TWI294781B - Pharmaceutical composition comprising n-[(1-n-butyl-4-piperidinyl) methyl]-3,4-dihydro-2h-[1,3] oxazino [3,2-a] indole-10-carboxamide or salt, and process therefor - Google Patents

Description

1294781 A7-B7 V. INSTRUCTION DESCRIPTION (i) The present invention relates to a novel method for preparing a pharmaceutical composition comprising SB 207266 or a pharmaceutically acceptable salt thereof, for example, a tablet or capsule, and a method obtainable by the method Or a pharmaceutical composition prepared by the method. A large number of fused hydrazine compounds as 5-HT4 antagonists are disclosed in WO 93/18036 (SmithKline Beecham), such as N-Ri-n-butyl of Example 3 on pages 17-18. _4_hexahydropyridyl)methyl]-3,4-dihydro-2-indole-[1,3]indole and [3,2_a]indole-10-carboxamide (SB 207266, generic name (International Non-exclusive name) = piboserod) and its preferred hydrochloride (SB 207266-A, piperazine hydrogenate). These compounds are disclosed for the treatment or prevention of gastrointestinal, cardiovascular and CNS disorders, particularly for the irritating large intestine syndrome, and for the treatment of urinary incontinence. W0 93/18036 is also indicated in general terms on pages 6-7. 'The specific cardiac 5-HT4 receptor antagonist that prevents atrial fibrillation and other atrial arrhythmias is also combined with 5-HT. It is expected to reduce the occurrence of strokes. See also 5,852,014, EP 0 884 319 A2, LM·Just et al., J. Med. Chem., 1995, 38, 4760-4763 and Future Drugs, 1997, 22(12), 1325-1332, Compound SB 207266, The 5HT4 receptor is highly selective over other 5HT receptors. The structure of SB 207266 is as follows: This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1294781 A7 B7 V. Inventions (2)

The Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperative, Printed SB 207266 (Pebole) SB 207266 and/or its salt synthesis method is described in WO〇10728, WO 98/11067; WO 00/03983; and W0 〇〇 / 03984 . A variety of methods for preparing the free base form or hydrochloride salt of SB 207266 are disclosed in the art. Example 3 on pages 17-18 of WO 93/18036

The method for preparing the free base form of SB 207266 is disclosed in Methods 1 and 2. A method of converting to an HCl salt and a method of crystallizing from ethanol/6 〇 80 gasoline to obtain a white solid are also disclosed in the method 2. A similar method is disclosed in L. Justin, Proceedings of the Invention, 1997, 22(12), 1325_1332, which comprises the use of SB 207266 free base for the anhydrous HC1 treatment of ethanol to form the HCl salt. Three novel methods for the preparation of the free base are disclosed in WO 98/07728 on page 6, line 5 to page 7, line 20. Two methods for preparing the HCl salt (SB 207266-A) are also disclosed in WO 98/07728 - Method A is on page 7, line 22 to page 8, line 9, and method B is on page 8, line 10. Go to page 19, line 19. On WO -4- ................... This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1294781 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employees Printed by the Consumer Cooperatives 5, Inventions (3) 98/07728, page 8, lines 10-19, Method B for the preparation of sb 207266 HC1 salt is as follows: · butyl-4-4 hexahydropyridyl) Base]-3,4-diar-argon-2Η·[1,3]_畤耕和[3,2_a]吲哚_1〇 Carboxamide (SB-207266) (100 g, 0.27 mol) dissolved in ethanol (87 ml) and filter the resulting solution to remove particulate matter. Add anhydrous ethanol (83 liter, 3.6 M, 〇·3 〇 Mo) containing ethanol to make the product from solution &gt The children came out. The raw material was heated to redissolve the solid and hexane (55 ml) was added. After cooling to room temperature, the mixture was cooled to 〇5. 〇 and stirred at this temperature for about 2 hours. The product was isolated by filtration and dried under vacuum at about 40 C to give the product, Ν-[(dibutyl_4_hexahydropyridyl)methyl]_3,4-dihydro·2Η-[1,3] Plowing [3,2_a]吲哚_1〇_carboxyguanamine hydrochloride, (1 The yield of 02.8 g) was 94%,. The present invention has now noted that there are problems with the preparation of SB 207266 HCl salt which is similar or identical to the process disclosed in WO 98/〇7728, Method B, page 8, line 1 _19. Is dissolved in ethyl yeast, industrial grade methylated spirits (IMS, for example, ethyl acetate containing about 1 〇曱 / sterol) or the like and by adding hydrocarbons (for example, hexane and / or gamma burning 'for example, N-heptane) and/or a solvent containing a C5_Ci 〇 hydrocarbon (for example, hexane and/or heptane, for example, n-heptane) crystallizes. A problem that has recently been noted in the first aspect is that the particle form of SB 207266 hydrochloride produced by these processes is a very small particle size. For example, the following table i shows a page similar to W〇 98/07728, page 8 - I*

1294781 A7 ________ B7 V. INSTRUCTIONS (4)^-- Method B, but in the crystallization step (similar method of using IMS instead of ethanol and replacing the hexane with n-heptane is disclosed in the description 1 below) Particle size data for the HC1 salt batch (SB 207266-A) prepared in place of the method of the Institute: Batch (micron) DV 50 (micron) DV 10 (micron) BDC-H-01C ^12.8 5 3 14 BDC -G-02C BDC-G-03C 5.7 1.5 ^_16.4 6.8 18 BDC-G-04C _UA 5.3 1.4 BDC-G-05C Average _〇4.6 5.8 1.5 5.8 1.5 DV9〇' DV50 and DV10 represent 90%, 50 respectively The % and 10% by volume materials are smaller than the specifically stated micron size. The reason for the small particle size printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs and the other recently noted problem is that under normal circumstances, the SB 207266 HC1 salt is produced only in the needle crystal form. For example, as shown in Figures 1 and 2 and illustrated in Note 2, SB 207266 HC1 salt (e.g., >75% or > 50% of its number, volume or weight) needle crystal Usually width > 100 microns or 200 microns. However, the length (side length) of the needle crystal (e.g., > 75 0 / 〇 or > 50 % of the number, volume or weight) is typically < 10 microns (e.g., as shown) or 夂 ^ micron (e.g. Figure 2). Trying to increase the particle size can only increase the length of the needle rather than the more crystalline form or crystallographic properties of the more flowable elongation. The operation of these needle crystals, such as mixing or other actions, tends to cause crystallization. The rupture produces a shorter needle-like body with a small particle size. The shortening -6- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) - 1294781 A7 B7 V. Description of invention (5) / ruptured needle-type crystals are usually (for example, > 50% of their number or volume or weight) being needle-shaped or lengthened; but usually the length of their (e.g., > 50% of their number or volume or weight) is <75 microns or < 1 〇〇 micron or < 200 microns and/or width < 10 microns and / or 25 microns, as illustrated by the example of Figure 3 and the explanation of Note 2. Recently noted The second problem is the discovery of this method (WO 98/07728 and / or this article) The SB 207266 HC1 salt produced in Note 1 and / or 2) is very viscous and has poor fluidity/flow characteristics. The third aspect of the recent notice of the Ministry of Economic Affairs Intellectual Property Office employee consumption cooperatives is the pharmaceutical preparations. At the above specific concentrations, when the SB-207266 HC1 salt is combined with the microcrystalline cellulose 'mannitol and magnesium stearate excipients, the viscous drug makes the composition very difficult to flow and is not easily formed into ingots or made. Capsules. SB 207266 composition for human oral administration is now found to contain: SB-207266 HC1 salt (about 5.0 mg as measured by free base), microcrystalline cellulose (30·0 mg), mannitol (112.0 mg) And magnesium stearate (3·〇mg), the total tablet weight = about 150 mg, can be directly bonded into the ingot technology by standard bonding, wherein the SB 2〇 7266 HC1 salt is about 33% of the bonding agent The weight is present. However, the higher concentration of this type of formula SB 207266 HC1 salt is not easily formed by direct compression. In particular, it is considered that the clinical maintenance dose used to treat or prevent atrial fibrillation may be about. 20 50, or 80 mg / day (see examples of clinical protocols and lozenge examples below); and the previous attempts to treat irritating colonic signs are applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 public) 1294781 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 invention description (6) Hou Qunshi, SB-207266 clinical dose is only 〇〇5, 〇·25, i and 5 mg / day, and administered four times a day For a 5 mg tablet, it is 2 mg/day. A problem with the fourth aspect of the near note is that the small particle size of SB-207266 HC1 salt has a low agglomerate density (see Table 1 below), and the added water is densified. This means that only a small amount of material can be added to a fixed-volume operating machine, while a large-volume device results in a relatively inefficient manufacturing process when used in relatively small volumes of drugs (small in the Wei Wei) Material throughput). At least some of the pending patent applications PCT/GB01/03590 and WO 02/11733 A1 published on February 14, 2002, which are filed by the s. Or all of these problems can be partially overcome or alleviated by forming SB 207266 HC1 salt particles which have a larger particle size than the original SB 207266 HC1 salt. These particles have been found to have better flow characteristics, for example, for tableting purposes. Some or all of the advantages of these particle formation methods are also expected to be achieved by free bases which are believed to also have a generally small particle size. For example, when crystallized by the addition of a hexane to mono-toluene solution, the free base is filtered very slowly (for example, as in WO 98/07728, page 6, lines 19-23, method A and page 7 η - 20 lines of method C). Other similar pharmaceutically acceptable salts other than the HC1 salt are believed to also benefit from the granulation process. In PCT/GB01/03590 (with WO 02/11733 A1, the application was filed on August 8, 2001, and the pending case was announced on February 2, 2002). This paper scale applies to the Chinese National Standard (CNS). ) A4 specification (21〇χ297 public)

1294781 A7 B7 V. INSTRUCTIONS (7) Mingzhong - in particular in Examples 4 and 5, and also in PCT/GB〇1/〇 3544 (with WO 02/11766 A2, as of August 7, 2001, The 207266 granulation method disclosed in Examples 7 and 8 of the pending case published on February 14, 2002 is a "wet granulation method", that is, the SB 2 〇 7266 or its salt The granules are formed in the presence of a granulating solvent, for example, water and/or ethanol. The wet granulation method of Example 4, which is disclosed in PCT/GB01/03590 (WO 02/11733 A1), is a comparative example, which is disclosed hereinafter as a comparison with the present invention. As can be seen, the SB 2〇 7266 system is mixed with a certain excipient in a high shear mixing granulator, and water (as a granulating solvent) is added to the stirred granulator for wetness. Granularization. The resulting granules have excellent flow characteristics after drying and are more concentrated than the pure 207266 HCl salt and can be compressed, for example, with a medium or local drug concentration with an extragranular excipient (% of the drug is in the form of a lozenge) The weight of the poem) and get the best lozenge. Printed by the Ministry of Economic Affairs, the Intellectual Property Bureau, and the Consumer Cooperatives. However, one or more of the _ people nowadays have encountered some unpredictable problems in the ''wet granulation method' of W〇〇2/11733 A1. It is the problem of the fifth aspect which has been recently noted by the present invention. ς It is surprisingly observed that uneven granulation (particularly, physical uneven granulation) and/or excessive agglomeration often occur in wet granulation. It has been found that when water (as a granulating solvent) is poured onto the drug-excipient mixture, the water droplets are absorbed/adsorbed almost immediately by a portion of the particle mixture of the near water droplets, thus often leading to the quality of partial partial dissolution (by suction bow) I form a "small ball" adjacent to the material and shrink and form. These small balls, usually in the wet winter, paper paper money M s 1294781 A7 __ B7 5, invention description (8) is a paste and hard when dry, adhere to the wall of the mixer. The pellets, in particular after drying, form a partially hard mass of semi-granulated material containing the drug. The degree of formation of the pellets/agglomerates increases as the time of the wet granulation process increases and as the concentration of the drug in the mixture of particles increases. The microcrystalline cellulose was used as a granulation aid in the wet granulation method in Example 4 of WO 02/11733 A1 to disperse water (granulating solvent) to a certain extent in the granulation method. Surprisingly, however, microcrystalline cellulose has been found to be effective in the general case where the water is dispersed throughout the granulated mixture (to achieve a uniform granulation method) rather than the wet granulation method. Without being bound by theory, we believe that these unpredictable problems are due to the very small particle size of the SB 207266 HC1 salt and the very high water solubility (which leads to the extreme rate of the SB 207266 or its salt in the water granulation solvent). Caused by the "Valley". The local SB 207266 or its salt is believed to dissolve very rapidly upon contact with water droplets, which results in the above; a portion of the semi-granulated material, small spheres, or (when dry) large hard agglomerates . When dried, these large agglomerates are hard and are not easily reduced to a small size because the semi-dissolved SB 2 〇 7266 or its salt is a strong binder for the surrounding excipients or active constituent particles. (This kind of pull-in property also tends to result in a rather long tablet disintegration time after ingot formation). Moreover, since a lot of water is concentrated in the pellets/clumps, there is still unrecorded after the granulation, and it is difficult to make money (4) to move some unaltered SB 207266 or its salt; L. Surprisingly, the mixture is a physical non-uniform sentence. -10- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm).

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

A7 B7 1294781 V. INSTRUCTIONS (9) These problems are minimal or controllable in batches of 2.5 kg according to the comparative examples below. However, on a larger scale (e.g., 14 kg), after granulation, pellet/clump formation and unaltered SB 207266 or salt become more frequent and/or to a greater extent. Therefore, while careful selection of large-scale granulation units and/or processes can reduce the risk of heterogeneous mixtures, these risks may increase as wet granulation synthesis increases to production scale. Such "balling" as a result of the upgrade may be due, at least in part, to the increased use of the impeller capacity in any high shear mixing-(wet) granulator when the tank volume is increased. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer consortium, the inventors of the present invention found that the problem of non-uniformity in the wet granulation method of WO 02/11733 A1 can be achieved by using a dry granulation method to prepare SB-207266 formulation. (medical composition) is minimized. Dry granulation can avoid or reduce/reduce (a) the solubility of the drug during handling and/or the formation of (b) "small balls" or hard agglomerates. Thus, it has been surprisingly found that the dry granulation method results in a stronger and more scaled formation than the wet granulation method of WO 02/11733 A1. When compared to wet granulation, the risk of expensive production batches failing at the factory (eg, due to "balling") is considered to be reduced, and it may require less process control estimates and/or less attention to The risk of batch failure is minimized. As indicated above, the dry granulation method also results in a shorter disintegration time than the wet granulation method. Dry granulation also helps to continue operation and automation compared to wet granulation. Therefore, the first aspect of the present invention provides a preparation of a N--11-containing paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294781 A7 B7 5. Inventive Note (10) [(1 -n-butyl-4-hexahydropyridyl)indolyl]-3,4-dihydro-2-indole-[1,3]^[3,2-a]吲哚-1 〇-carboxamide ( Sb 207266) (piboserod) or a pharmaceutically acceptable salt thereof and a pharmaceutical composition of one or more pharmaceutically acceptable excipients, the process comprising the step of using part or all of SB 207266 or a salt thereof Dry granulation is carried out. The pharmaceutical compositions prepared by this method are believed to be novel over the wet granulation formulations disclosed in Examples 4 and 5 of PCT/GB01/03590 (WO 02/11733 A1). Accordingly, a second aspect of the present invention provides the pharmaceutical composition obtained in the process of the first aspect. A third aspect of the invention provides the pharmaceutical composition prepared in the process as defined in the first aspect. A fourth aspect of the present invention provides a preparation comprising N_[(1-Zheng Ding Economics Bureau Intellectual Property Office Staff Consumer Cooperative Printed Group-4·hexahydropyridyl)methyl]_3,4_dihydro-2H-[ 1,3; K cultivating [3,2-a] 吲哚-10-carboxyguanamine (SB 207266) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients Among them, part or all of SB 207266 or a salt thereof is present in the granules which can be obtained or obtained by dry granulation. By "dry granulation method", it refers to a process in which the granules are formed substantially in the presence of an external granulation solvent, for example, in the absence of water and/or ethanol. For example, the granules are preferably less than 2% by weight, more preferably It is less than 1% by weight, and more preferably less than 0.3% by weight, most preferably less than 〇1% by weight of a granulating solvent, for example, in the presence of water and/or an alcohol, -12-1274981 A7 B7 V. INSTRUCTION DESCRIPTION (11) In one preferred embodiment of the present invention, the dry granulation method of the present invention is a process in which the particles are all added to an external granulation solvent, for example, water and/or ethanol. Formed in the presence of the dry granulation method of the present invention, wherein one of the solvents, for example, water is adsorbed on the drug and/or adsorbed in any type of excipient, such as water in crystallization (for example, CaHP04.2H20 The appearance of "particles" in the content of pharmaceutical compositions has a definition known to scientists skilled in the formulation of techniques (for example, as described in the Pharmaceutical Granulation Technical Manual, DM Perry Editor, 1997, Marshall Corporation) Merging As used herein, "particles" do not include particles of pure SB 207266 or a salt thereof that have not undergone a process of increasing particle size, and "particles", for example, are not included directly by the following description 1 SB 207266 HC1 salt prepared and having the particle size according to Table 1. N-[(l-n-butyl-4-cyclohexyl)methyl]-3,4-dihydro-2H-[1,3 ] [3,2-a]吲哚-10-Carbodecylamine (SB 207266) or a pharmaceutically acceptable salt thereof is often referred to herein as ''SB 207266 or its salt piroxicam or a salt thereof "," an active substance", "active ingredient" or "the drug" or the like. Preferably, the preferred method of the first, second, third and fourth aspects of the invention, the method of the invention also comprises some or all of SB 207266 or a salt thereof and one or more pharmaceutically acceptable Excipients (Part 13 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

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Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1294781 A7 __B7 V. INSTRUCTIONS (12) Intragranular excipients are reconciled prior to the dry granulation method. The one or more intragranular excipients preferably include a lubricant; this results in slippage during the dry granulation step and reduces the difficulty of the process, e.g., the granulated component adheres to a portion of the metal instrument such as a drum compressor. The one or more intragranular excipients preferably comprise a filler (diluent) and/or a compression aid. The one or more intragranular excipients may optionally include a binder and/or a disintegrant. The intragranular lubricant, filler, compression aid, binder and/or disintegrant can be as defined herein. Preferably, the dry granulation process of the present invention comprises compressing (i.e., applying pressure) and/or compacting (i.e., thickening) SB 207266 or a salt thereof. Preferably, the process is carried out by compressing SB 207266 or a salt thereof with drug particles, optionally together with intragranular excipients, to increase particle size (eg, average, intermediate (D50) 'D90, and/or D10 particle size). Larger particles are formed. For comparison, the wet granulation process utilizes a granulating solvent to form a mixture of granules which form a granule after drying, but generally does not employ compression. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperative. Preferably, the dry granulation method of the present invention comprises squeezing SB 207266 or its salt. Alternatively, the dry granulation process can include smashing SB 207266 or a salt thereof. In this alternative, "roller pressing, and "slamming" compression can be found in, "Pharmaceutical Granulation Technical Manual", DM · Perry Editor, 1997, Marshall Corporation, New York, Chapter 6" Pressing techniques, in particular pages 119-132 (IV. Rolling press design), and pages 1-3-107, 112, and pages 115-116 are incorporated herein by reference. As for the rolling method, see also, for example, the Philippine company's '辗压法,,小-14- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^ ^~一- A7 B7 1294781 V. INSTRUCTIONS (13) The manual and the literature "Introduction to the Pressure Method and the Philippine Cui Chixun", both of which are incorporated herein by reference and both are available from: Philippe's website -www.fitzpatrick.be; and/or from Philippine company NV Entrepotstraat 8 » B-9100 Sint-Niklaas , Belgium 5 fax : +32/3-766-10-84, email · Fitzpatrick-Europe @compuserve.com; and/or from Philippine, Inc., 832 Industrial Road, Elmhurst, Illinois 60126, USA, Fax · +1-630-530-0832, www.fitzmill.com. The rolling process typically involves feeding the pre-granulated powder to be compressed by gravity and/or auger to between a pair of counter-rotating rolls having substantially parallel longitudinal axes. Both rollers can be attached to their axes. More preferably, the shafts of the rollers are movable relative to each other, for example, the shaft of one of the rollers is fixed to the frame and the other roller shaft is movable relative to the frame. The drum may have a smooth circumferential appearance but preferably have a textured circumferential outer surface' such as a radial sine wave drum or, more preferably, an interlocking anilox roll. The drum having a textured outer surface is generally preferred to align the grooves (crests and troughs) in the direction of the drum shaft ("fluent drum"). More preferably, the fluted roller is an interlocking anilox roll; the rollers include first and second rollers, wherein when the roller is in a basket-type opposing relationship, the circumferential surface of the first roller is fluted (crest and The trough is parallel to the circumferential surface flutes (peaks and troughs) of the second roller and/or partially or completely interlocked with the sigma roller (for example, an interlocking anilox roll), and the cross-section of the groove peak may be For example, tip-15* This paper scale applies to the Chinese National Standard (cns) A4 specification (21G 297 297 public)

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Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1294781

, invention description (14) sharp round or flat, but the transverse section of the groove peak should be rounded. In this special medicine, in the special medicine, in the fluted drum, the groove greatly increases the total amount of time ("stagnation time" spent in the drum, "entraining" (see below). ,) Improve the degree of deaeration and the pressure of SB-207266 or its salts. During the rolling action, a pressure, for example, a water pressure, is applied to one or both of the rolls, usually to the drum of the movable shaft, in a direction in which the drum can be driven. In this way, the pressure of the rolling is transmitted to the drum. The force fed to the gap of the drum rubs the surface of the drum to the gap of the drum and is then pulled to the "corner zone" or, entrainment, medium, where the pre-densification of the drum gap occurs. The force is then passed through the rollers and transferred to the drum ± the pressing force; the force is then pressed (burst). During this rolling action, the pre-granulated powder to be crushed is preferably fed into the drum gap by a rotary screw feeder (e.g., a drill feeder) in abutting direction and toward the drum. In one embodiment, "Huiwan Bay can be substantially horizontal and substantially balanced with each other and a "vertical screw feeder" located above and facing the drum can be used. In another embodiment, the drum may be substantially horizontal and located one above the other, and a horizontally spiral feeder may be used that is substantially balanced and oriented toward the drum." A preliminary spiral may be used arbitrarily. A feeder, for example, a horizontal screw feeder to feed the product by a human π hopper (pre-granulation of the drug is pushed 16_ This paper is a standard for the amount of money (CNS) A4; ϋ210χ297 public)

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Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Staff and Consumers Co., Ltd. A7 B7 1294781 V. INSTRUCTIONS (15) Compounds are metered to the pre-compression (pre-compression) stage. The speed of the preliminary screw feeder (e.g., horizontal preliminary screw feeder speed) is typically from 0 to about 62 revolutions per minute (rpm) and/or preferably at least about 10 rpm or at least about 15 rpm or at least about 20 rpm. And/or preferably up to about 40 rpm or up to about 62 rpm. The speed of the preliminary screw feeder is preferably from about 10 rpm to about 62 rpm, or from about 20 rpm to about 62 rpm; and more preferably from about 10 rpm to about 40 rpm or from about 15 rpm to about 40. Rpm; for example, about 30 rpm (eg, Example 11), about 17 to about 20 rpm (eg, Example 12), or about 20 rpm (eg, Example 13). The Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, shall use a main screw feeder close to the drum (in the direction of any arbitrary preliminary screw feeder), preferably a vertical main screw feeder, for example, to pre-granulate the powder. Pre-compression and/or degassing (pre-compression) and feeding the powder into the drum. The speed of the main screw feeder (e.g., vertical main screw feeder) can be, for example, up to 600 rpm, but typically from 0 to about 270 rpm, preferably from about 30 to about 270 rpm or from about 30 to about 100. The rpm is more preferably from about 40 to about 90 rpm. For example, the speed of the main screw feeder can be about 100 rpm, or about 70 rpm (e.g., Example 11), or about 49 to about 53 rpm (e.g., Examples 12 and 13). Since the main screw feeder directly transfers material to the drum, the speed of the feeder is important for good rolling. a vertical main screw feeder comprising a drum (which is substantially horizontal and substantially balanced with each other), located above, adjacent to and facing the drum, and a horizontally preliminary spiral to the vertical main screw feeder -17-sheet The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294781

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1294871 A7 B7 V. Invention Description (η) The cylinder pressure is from about 20 Newtons/cm to 28.93 Newtons/cm, and ideally from about 24 to about 26 Newtons/cm ( See, for example, Examples 11-13). The drum speed may typically range from 〇 to about 17 rpm, but it is preferably from about 1.5 rpm to about 17 rpm or from about 1.5 rpm to about 10 rpm, for example, about 10 rpm. Slow roller speeds have been found to increase stagnant time and increase the desired drug pressure, but at too slow a risk of filling the drum with the drug-containing material. Accordingly, the speed of the drum is preferably from about 1.5 rpm to about 7 rpm, more preferably from about 2 rpm to about 6 rpm, still more preferably from about 2.5 rpm to about 5.5 rpm, and most preferably from about 3 to about 5 rpm (e.g. See examples 11-13). Perhaps due to the low density of the drug (SB207266 or salt), it has been found (e.g., in Examples 12 through 11) that as the drug concentration of the pre-granulated blend increases, the flow rate through the screw feeder decreases. In this case, in order to obtain a desired compression, it is desirable to increase the initial screw feeder speed and/or the main screw feeder speed to provide a desired material feed rate to the drum and/or to increase the dead time in the drum. Thus, in particular, when SB-207266 or a salt thereof is present in the granules (i.e., during dry granulation) at least 22% or at least 27% or at least 32% or at least 35% of the granules: - preliminary spiral feedstock Preferably, if such a feeder is present, the speed is at least about 20 rpm or at least about 25 rpm or at least about 30 rpm, for example, from about 20 rpm to about 62 rpm, and more preferably from about 25 rpm to about 62 rpm. -19- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

1294781 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (18) = from about 25 ah to about 40 rpm, for example, by about 3 rpm (for example, examples 11 and 14); and / or - main spiral feeding The machine speed (eg, vertical main screw feeder speed) should preferably be at least about (four) or at least about 60 rpm or at least about 65 or at least about, for example, _56 ah to about _ ah or to about 27 〇, and more Preferably, it is from about 56 to about (10) or from about to about ', and most preferably from about 6 〇 to about 8 ,, for example, from about (9) to about 70 rPm (for example, examples 11 and 1; Preferably, the speed of the tube is at most about 5 rpm or at most about 4 ah or at most about .5 rpm and/or preferably at least about 卿5 qing; more preferably from about 1 5 rDm S ～ 乂/衣The degree of confusion. Pm to,,, spoon 4 rpm, and more preferably about 2 ah to about rpm 'equivalently from about 25 ah to about 3 handsome, for example, about: rpm (for example, see examples 11 and 14) The two-tube notch may be, for example, about 〇5 to about 2 mm, for example, 〇7 to about ι·3 mm. The compound, when it is present, the roller is called, the compact, the layer ,, , /带带". /ml = strip density should be about (10) centimeters / cubic centimeter (the granules made by the gram method should be ground to be suitable for tablets or better, such as 'in the case of rolling, The compact (layer, strip) released from the (roller) is, for example, ground to a particle size suitable for the bonding agent or capsule using a pulverizing mill.

4 if the paper size is applicable to China A7 B7 1294781 V. Inventive Note (19) For example, the granules can be ground so that the hole size is 0.110 吋 (2.80 mm), 0.097 ft (about 2.46 mm), 0.093 英吋 (2.36 mm), 1.70 mm, 0.065 ft (1.65 mm), 0.063 English (1.60 mm), 0.055 ft (1.40 mm), 0.032 ft (0.81 mm), 500 μm, or 250 μm sieve or Filter screen. Preferably, the sieve has a pore size of 0.110 inch (2.80 mm) to 0.032 inch (0.81 mm), more preferably 0.097 inch (about 2.46 mm) to 0.055 inch (1.40 mm) of pore size or 0. · 097 inches (about 2.46 mm) to 0.063 inches (1.60 mm) of hole size; this is best for particles added to the recording: agent. In use, the mill, such as a pulverizing mill, can be rotated, for example, at 1000 to 10000 rpm or 3000 to 8000 rpm, for example, about 5000 rpm. A preferred pulverizing mill is a grinder having a hammer and/or a knife. As is known to trainers, such comminuting mills include a tank chamber having a feed port (usually located above) for the particles to enter, a sieve or screen for releasing the ground particles (usually located below) And a rotatable shaft in the chamber between it and the plurality of perforated blades that are generally radially radiated therefrom, which typically have a sharp or knife-like edge as a The direction of the rotation of the edge and a flat or edge as the edge of the other direction of reverse rotation. The lower part of Fig. 6 is an example in which the rotating shaft (which can be rotated in two directions) is 18, the knife is 20, the hammer is 22, and the sieve is 24. According to the rotation of the rotating shaft -21- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Ministry of Printing and Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1294871 A7 B7 V. Invention Description (2〇) To, the "knife" edge of the shaft paddle and / or "hammer" edge system" "Forward" (ie, forming a leading edge that can strike particles/particles in the grinding chamber when rotated) - typically the knife forward or hammer forward. The grinder can be arbitrarily a pulverizing mill having a "hammer forward", but the grinder is preferably a pulverizing mill having a "knife forward". The "knife forward" version is more controllable in particle size (e.g., less detailed) and is generally more suitable for tablets. For example, a FitzMill L1A (as illustrated in Example 1) can be used to pulverize the mill (for example, available from Philippine, Inc., see Example 1 for an address) with a hammer and/or knife forward, preferably 0.065 inches or A 0.093 inch (2.36 mm) sieve and should be rotated at 5000 rpm. Another alternative to the grinder is the "buffing mill". Such a grinder includes a rotor having a connection (e.g., by conventional radiant struts) to a plurality of rods or elements (generally oriented toward the center bearing but spaced from the center bearing) for central rotation or Swing bearing. The bars are typically spaced about the same distance from the center bearing. Such a grinder typically also includes a curved "smoothing screen" that is spaced from the rotor bars and is radially located on the periphery of the rotor bars (usually spaced very close to the bars) and can be rotated or oscillated The particles are screened or polished between the bars and thus the buffing screen can reduce the particle size of its particles. The buffing screen typically has a partial circumferential cross-section and is coaxial with the central rotor bearing and/or may be the size of the hole described elsewhere. Another alternative to the grinder is the rotor granulator (swing granulation • 22- this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

A7 B7 1294781 V. Description of invention (21) Machine). An alternative to another pulverizing mill may include a three-dimensional conical screen forming a grinder wall (eg, 0.093 inches (2.36 mm), 1.70 mm, 0.065 inches (1.65 mm), 0.055 inches (1.40 mm). , 0.032 inch (0.81 mm), or 500 micron hole size), and a coaxially rotatable, three-dimensional conical thruster that is closely spaced from the screen to be poured between the screen and the rotary thruster The particles are crushed. Once crushed to the required size, the particles can escape through the holes in the screen. Optionally, the grinder can be integrated with the drum press, for example as shown in Figure 6. Regardless of the type of mill used, the dry granulation (e.g., drum compression) and the patted density of the ground particles are from about 1.0 to about 1.5 grams per cubic centimeter (grams per milliliter) and/or from about 0.8 to about L3 g/ml is more preferably (e.g., for preferred solubility) from about 0.8 to about 1.2 g/ml, and more preferably from about 1.0 to about 1.2 g/ml. Printed by the Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Cooperatives. Any abrasive material can be used to prepare pharmaceutical ingredients (eg, keys or capsules). Alternatively and preferably, the ground particles can be "classified", that is, portions having a predetermined range of specific particle sizes can be separated (selected), for example, to be incorporated into the composition, by Substances above a predetermined particle size are removed (e.g., by sieving) and/or materials below a predetermined particle size are removed (e.g., by sieving). For example, the ground particles can pass two (or -23- paper scales applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1294781 A7 B7 V. Description of invention (22)

a plurality of sieves that continuously reduce the size of the pores, and for example in two sieves, the material passes through the first sieve (for example, a 2.00 or 1.00 or 0.85 or 0.81 mm sieve) but is passed through a second sieve (for example, 75 or 106). Or 150 or 180 micron sieves can be selected, for example, incorporated into the composition. The large particles intercepted by the first sieve and/or the small particles passed through the second sieve can be arbitrarily recovered, for example, by feeding them to the pre-granulation stage/feed hopper. The ground and/or "classified" particles can have a particle size distribution as described below. line

Preferably, after forming the granules (for example after tumbling) and optionally grinding into a suitable size, the granules (1) are then optionally combined with one or more pharmaceutically acceptable excipients (extragranular excipients) Mixing and (ii) any rolling into a tablet or filling into a capsule. Such extragranular excipients preferably include a disintegrant and/or lubricant, and/or optionally include a compression aid and/or a filler (diluent) and/or a binder, such as herein. Definer. The Ministry of Economic Affairs, the Intellectual Property Office, the Staff Consumer Cooperative, which prints the preferred composition of the first, second, third and fourth aspects of the present invention, wherein the granule contains one or more pharmaceutically acceptable granules. excipient. Preferably, 90% or more by weight or 95% or more, or substantially all or all of SB 207266 or a salt thereof is present in the granules obtained or prepared (formed) by dry granulation . -24- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). A7 B7 1294781 V. Description of invention (23) Preferably, the pharmaceutical composition can be administered orally, for example, oral. Administration to humans. Preferably, the pharmaceutical composition is a tablet (e.g., a swallowable tablet), or the inventors may be a capsule containing a pharmaceutical composition. The tablet may, for example, be circular on the main transverse plane but the lozenge is preferably elliptical on the major transverse plane (longitudinal section).

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Preferably, 50% or more by weight or volume of the particles of SB 207266 or a salt thereof has a particle size of 75 microns, for example, 75 to 1000 or 75 to 500 microns, more preferably -100 microns, for example , 100 to 1000 or 100 to 500 μm, more preferably ^106 μm, for example, 106 to 1000 or 106 to 500 μm, more preferably 150 μm, for example, 150 to 1000 or 150 to 500 μm, and more preferably - 200 microns, for example, 200 to 1000 or 200 to 500 microns. Preferably, the particles comprising SB 207266 or a salt thereof have a particle size defined by ''D50', or -100 micron intermediate particle size, for example, by weight (DM50) or by volume (DV50), or other One of the particularly appropriate size ranges. The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, which prints better, including 70% or more of the weight or volume of SB 207266 or its salt particles, has a particle size of -40 microns. For example, 40 to 1000 or 40 to 500 microns, preferably -50 microns, for example, 50 to 1000 or 50 to 500 microns, more preferably -53 microns, for example, 53 to 1000 or 53 to 500 microns, and more preferably ^63 microns, for example, 63 to 1000 or 63 to 500 microns, most suitable for ^ -25- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1294781 V. Description of invention (24 75 microns, for example, 75 to 1000 or 75 to 500 microns.

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Preferably, 90% or more by weight or volume of the particles of SB 207266 or a salt thereof has a particle size of 210 microns, for example, 10 to 1000, more preferably -20 microns, for example, 20 to 1000 or 20 Up to 500 microns, more preferably -50 microns, for example, 50 to 1000 or 50 to 500 microns, and more preferably 253 microns, for example, 53 to 1000 or 53 to 500 microns, most preferably 2 to 75 microns, for example, 75 to 500 microns. Preferably, the particles comprising SB 207266 or a salt thereof have a particle size defined by "D10", such as -10 microns, for example, by weight (DM50) or by volume (DV50), or other particularly suitable size ranges described above. One of them. Another definition is that 10% or less by weight or volume of SB 207266 or its salt particles has a particle size of $10 micron, more preferably $50 micron, and more preferably S 75 micrometers. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, the composition of the present invention containing particles of the above average to larger particle size is generally less viscous, has better fluidity, and is generally easily or acceptable for easy rolling into tablets. And therefore less likely to cause the above formulation problems. Particles having a particle size of less than 75 or 100 micrometers may cause problems such as tablet compaction and/or unevenness, and particles having a particle size larger than 1000 μm may cause dissolution when they account for a large percentage. The latter, the weight or volume of SB 207266 or its salt particles is 50% or more (for example, before particle formation and/or in the formation of particles -26) This paper scale applies to the Chinese National Standard (CNS) A4 specification. (2丨0 X 297 mm) A7 B7 1294781 V. Description of the invention (after 25, for example, within the granule) having a particle size of $75 μm, more preferably $50 μm or S53 or $63 μm, and more preferably $2 〇micron, more preferably $10 micron, most preferably micron. In other words, this means that the particles of SB 207266 or a salt thereof (for example, before particle formation and/or after particle formation, for example, within the particle) have a particle size defined by ''D50', or a medium particle such as $75 micron or $5 or 53 or 63 micron, for example, by weight (DM5〇) or by volume (DV50)' or other particularly suitable size described above One of the scopes. The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints better, 10% or more of the weight or volume of SB 207266 or its salt particles (for example, before particle formation and/or after particle formation) , for example, in the The particles have a particle size of $2 〇 micrometer, more preferably $10 micron, more preferably micron, and more preferably $2. 5 micron, most preferably $2 micron. In other words, this means the SB 2〇 7266 or The particles of the salt (for example, before and/or after the formation of the particles, for example, within the particles) have a particle size defined by "D10", for example, by weight (DM10) or by volume (DV10), $2 〇micron or one of the other particularly suitable size ranges described above. Preferably, 90% or more by weight or volume of the particles of SB 207266 or a salt thereof (eg, prior to particle formation and/or after particle formation, For example, within the particle) has a particle size of $1 〇〇 micron, more preferably S 75 or $ 53 or $ 50 micron, and even more preferably $ 20 micron. In other words, this means that the SB 207266 or its salt particles (for example, in Shape 27-

A7 B7 1294781 V. Description of the invention (26) Before particle formation and/or after particle formation, for example within a particle, it is preferred to have a particle size defined by 'D90', for example, by weight (DM90) or by volume ( DV90), $100 micron, more preferably $75 or $53 or $50 micron, and more preferably $20 micron. As discussed above, SB 207266 or salt with such small particle size is the most prone to the above problems, and is the most Easily benefited by the present invention. Typically, particle size (D50, D10, D90, etc.) can be measured by sieving with one or more sieves (eg, for measurement of particles prior to further processing as a #agent, and/or for measurement) Powder in capsules. Suitable sieves include 53, 63, 75, 90, 106, 125, 150, 18, 212, 250, 300, 355, 425, 500, 600, 630, 71, 810, or 850 Micron sieve, or 1.00, 1.18, 1.40, 1.6〇, 1.65, 1.70, 2.00, 2.36, 2.46, 2.80, 3.35, or 4·〇〇 millimeter sieve. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed or particle The size of the available laser diffraction is also known as low Rayleigh & Light Scattering (LALLS) is used to measure the laser diffraction system according to the angular distribution of the scattered light. Laser diffraction is known to those who are trained and can be used by people who are highly skilled and experienced. Known according to the calculation formula of Fraunhoefer or Mei optics. Further details of the laser diffraction technique can be found as follows: Clive Washington, "Particle Size Analysis, Theory and Applications in Medicine and Other Industries", Ellis Horwood Limited, 1992, See, in particular, Chapter 6, pages 109-133, the details of which are incorporated in this -28- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 1294781 V. Description of invention (27) As a reference, the Fraunhoefer calculation method is described therein and is performed as usual by an analysis kit, which is part of a commercially available laser diffraction device, for example, as explained now. The radiation diffraction device includes (a) Malvern Mastersizer S available from Malvern Instruments Limited, Enigma Business Park, Grovewood Road, Malvern, Worcestershire WR14 1XZ ' Country, Email: www.malvern.co.uk: and (b) Symatec HELOS/QUIXEL, available from Sympatec UK and Ireland, Bury Business Centre, Kay Street, Bury BL9 6BU, Central Country' email: sympatec.uk @btinternet.com 〇Or, the particle size can be measured directly (for example by any means such as a microscope or other), especially for tablets. For example, the particle size can be measured via a section of a lozenge (for example by breaking or cutting a tablet into two pieces and observing the cross section); the diameter of a particular particle can be measured so that it can be estimated by volume and weight. Particle size. The Department of Economic Intelligence's Intellectual Property Bureau employee consumption cooperative prints the particle size analysis method. The typical assumption is that the particles in the calculation of the distribution are spherical. When analyzing non-spherical particles, the interpretation of the desired technique is used to understand the distribution of the shape's possible misinterpretation. However, particle estimation using particle images, for example, the microscope can correctly infer particle shape and size. Although typical, the size is still expected to be estimated by a sphere. Preferably, the SB 207266 or a salt thereof (for example, the HCl salt) is a form obtainable by the following method, for example, preferably prepared by a process wherein the SB 207260 or a salt thereof (for example, an HCl salt) ) Dissolved in -29- This paper ruler money standard (CNS) A4 specification (21〇X 297 public) 1294781 A7 B7 V. Invention description (2〇

4 alcohol to form a solution and by adding a C5-C1 () hydrocarbon (for example, hexane and / or heptane, for example, n-heptane) and / or a C5-C1G hydrocarbon (such as 'hexane and / or The solvent of heptane, for example, n-heptane, crystallizes from the solution. The Cm alcohol includes or is: methanol, propanol (for example, isopropanol), butanol (for example, n-butanol or tert-butanol), and/or ethanol or a solvent containing ethanol, for example, industrial methylation. Alcohols (IMS, for example, ethanol containing about 1% sterol). Ethanol or a solvent containing ethanol is preferred. These processes often form SB 207266 having a small particle size or a salt thereof - at least an HCl salt - such products are most likely to cause the above problems and are most likely to benefit from the present invention. line

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, N-[(l-n-butyl-4-hexahydropyridinyl)methyl]-3,4-dihydro-2H-[1,3]噚Ploughed [3,2-a]indole-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof includes (for example,) SB 207266 hydrochloride (SB 207266-A), It is preferably a needle crystal form of the hydrochloride of SB 207266. The needle crystal form can be, for example, any of the above, and/or can be, for example, substantially as shown in one or more of Figures 1, 2 and 3, particularly as shown in Figure 3 and/or substantially As described in Note 2, and/or may be defined by the number or volume or weight > 50% of the needle or elongated crystal; and/or may be, for example, in number or volume or weight > 50% length < A crystal of 75 microns or < 100 microns or < 200 microns and/or width < 10 microns or < 25 microns is defined. The needle-type crystalline form is substantially a crystalline (e.g., anhydrous) crystalline form of SB-207266-A. Therefore, SB-207266-A should include (for example, 70% or -30- this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1294781 V. Description of the invention (29) 80% or more or 90% or more), or predominantly a substantially anhydrous or anhydrous crystalline form. The water content in the hydrate can be measured by known methods, for example, the Karl Fischer method (for example, as described in US Pharmacopeia, (for example, 1990 edition, pages 1619-1621), or in European Pharmacopeia (for example, The second edition, 1992, Part II, Volume 16, V. 3.5.6-1). The infrared (IR) of the SB 207266 hydrochloride (eg, needle and/or anhydrous crystalline form) The spectrum (medical lubricant rim) is substantially shown in Figure 4; and / or its infrared (IR) spectrum (medical lubricant rim) has three, four, five, six or more (for example, all) of the following Crests: 3423, 3044, 2502, 1628, 1582, 1502, 1531, 1184, 748 cm^ allow some peak changes, for example, soil about 2 cm·1 or soil about 1 cm·1); and/or its infrared (IR) The spectrum (medical lubricant rim) has three, four, five or more (for example, all) of the following peaks: 1628, 1582, 1502, 1531, 1184, 748 cm · 1 (allowing some peak changes, for example, soil About 2 cm·1 or about 1 cm·1 of soil). See, for example, description 2 for the description of FIG. Preferably, the SB 207266 or its salt is at least 3.5% by weight, more suitably at least 4% by weight or at least 4.4% by weight, or more preferably at least 4% by weight or at least 4.4% by weight, based on the weight of the composition and/or the weight of the granules, respectively. At least 5% by weight or at least 6% by weight or at least 7% by weight or at least 8% by weight or at least 11% by weight or at least 15% by weight or at least 20% by weight are present in the composition and/or in the granules. Preferably, the SB 207266 or its salt is applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) by the weight of the composition and / - 31 - the paper scale, respectively. Printed by the Intellectual Property Office of the Ministry of Economic Affairs. 1294781 at B7 V. Description of the invention (3〇) or up to 95% by weight of the weight of the particles, more suitably up to 70% by weight or up to 60% by weight, most suitably up to 50% by weight or up to 40% by weight, present in the composition and / or in the particles. Most preferably, the SB 207266 or its salt is present at 4.4-95 or 6-95 or 6-88°/〇 or 11-70% or 11-60% or 15-60%, respectively, based on the weight of the composition and/or the weight of the granules. In the composition and / or in the particles. For example, in Examples 1-9, SB 207266 or a salt thereof is present in the composition from 4.4% by weight to 35.2% by weight. These preferred percentages are calculated based on the true weight of the SB 207266 or its salt and any emerging counterions or added acids (e.g., HC1 for the HCl salt). For example, for every 250 milligrams of composition (e.g., per 250 milligrams of embedded or unembedded tablet weight), the composition desirably contains from about 10 to about 150 milligrams or from about 11 to about 150 milligrams (e.g., 10). , 11, 22, 27.5, 33, 44, 55, 82.5, 88, 110 or 132 mg) of SB 207266 or a salt thereof, such as a hydrochloride (calculated as the true weight of the counterion or added acid); or From about 10 to about 120 mg (eg, 10, 20, 25, 30, 40, 50, 75, 80, 100 or 120 mg) of SB 207266 or its salt (calculated as the free base). Preferably, the composition is in unit dosage form (preferably a tablet or capsule, for example, a 250 mg tablet is calculated as the weight of the unembedded tablet). In this case, a preferred unit dosage form (e.g., a lozenge or capsule) contains a composition comprising from about 10 to about 150 mg, or from about 11 to about 150 mg, or from 44 to 132 mg, or 44- 32- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

1294781 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Print 5, invention instructions (31) to 110 mg, or 82.5 to 110 mg (for example, 10,11,22, 27.5,33,44,55,82.5,88, 11 〇 or 132 mg, preferably 55 or 88 mg) SB 207266 or a salt thereof, for example, hydrogen hydride (calculated as the true weight including the counterion or the added acid). Preferred unit dosage forms (eg, lozenges or capsules) are or contain compositions comprising from about 10 to about 120 mg, or from 40 to 120 mg, or from 4 to 100 mg, or from 75 to 1 mg (including For example, 1 〇, 20, 25, 30, 40, 50, 75, 80, 1 〇〇 or 120 mg, preferably 50 or 80 mg) SB 207266 or its salt (calculated as the free base). Preferably, the granules comprising SB 207266 or a salt thereof also contain a filler (diluent). Mixing the filler with SB 207266 or a salt thereof prior to granulation often aids in the formation of granules. Pure SB 207266 or salt granulation is difficult. The car owner's filler (diluent) is a grinding agent. This helps to alleviate the viscosity of SB 207266 or salt and aids in the flow of particles. Preferably, the filler is frangible (as opposed to being elastic or plastic). Brittleness can be determined by tests known to the trained person, for example, by pressing the mimetic test, which is used, for example, to determine the Young's modulus of the filler. Preferably, the filler is insoluble, practically insoluble, very sparingly soluble or sparingly soluble (more preferably insoluble or substantially insoluble) in a granulating solvent, for example, water and/or acetamidine and/or Isopropyl alcohol. ,, in fact, insoluble,,, "very slightly soluble" and / or, slightly soluble, the word can be like Britishpharmac〇p〇eia, -33- This paper scale applies to the Chinese National Standard (CNS) A4 regulations ^ 210x297 Love ^

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A7 B7 1294781 V. Description of invention (32)

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European Pharmacopoeia and / or US Pharmacopoeia. According to British Pharmacopoeia 1999 (page 11), the term "actually insoluble" means that at least 10 liters of solvent is required to dissolve 1 gram of filler/solute (e.g., at ambient temperature, such as 15 or 20 or preferably 25. 〇. According to British Pharmacopoeia, the term "very sparingly soluble" means that at least 1 liter and up to 10 liters of solvent are required to dissolve 1 gram of filler/solute (for example, at 25 ° C.) According to British Pharmacopoeia, the term "slightly soluble" Means at least 100 ml and up to 1 liter of solvent to dissolve i grams of filler/solute (for example, at 25 ° C.) According to British Pharmacopoeia 1999, the term "soluble" means 10 to 30 ml at ambient temperature. Solvent to dissolve 1 gram of solute (for example, at 15 to 25 ° C.) According to British Pharmacopoeia, the term "easy to dissolve" means that 1 gram of solute needs to be dissolved from 1 to 10 ml of solvent (for example, at 25 cc). Pharmacopoeia, the term "very soluble" means that less than 1 ml of solvent is required to dissolve 1 gram of solute (for example, at 25. ^. Ministry of Economic Affairs, Intellectual Property Office, Employees' Cooperatives, Printed Better, 'The filler includes (eg Any pharmaceutically acceptable metal (e.g., calcium or magnesium) salt which is insoluble, practically insoluble, very sparingly soluble or sparingly soluble (preferably insoluble) in water and/or ethanol. The salt may, for example, be squama Acid salts, hydrogen phosphates, carbonates, hydrogencarbonates or lactates. These insoluble-to-slightly soluble salts include calcium phosphate, calcium dibasic calcium phosphate (calcium hydrogen phosphate), calcium carbonate, magnesium carbonate, magnesium phosphate, Calcium lactate (eg, pentahydrate), etc.; thus the filler may include, for example, one or more of these salts. -34- Ministry of Economy, Intellectual Property Office, Staff Consumer Cooperative, Printed 1279481 A7 B7 V. DESCRIPTION OF THE INVENTION (33) Preferably, the filling comprises, for example, calcium dibasic phosphate (i.e., dicalcium phosphate, calcium hydrogen phosphate, CaHP04). More preferably, the filling comprises (for example, two) Calcium phosphate hydrate, for example, dihydrate (i.e., calcium hydrogen phosphate hydrate, for example, dihydrate or CaHP〇r2H20). Divalent calcium phosphate can also be used. CaHP04, such as hydrate or anhydrate, is an abrasion. And help relieve SB 207266 or salt stickiness And it is insoluble in water. Alternatively or additionally, the filler may include calcium phosphate, that is, trivalent calcium phosphate, Ca3(P04) 2. Calcium hydrogen phosphate may be used as a flow aid, for example, in a dry granulation method. During the period; it generally helps with rolling and it is thick. Optionally, a fine-grained filler (having an average of about 5 to 30 microns, for example, 5 to 20 microns or about 9 to about 15 microns) can be used. Or medium particle size). For example, fine-grained grades of CaHP〇4 (dihydrate or anhydrous), for example, CalipharmTM, for example, Calipharm D (dihydrate) or Calipharm A (anhydrous), may be used as disclosed, for example, in pharmaceutical morphing. Handbook, Third Edition, 2000; or fine-grained Ca3(P04)2. However, it is preferred to use a coarse-grained filler, that is, having the following average or medium particle size: -50 or -53 or -100 or -106 microns, and/or S425 or $300 or $250 or $200 microns. , for example, 53-300 microns or 106-300 microns or 106-250 microns, for example: coarse-grained grades of CaHP〇4 dihydrate, for example, EmcompressTM or DI-TABtm (average particle size = about 180 microns), or coarse Size-35- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

A7 B7 1294781 V. Description of invention (34)

CaHP 4 anhydrate, for example, Emcompress AnhydrousTM or A-TABtm (average particle size = about 136 and about 180 microns, respectively), as disclosed in Pharmaceutical Excipients, Third Edition, 2000. EmcompressTM and Emcompress AnhydrousTM are available from Pan Weisi Pharmaceuticals, Inc., at 801 First Street S.W., P.O. Box 99, Cedar Rapids, ΙΑ·, USA, or at 2981 Route 22, Patteron, Ν·Υ·12563, USA. DI-TABT1 CalipharmTM is available from Rodia, Rhodia Inc., 259 Prospect Plains Road CN 7500, Cranbury, USA 08512-7500, or Rhodia Organique, 190 avenue Thiers, 69457 Etoile Part-Dieu, France o Ministry of Economics Intellectual Property The filler printed by the bureau employee cooperative is preferably present at up to 95% by weight of the granules and/or up to 85% or up to 70% or up to 60% by weight of the composition and/or granule weight. Preferably, the filler is - 15 weight ❶ or ^ 20 ° / by weight of the composition and / or the weight of the granule. Weight or - 30 weight ° / 〇 exists. For example, the filler is preferably present from 15 to 85% by weight of the composition and/or from 15 to 70% by weight of the particles. For example (for example, by example or $9) the filler may be present from 3 3 · $ % to 64.6 % by weight of the composition and/or from 38.8% to 69.6%. Preferably, the filler comprises from about 10 to about 90% by weight of the particles. Preferably, the filler is at least partially (e.g., all) within the particle. Preferably, the filler (for example, as defined herein) and the drug (i.e., SB-207266 or a pharmaceutically acceptable salt thereof) are applied to the composition of the country and the standard of the national standard ( CNS) A4 specification (2iqx297 public love) one - _ ----------------- ---

I 294781

5. Description of the invention The Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative prints or has a weight ratio of at least 1:3, preferably at least i · 2 5 or at least 1:2 or at least 2:3; and/or It should be about 1 〇: i or $5: 1 or: i. For example, the filler is in a ratio of the weight of the drug to the granules and is from 1-3 to about 1 〇: 1 (for example, from ι:3 to ι〇·1) or from 1·2 to about 10:1 (for example, From 1:2 to 1〇:1), for example, from 2:3 to 10:1 or from 1:3 to 3:1 or from 1:2 to 3:1 or from 2:3 to 3:1. Suitably, the weight ratio of the filler to the drug in the composition and/or in the granule is as defined above, wherein the filler comprises, for example, one or more calcium phosphates, calcium hydrogen phosphate (eg, hydration) And/or anhydrate), calcium carbonate, magnesium carbonate, magnesium phosphate and calcium lactate (eg, pentahydrate); more suitably, the filler comprises (eg,) acid and/or hydrogen acid. (for example, hydrates and/or anhydrates). The filler (for example, as defined herein, for example, may be intragranular, extragranular, or partially-intragranular and partially-extragranular; see, for example, 'Example 1-3 CaHP® 4. Preferably, at least Part of the filler (for example, some or all of, for example, 5 % or more or 7 % or more or 90 % or more thereof) is in the particle, for example, see Examples 2-9. More preferably, The filler is all in the particle, for example, see Example 2 'Example 4 _ H) Modified Example 2, and examples if the filler is at least partially present in the granule (ie, in dry granulation), then the filler The intra-particle ratio with the drug (i.e., in dry granulation) is from about 1:1 to about 1 : i, preferably -37- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210). X 297 public love: Γ

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A7 B7 1294781 V. INSTRUCTIONS (36) At least 1: 3 or at least 1: 2 or at least 1: 2.5 or at least 2: 3 or 2 1 : 1; and/or preferably S5: 1 or S3: 1. More preferably, the ratio of the filler to the intragranule of the drug, that is, during the dry granulation, is from 1:3 to about 10:1 (for example, from 1:3 to 10:1) or 1 : 2 to about 10 : 1 (for example, from 1: 2 to 10 : 1) or from 1: 3 to 3 : 1, for example, from 1:1 to about 10:1 or from 1: 2 to 3: 1 Or by 1:1 to 3: 1. Preferably, the composition comprises an excipient which acts as a compression aid, for example, comprising or being microcrystalline cellulose (MCC). Preferably, the compression aid is present at least 3% by weight or at least 5% by weight and/or $60% by weight or $50% by weight or $30% by weight, more preferably by weight of the composition, and/or by weight of the granules. Or at least 10% by weight or at least 15% by weight of the weight of the particles, more preferably from 10 to 50% by weight or from 15 to 50% by weight or from 15 to 30% by weight based on the weight of the composition and/or the weight of the particles (for example, About 20% by weight) is present. Preferably, the Ministry of Economics Intellectual Property Office employee consumption cooperative prints, including, for example, microcrystalline cellulose (MCC) having from about 25 microns to about 150 microns, more preferably from about 50 microns to about A typical average particle size of 100 microns. Suitable grades for MCC include Avicel PH-102 (approximately 100 micron nominal particle size) and Avicel PH-101 (a nominal particle size of about 50 microns) available from FMC Corporation. Alternatively, mannitol and/or lactose (for example, compressible lactose, for example, anhydrous lactose or spray-dried lactose) can be used as a compression aid - 38 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1294781 V. Inventive Note (37) Agent. These compression aids, which can also be classified as tree-filled, are classified as compression aids for the purposes of this patent. CaHP®4 and similar metal salts (e.g., as described above) are filled with a filler. "Compression aid" means an excipient which aids in the overall compressibility, for example, in a dry granulation process and/or during any compression into a tablet. For example, MCC is used to help plastics deform when ingots and to help with rolling.

The hydrazine compression aid may be present inside the granule (i.e., within the granule) and/or outside the granule (i.e., outside the granule). The compression aid may be present inside the particles of the composition (i.e., within the particles) and/or outside the particles (i.e., outside the particles). Preferably, the compression aid is at least partially (e.g., all) within the particle. meter

The Ministry of Economic Affairs, the Intellectual Property Office, and the Consumer Cooperatives, which are better printed, in the dry granulation process, a filler (such as, for example, calcium hydrogen phosphate as defined herein) and a compression aid (for example, microcrystalline cellulose, for example, The intra-particle weight ratio of Avicel PH-102 or PH_101), ie the weight ratio is -15: 1 or -7: 1 or -5: 1 or ^ 4· 1 or -3· 1 or -5: 2' and / Or preferably: 3 or: 2 or $2:3 or $1:1 or $3:2. For example, the intraparticle weight ratio of the filler to the compression aid is from 7:1 to 1:2, preferably from 5:1 to 2:3, more preferably from 4:1 to 1:1, and more preferably It is from 3:r to 3:2 or from 5:2 to 3:2, and most suitably about 2:1 (for example, from 2.2:1 to 1:8:1, from 2·1:1 to 2· 0 : 1, or from 2 〇 7 : i to 2.04 ·· 1). Optionally, the composition can include a binder. The adhesive is applied to the other particle by the Chinese National Standard (CNS) A4 specification (210x297 mm) 1294781 Λ7 B7 5. Inventive Note (38) to adhere the drug (SB 207266 or its salt) to another particle. The inner component is used to increase the strength of the particles, and thus, for example, a stronger bond can be formed upon compression. The binder is preferably a fibrous binder, for example, comprising or being a hydroxypropylmethylcellulose (hpmc) (e.g., low viscosity HPMC, for example, Pharmacoat 603, manufactured by Shinogi Co., Japan). Other possible fibrous binders may include hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxymethyl cellulose (HMC), methyl cellulose (eg, low to medium consistency), Ethyl cellulose and the like. Other suitable binders include povidone (polyvinylpyrrolidone, PVP; which is a predominantly linear, non-crosslinked polymer, see Handbook of Pharmaceutical Excipients, Third Edition) , 2〇〇〇), for example, K25, K30, K60 or K90 grades of povidone and/or Boeing having a molecular weight of about 50,000 to about 1, 〇〇〇, 〇〇〇. The binder is preferably present at from about 1 to about 10% by weight of the composition, for example, from about 2.5 to about 1% by weight of the composition or from about 5% to about 5% by weight (e.g., about 5% by weight). The HPMC is preferably present at about 5% by weight. The binder may appear inside the particles (i.e., within the particles) and/or outside (i.e., outside the particles) of the composition (any possibility of not removing a portion of the binder in the particles and in the unfixed area). Preferably, however, the composition comprises a non-Hpmc binder; more preferably a binder free composition (see, for example, Examples 9 and 11-16). Preferably, the composition comprises a disintegrant (for example, a tablet disintegrant) such as 'starch glycolate (for example, prim〇jel or -40- this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public)

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Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. A7 B7 1294781 V. Inventions (39)

ExplotabTM, the latter available from Pan Weisi Pharmaceuticals, at 801 First Street SW· ' POBox 99, Cedar Rapids, ΙΑ · 'USA), or at 2981 Route 22, Patterson, Ν·Υ· 12563, USA, cross-linked cards Croscarmellose sodium (eg, Ac-Di-SolTM)' or cross-linked povidone (cross-linked polyvinylpyrrolidone). The disintegrant is preferably from about 1 to about 1% by weight of the composition. It is present, for example, in the range of from about 2.5 to about 10% by weight or from about 3.7 to about 10% by weight or from about 5 to about 1% by weight or from about 1 to about 5% by weight (e.g., about 5% by weight) of the composition. Preferably, the sodium starch glycolate is present at about 5% by weight. The disintegrant may be present inside the particles (in the particles) and/or outside (out of the particles) of the composition (any particles in the particles and outside the particles are not removed) Preferably, the dissolving agent is present in the unfixed zone. Preferably, the disintegrant is at least partially, for example all, extragranular. Preferably, the composition comprises a slippery agent, for example, comprising or being an alkaline earth metal stearate, for example, calcium stearate or more preferably stearic acid. The lubricant may comprise, by weight of the composition and/or the weight of the granules, for example, from about 0.2% to about 5% by weight or more preferably from about 〇2 to about 2% by weight or from about 5% to about 2% by weight of the Ministry of Economic Affairs, Intellectual Property Office employees. % (for example, about i% by weight or about 2% by weight) is present. Preferably, at least a portion of the lubricant is present inside the particles (within the particles) (which does not exclude the possibility of a portion of the lubricant appearing outside the particles). This results in slippage during the dry granulation step and reduces the difficulty of the process, for example, the granulated component adheres to a metal mechanical knife such as a rolling press. Moreover, the lubricant can occur within and outside the particles. Any printing • 41-

:294781 A7 B7 5. Inventive Note (40), the in-particle lubricant is from about i% to about %%, or from about 1% to about 25%, or more preferably from about 1% to about 12% by weight of the particles. %presence. The granules (i.e., intragranular components) may optionally form from about 2 〇/〇 to 99.8% by weight or from about 2% to about 99% by weight, for example, from about 4% to about: 5% by weight or about 4% by weight. % to about 75 〇 /. Weight or from about 2% to about 75% of the composition. The granules (i.e., the granules) preferably form from about % to about 99.8% or from about 75% to about 99% by weight of the composition. More preferably, the granules are formed from about 5G% to about 99% or from about 75% to about 99% by weight. For example, the particles may form a composition of from about 卯% to about 99. 8 m, or from about 90% to about 99%, or from about 95% to about 99% by weight. Alternatively, the granules can form a composition of the weight percent (i.e., no extragranular excipients). According to a fifth aspect of the present invention, there is provided a method for preparing a pharmaceutical composition comprising N-[(l-n-butyl|hexanitroguanidine)methyl]heart dinitrogen][1,3] 十井[ 3, 2♦ Nasaloreline (SB 2〇 7266) or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable excipients (carriers), the process comprising: (4) SB 207206 or The salt is dissolved in a & alcohol to form a solution, (b) the SB 2 〇 7266 or its salt from the solution is added by adding a C5_c10 hydrocarbon (such as hexane and/or heptane) and/or a C5_CM containing hydrocarbon. Crystallization (for example, calcined and / or heptane) solvent, and (c) to) some SB 207266 or its salt by dry granulation method paper size applicable to China National Standard (CNS) A4 specifications (210x297 Public love)

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Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 1294781 A7 B7 V. Invention Description (4!) into particles. The <^_4 alcohol includes or may be: methanol, propanol (for example, isopropanol), butanol (for example, n-butanol or tert-butanol), and/or ethanol or a solvent containing ethanol, for example, Industrial mercapto alcohols (IMS, for example, ethanol containing about 1% methanol). Ethanol or a solvent containing ethanol is preferred. Dry granulation and/or excipients can be as described herein. In a fifth aspect of the invention, it is especially preferred that the SB 207266 or a salt thereof comprises (e.g.,) a hydrogenate salt of SB 207266, for example, a needle crystal form thereof. SB 207266 or a salt thereof can be easily administered by any conventional administration route, for example, parenterally, orally, topically or by inhalation. The process of preparing the compositions and/or lozenges and/or capsules can include the proper mixing of the ingredients of the compositions, granules and compression into the desired formulation. The excipient/carrier used in the composition should be "pharmaceutically acceptable;" meaning compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The pharmaceutically acceptable carrier used may, for example, be a solid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Similarly, the carrier may comprise a time delay material which is well known in the art, for example, glyceryl monostearate or glyceryl distearate alone or together with a wax. 0 «43- This paper scale applies to the Chinese National Standard (CNS) )A4 size (210 X 297 mm)

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Printed by the Intellectual Property Office of the Ministry of Economic Affairs, A7 B7 1294781 V. Invention Description (42) A wide range of pharmaceutical types can be used. Thus, if a solid carrier is used, the preparation may be in the form of a lozenge, or may be placed in a hard gelatin capsule in powder or pellet form or may be a tablet or tablet. The amount of the solid carrier varies widely but is preferably from about 25 mg to about 1 gram. Utilization / industrial application

The pharmaceutical composition comprising SB 207266 or a salt thereof obtainable or prepared according to the process of the present invention can be used to treat or prevent atrial arrhythmia, for example, atrial fibrillation (AF), and/or to treat or prevent atrial remodeling. Atrial fibrillation is preferred. In particular, it is believed that compositions such as tablets containing SB 207266 or a salt thereof can be administered to patients who continue to have atrial fibrillation (AF) symptoms to inhibit recurrence of symptoms of atrial fibrillation in these patients. The proposed clinical protocol is listed in Example 17 below. line

The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, therefore, the present invention also provides a method of treating or preventing atrial arrhythmia, for example, atrial fibrillation, which includes defining an effective amount herein or by The pharmaceutical compositions obtained or prepared by the defined methods are administered to mammals (e.g., humans) in need of such treatment or prevention. The present invention also provides a method for inhibiting recurrence of atrial fibrillation symptoms in mammals (eg, humans) suffering from persistent atrial fibrillation, including the definition of an effective amount herein or by the method defined herein. The obtained or prepared pharmaceutical composition is administered to the mammal. The composition of SB 207266 can also reduce the incidence of stroke in AF patients. -44- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 1294781 'Inventive Note (43) SB 207266 composition can also be used to treat and / or prevent urinary incontinence, and / or other The use disclosed in WO 93/18036. All publications referred to in this specification, including but not limited to patents and patent applications, are hereby incorporated by reference in their entirety in their entireties in the the the the the the the The invention is described herein with reference to the following description and examples, which are intended to be illustrative only and not to limit the scope of the invention, particularly as defined in the appended claims. This description is exemplified by certain non-limiting methods by which SB 207266 and/or its hydrogenate can be prepared; other methods are also possible. According to a specific example of the present invention, the non-limiting example (other than the comparative example) is to prepare a pharmaceutical composition comprising SB 207266 or a pharmaceutically acceptable salt thereof, starting from SB 207266 or a pharmaceutically acceptable salt thereof The dry granulation method is exemplified, and the dry granulated pharmaceutical composition thus obtained is exemplified. Printed by the Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives. This example and/or description is partially illustrated by the illustrations. Figure 1 is a scaled photomicrograph (photograph) showing the crystallization of the description 2 In the step, N-[(1-n-butylhexahydropyridinyl)indenyl]-34_dihydro-2H-[ 1,3] K # [3,2-a]-injection (sb_ 207266-a) The initial stage of needle crystal formation. Slender needles can be seen. Figure 2 is a scaled photomicrograph showing the knot of 2 -45- A7 B7

1294781 The final stage of the formation of the SB-207266-A needle junction shown in Figure 1 at the end of the crystallization step. The needle becomes wider. Figure 3 is a graduated photomicrograph showing the SB-207266-A crystal of Scheme 2 after being stirred, washed and transferred to a vacuum oven for drying. The long needle of Figure 2 breaks into a shorter crystal. The drawings 1 to 3 are intended to be illustrative and to limit the scope of the invention, particularly as defined in the claims. Different crystal formation and/or crystallization conversion results, as well as different crystal sizes, are possible and are within the scope of the invention unless otherwise indicated. Figure 4 shows the needle-type infrared lubricating oil (IR) spectrum of the SB_2〇7266 hydrochloride (SB_2〇 7266_A) needle-type substantially anhydrous crystalline type (infrared nujol mull spectrum) As described in the descriptions 1 and 2 and described in the description 2. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing chart 5 is a cross-sectional figure of a specific part of the Philippine Cuiqixite IR22 rolling machine, which is used in the examples u and u and in the example More detailed in step 2. Figure 6 shows the specific part of the FitzMill L1A pulverizing mill with the center bearing/shaft 18 and the extension knife 2 and the hammer 22 and the screen/screen Phillips IR220 press (top) and (bottom). A cross-sectional view, as detailed in the previous description. 'Describe the paper scale applicable to China National Standard (CNS) A4 -46-1294781 A7 ---B7 V. Description of invention (45) SB-207266-N-[(l-n-butyl-4-hexahydropyridinyl) Indenyl]_3,4-dihydro-2H-[1,3]畤σ and [3,2-a]吲哚-10-treazone can be synthesized using the synthesis described in the introduction, for example, preferably It is made by one or more of WO 98/07728, WO 98/11067; WO 00/03983; and/or WO 00/03984.

For the method of producing SB 207266 hydrochloride from the free base, see in particular the method B of the 9819 line on page 8 of WO 98/07728 and its small variations, which are described in the foregoing, introduction, full text And, the present invention, the chapter (for example, see page 3 above). One of the minor and all equal variations of WO 98/07728 Method B is described in detail in the following description, wherein in the crystallization step, industrial methylated spirit (IMS) is used instead of ethanol and n-heptane is used instead of hexane. . In the descriptions 1 and 2, the specific type of IMS used is ethanol containing about 1% methanol. Description 2 provides an alternative to the manufacture of SB 2G7266 hydrochloride from the free base, which replaces anhydrous HCl with acetonitrile. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperatives: N-[(l-n-butyl-4-hexahydropyridinyl)methyl]-3,4·dihydro-2H-[1,3] And [3,2-a]吲哚-10-carboxyguanamine hydrogenate; anhydrous HC1 is prepared by N_[(l-n-butyl-4-hexahydropyridyl)indolyl]-3,4_2 Hydrogen-2H-H, 3l·啐耕和[3,2-a]吲哚-10-Carbodecylamine (SB-207266) (100 g, 0·27 mol) dissolved in industrial methylated alcohol (IMS (825 ml) and the resulting solution was filtered to remove particles. Anhydrous HCl was added to IMS (174 mL, 1.7 Torr, 0.29 mol) to precipitate the product from the solution. The raw-47- paper size is applicable to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) ^~ 1294781 A7 Β7 5. Inventive Note (46 material is heated to solid and redissolved and n-heptane is added (55 〇ml). After cooling to room temperature, the mixture is cooled to 0-5. (: and stirred at room temperature for about one hour. The solid is isolated by filtration and dried at about 4 (rc vacuum to give the product, N_ [(l-n-butyl_4_hexahydropyridinyl)methyl]_3,4_dihydro 1_[1,3]_ 44 and [3,2-a]吲哚-10-carboxyguanamine hydrogen Chloride (SB 2 〇 7266:), (98 g) 89% yield. SB-207266-A of Description 1 (and/or a change in IMS with ethanol) has a low bulk density and is measured as follows: BDC-H-Olc BDC-G-02c BDC-G-03c BDC-G-04c BDC-G-05c Inflated bulk density by tapping density - ml / ml 0.136 0.142 0.173 0.146 0.152 0.250 0.300 0.339 0.310 0.308 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Description 2 : N-[(l_n-butyl-4-hexahydropyridinyl)methyl b 3,4-dihydro-2H- [1,3]_畤Ploughing [3,2-a]吲哚-10_carboxyguanamine hydrogenation; acetonitrile gas production method and particle fraction 1. N-[(l-n-butyl-4-hexahydropyridyl)methyl]-3,4-dihydro-2H-indole, 3]-indole and [3,2_a]吲哚-10_carboxylate Indoleamine (SB-2〇 7266) (2 gram, 54 moles of '1 molar equivalent) was dissolved in industrial methylated spirit (IMS) (16 mL) and the solution was filtered to a 5 mL In the container. [It is best to use a filter to remove the inorganic substances that can be present as fine powder.] Wash the residue with IMS (20 ml). 2. Filter the acetonitrile (4·6 ml, 64) Millions, L2 molar equivalent) • 48-

A7 B7 1294781 V. Inventive Note (47) is slowly added to the IMS solution containing SB-207266 in IMS at <45 c (for example, at room temperature, for example, about 15-25 ° C). It is at <45 ° C (for example, room temperature). The reaction is exothermic, so the rate of addition of acetamidine should be controlled so that the temperature of the reaction mixture can be kept below the acetonitrile point (5 〇 C) and preferably below 45 °C. In this specific example, the acetamidine system was added over 30 minutes. [Acetyl chloride and metal-containing ferrous iron should be avoided, as this can cause the aqueous solution to appear blue]. The residue of the acetonitrile container was rinsed into the reaction mixture containing filtered IMS (20 mL). 3. The resulting mixture is heated to 70-80 ° C to give a solution. Once the solution is obtained, step 4 can be performed immediately; or alternatively, the hot solution is retained before step 4 and stirred at 70-8 (TC for 10 minutes. 4. Filtered n-g-burn (1 〇〇 ml at room temperature) ) added to the hot solution (60-8 (TC, eg 6 〇 -70 ° C) after about 1 hour, maintaining the solution temperature at 60-80 C 'eg 60-7 (TC. Then immediately or after a short period) After the time (for example, 10 minutes), proceed to step 5. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives. 5. Determine the mixture according to the size of the container and the cooling capacity, and cool it to 0-5 °C for a period of time (for example, The mixture may be cooled for about 30 minutes to about 2 hours. The cooled crystal-containing mixture is stirred for 1 hour. 6. The crystalline product is separated from the cold solvent by filtration, for example, with a Buchner funnel, and Filter 1 : 1 of IMS: n-heptane (2 〇 ml), too washed. The product is a fine solid, which is filtered quite slowly. The product is dried in a vacuum oven, for example, in a vacuum oven. And obtained Ν-[(1·n-butyl_4_heptadinyl)methyl]-3,4-dihydro-2Η-[1,3]- [3,2-a]吲n-------------------------------------------------------- The product of guanamine oxychloride (SB 2 (7266_A, 2 (4 g, yield 93%)) as white crystals is printed. The yield can vary, and can be typically from about 95 to about 95%. Typical density Values are: aerated bulk density = about ο·" g/ml, tapped bulk density = about 0. 31 g/ml. Sites, schemas 1, 2 and 3 are illustrated in the description of change 2 In the step, the crystallization of the gas salt SB-207266-A is formed and converted. It should be noted that Figures 1 to 3 are for the purpose of _ and, unless otherwise indicated, are not intended to limit the scope of the invention, particularly as an application As defined in the patent scope, different crystal formation and/or crystallization conversion results, and different crystal sizes, are possible and within the scope of the invention unless otherwise indicated. Figure 1 illustrates the formation of crystals. In the initial stage, it is added at 6〇-7〇 (step 4) when n-heptane is added and/or after 1 hour of addition, and/or after being cooled by 60-70 C. However, it occurred at -5 ° C (step 5). It was found that the SB-207266-A which was originally produced was a slender (general > 1 μm) needle. Figure 2 illustrates the final stage of crystal formation. It is stirred at 〇_5 C for 1 hour at the end of step 5. The long (>100 μm) needle-shaped crystal SB-207266-A still exists, but due to crystal growth, it has a slightly larger width. (diameter). As shown in Figures 1 and 2, the length of the formed SB-207266-A needle crystal (e.g., > 75%, etc., or volume or weight) is generally > 100 microns or > 200 microns. However, the width (lateral dimension) of needle crystals (e.g., > 75% of their number or volume or weight) is typically < 10 microns (e.g., Figure 1) or < 25 microns (e.g., Equation 2). -50- This paper size is applicable to China National Standard (CNS) A4 specification (2丨0x297 mm)

1294781 Λ7 一一 B7 V. INSTRUCTIONS (49) Figure 3 illustrates the SB-207266-A crystals which were stirred, washed and transferred to a vacuum oven for drying. It can be seen that the long needle of Figure 2 has broken into shorter crystals, which are generally (for example, > 50% of their number or volume or weight) still needle-shaped or lengthened but length < 75 microns or < 100 microns or < 200 microns. Some very small crystals can be found in Figure 3. The particle size analysis of the cracked/shortened crystal in Scheme 3 is considered to be similar to that shown in Table 1. The number of spectra 图: Fig. 4 shows the infrared (IR) spectrum (medical lubricating oil rim spectrum) of the hydrogen sulfate SB-207266-A from the crystals of the description 1 and/or 2. This is essentially an anhydrous crystalline form of SB-207266-A. Due to SB-207266-A, the IR peak can be seen on wave numbers 3423, 3044, 2502, 1628, 1582, 1502, 1531, 1184, 748 cm (accurate to approximately: ± 2 cm "or ± 1 cm -1) Due to the use of pharmaceutical lubricants, the peak is considered to be around 2960-2850, about 1466, about 1327 and about 721 cm. The IR wave of SB_2〇7266_A is tentatively arranged as follows:

• 计 · • 丨

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing wave number (cn^1) arrangement 3423 NH amide bond lengthening 3044 CH (aromatic) key lengthening 2502 N+-H key lengthening 1628 〇〇 key lengthening 1582 and 1502 ring mode 1531 guanamine II 1184 co bond elongation 748 CH (4H) detachment plane key deformation -51- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1294781 V. Description of invention (5〇Change in Note 2: especially on a larger scale, the dryer-dryer), for example, when drying, slowly stir instead of using a porcelain funnel and vacuum in the alternative example of Note 2, The crystallization product is placed in a single piece (ie, filtered, washed, and dried under vacuum, crystallization product, any machine (eg, machine agitation), oven. Comparative Example - Lozenges made by wet granulation according to the following table The composition was prepared as a tablet of SB 2〇 7266 Nitroate (8) 207266-A) in an amount of 10, 25 or 4 mg (measured as a free test). The method and composition are not according to the invention but to example 4 of w〇 〇 2/11734 A1. Comparative Example Composition Functionality Number (mg/suspect) Active Ingredient 10 mg 25 mg 40 mg Lozenges Lozenges Lozenge Strength Strength SB-207266-A (Hydrate) API 11.0* 27.5* 44.0* Other Ingredients Microcrystalline cellulose compression and 50.0 50.0 50.0 (eg, Ph. Eur· or NF) Mercaptopropyl methylcellulose granulation aid binder 12.5 12.5 12.5 (eg, USP) (eg, Pharmacoat 603) Starch glycolic acid Sodium disintegrant 12.5 12.5 12.5 (for example, NF or Ph·Eur·) Hydrogen sulfate momahydrate main diluent 161.5 145.0 128.5 Valence calcium phosphate dihydrate) (eg, Ph. Eur. or USP) Hard fat Magnesium Oxide Lubricant 2.5 2.5 2.5 (for example, Ph·Eur. or NF) Pure water** Granulated solvent* 氺氺氺氺本-52· This paper scale applies to the National Standard (CNS) A4 specification (210x297 mm) ) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1294871 at ________B7 V. Invention Description (51) (For example, Ph. Eur. ^USPj' -- I --- Ou Qiao Bai YS-1-7003 Film Encapsulation 6·25 6 ·25 6·25 pure water* * * * * * Total weight of suspects 256.25 2 56.25 *10,25,40 mg of pure free base** were removed in the process. The SB_207266_A tablet of the comparative example was pressed into a plastic, child-resistant, induction-sealed high-density polyethylene (HDpE) In the bottle, the comparative example was formed by wet granulation using an insoluble primary excipient, calcium dicalcium phosphate dihydrate (or dicalcium phosphate). The dibasic calcium phosphate dihydrate was the main component. The diluent is added together with the microcrystalline cellulose to disperse the granulating solvent and to help the overall compressibility. The added binder is hydroxypropyl decyl cellulose and the granulation is carried out in a conventional mixing granulator. The granule mixture is dried, sieved and mixed with starch ethanol &L sodium as a disintegrant and stearic acid as a > slip agent to form a compressed mixture. The tablet is at a suitable rotary tablet pressure Made on board, and the shape can be elliptical or round. The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing comparison example - detailed manufacturing process, process control, and assembly process will be SB-207266-A, microcrystalline fiber Bivalent phosphorus The acid to dihydrate is mixed with hydroxypropylmethylcellulose. When mixing in a high shear mixing granulator, pure water is added to the mixed powder. The granules are dried in a fluid bed dryer and then transferred to a mixer for mixing with the sodium sulphate sodium sulphate and magnesium stearate. Lubricated mixing with a rotary tablet press -53· The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) A7 B7 1294781 V. Description of the invention (52) The material is pressed into the ingot core. The ingot core was embedded in a thin layer with an Opa dry white YS-1-7003 aqueous dispersant. Procedure: 1.0 Granulation 1.1 SB-207266, microcrystalline cellulose, hydroxypropyl methylcellulose and calcium dibasic phosphate dihydrate were blended in a suitable high shear mixing granulator. 1.2 Add pure water to promote granulation. 1.3 The granules are dried in a fluid bed dryer. 1.4 Use a suitable grinder to pass the dried granules through a stainless steel screen. 1.5 Determination of the yield of granules 2.0 Manufacture of compressed mixture 2.1 The desired amount of sodium starch glycolate and magnesium stearate were blended with dry granules. 2.2 Determination of the yield of the compressed mixture 3.0 Tablet compression 3.1 Transfer the compressed mixture to a suitable tablet machine. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives 3.2 Compressing Tablets 3.3 Determine the yield of compressed tablets. 4.0 Film Embedding 4.1 Move the ingot core to a suitable embedding machine. 4.2 • Rotate the core and spray the opal dry aqueous dispersion. 4.3 Randomly select release test samples from the batch and label them appropriately. -54- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1294781 V. Description of invention (53) 5.0 Bottling 5.1 Filling the appropriate filling amount into the HDPE bottle with appropriate automation Medium, sealed by induction and equipped with child protection cover. The following data is recorded for some of the embedded thin layer tablets according to the comparative example: Average hardness (Κρ) 13.7

(Core hardness (without embedding) may be very close to less than 2 Κ ρ) Disintegration time (minutes) 15 Dissolution time Τ 75 (minutes) 14.8 Example according to the invention - SB 207266 Dry-granulation pharmaceutical composition Example 1 - SB_207266-A The tablet is made by a dry granulation process and a part of the intragranular magnesium stearate.

A tablet of sb 207266 hydrochloride (SB 2〇 7266-A) in an amount of 10, 20, 25, 40, 50 or 80 mg (calculated as a freeway) was prepared according to the composition in Table 2 below. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed Moderate Ruler, Paper, Standard, Secret, 97 9794781 at B7 3 0OS s 0·0? f^.I ς ς (Ν·Ι (%ΪΓςε) (%£s 4 )%保00000ϊοςς 5 /1\ Say *^$08 β^ος 明- 发5ΓΙ?_οο·εε) 3 ς.inch oo 3 芩3 W 二ΓΙ (%ϊοέ V唞SI 爹SC4I 33

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Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Νίβ«铍#哒凛1 f#^:<N< shed ic^Mie εοοζτιώΛ 疝^銮铋辋璨荼铋劫初^ (2 Bu SSJduIOOUIg wfflvl.Ia^is^ # * 荽Φ^Μ^ΊΙ 潜綦毽綦毽«ο#褰(S9td§ 璧£ ί) ί dH)- _ Fees 砩1办^硪澈-56 (SI-HdI8>v (C# step) disc dive锼 _ (alkaline alkali) ν·99<Νδζώ00 (趔审^si φίίΜ^.dsn 嘁fcN^sa ΗΡΗ ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 07 0 inch two 70701 food #玩虿令* 丨tt· •线丨

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). A7 B7 1294781 V. Inventive Note (55) The method used to manufacture the tablet of Example 1 will now be described. The equipment used (for small scale R&D work up to about 1 kg) includes: - Philippine Trinity IR220 press (detailed in step 2 of Example 11 and shown in Figures 5 and 6). - a FitzMill L1A mill with a knife or hammer and a screen (for example, as described in the foregoing description and as shown in the lower half of Figure 6, which can be separated from or integrated with the press. It is produced by Philippine Pai, and its head office is in the US. The equipment is also available at its European subsidiary: Fischer Europe, Entrepotstraat 8, B_9100, Saint-Nikolas, Belgium; Fax: +32/3- 766-10-84, Email: Fitzpaatrick-Europe@compuserve.com; www.fitzpatrick.be. Example 1 - Detailed Process 1 · Pass SB_207266-A and magnesium stearate to the internal part of the particle through a general term 1250 The micron sieve, if necessary, is sent to the appropriate mixer with an oscillating filter. Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 2 · Blend for 5 minutes at approximately 17 revolutions per minute (rmp). The material is loaded into a rolling machine (Fei Pai Cuitson IR220 rolling machine) and starts rolling. The following parameters are recommended for use in the rolling operation: * Light roller (relative rotation, pressure applied to the floating roller) * Horizontal screw feeder (measuring the product from the funnel into the pre-compression stage): The speed of the screw feeder is from 〇 to about 62 rpm, for example -57- This paper scale applies to China National Standard (CNS) A4^ (210x297 public) *" · 1294781 μ B7 V. Invention description (56) , about 20 rpm. *Vertical screw feeder (pre-compression of the material and degassing and pressing the material onto the roll, actual compression and final densification in the pinch area of the roll): screw feeder The speed is from 〇 to about 270 rpm, for example, about 100 rpm. * Rolling pressure · from about 2,000 to about 16,500 pounds per plit, for example, about 8000 pli. * Rolling circumferential speed · by 〇 to about 17 rpm, for example, about 10 rpm ° 4 · The measurement records in the process are as follows: * Strip thickness (mm) * Strip density (g / ml) - the density of the label is from about 1.0 to about 1.5 g / ml * Strip width (mm) * Strip length (mm) * Strip weight (g) The method for determining strip density is as follows: using a pycnometer, adding 70 ml of oil (preferably liquid paraffin) and adding compacted material The strip can be up to 80 ml. Then the density of the strip can be calculated from the weight of every 10 ml. To. 5. The strip collected into a suitable container. 6. comminuted using a suitable mill, for example, with hammers and / or knives of a grinding mill having appropriate for the hammer before, using a sieve of 0.065 inches

FitzMiULlA grinds the roll compaction strip. -58- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 1294781 A? ------- B7 V. Description of Invention (57) 7 · Determine the bulk density of the ground particles. 8 · Excipients outside the particle (in this case · calcium hydrogen phosphate dihydrate, microcrystalline cellulose, sodium starch glycolate and HPMC), no extragranular magnesium stearate, through a commonly known 500 micron Filter the sieve, use an oscillating sieve, and if necessary, enter the appropriate blender. 9 - These extragranular excipients were mixed with the ground granules at about 17 rpm for 15 minutes. 10 The outer portion of the hard lauric acid granules is passed through a 500 micron sieve into a mixer containing a mixture of excipients and granules. 11 · Blend at about 17 rpm for 2 minutes. I2. The compressed mixture produced is compressed on a suitable tablet press, for example, a Picola rotary press or a Qilin T100 rotary press to prepare a tablet. The main cross section of these tablets may be circular or elliptical. Example 2 - Calcium hydrogen phosphate dihydrate in all granules Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed This system uses the same composition and method as in Example 1, but all of the calcium hydrogen phosphate dihydrate system and SB-207266 -A and magnesium stearate are to be granulated in step 2 of the process and the resulting blended rolls are compressed in step 3 of the process. Therefore, the calcium hydrogen phosphate dihydrate is in the entire pellet in the tablet. In Example 2, the weight ratio of the CaHP04.2H20 filler to the drug in the granules is, for example, 2.14:1 (when 50 mg tablet strength/dose); -59- The New Zealand Scale for Money (CNS) A4 Specifications (210x297 public Chu) '一""" A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1294781 V. Invention description (58) or 0.96 : 1 = 1 : 104 (when the lozenge strength is 80 mg Time). Example 3 - Part _ granules and parts _ extragranular calcium hydrogen phosphate dihydrate This is the same composition and method as in Example 1, but half of the calcium hydrogen phosphate dihydrate system and SB-207266-A And the magnesium stearate is to be granulated in the step 2 of the method and the resulting blended roll is compressed in the step 3 of the process. The remaining half of the calcium hydrogen phosphate dihydrate was sieved and blended with the ground granules in steps 8 and 9 of the process. Therefore, in the tablet, the calcium hydrogen phosphate dihydrate is partially/inside the granules.

Example 4 - jjpMC in all granules This is the same composition and method as in Example 2 or Example 3 (calcium hydrogen phosphate dihydrate is in all granules, or part _ granules and parts - granules outside) All of the HPMC binders are blended with the SB 2 〇 7266_A and magnesium stearate granule internalization portion and the calcium hydrogen phosphate dihydrate in step 2 and the resulting blended rolls are compressed in step 3. Therefore, in the tablet, the HPMC system is entirely in the particles. Example 5 - Microcrystalline oryzanol in all granules This is the same composition and method as in Example 2 or Example 3 (filled with sulphuric calcium hydrate monohydrate in all granules, or partially - granules and parts) _ extragranular but all microcrystalline cellulose with SB-207266-A and stearic acid locks (four) part and Wei hydrogen mom dihydrate in step 2 and the resulting blended roll It is compressed in step 3. Therefore, among the suspects, the microcrystalline cellulose is all in the particles. Example 6 - Partial - Partial, Partial, Microcrystalline Weaving Dimensions __ - 60- The paper scale Applicable to China National i^CNS)A4 Regulations----

1294781 A7 B7 Description of Invention (59) Printed by the Ministry of Intellectual Property of the Ministry of Intellectual Property, the Department of Consumer Cooperatives, using the same composition and method as in Example 2 or Example 3 (phosphoric acid dance dihydrate is all particles, or part of _ and part - extragranular), but half of the microcrystalline cellulose and Sb_2〇7266_a and stearic acid to be internalized part of the granules and hydrogen sulphate dihydrate in step 2 and the resulting blend The rolling stock is compressed in step 3. The remaining half of the microcrystalline cellulose was sieved and blended with the ground particles in steps 8 and 9. Therefore, in the bonding agent, the 'microcrystalline-yellow part is difficult to be inside and part of the particle. Example 7 - Sodium starch glycolate in all granules This is the same composition and method as in Example 2 or Example 3 (hydrogen phosphate about dihydrate is all _, or partial _ and part granules) 'But all the starch sodium glycolate is combined with sb_2〇7266_a and the magnesium stearate suspension and the Wei hydrogen hexahydrate in step 2 and the resulting blended roll is in step 3. compression. Therefore, in the tablet, sodium starch glycolate is contained in all the particles. Example 8 - Partial - Partially Partially Extragranular Sodium Starch Glycolate This is the same composition and method as in Example 2 or Example 3 (calcium hydrogen phosphate dihydrate is in the whole particle, or part _ granules and parts _ extragranular) 'but half of the powdered sodium sulphate system and SB-2 〇 7266_A and stearic acid to be treated with the granule internalization part and calcium hydrogen phosphate dihydrate in the second step The resulting blended roll is compressed in step 3. The remaining half of the microcrystalline cellulose was sieved and blended with the ground particles in steps 8 and 9. Therefore, in the tablet, 'starch sodium glycolate part _ granules and parts - granules outside 0

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-61- 4297 mm) 1294781 at B7 V. Inventive Note (6〇) Example 9 - Excluding HPMC Adhesive This is the use of the same composition as in Examples 1 to 3 or 5 to 8 - Chess W. , but the formula does not contain HPMC binder. HPMC is sticky, the gap is complemented by an equal amount of hydrogen phosphate dance dihydrate (intragranular or extragranular), such that (a) total embedded tablet weight 256.25 mg, (1)) total pre-embedded ingot The amount of the agent is 250 mg, and (c) the amount of other excipients remains unchanged. Thus, for example, in Example 9, the amount and weight % of the composition of the calcium hydrogen phosphate dihydrate are as follows for the tablet strength (dose, calculated as SB_207266 free base): 174.0 mg or 69.6% by weight ( When the lozenge strength/dosage is 10 mg); 163·〇 mg or 65.2 wt❶/〇 (20 mg strength); 130.0 mg or 52.0 wt% (5 mg strength); 97 mg or 38.8 wt% (80 mg strength). Wherein Example 9 Modification Example 2 or another example itself modified Example 2 (i.e., the CaHP04*2H20 system is entirely intragranular' and assumed to be maintained), and then in the granule, CaHP (the weight ratio of the V2H20 filler to the drug is, for example, 15·8: 丨 (when tablet strength/dosage is 10 mg); 6.84: 1 (2 〇 mg tablet strength); 2·36: 1 (50 mg tablet strength); or 1·1〇 : 1 (8 〇 mg tablet strength). Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print Example 10 - Dose Change In any of the variations of Examples 1 to 9, each tablet contains 30 mg, 75 mg or 120 mg SB Formulation of -207266 (present as hydrochloride, but the dosages described herein are calculated as the free base) can be used to make tablets; instead of each of the formulations of Examples 1-8, given 1 , 25 and 40 mg The amount of these formulas (a) total embedded tablet weight 256.25 mg, (b) total pre-embedded ingot-62- This paper scale applies to the Chinese national standard Fantasy gossip specifications (21〇χ297 public Chu) 1294781 Α7

诏 weighs 250 mg, and (c) remains unchanged in Example i, but adjusts the amount of change in the amount of excipients. Examples of variations of SB 207266 in the stolen goods 11 to 16 The Ministry of Economic Affairs Intellectual Property Office employees consumption cooperatives printed the method and composition of the present invention, which do not contain any examples of n] A ~ adhesive For example, HPMC. The ear 11-16 series outlines the preparation of a 1D eight-cold 7266 (in purely free test) containing 8 ounces of measurement. The kg batch of the key agent is as follows: 八 克 SB-207266 (measured by pure liberation test) (Example 12); ι 〇 2 times of the lozenge contains 40 mg SB 2 〇 7266 (measured as pure free base) The disintegrant was 5 G% extragranular (Example 13). Example 14 is a variation of Example 1曰1, which is 12 metric; t batch contains a granule phase microcrystalline cellulose. Example 15 provides a selective thin layer entrapment onto the tablet. Example 16 changes the dosage of SB 2 〇 7266 in the Example 1M5 lozenge. Example 11 - a tablet containing 80 mg of SB 2 〇 7266, containing no binder, containing all of the microcrystalline cellulose and calcium hydrogen phosphate in the granules, part _: internal parts - 遡 丨 丨 丨,"M a ^ group composition formula (weight / key, gram) batch quantity ^ (g) weight of unembedded bond ° / 〇 SB-207266 A (hydrogenate) 87.90 gram 3516 grams 35.16 % microcrystalline cellulose 48.12 mg 1925 g 19.25 % calcium hydrogen phosphate monohydrate 98.98 mg 3959 g 39.59 % 2 3 -63- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

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1294781 V. Description of invention (62) A7 B7 ^ sodium glycolate 12.50 mg 500 g __ 2.50 mg 1 gram 5.00 % 1.00 % 4 5 250.0 mg Remarks 10 (10) 0 g 100 % (10 kg) _ according to instructions 1 or The SB-2〇7266-A system formed by 2 is equal to 80 〇 克 pure SB-207266 free 絵 and is all particles, which is 37.21% by weight of the granules. 2 Microcrystalline cellulose is graded Avicel PH102TM (commonly known as an average particle size of about 100 microns) and is 20.37% by weight of the total particles. The hydrogen phosphate 4 bow dihydrate grade is EmcompressTM, and within the entire particle, it is 41.89 wt% of the particles. 4 Temple powder sodium glycolate is Explotab TM, all outside the particles. The hard acid g acid town is divided into 50% particles (which is 37.21% by weight of the particles) and 50% outside the particles. 6 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Total granules (composition in granules) = 9450 g/10 kg tablets = 236 · 25 mg / 250 mg tablets = 94.5 wt% of the composition. Total granules (composition in granules) = 9450 g / 1 〇 kg of tablet = 236.25 mg / 250 mg of bonding agent = 94.5% by weight of the composition. Method: 1. Enter SB-207266 through a 1 mm stainless steel filter into the hopper mixer. Similarly, microcrystalline fiber I, hydrogen phosphate about dihydrate and _ half of magnesium stearate (50 grams) are fed into a mixture through a 630 micron stainless steel filter. 64- This paper scale applies to China National Standard (CNS). A4 size (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1294871 Λ7 ____B7 V. Invention Description (63) Mix the mixture in a smasher at 15 rpm (rpm = revolutions per minute) . 2. Pass the mixture from step 1 through a press equipped with interlocking anilox rolls (Philippines Ridger IR220). Referring to Figure 5, the special rolling press 2 comprises: a funnel 4 for receiving the intra-particle component 6 blended in the step 1, and a preliminary horizontal screw feeder 8 for metering from the funnel 4 into the pre-preparation The blending stage 6 and a main vertical screw feeder are directly downstream of the preliminary horizontal screw feeder 8 and are directly used by the feed, and the main vertical screw feeder 1 is used to pre-compress the blend. /Pre-compacting and degassing and feeding the feed directly downward into the biting corner zone (pressing zone) 14 of the roll 12. The rolls 12 are horizontal and substantially horizontal to each other. The compact (sheet or strip) 16 is released from under the roll 12. In this example, the peripheral speed of the compactor rolls is set at 3 rpm, the (primary) horizontal screw feeder speed is 3 rpm, the main vertical screw feeder speed is about 60-62 rpm or 7 rpm, and the rolling force (rolling pressure) is set to "仟 Newton / cm. The compacted material formed by the rolling press is a pulverizing mill with a front knife type (FitzMUlLlA', for example, as described in the previous description and as shown in Figure 6 The one shown in the half, which can be separated from or integrated with the press, is screened at a speed of 5000 _ and using a sieve of size 〇.〇93 inches (2.36 mm). The yield of the product is 9173.克_The particle mixture with a secret degree of 1〇6 = /ml was partially analyzed by particle size analysis using a sputum sieve.

-65- 1294781 A7 B7 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives V. INSTRUCTIONS (64) 3. Feed the pellet mixture from step 2 (9061 g) into a hopper mixer. A proportional amount of sodium starch glycolate (467 g) and magnesium stearate (46.7 g) were fed into a mixer (preferably through a 630 micron stainless steel filter into the mixer) and the mixture was mixed at 15 rpm. 5 minutes. 4. A portion of the compression mixture was compacted into a tablet with a single punch press (Manesty F3) having an elliptical positive concave punch of 10.5 mm X 5.0 mm. The standard unembedded tablet has a weight of 250 mg and a standard hardness of between 9 and 15 Kp. The tablets were subjected to hardness, thickness, weight change, disintegration and dissolution tests. The following data is used to record the intermediates used in the above process: The bulk density of the powder mix from step 1 before rolling is 0.36 g/ml. The tapped density of the mixture from step 1 before tapping is 0.68 g. /ml After rolling and grinding (step 2), the bulk density of the particle mixture is 0.69 g/ml. After rolling and grinding (step 2), the tapped density of the particle mixture is 1.06 g/ml. Screen analysis of the pressed and ground granule mixture (particle size analysis using a sieve) is as follows:

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Screen size (micron) Retained weight (g) Retained accumulated weight (% w/w) 1000 0.483 5.0 710 0.799 13.3 500 0.920 22.9 355 0.841 31.7 250 1.191 44.1 -66- This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1294781 V. Description of invention (65) A7 B7 ο This 1863 base 1.372 2.356 1.633 58.4 83.0 100.0 The following data is used to record the tablets manufactured in step 4: Average hardness (Kp) Average thickness ( Mm) Average weight (mg) Weight uniformity Disintegration time (minutes) 12.4 4.6 248.2 Compatible with Ph Eur 16 Dissolution time T75 (minutes) 17.9 Example 12-40-mg-dose lozenge, which does not contain adhesive , containing microcrystalline cellulose and calcium hydrogen phosphate in all particles, containing part-particle internal parts - extra-granular lubricant, and disintegrating agent containing all particles. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing composition Formulation unit (weight/ingot, mg) Batch amount (g) % by weight of unembedded tablet Remarks SB-207266 A (hydrogenate) 43.95 mg 1758 g 17.58 % 1 microcrystalline cellulose 62.50 mg 250 0 g 25.00 % 2 Argon calcium phosphate dihydrate 128.55 mg 5142 g 51.42 % 3 Sodium starch glycolate 12.50 mg 500 g 5.00 % 4 Magnesium stearate 2.50 mg 100 g 1.00 % 5 Total 250.0 mg 1 (10) (10) g (10 kg) 100 % 6 Remarks: -67- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

1294781 V. INSTRUCTIONS (66) The SB 2 〇 7266_A formed according to the description 1 or 2 is equal to 4 〇 ο pure SB-207266 free base, and is all particles, which is 18.60% by weight of the granules. 2. The grade of microcrystalline cellulose is Avicd ρη1〇2γμ (commonly known as an average particle size of about 100 μm), and in all particles, it is 26.46% by weight of the particles. The level of the phosphonium oxygen monohydrate is Emcompress® and is within the entire particle, which is 54·4ΐ weight/0 of the particle. 4 · Sodium starch glycolate is ExplotabTM, all outside the pellet. 5 Magnesium stearate is divided into 50% granules (the granules are granules · 53 weights and 50% granules. 6. Total granules (composition within granules) = 9450 g / 1 〇 kg tablets = 236.25 mg / 250 mg tablets = composition of the material is weight 〇 / 〇. Method: Ministry of Economic Affairs Intellectual Property Bureau staff consumption cooperative printing 1 · Microcrystalline cellulose through the 710 micron stainless steel filter into the hopper mixer. SB- 207266-A enters the mixer through a 1 mm non-pound steel screen. Half of the amount of magnesium stearate (50 g) and calcium hydrogen phosphate dihydrate (5142 g) are likewise filtered through 71 μm stainless steel. Sieve into the mixer and mix the mixture at 15 rpm for 10 minutes. 2· Pass the mixture from step 1 through a rolling press (Philippines Citson IR220) 'Equipped with interlocking reticulated rolls And the peripheral speed of the roller is set at 5 rpm, the (preliminary) horizontal screw feeder speed is set at 17 to 2 rpm, the speed of the (main) vertical screw feeder is set at 49 to 53 rpm and the rolling force is -68- Paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1294781 A7 B7 V. Description of invention ( The Ministry of Economic Affairs' Intellectual Property Office employee's fee cooperative printing (rolling pressure) is set at 24 to 25 仟 Newtons/cm. The compacted material formed by the rolling press is '5 _ _ and the filter is used. The pulverizing mill (5) with a size of 0.093 inch (2.36 mm) was crushed. The yield of the product was 9306 g of a granule mixture of 1 〇9 g/ml. 2 (9306 g) of the granule mixture was fed into a hopper mixer. Magnesium stearate (49.3 g) and sodium starch glycolate (493 g) were similarly passed through a 710 micron stainless steel filter screen into the mixer and The mixture was mixed for 5 minutes at 15 rpm. 4. A part of the compressed mixture was compacted into a tablet with a single punch press (Manesty F3) having an elliptical positive concave punching device of 1 mm·5 mm X 5 mm. The weight of the standard unembedded tablet is 250 mg and the hardness is between 9 and 15 Kp. The tablet is subjected to hardness, thickness, weight change, disintegration and dissolution test. The following data is recorded in the middle of the above method. Body·· The powder mixture from step 1 is loose before rolling Degree 47.47 g/ml The density of the mixture from step 1 before tapping by tapping 〇·88 g/ml After rolling and grinding (step 2), the bulk density of the mixture of particles is 0.73 g. /ml After squeezing and grinding (step 2), the tapped density of the granule mixture is 1·09 g/ml. The sieve analysis of the pulverized and ground granule mixture (step 2)

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• 69- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) A7 B7 1294781 V. The invention description (6〇 last) is as follows: Screen size (micron) Retained weight (克) retained accumulation weight (% w/w) 1000 0.578 5.8 710 0.935 15.1 500 1.146 26.5 355 0.971 36.1 250 1.223 48.3 180 1.248 60.7 63 2.475 85.4 Basic 1.467 100.0 The following data is recorded for the tablets manufactured in step 4: Average Hardness (Kp) 15.9 Average thickness (mm) 4.30 Average weight (mg) 244.5 Weight uniformity in accordance with Ph Eur Disintegration time (minutes) 7.5 Dissolution time T75 (minutes) 17.2 Example 13-40-mg-dose lozenge, It does not contain adhesives, including all microcrystalline cellulose and phosphorus strontium calcium in the granules printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs, and contains some of the internal components - internal lubricants and disintegration. Formulation unit (weight/ingot, mg) Batch amount (g) Unembedded tablet weight °/〇Remarks SB-207266 A (hydrogenate) 43.95 mg 1758 g 17.58 % 1 microcrystal 2500 g cellulose 62.50 mg 128.55 mg calcium hydrogen phosphate 25.00% 2 51.42% 3 5142 g paper scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) -70-

V. Description of the invention (69^ 1294781 monohydrate powder, sodium glycolate 12.50 mg 500 g 5.00 % 4 barium stearate 2.50 mg 100 g 1.00 % 5 -1 ^---^S ^2S〇T 10000 g - ( 10kg) ~100~" %- Remarks: • SB_207266-A formed according to Note 1 or 2 is equal to 40.0 mg pure SB-2〇7:266 free test, and all are in the particle. 2 ·Microcrystalline fiber The grade is Avicel PH102TM (commonly known as average particle size is about 100 microns), all in the particles. 3 · Calcium hydrogen phosphate dihydrate grade is Emcompress TM, all in the particles. 4. Starch glycolate is Explotab TM, divided into 50% granules and 50% granules. 5 · Magnesium stearate is divided into 50% granules and 50% granules. Method: Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1. Microcrystalline cellulose passed through 710 micron stainless steel Filter the sieve into the hopper mixer. Pass SB-207266-A through a 1 mm stainless steel filter into the mixer. Sodium starch glycolate (250 g), half the amount of magnesium stearate (50 g) And the hydrogen-filled dance dihydrate (5142 g) is the same through 710 microns without money The sieve was passed into the mixer and the mixture was mixed at 15 rpm for 1 minute. 2. The mixture obtained from the step 辗 was passed through a rolling press (Philippines Cincinnati IR220) 'It was equipped with an interlocking net The roll and the peripheral speed of the roll are set at 5 -71-. The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). 1294781 at B7 5. Inventive Note (7〇) rpm, (Preliminary) Horizontal Spiral Feed The machine speed is set at 20 rpm, the speed of the (main) vertical screw feeder is set at 49 to 53 rpm, and the rolling force (rolling pressure) is set at 24 to 26 Newtons/cm. The pressure formed by the rolling machine The physical tool was sifted at a speed of 5000 rpm and sieved using a pulverizing mill (FitzMill L1A) with a sieve size of 0.093 inches (2. 36 mm). The yield of the product was 9528 g. A mixture of particles of ι·〇6 g/ml.

3. Feed the pellet mixture from step 2 (9528 grams) into the hopper mixer. The stearic acid town (49. 2 g) and the proportion of the remaining powder of sodium glycolate (245 g) were passed through a 710 micron stainless steel sieve and the mixture was mixed at 15 rpni for 5 minutes. 11 4. A part of the compression mixture was compacted into a tablet with a single punch press (Manesty F3) having an elliptical positive concave punching device of 10·5 mm χ 5 mm. The standard unembedded tablet has a weight of 250 mg and a hardness of 9

Up to 15 Kp range. The tablets were subjected to hardness, thickness, weight change, disintegration and dissolution tests. The following data are used to record the intermediates used in the above process: Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed the bulk density of the powder mix from step 1 before rolling. 49 g/ml of the mixture from step 1. The density of the tap before the rolling is 8181 g/ml. After rolling and grinding (step 2), the bulk density of the mixture of particles is 0.70 g/ml, which is pressed and ground (step 2) Post-particle mixture patted secret•72- This paper size applies to China National Standard (CNS) A4 specification (210x297 public) 1294781 A7 B7 V. Invention description (7i) Degree 1.08 g/ml Pressed and ground The sieve analysis of the crushed particle mixture (as in the last step 2) is as follows: • Screen size retained weight retained accumulation weight (μm) (g) (%w/w) 1000 0.245 2.3 710 0.373 5.8 500 0.645 11.8 355 0.636 17.8 250 1.574 32.5 180 2.168 52.7 63 3.091 81.6 Basic 1.964 100.0 The following data is used to record the average hardness (Kp) of the tablet made in step 4. Average thickness (mm) Average weight (mg) Weight uniformity Disintegration time (minutes) Solubility time Τ75 (minutes) 14.7 17.7 4.32 247.0 Complies with PhEur 14.2 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Example 14 -80-mg-dosage tablet, which contains no binder and contains some extragranular microcrystalline fibers Prime component formula unit batch quantity unembedded ingot remark (weight/ingot, (g) weight % mg) SB-207266 A (hydrogenate) 87.90 mg 3516 g 29.30 % 1 -73- paper scale Applicable to China National Standard (CNS) A4 specification (210x297 mm) 294781

V. Description of the invention (microcrystalline cellulose 48.12 mg (intragranular) calcium hydrogenate 98.98 mg dihydrate starch sodium glycolate 15.00 mg magnesium stearate microcrystalline cellulose (granules) 3.00 mg 47.00 mg 300.0 g : 1925 g 3959 g 600 g 120 g 1880 g 12000 g (12 kg) 16.04 % 32.99 % 5.00 % 1.00 % 15.67 % "Ϊ00~~% 2 3 4 5 6 2. 3. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumption Cooperative SB-207266-A formed according to Note 1 or 2 is equal to ^, found in "80·〇mg pure SB-207266 free base, and is in all particles. Microcrystalline cellulose grade is Avicel PH102TM (Generally known as Pingyu sentence size is about 100 microns) 'and this is the part inside the granule. The grade of citrate oxygen #5 dihydrate is Emcompress TM, into the Ministry of filial piety. / 4 · Temple powder glycolate For Explotab TM, all particles are out. 5. Magnesium stearate is divided into 50% particles and 50% particles. 6. Microcrystalline cellulose grade is Avicei PH102tm (commonly known as average particle size is about 100 microns), and this system It is extragranular. Method: This method is generally the same or class In Example 11, except that additional microcrystalline cellulose (MCC) was added extragranularly to increase the compressibility of the tablet compression mixture (within about 50% 〇MCC particles, about 50% of the MCC particles). 1,3 and 4 are improved, and the preparation method is as follows: 1. SB-207266-A (3516 g) is passed through a 1 mm stainless steel sieve -74- This paper scale is applicable to China National Standard (CNS) A4 specification. (210x297 public Chu) A7 B7 1294781 V. Description of invention (73) Enter the hopper mixer. The microcrystalline cellulose in the granules is 925 g), calcium hydrogen phosphate dihydrate (3959 g) and half The amount of magnesium stearate (6 gram) was similarly passed through a 630 micron or 710 micron stainless steel filter screen into the mixer and the mixture was mixed at 15 rpm for 1 minute. 2. As in step 11 of Example 11 3. Feed most or all of the granule mixture from step 2 into the hopper mixer. A proportional amount of sodium starch glycolate (6 gram, if the yield in step 2 is 1 〇〇〇 / 0 and if all the granule mixture is used " magnesium stearate (60 g, if the yield is wo) % and if all of the particle mixture is used) and the outer portion of the microcrystalline cellulose (188 g, if the yield is 1% and if all of the particle mixture is used) through 63 〇 micron or 710 micron stainless steel The sieve is passed into the mixer and the mixture is mixed for 15 minutes at 15 Torr (7). 4. A part of the compression mixture is applied to a single punch press with an elliptical positive concave punch (for example, Manesty F3). The tablet is compacted into a tablet. The weight of the standard unembedded tablet is 300 mg. Example 15 - Film Encapsulation of Examples 11 to 14 The Intellectual Property Office of the Intellectual Property Bureau is printed in a variation of any of Examples 11 to 14, The tablet may be provided with a film-embedded, for example, Opa dry white YS-1-7033 embedded, preferably about 6 mg/ingot. In such a method of embedding, the ingot core is transferred to a suitable house. On the embedding machine, rotate the core and spray the aqueous dispersion of opal The test samples were randomly selected from the batch and appropriately labeled. Example 16—Examples 11 to 15 SB_2〇7266 Dose change-75- This paper scale is suitable for financial specifications (2) Gx297 publicity)------ 1294781 A7 B7 V. INSTRUCTIONS (74) In the variation of any of Examples 11 to 15, each ingot contains 1 mg, 20 mg '25 mg, 30 mg, 40 mg, 50 mg, 75 mg, 80 mg or 120 Formulations of milligrams SB_207266 (present in the form of hydrochloride, but described herein as free base) can be used to make tablets. This is in place of SB-207266 (calculated as free base) in Example 1M5 for a dose of 40 mg or 80 mg per suspect. Since the amount of SB 207266-A (chlorate) will change, the formula can be changed by one of three alternatives A, B or C: (A) due to the change in the amount of SB 207266-A, to make it unembedded The total amount remains the same 'for example, the pre-embedded tablet weight is 250 mg or 300 mg, and the amount of strontium sulphate calcium dihydrate used can be varied accordingly. Therefore, for example, if the dose is increased, CaHP (the amount of V2H20 reduction is roughly the same as the amount of SB207266-A increase).

Printed by the Department of Intellectual Property of the Ministry of Finance and Intellectual Property Office (B) As the amount of SB 207266-A changes, the amount of calcium hydrogen phosphate dihydrate and microcrystalline cellulose (the internal fraction of the particles) is changed. Thus, the ratio of the calcium hydrogen phosphate dihydrate in the particles to the microcrystalline cellulose in the particles is kept approximately at about 2:1 (for example from 2.2:1 to 1.8:1, for example from 2.1:1 to 2.0: 1, for example 2·07 · 1 to 2·04 : 1). The total amount of unembedded, for example, pre-embedded bond weight: S: 250 mg or 300 mg remains unchanged. Therefore, if the amount of SB 207266-Α increases, the amount of [CaHp〇4.2H2〇 and MCC] in the particles decreases at an approximately constant ratio. (C) Due to the change in the amount of SB 207266-A, the total amount of unembedded, for example, the line

V. 1294781 at B7 Description of Invention (75) The weight of the pre-embedded tablet is 250 mg or 300 mg which is increased or decreased by the same amount of increase or decrease in SB 207266-A. All excipients remained unchanged. In all three substitutions, these formulations remained unchanged: the amount of other excipients in the compositions of Examples 11-15, and the method of making all the changes required, for example, the amount produced. For example, the 80-mg-dosage tablet of Example 11 was modified to a 50-mg-dosage tablet (calculated as the free base) according to the previous selection (B), and the resulting tablet was shown in the table below (Example 16 (B)-50): Example 16(B)-50 Composition-50-mg-dosage tablet (calculated as free base) Component weight/tablet mg Batch amount (g) Unembedded tablet Weight ° / 〇 Remarks SB-207266 A 54.93 mg 2197 g 21.97 % 1 microcrystalline cellulose 59.12 mg 2365 g 23.65 % 2 calcium hydrogen phosphate dihydrate 120.95 mg 4838 g 48.38 % 3 sodium starch glycolate 12.50 mg 500 g 5.00 % 4 Magnesium stearate 2.50 mg 100 g 1.00 % 5 Total 250.0 gram 1 (10) (10) gram 100 % 6 Remarks: As in Example 11, except: 1 · SB-207266-A formed according to Note 1 or 2 is equal to milligrams of pure SB -207266 free base, in all granules, granules: % by weight. -77- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

.丨丨丨丨

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative 1294781 A7 B7 Inventive Note (76) 'The grade of microcrystalline cellulose is Avicel PH102TM (commonly known as average particle size is about 100 microns), and the total particle size is 25.03% by weight of the particles. 3 · The grade of the hydroquinone dihydrate is EmcompressTM and is 51.20% by weight of the total particles. Example I7 - Scheme for the Treatment or Prevention of Atrial Fibrillation and/or Atrial Restruction in Humans Using SB 207266 Orally Administered Now, a pharmaceutical composition for oral administration using SB 207266 or a salt thereof is described in detail for treatment Or a proposed clinical regimen for preventing atrial fibrillation and/or atrial reorganization, which may be an oral composition of the invention. In this protocol, SB 207266 or salt (hereinafter referred to as "SB 207266") is administered to patients suffering from refractory atrial fibrillation (AF). The goal is to inhibit recurrence of atrial fibrillation in these refractory AF patients. It is suitable for patients with persistent refractory AF, 248 hours of disease and <6 months requiring cardioversion (eg DC heart rhythm conversion). The symptoms of refractory AF may, for example, include heart palpitations and the like. The patient should be one of the following: · Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative* * Treated anticoagulation (for example, warfarin or coumarin) for 23 weeks before starting treatment. Preferably, the anticoagulant reaches at least 2 international normal ratio (INR), or * no therapeutic anticoagulant for more than 3 weeks, and the blood clots through the esophagus are diagnosed by ultrasonic echocardiography (TEE). Negative and already received intravenous heparin until aPTT is stable and in the therapeutic range. Patients should receive SB 207266 after such therapeutic anticoagulation or after TEE, except -78- This paper scale applies to Chinese National Standard (CNS) A4 specification (2〗 297 297 mm) A7 B7 1294781 Description (" In addition to intravenous heparin. SB 207266 (for example, as a free base, but more preferably as SB 2 〇 7266-A hydrochloride) is generally 20 mg, 50 mg or 8 〇 uid per ( ( - once daily) (calculated as free base) for oral dosing. However, on the first day of administration of SB 207266, it is generally assigned to one-fifth (I·5 X) or 2 of 2 doses of maintenance therapy for one day. A single oral dose of doubling (2 X). Therefore, for a 1.5 X loading dose, it is preferred to give a single dose of 30 mg, 75 mg or 12 mg (calculated as free base) on the first day. Oral loading dose, followed by 20 mg, 50 mg or 8 mg of each dose for subsequent days (calculated as free base). Or, for 2 χ load dose, 4 〇 mg on the first day, just A single oral loading dose of milligrams or just milligrams (calculated as free base) followed by 2 mg, 5 The daily dose of milligrams or 80 milligrams is administered on the following days (calculated as the free base). When using a 1.5 liter load, these three given 1 〇, 25 or 40 mg tablets can be used on the first day. At the same time, the dosage can be administered at the same time for the given 10, 25 or 40 mg tablets; the 10, 25 and 4 mg tablets used should be the above examples to 16 - as described in the example. For those who use 2 χ load, they can take two given 2G, 5G or 8G mg tablets at the same time on the first day; the daily maintenance dose can give - 20 5 〇 4 8 〇 键 键 键 ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; L5 x or 2 口服 Oral load dose-79- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

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Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed A7 B7 1294781 V. INSTRUCTIONS (78) After about 2 or about 5 hours, the patient continues to have atrial fibrillation (and/or is not pharmacologically transferred) and then Direct (DC) current rhythm transfer. Any of the following single or dual-phase rhythm transfer algorithms can be followed. Shock sequence single phase duplex (option 1) dual phase (option 2) first shock 200 joules 170 joules 120 joules second shock 250 joules 200 joules 150 joules third shock 300 joules 230 joules 170 joules 170 joules using the above sequence After a third shock, if the patient cannot return to normal sinus rhythm (NSR), the doctor can continue to try further with different energies at his discretion. Maintaining NSR 2 1 hour after the heart rhythm is reversed is defined as a successful heart rhythm reversion. Once the DC heart rhythm is transferred to NSR, SB 207266 can be administered to the patient for up to 6 months (for example), or a little shorter or longer. Patients who spontaneously return to normal sinus rhythm (NSR) may also receive SB 207266 once daily for (for example) 6 months. Patients who have undergone AF recurrence can return DC rhythm to sinus rhythm during each treatment and continue to receive SB 207266. With a successful heart rhythm, patients should preferably continue anticoagulant therapy (eg, wolfin or coumarin) for at least the first four weeks, and better to administer SB 207266 during the full sputum. Preferably, it is equal to some or all of the period, for example, most or all of the periods are anticoagulant therapy, and the patient's anticoagulation reaches an international normal ratio (INR) of at least 2. This reduces the risk of blood clotting and/or stroke in the heart in the case of AF recurrence. -80-

1294781 Λ7 B7 V. INSTRUCTIONS (79) Therefore the best solution is as follows: Symptoms of persistent disease AF, whose duration &gt; 48 hours with &lt;6 months, plus: [Therapeutic anticoagulation 2 3 weeks] or [TEE (-ve) in blood clot + IV heparin]

Inject SB 207266 (loading dose) and observe for 2 or 5 hours 丄 DC rhythm reversion (if needed) 丄 if continue to take SB207266 daily + preferably anticoagulant therapy, for example, up to 6 months

The "unstable condition" of AF includes or refers to seizures or other symptoms typical of the disease. This may further establish an ECG (e.g., 12-lead ECG) record showing evidence of atrial fibrillation or a rhythm bar recorded on the event recording device and reviewed by the physician. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm).

Claims (1)

Nian Zhouyue (more) Original Application Patent Fan YuanΑ8 Β8 Patent Application No. 92122183· t ^ r〇ROC Patent Appln. No. 92122183 Corrected unlined patent application text - Attachment (2) -0 ΑΐϋΠ1ίΐ £ί}_〇5ΐΡ15^ίΐ!_Οΐίΐ1£^£_^_ΕΐΙίΐΙ·0Τ, (presented on November 16, 1996) (Submitted on November 16, 2007) 2. 3· 4· 5. Ministry of Economic Affairs Intellectual Property Bureau A method for printing a garment composition for a pharmaceutical composition by an employee consumption cooperative, which comprises N_[(i_n-butyl-4", hydropyridyl)methyl]_3,4_dihydro-2H-[1,3] Sashimi and [3,2-a] 吲哚-10-carboxyguanamine (SB 207266) or a pharmaceutically acceptable salt thereof or a plurality of pharmaceutically acceptable excipients, the process comprising Or all of SB 207266 or a salt thereof is formed into a granule by a dry granulation method, and wherein SB 2 〇 7266 or a salt thereof is present in the composition at least 4% by weight of the composition. The method of preparing the dry granulation method comprises compressing and/or compacting the SB 207266 or a salt thereof. Wherein, the particle size of the SB 207266 or a salt thereof is compressed by the particles of the drug and the particles formed in the particle to form a larger particle, as in the method of claim 1, wherein the dryness is The granulation method comprises the pressing action of the SB 207266 or a salt thereof, as in the method of claim 4, wherein the drum (roller) has a textured outer appearance, for example, an interlocking netting light. The method of claim 4, wherein, in the case of rolling, the pre-granulated powder to be compacted is fed into the drum by a rotatable main screw feeder adjoining and directed to the drum. The method of claim 6, wherein the rollers are substantially horizontal and substantially parallel to each other and one of the vertical main screw feeders is located above and points to the roller used. -82 - The paper size is applicable to the Chinese country Standard (CNS) A4 specification (21〇χ297 mm) 92390B-connection 1 • The method of claim 6 wherein the speed of the main screw feeder is 30 to 100 revolutions per minute (rpm). 9. The method of claim 6, wherein the primary-feeder is used to meter the product (pre-granulated mixture containing the SB 207266 or its salt) from the inlet hopper to the hopper Pre-compression (pre-compacting the mask) and its _, the main screw feeder is compliant with the preliminary screw feeder. 1〇. The method of claim 9 of the patent scope, wherein the preliminary spiral, the seven-hopper machine The speed is from 1 〇 rpm to 4 rpm. U.=The method of claim 9 of the patent scope, wherein the ratio of the speed of the preliminary screw feeder to the speed of the main screw feeder is 1: 5 to 1: ι · 5. 12. The method of claim 4, wherein the drum pressure is from 2,000 to 16,500 pounds per ton (ie, from 3.51 to 28.93 仟 Newtons per centimeter). 13mt full-time circumference 12th method, the towel, the drum speed is 1.5 rpm to 1 rpm. 14 · The method of claim 9 of the patent scope, wherein when the sb_ 207266 or its salt is at least 22% of the particles When present in the granules (ie during dry granulation), then: - the initial snail The speed of the rotary feeder is at least 25 rpm; and - the speed of the main screw feeder is at least 56 rpm; and - the same speed is from about 1.25 rpm to 4 rpm. -83 - 1294781 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, Printed Clothes 5. The method of claim 4, wherein the strip density (the pressure mixture released by the drum) is from about 1.0 to about 5^/cm3 (g/ml). 16. The method of claim 4, wherein the compact (layer, strip) released by the drum is ground to a particle size suitable for use in the capsule. Λ 17. The method of claim 9, wherein the compact (layer, strip) released from the drum (pro) is ground to a particle size suitable for the tablet or capsule. Μ 18. The method of claim 11, wherein the compact (layer, strip) released from the drum (roller) is ground to a particle size suitable for the tablet or capsule. 19. The method of claim 14, wherein the compact (layer, strip) released from the drum (roller) is ground to a particle size suitable for use in a tablet or capsule. 2. The method of claim 1, wherein the particles formed by the dry granulation method are ground to a particle size suitable for use in a tablet or capsule. 21. The method of claim 16, wherein the grinding is performed using a pulverizing mill having a hammer and/or a knife. 22. The method of claim 21, wherein the grinder is a pulverizing grinder having a forward knife. For example, the method of claim 17 of the patent scope, wherein the grinding is used This paper scale is suitable for the _ family standard (CNS) A4 specifications (2lG χ 297 public 1294781 Α8 Β8 C8 Six Patent application scope D8 A pulverizing mill with a hammer and/or a knife. For example, in the method of claim 16, wherein the particles are ground such that they can pass through a sieve having a pore size of from 〇11〇英吋(2·8〇mm) to 0.032 inches (0·81mm). Or sieve. 25. The method of claim 21, wherein the granules are ground such that they pass through a sieve having a pore size of 〇·11〇英吋(2.80 mm) to 032·032 inches (〇·81 mm). Or sieve. 26. The method of claim 16, wherein the dry granulated and ground granules have a tap density of 〇·8 to g/ml. For example, please refer to the method of 24 (4) and (4), in which the density of the dry granulated and ground granules is 〇·8 to 1.2 g/m. 4 The Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives print clothes The method of claim 3, wherein the dry granulation method comprises pressing SB2〇7266 or a salt thereof by a roller. 29·If you apply the patent scope of item 16 of the radish, the book, after the grinding to the appropriate size, the _) is mixed with the _:=:=17 method, where — after, _- or (9) Compressed into tablets or: excipients This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm). VI. Patent application scope. 31. If the patent application scope is the second method, after granulation and grinding into appropriate size, it is formed. More than one, on the _ (particle:::: two or GO pressure, 纟fg into a tablet or filled into a capsule. ❿口 and 32. If the patent system of the scope of the 21st method, the dragon r and grind into the appropriate After the size, the ::) = two pharmaceutically acceptable excipients (extragranular excipients) are mixed: = ((4) compressed into tablets or filled into capsules. 33. After the granules are ground and sized into appropriate sizes, the granules are mixed with the excipients (granular excipients) which are received and formed into a tablet or filled into a capsule. 34. = Patent Application No. 1 to The method of any of η, which comprises mixing some or all of SB 7266 or a salt thereof with one or more pharmaceutically acceptable excipients (intragranular excipients) prior to dry granulation. = the method of claim 34, wherein the one or one granule excipient includes a moist The method of claim 35, wherein the lubricant is present in an amount of from about 2 to about 5% by weight of the granules. 37. ^ The method of claim 34, wherein The one or more intragranular excipients comprise a filler (diluent), ie the particles comprising 7266 or a salt thereof also contain a filler (diluent). -86 - : 297781 A8 B8 C8 D8 VI. 3 &amp; The method of claim 37, wherein the filler comprises one or more calcium phosphate, calcium dibasic phosphate (calcium hydrogen phosphate), calcium carbonate, magnesium carbonate, magnesium phosphate, and calcium lactate. For example, the method of claim 37, wherein the filler comprises dibasic calcium phosphate (ie, dicalcium phosphate, calcium hydrogen phosphate, CaHP04) and/or filled with acid (ie, trivalent acid #5, Ca3 (P) 〇4) 2) 40. The method of claim 37, wherein the filling comprises dibasic calcium phosphate (ie, dicalcium phosphate, calcium hydrogen phosphate, CaHP04). The preparation method of item 37, wherein the filler is dibasic calcium phosphate (that is, phosphorus 42. The method of claim 40, wherein the calcium strontium phosphate is calcium hydrogen phosphate dihydrate (CaHP04*2H20). 43. The method of the invention, wherein the filler is a coarse-grade filler having an average or medium particle size of 53-300 micrometers. The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, prints 44. Wherein the CaHP04 and/or Ca3(P04)2 filler is a coarse filler having an average or medium particle size of 53-300 microns. 45. The method of claim 40, wherein the calcium hydrogen phosphate filler is a coarse filler having an average or medium particle size of 53-300 microns. -87 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) The method of claim 37, wherein the filler comprises from 1 to 90% by weight of the granules. 47. The method of claim 38, wherein the filler comprises from 10 to 90% by weight of the granule. 48. The method of claim 39, wherein the filler comprises from 10 to 90% by weight of the granule. 49. The method of claim 44, wherein the filler comprises from 10 to 90% by weight of the granule. 50. The method of claim 37, wherein the filler is present in an amount of from 15 to 85% by weight of the composition and/or by weight of the granule. 51. The method of claim 39, wherein the filler is present at 15 to 85% by weight of the composition and/or by weight of the granule. 52. The method of claim 37, wherein the ratio of the filler to the SB-207266 or its salt in the granule is at least 1: 3 ° Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printed clothing, etc. The method of claim 39, wherein the filler has a ratio of the SB-207266 or a salt thereof to the granules of at least 1:3. The method of any one of claims 1 to 33, wherein the granule comprises SB 207266 or a salt thereof and a filler (diluent), wherein the filler comprises calcium dibasic phosphate (ie, phosphoric acid) Calcium, calcium hydrogen phosphate, CaHP04) and/or calcium phosphate (ie, trivalent calcium phosphate, Ca3(P04)2), and wherein the filler includes particles from 1〇 to -8 8 - the paper scale applies to Chinese national standards ( CNS) A4 specification (210 X 297 mm) 1294781 Peripheral, the patent application model 9 〇% by weight 'and the ratio of the filler to the sb_2Q7266 or its salt in the granule is at least i · 3, and wherein the 266 Or a salt thereof is present in the granules in at least 4% by weight of the granules. 55. The method of claim 34, wherein the one or more intragranular excipients comprise a dusting aid. Wherein, the compression aid 56. The preparation agent as claimed in claim 55 includes or is microcrystalline cellulose. Wherein, the microcrystalline fiber 57 is produced according to the method of claim 56, and the halogen has a general particle size of 25 to 150 micrometers. 58. The method of claim 38, wherein the one or more particles The internal excipient includes a microcrystalline cellulose as a compression aid. The method of claim 54, wherein the one or more intragranular excipients comprise a microcrystalline cellulose as a compression aid. 6〇·If the patent system of claim 56 is applied, the compression aid The agent is present in an amount of 1 〇 5 % by weight based on the weight of the composition and/or the weight of the granules. 61. The method of claim 34, wherein the composition does not include a binder. &amp; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; . 63. The method of claim 54, wherein the granule (i.e., the compositional damage within the granule) is from 0.01% to 99% by weight of the composition. 89 - The paper size applies to the Chinese National Standard (CNS) A4 specification (21〇X 297 mm) [294781 A8 B8 C8 D8 Patent application scope 64. If the patent application is in any one of the methods 1 to 33, 90% or more of SB 207266 or a salt thereof is present in the granule which can be obtained or prepared (formed) by dry granulation. 65. The method of claim 54, wherein 90% or more of SB 207266 or a salt thereof is present in a granule which can be obtained or prepared (formed) by a dry granulation method. The method of any one of claims 1 to 33, wherein 5% of the particles or 50% by volume or more of the particles include SB 207266 having a particle size of 75 μm or a salt thereof. 67. The method of claim 66, wherein 50% or more of the particles by weight or volume comprises SB 207266 having a particle size of -100 micrometers or a salt thereof. 68. The method of claim 66, wherein 50% or more of the particles by weight or volume comprises SB 207266 or a salt thereof having a particle size of 75 to 1000 microns. The method of any one of the preceding claims, wherein the granules of 90% or more by weight or volume include the Ministry of Economic Affairs, the Intellectual Property Office, and the consumer cooperative printing garment having 10 to 1000 micrometers. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; -3,4-dimur _ 2Η·[1,3] 畤耕和[3,2-a]吲哚-10-carboxyguanamine (SB 207266) or a pharmaceutically acceptable salt thereof is hydrogen of SB 207266 Chlorate. -90 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) [294781 A8 B8 C8 D8 VI. Patent application scope 71. If the patent application scope 54 is adopted, the N-[(l -n-butyl-4-hexahydropyridyl)indolyl]-3,4-dihydro-2H-[1,3]_indano[3,2-a]indole-10-carboxamide SB 207266) or a pharmaceutically acceptable salt thereof is the hydrochloride salt of SB 207266. 72. The method of any one of claims 1 to 33, wherein the N-[(l-n-butyl-4-hexanitrogen)-methyl group-3,4-di Nitrogen _ 2H-[1,3] argon and [3,2-a] fluorene-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof, including the needle form of SB 207266 hydrochloride A crystalline form and/or a substantially anhydrous crystalline form. 73. The method of any one of claims 1 to 33, wherein the N-[(l-n-butyl-4-hexamethylpyridin*11-decyl)methyl]-3,4-di mouse -2H-[1,3] crystallization of the hydrochloride salt of SB 207266 which is included in [3,2-a]吲哚-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof The type is characterized by infrared (IR) spectroscopy (medical lubricant wheel milling) with three, four, five or more of the following peaks: 1628, 1582, 1502, 1531, 1184, 748 cm -1 (allowable to contain 2 cm _1 peak deviation). Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives, Printing and Clothing Co., Ltd. 74. For the preparation of Patent No. 54, the N-[(l-n-butyl-4-hexahydropyridinyl)methyl]-3,4- Dihydro-2H-[1,3]-oxime. The crystalline form of chlorinated salt of SB 207266, which is included in the well [3,2-a]吲哚-10-carboximine (SB 207266) or a pharmaceutically acceptable salt thereof, is characterized by having three or four Five or more infrared (IR) spectra of the following peaks (medical lubricants): 1628,1582, -91 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1294781 VI. Patent application Range A8 B8 C8 D8 1502, 1531, 1184, 748 Eight-eight-I, 48 A-knife (allows a peak deviation of about 2 cm for soil). % 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 I. For example, SB 207266 or its salt system is present in the composition at least 6 weight percent of the weight of the composition. R, as in the method of the ninth aspect of the patent, wherein the SB 207266 or its salt is present in the composition and/or the granules at a weight of the composition and up to 60% by weight of the domain granules, respectively. . 78. The method of claim 1, wherein the pharmaceutical composition is orally administrable to a human. 79. The method of any one of clauses i to 33, wherein the composition of Hexi is a lozenge, or the pharmaceutical composition can be contained in a capsule. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed 80. A pharmaceutical composition, including N_[(1_n-butyl_heart hexahydropyridyl)methyl]-3,4-dihydro--] Ploughing [3 2_a] 吲 〇 〇 〇 SB ( ( SB ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The salt system appears in the particles prepared by a dry granulation method, and wherein SB207266 or its salt is composed of -92 1294781 A8 B8 * C8 D8_ 6. At least 4% by weight of the claimed patent is present in the composition, wherein the granule comprises SB 207266 or a salt thereof also comprising a filler (diluent), wherein the filler comprises a divalent Calcium phosphate (ie, dicalcium phosphate, calcium hydrogen phosphate, CaHP04) and/or calcium phosphate (ie, trivalent calcium phosphate, Ca3(P04)2), wherein the filler is an average or medium particle size of 53-300 microns. a coarse filler, and wherein the filler comprises 10 to 90% by weight of the particles, and the ratio of the filler to the SB-207266 or a salt thereof in the particles is at least 1:3, and wherein the SB 207266 or The salt is present in the granules in at least 4% by weight of the granules. 81. The pharmaceutical composition of claim 80, wherein the dry granulation method comprises pressing SB 207266 or a salt thereof by a roller. 82. The pharmaceutical composition of claim 81, wherein in the manufacturing method, the compact (layer, strip) released from the roller (roller) is ground to be suitable for tablets or capsules. Particle size. Printing by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives 83. The pharmaceutical composition of claim 82, wherein the pharmaceutical composition is a key agent, or the pharmaceutical composition is or is contained in a capsule. 84. The pharmaceutical composition according to claim 80, wherein the particles having a weight or volume of 50% or more comprise SB 207266 having a particle size of -75 μm or a salt thereof. -93 - This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) [294781 A8 B8 C8 D8 VI. Patent application scope 85. If the pharmaceutical composition of Article 80 of the patent application scope, the N-[ (1-n-butyl-4-hexahydropyridinyl)methyl]·3,4-diindole-2H-[1,3]- and argon [3,2-a]indole-10-carboxylate Indoleamine (SB 207266) or a pharmaceutically acceptable salt thereof is the hydrochloride salt of SB 207266. 86. The pharmaceutical composition of claim 82, wherein the N-[(1-n-butyl-4-hexahydropyridinyl)methyl]-3,4-dihydro-2H-[1,3 ]_畤耕和[3,2-a]吲哚-10-Carboguanamine (SB 207266) or a pharmaceutically acceptable salt thereof is the hydrochloride salt of SB 207266. 87. The pharmaceutical composition of claim 85, wherein the N-[(1-n-butyl-4-hexahydropyridinyl)methyl]-3,4-dihydro-2H-[1,3 ]- slogan [3,2-a]吲哚-10-carboxamide (SB 207266) or a pharmaceutically acceptable salt thereof includes the needle crystal form of the hydrochloride salt of SB 207266. 88. The pharmaceutical composition of claim 87, wherein the chlorate of SB 207266 has an infrared (IR) spectrum of three, four, five or more of the following peaks (medical lubricating oil wheel): 1628 , 1582, 1502, 1531, 1184, 748 cm _1 (allows a peak deviation of approximately 2 cm 4 for soil). 89. The pharmaceutical composition of claim 80, wherein the SB 207266 or a salt thereof is present in the granule at least 6% by weight of the granule. 90. The pharmaceutical composition of claim 80, wherein The composition contains lubricants that are present in both the particles and the particles, and -94 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 4 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing and Garment 1294781 VI. Patent Application Scope The lubricant is present in the composition of 2 to 5% by weight. The pharmaceutical composition of claim 8 wherein the composition comprises an excipient as a shrinking aid, wherein the compressing aid is microcrystalline cellulose, wherein the compressing aid is at least the weight of the composition % is present, and the compression of the towel is in the interior of the particle (ie, within the particle). 92·=Applicable to the pharmaceutical composition in Article 8 of the scope of patent application, wherein the definition of the i system is as defined in Items 2 to 33 of the scope of application. 0 η Printed by the Ministry of Economic Affairs, Intellectual Property Officer, Consumer Cooperative This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1294781 一二图, --- (2), a simple description of the symbol of the representative figure of this representative figure. If there is a chemical formula in this case!讲面纤__:▼ __围|^,1__ 图·Chemical formula. ‘V〉, 擎... None Page 2-2