 g Ion-exchanged water 4000 g (2-3) Lubricant Powder carnauba wax 5 g Example 5 (1) Mixing step For mixing the ingredients, a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method . 1000 g of crystalline cellulose and 50 g of light silicic anhydride shown in the mixture formulation below are introduced into the mixing machine and mixed for 5 minutes. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 8900 g crystalline cellulose (trade name: Abicel PH-301 (average particle diameter: 40 microns) 1000 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 30 g/l) 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Example 6 (1) Mixing step For mixing the ingredients, a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 1000 g of crystalline cellulose and 50 g of light silicic anhydride shown in the mixing formulation below are introduced into the mixing machine and mixed for 5 minutes. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 8900 g crystalline cellulose (trade name: Abicel PH-302 (average particle diameter: 120 microns) 1000 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 30 g/l) 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Example 7 Tablets prepared by the tabletting step according to Example 1 without the coating step. Comparative Example 1 (1) Mixing step For mixing the ingredients a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 1000 g of crystalline cellulose and 50 g of light silicic anhydride shown in the mixture formulation below are introduced into the mixing machine and mixed for 5 minutes. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. Because it was difficult to mix Compound 1 with water, 890 g water were added by spraying. (1-2) Mixture formulation (10 kg) Compound 1 8010 g water 890 g crystalline cellulose (trade name: Abicel PH-F20 (average particle diameter: 17 microns) 1000 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 30 g/l) 50 g Comparative Example 2 (1) Mixing step For mixing the ingredients, a POWREX v-type mixing machine FMV100 has been used. (1-1) Mixing method 50 g of light silicic anhydride in the mixture formulation below are introduced into the mixing machine. The total amount of Compound 1 is divided into 4 portions and each portion is added to it at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 9900 g magnesium stearate 50 g light silicic anhydride (apparent specific gravity (bulk density) 30 g/l) 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Comparative Example 3 (1) Mixing step For mixing the ingredients, a POWREX V-type mixing machine FMV100 has been used (1-1) Mixing method 1000 g of crystalline cellulose in the mixture formulation below are introduced into the mixing machine. The total amount of Compound 1 is divided into 4 portions and each portion is added to said mixture at 5-minute intervals and mixed. Thereafter, 50 g of magnesium stearate are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 8950 g crystalline cellulose (trade name: Abicel PH-F20 (average particle diameter: 17 microns) 1000 g magnesium stearate 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. comparative Example 4 (1) Mixing step For mixing the ingredients a POWREX V-type mixing machine FMV100 has been used. (1-1) Mixing method 9950 g of Compound 1 and 50 g of magnesium stearate shown in the mixture formulation below are introduced into the mixing machine and mixed for 1 minute. (1-2) Mixture formulation (10 kg) Compound 1 9950 g magnesium stearate 50 g (2) Tabletting step, coating step The tabletting step and coating step were carried out in the same manner as in Example 1. Test Example 1 In tablets obtained by a tabletting pressure of 2 tons or less, powder fluidity due to scattering of the weights of base tablets was indicated in the frequency of occurrence of fracture and cracking in coating. The present article showed compressibility in this appearance test because it is highly hygroscopic and therefore its weight increases during a wearing test. The test results are shown in Table 1. Scattering in weights of base tablets Fracture & cracking Tabletting properties Example 1 Small None good Example 2 Small None good Example 3 Small None good Com. Ex. 1 unable to tablet - - Ex. 5 Small cracks on surface significantly deteriorated Ex. 6 Small cracks on surface, fracture at edge significantly deteriorated Com. Ex. 2 Small cracks on surface, fracture at edge significantly deteriorated Com. Ex. 3 Middle None moderate Com. Ex. 4 Large cracks on surface, fracture at edge poor Comparative Example 1 to which water was added could not be sufficiently mixed because of its deliquescence and stringing caused by water, and even its tabletting was unable. In the preparations without adding water, tabletting and coating were possible in any examples and comparative examples, and tablets free of problems as regards powder fluidity and compressibility were obtained in Examples 1, 2 and 3. A formulation free of crystalline cellulose is shown in Comparative Example 2, a formulation free of light silicic anhydride is shown in Comparative Example 3, and a formulation free of crystalline cellulose and light silicic anhydride is shown in Comparative Example 4. If crystalline cellulose is not present, tabletting properties (compressibility) are significantly deteriorated, and cracks appear on the surfaces of the tablets. In the formulation free of light silicic anhydride, powder fluidity is lowered and scattering of tablet weights is very high. When both of them are not present, scattering of tablet weights is extremely high, while there are many cracks and fractures, and tabletting properties are poor. In addition, a formulation to which crystalline cellulose with an average particle diameter of 40 microns is added is shown in Example 5, and a formulation to which crystalline cellulose with an average particle diameter of 120 microns is added is shown in Example 6. In both examples light silicic anhydride with an apparent specific gravity (bulk density) 30 g/l was used. These comparative examples show that even if the average particle diameter of crystalline cellulose added is larger, tabletting is made feasible by adding light silicic anhydride with low apparent specific gravity (bulk density) (Example 2), but if light silicic anhydride with large apparent specific gravity (bulk density) is added, cracking and fractures frequently occur while tabletting properties are made poor. Further, tablets with a high drug content can be produced by use of light silicic anhydride with low apparent density (bulk density) and crystalline cellulose with low average particle diameter as shown in Example 1, thus contributing to a reduction in the dosage of the pharmaceutical preparation. The formulation of the tablets according to the present invention enables stable and direct tabletting using only the mixing step without any granulation step, to sufficiently cope with successive production. Test Example 2 The present tablets are deformed when the water content exceeds 7 %, and they deliquesce upon further absorption of water. The increase in stability by coating was compared in terms of deformation after storage at 60 °C under a relative humidity of 90 % for 20 minutes. The astringency of the tablets when placed for 30 seconds in the mouth was also compared. The results of the test are shown in Table 2. Deformation Astringency Example 1 absent absent Example 4 absent absent Ex. 7 present present It is understood that by coating the stability of tablets is increased and their stringency is masked, so that tablets are obtained, which can be administered easily. As described above, the pharmaceutical compositions and tablets of the present invention have the great advantages that they are superior in dosage and administration methods compared with peroral cholesterol depressants containing a conventional anion exchange resin, and that even at the time of manufacturing, no granulation step is required. Further, by coating the obtained tablets with cellulose, it is possible to provide tablets which can easily be administered without any stringency of the drug.

Claims: A water-free pharmaceutical composition comprising an anion exchange resin, silicon dioxide, crystalline cellulose, and pharmaceutically acceptable carriers. Tablets containing an anion exchange resin obtainable by mixing the anion exchange resin with silicon dioxide and crystalline cellulose without adding water and tabletting the mixture. Tablets according to claim 2 wherein the anion exchange resin is non-crosslinked anion exchange resin. Tablets according to claim 2 or 3 wherein the anion exchange resin is non-crosslinked anion exchange resin represented by the formula (I): (wherein R 1 is an aralkyl group having from 7 to 10 carbon atoms or An alkyl group having from 1-20 carbon atoms; R 2 and R 3 are each independently the same or different and represent a lower alkyl group having from 1-4 carbon atoms; R 4 is a hydrogen atom or a lower alkyl group having 1-4 carbon atoms; X is a physiologically acceptable counter ion; n is an integer of from 1 to 3; and p is an average degree of polymerization of from 10 to 10,000). Tablets according to any one of claims 2 to 4 wherein the anion exchange resin is poly(acryloyloxyethyl-N,N-dimethyl-N-benzylammonium chloride). Tablets according to any one of claims 2 to 5 wherein the proportion of silicon dioxide added is 0.1 to 5 % by weight. Tablets according to any one of claims 2 to 6 wherein the proportion of crystalline cellulose added is 1 to 30 % by weight. Tablets according to any one of claims 2 to 7 wherein the apparent specific gravity of silicon dioxide is 70 g/l to 20 g/l, and the average particle diameter of crystalline cellulose is 50 to 10 microns. Tablets according to any one of claim 2 to 8 as base tablets which are coated. Tablets according to claim 9 wherein the coating agent contains cellulose. Tablets according to claim 10 wherein the cellulose is hydroxypropyl methyl cellulose. Tablets according to any one of claims 9 to 11 wherein the coating agent is applied in an amount of 1 to 10 % by weight relative to the base tablets.

Inventors: GOTO TAKESHI, MENO TATSUYA, GOTO, TAKESHI, MENO, TATSUYA, GOTO, TAKESHI, HISAMITSU PHARMACEUTICAL CO., INC., MENO, TATSUYA, HISAMITSU PHARMACEUTICAL CO., INC.
Applicants: HISAMITSU PHARMACEUTICAL CO, HISAMITSU PHARMACEUTICAL CO. INC.
Application year: 1996
Main classification: A61K31
IPC codes: A61K9, A61K31