TW201249480A - Pharmaceutical compositions - Google Patents

Abstract

The present invention relates to pharmaceutical compositions comprising fixed dose combinations of a DPP-4 inhibitor drug and/or a SGLT-2 inhibitor drug, and metformin XR, processes for the preparation thereof, and their use to treat certain diseases.

Description

201249480 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a medicament comprising a DPP-4 inhibitor (especially 1-[(4-methyl-quinazolin-2-yl)methyl]-3- Methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, also known as linagliptin And/or SGLT·2 inhibitor drugs (especially 1-gas-4-(pD-glucopyran-1-yl)-2-[4-((S)_tetrahydrofuran-3-yloxy)·benzene a pharmaceutical composition of a fixed dose combination (FDC) of metformin (especially referred to as compound "A") and a sustained release form (diterpenoid XR) of metformin (especially metformin hydrochloride); a method of preparing the same And its use in the treatment of certain diseases. SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition having a fixed-dose combination of diterpene hydrochloride in a sustained release form, which is optionally applied in a sustained release form, further by the form of immediate release.曱 曱 _ quinazoline-2-yl) methyl]·3-mercapto-7·(2-butyn-1-yl)-8-(3-(R)-amino-piperidine_ι ·Base)_xanthine (lilastatin) and/or 1-gas-4-(β-ϋ-glucopyranose-丨-yl)_2_[4-((S)_tetrahydrofuranyloxy)- Benzoyl]-benzene (compound "A") is coated. Furthermore, the invention relates to a pharmaceutical composition, in particular a solid preparation (for example an oral solid dosage form, such as a lozenge), which comprises or consists essentially of: a formamidine (especially diterpenoid hydrochloride) and one or more An internal sustained release core of the excipient; b) an optional intermediate seal coat; and Ο including at least _, heat, one selected from the group consisting of DPp-4 inhibitors (preferably linagliptin) and 162339.doc 201249480 SGLT An active immediate release coating of the active pharmaceutical ingredient of the -2 inhibitor drug (preferably compound ra) and one or more excipients. In a more detailed aspect, the invention relates to a pharmaceutical composition, in particular a selected dipeptidyl peptidase 4 (DPP-4) inhibitor (preferably linali > Forms and solid preparations of metformin (especially metformin hydrochloride) (monoformin XR) in a sustained release form (for example, an oral solid dosage form such as a lozenge). In one embodiment of this aspect, the present invention is directed to a pharmaceutical composition 'particularly a solid preparation (e.g., an oral solid dosage form, such as a key), which comprises, if desired, a sustained release form of metformin hydrochloride in a sustained release form. And a fixed dose combination further coated with linagliptin in an immediate release form. In another more detailed aspect, the invention relates to a pharmaceutical composition 'particularly selected SGLT-2 inhibitors (preferably Chloro-'(3)-!)-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxybenzyl iphenyl, especially in immediate release form) A solid preparation of metformin (especially metformin hydrochloride) in a sustained release form (diterpenoid XR) (for example, an oral solid dosage form such as a tablet). In one embodiment of this aspect, the present invention is directed to a pharmaceutical composition 'particularly a solid formulation (eg, an oral solid dosage form, such as a lozenge) comprising metformin hydrochloride in a sustained release form, optionally applied in a sustained release form. And further by the immediate release form of 1_gas-heart (3)-!) • grape pipetose "· base) 2 - [4 · ((S)-tetrahydrofuran _3 yloxy) benzyl] benzene A fixed dose combination of the coating. In another more detailed aspect, the invention relates to a pharmaceutical composition, especially a solid preparation (e.g., an oral solid dosage form, such as a lozenge), which comprises: 162339.doc 4 - 201249480 includes a first component, part or composition of metformin in a sustained release form (especially metformin hydrochloride) and/or a plurality of excipients, and a selected dipeptidyl peptidase 4 comprising, in particular, an immediate release form ( Dpp_4) Inhibitor (preferably linagliptin) and a second component, part or composition of one or more excipients" In particular, the present invention relates to a pharmaceutical composition, especially including After (4) coating < sustained release form of hydrochloric acid A solid preparation (for example, an oral solid dosage form such as a lozenge) coated with linaliride in an immediate release form. In another more detailed aspect, the invention relates to a pharmaceutical composition, especially a solid preparation (e.g., an oral solid dosage form, such as a lozenge) comprising: a first component, portion or composition comprising metformin in a sustained release form, especially metformin hydrochloride, and one or more excipients, and including Selected SGLT-2 inhibitor in immediate release form (preferably 1-methoxy-4-(β-ϋ·glucopyran-1-yl)_2-[4-((S)-tetrahydrofuran_3 a second component, moiety or composition of one or more excipients. In particular, the invention relates to a pharmaceutical composition, especially including Sealed coated diterpene guanidine hydrochloride in a sustained release form and further 1-chloro-4-(β-ϋ-glucopyranose _i yl)_2_[4_((s)_tetrahydrofuran in an immediate release form -3-yloxy)-stupylmethyl]-stably coated solid preparations (for example, oral solid dosage forms such as lozenges). In another more detailed aspect, the invention relates to a pharmaceutical combination 162339.doc 201249480, in particular a solid preparation (for example an oral solid dosage form, such as a lozenge), which comprises: a) including monomethine (especially hydrochloric acid) Metformin) and an internal sustained release core of one or more excipients; b) an optional seal coat; and C) an optional dipeptidyl peptidase 4 (DPP-4) inhibitor (preferably Lila) An external immediate release coating of one or more excipients. In another more detailed aspect, the invention relates to a pharmaceutical composition, especially a solid preparation (eg, an oral solid dosage form, such as a squeezing agent), which comprises: a) including metformin (especially metformin hydrochloride) and one or more Internal slow release core of the agent; b) optional seal coat; and c) including selected SGLT-2 inhibitors (preferably 1_gas_4_(|3_]:)_glucopyranose-1 An external immediate release coating of 2-[4-((S).tetrahydrofuran-3-yloxy)-benzyl]benzene) and one or more excipients. The pharmaceutical compositions of the present invention comprise, inter alia, an internal core formulation comprising metformin hydrochloride which is a swellable and/or sustained release material. In one embodiment, the pharmaceutical compositions of the present invention comprise an internal sustained release core which is a formulation comprising metformin hydrochloride, a swellable and/or sustained release material, and one or more other excipients (e.g., a matrix formulation). The pharmaceutical composition of the present invention particularly comprises an active pharmaceutical ingredient (API) in the form of an immediate release polymer film (Lilaride and/or 丨-chloroglucopyranose _ ^ group)-2-[4-((S) - Tetrahydrofuran-3-yloxy)-stupidyl]-benzene) external package 162339.doc 201249480 clothing. Moreover, the present invention relates to a coating method (e.g., coating technique and processing conditions) and to a tablet core comprising a high dose (generally 500 to 1 500 mg dose) of active pharmaceutical ingredient (API) (preferably but not An immediate release coating formulation of the active pharmaceutical ingredient (Αρι) at a low dose (generally 0.5 to 25 mg dose) on a sustained release lozenge. In any event, the substantial portion of the formulation and the method of the invention may be applied to any other fixed dose combination as described. It is an object of the present invention to provide a pharmaceutical composition comprising a selected combination of a Dpp_4 inhibitor (preferably linagliptin, especially in an immediate release form) and a sustained release form of metformin (especially metformin hydrochloride). Another object of the present invention is to provide a pharmaceutical composition comprising a selected SGLT-2 inhibitor (preferably i•gas grape (tetra) sugar small base 2 [heart (10)·tetrahydroanthraquinone·3·oxyl A combination of metformin (especially in immediate release form) and metformin (especially metformin hydrochloride) in a sustained release form. The aim is to determine the appropriate formulation and processing conditions, such as linagliptin on the dimethyl double pulse XR core or! _ gas.4•((iv)_grape (tetra) sugar small group k [Μ(8)-tetrahydro...-yloxy)_phenylmethyl]_benzene coating, thus providing a film coating (especially linali (1) Chemical stability - Lilacidase in API film coating) 2-[4-((S)-tetrahydrofuran_3 95 to 105〇/〇), juice or 1-gas-4-(β- Determination of ϋ-Grapeperanol · L -based gas group, benzyl]-benzene (for example - Lilacidyl coated with API film)-2-[4-((S)-tetrahydrofuran_3 / D or I - gas - 4 (pD - grape mother squid _ oxy) - stupid methyl] - benzene content are 162339.doc 201249480 sex (eg RSD < 3%), • during the film coating process The low defect ratio of the API film, -API is not dissolved from the rapid dissolution of the API film coating and the dissolution of the parental metformin hydrochloride, because the API releases the linagliptin or the chloroform_4_(p_D_glucopyran) Sugar-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)benzyl] succinct coating, - coating method/technical, processing conditions and immediate release AI> Treatment of Lalitin or Compound A") Coating Formulation (API Film Coating), Coating Method/Technology, Processing Conditions and Metformin Release Lozenge A treatment aspect of the immediate release API (linagliptin or compound "a") coating formulation. One of the specific objects of the present invention is to provide a drug having a wide range of 1:4 〇〇 to 1:4 〇. a pharmaceutical composition (in the ratio of linagliptin or compound "A") / drug (metformin) and a suitable coating method, and provides a very low dose of API (for example, 1 mg or 2.5 mg of linagliptin) and extremely high The ratio of metformin (1000 mg and greater) is administered, and an immediate release dissolution of a low dose API with a high dose of sustained-release metformin is provided. [Embodiment] Metformin hydrochloride is incorporated into the fixed dose combination of the present invention. Unit dose strength is 500, 750 ' 850 or 1 〇〇〇 mg or even larger (eg 15 〇〇 mg) 此类 单位 甲 胍 胍 胍 胍 单位 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示 表示Dose strength. The unit dose strength of linagliptin incorporated into a fixed dose combination of the invention is 2.5 or 5 mg ' or even lower (e.g., 〇5 or 丨mg). I62339.doc 201249480 incorporating the present invention Fixed dose combination 1 _ gas_4_(P_D_ The unit dose strength of the grape pentose _ 1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene is 5, 10, 12.5 or 25 mg » Specific examples of the dosage strengths of linagliptin and diterpene hydrochloride in the fixed dose combination of the present invention are as follows: (1) 5 mg of linagliptin and 1 00 mg of metformin hydrochloride; (2) 2.5 mg Lalide and 1 mg of metformin hydrochloride; (3) 2.5 mg of linagliptin and 75 mg of metformin hydrochloride. In the fixed dose combination of the present invention, the gas_4_(P_D_glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxyphenylhydrazinobene and Specific examples of the dosage strength of diterpene hydrochloride are as follows: (1) 25 mg 1-gas-4-(β-〇·glucopyran-1-yl)-2-[4-((S)- Tetrahydrofuran-3-yloxy)-benzylbendazole and 100 mg of dioxindole hydrochloride; (2) 12.5 mg of 1-chloro-4-(β·ϋ-glucopyran-1-yl)-2 -[4-((S)-tetrahydropyran-3-yloxy)-phenylindole]- stupid and 1 mg of metformin hydrochloride; (3) 12.5 mg 1 · gas-4-(β· ϋ-Grape phalose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and 750 mg metformin hydrochloride; (4) 10 mg 1- Gas-4-(β-〇_glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzoinyl]•benzene and 1〇〇〇mg Metformin hydrochloride; (5) 10 mg 1 · chloro-4-(β-ϋ-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzene Benzene and 750 mg metformin hydrochloride; (6) 5 mg 1-chloro-4-(β-Ε)-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran -3-yloxy)-benzyl] -Benzene and 1000 mg of metformin hydrochloride' (7) 5 mg 1-gas-4-(β·ι>-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran 162339 .doc 201249480 喃-3-yloxy)-stupidyl]-benzene and mo mg diterpene dihydrochloride. (a) a diterpene moiety The first part of the invention is a part comprising metformin in a sustained release form (especially diterpenoid hydrochloride) (composition, especially a solid composition, such as a solid pharmaceutical orally administered A composition such as a lozenge, especially a sustained release formulation of metformin. An exemplary sustained-release formulation of metformin is disclosed in us 6,34〇, 475, us

6' 488, 962, US 6, 635, 280, US 6, 723, 340, US 7,780, 987, US 6, 866, 866, US 6, 495, 162, US 6, 790, 459, US 6, 866 866, US 6, 475, 521, and US 6, 66, 3, The full text of the content is incorporated herein by reference. One of the specific sustained release formulations of diterpene bismuth is described in us 6, 723, 34, the disclosure of which is incorporated herein in its entirety by reference. In the embodiment, the fixed dose combination of the present invention comprises, as a first part, an internal core matrix formulation in which metformin hydrochloride is dispersed, the matrix formulation comprising a sustained release material. The matrix is formulated to form a tablet form. The fixed dose combination of the present invention is included as an eight. σ巴枯冯弟- Injury 3 has metformin hydrochloride, hydroxy H-Kan & methylcellulose (hypromellone), polyoxyethylene acetoin, microcrystalline cellulose and release formulation.峨 < bucket 4 core ~

The following is described in US-M-biguanide-specific sustained-release formulations as in 6,723, 340: In one embodiment, the sustained release material of the substrate comprises poly(ethylene oxide) and/or I62339.doc 201249480 propyl sulfhydryl Cellulose (HPMC), preferably a combination of poly(ethylene oxide) and hydroxypropyl decyl cellulose (HPMC), preferably in a state in which the matrix expands to a sufficiently large size upon contact with gastric fluid Provides a weight ratio of gastric retention. The poly(ethylene bromide) component of the matrix can limit the initial release of the drug and the swellable effect of the stagnation of the hydroxypropyl fluorenyl cellulose (HPMC) component to reduce the desired poly(ethylene oxide). The amount still allows for expansion. Preferably, the poly(ethylene oxide) has from about 2, 〇〇〇, 〇〇〇 to about 10,000,000 Daltons, more preferably from about 4 Å to about 7, 〇〇〇〇 The viscosity average molecular weight of Dalton. Preferably, hydroxypropyl methylcellulose (HPMC) has from about 4,000 centipoise to about 2 Torr as measured as a 2% aqueous solution, more preferably about 50 centipoise, more preferably about 50, to About 2 〇〇, 〇〇〇 泊 泊, especially better than 8 〇〇〇〇 至 to about 120, 〇〇〇 PCT PCT. More preferably, the poly(ethylene oxide) has a viscosity average molecular weight of from about 4 Torr to about 7, and the hydroxypropyl methylcellulose (HpMC) It has a viscosity of from about 8 centipoise to about 12 centipoise as measured as a 2% aqueous solution. In one embodiment, the weight ratio of poly(ethylene oxide) to hydroxypropyl methylcellulose (HPMC) is in the range of about 1:3 to 3:, preferably 1:2 to 2, In another embodiment, the weight ratio of poly(ethylene oxide) to hydroxypropyl decyl cellulose (HPMC) in the combination is from about 1 5 /〇 to about the weight of the dimethyl double pulse portion. 90%, or about 3% to about 65% or about. To about. The lozenge core according to the present invention can be manufactured by a conventional tableting process which is well practiced and well known, including mixing, milling and manufacturing steps, by techniques which are good at making pharmaceutical formulations. Examples of such techniques are: (1) direct compression using suitable presses and dies that are typically placed in a suitable rotary tablet machine; (2) injection film formation or compression film formation; (3) by fluid bed system The granules are granulated by low or high shear, or by roller pressing, and then by compression; and (4) the paste is extruded into a mold or the extruded product is cut into strips. When a bond is made by direct compression, the addition of a slip agent is useful and sometimes important to promote powder flow and to avoid bond cracking when pressure is released. Examples of typical lubricants are magnesium stearate (in the powder mixture, from 0.25% to 3 weight%, preferably about 1% by weight or less), stearic acid (0.5% to 3 weight ° / 〇) and hydrogenated vegetable oil (preferably hydrogenated and refined from about iy to 5% by weight, preferably about 2% by weight of stearic acid and palmitic acid triglyceride). Other excipients such as granulation aids (for example, low molecular weight HPMC of 2 to 5 weights 〇/〇), binders (such as microcrystalline cellulose), and improved powder flowability, bond hardness and An additive that is brittle and reduces the adhesion to the mold wall. An exemplary sustained release diterpene bismuth tablet core comprises a combination of metformin hydrochloride, a poly(ethylene bromide) as a matrix for an expandable sustained release bond, and a propylmethylcellulose (eg, Methocel® 00M). Microcrystalline cellulose as a binder, low molecular weight hydroxypropyl methylcellulose as a granulation aid (for example, Methocel E5), and magnesium stearate as a lubricant 162339.doc 201249480 Representative metformin nucleus, agent The composition is provided as follows: Diterpenoid bismuth hydrochloride, for example, 49 97% by weight of the first part (polyethylene oxide)', for example, the first part of the 2 6 _ 50% by weight of propyl fluorenyl cellulose (eg K1〇〇M) part of 16.08 weight 0 / 〇, such as 彳 第 - microcrystalline cellulose, for example, 4.99 weight 〇 / 占 of the first part, low molecular weight propyl fluorenyl cellulose (such as E5), the 1.70 weight of the first part of the example. /. And , hard magnesium strontium silicate, for example, accounts for 75 wt% of the first portion. Tablets can be prepared by dry blending granules comprising metformin hydrochloride and low molecular weight HPMC (e.g., Methocel E5) and the remaining excipients listed above, followed by compression on a cash machine. The sustained release matrix formulation of the diterpene is disclosed in US 6,723,340 (e.g., Example 3), the disclosure of which is incorporated herein in its entirety by reference. As another example of the lubricant, mention may be made of sodium stearyl fumarate (e.g., about 0.25 to 3 weights ❶/〇). In another embodiment, the metformin sustained release formulation allows for targeted, controlled release of the two bipartites to the upper gastrointestinal (〇1) tract. In another embodiment, the metformin sustained release formulation is a hydrogel matrix system and comprises a swellable hydrophilic polymer and other excipients that allow the core of the metformin tablet to remain in the stomach ("stomach retention") About 8 to 9 hours. During this time period, the metformin core of the tablet core is stably released to the upper gastrointestinal tract at the desired rate and time without potentially stimulating the "burst release" of the drug. This progressive, sustained release generally allows more metformin to be absorbed in the upper GI tract and will be minimized by the lower GI 162339.doc •13·201249480. (bl) Ltilatin Part: In a variant, the second part of the invention is a part (composition, especially a coating) comprising linagliptin in an immediate release form. In a specific embodiment, the fixed dose combination of the present invention comprises as a second portion a film coating formulation of linagliptin, the film coating formulation comprising linagliptin for use in making linali Stabilizers (eg, alkaline and/or nucleophilic excipients are preferably L-arginine as stabilizer), film coating agents (such as hydroxypropyl methylcellulose, such as Hypr〇mell) 〇se 2910, Methocel E5 or Methocel E15), plasticizers (such as polyethylene glycol, such as Macro go 1 400, 6000 or 8 000' or propylene glycol) and optional slip agents (such as talc). In one embodiment, the weight ratio of L-arginine to linagliptin is in the range of from about 2: i to about 1:1 ' up to about 0.2:1. A representative film composition comprising linagliptin is provided as: - linagliptin, for example 2.5 mg or 5 mg; -L-arginine, for example, depending on the need for a safe dose, for example at about ο.〗 mg to a range of about 10 mg (for example, 5 mg); - propyl decyl cellulose (such as Methocel E5, Methocel E15, or Pharmacoat 603 or 606) ' For example, about 25 mg to about 40 mg (especially 34.5 mg to 38 mg, or 34.5 mg); • Polyethylene glycol (eg Macrogol 400, 6000 or 8000), for example from about mg to about 12 mg; - Propylene glycol, for example from about 〇 mg to about 15 mg (especially 9 mg) And 162339.doc 201249480 _ talc such as from about mg to about 15 mg (especially 9 mg) > depending on the stability of the stabilizer, the L-arginine content can range from 〇5 „^ to 1〇mg The arginine content can be replaced by propylmethylcellulose (HPMC) for different doses and different arginine content. In one embodiment, polyethylene glycol and propylene glycol are mutually exclusive in the above composition, ie If polyethylene glycol is present, propylene glycol is not present, or if propylene glycol is present, polyethylene glycol is not present. The composition of the film coating suspension of Ting further comprises water, for example from about 240 mg to about 1440 mg, especially in the range of from 904 mg to 1440 mg. The total solids concentration of the suspension is from about 4% to about 12 5 . 〇w/w, especially 4% to 6% w/w. The viscosity may be about 1 〇 ^ ^ & 3 to 11 mpas (for example, 46 to 56 mPas). The total solids content of the linali coating and the lysing suspension is from about 5 〇 mg to about ι 2 〇 mg. For example, the total solids is 6 〇 111 § the solids amount of the film coating suspension (for 2.5 mg of linagliptin), and the total solids of 12 〇 mg of the film coating suspension (for 5 mg of linali) For Ting). Thus, for the same formulation of linagliptin and double coating time (i.e., double the amount of coating suspension), a further dose range of linagliptin can be prepared. Therefore, different dose strengths can be achieved by changing the coating (spraying) time. (*>2) 1-gas-4-(pD·glucopyranosyl)·2·[4·((8)_tetrahydrofuran·3_yloxy)-phenylmethylbenzene moiety: in another In a variant, the second part of the invention comprises 1-ox-4-(β-ϋ-glucopyranose-1.yl)_2_[4_((s)·tetrahydrofuran·3• in an immediate release form. Part of the group of oxy)-benzylidene-benzene (composition, especially film coating 162339.doc •15·201249480) In another specific embodiment, the fixed dose combination of the invention comprises as a second part Membrane package of 1-qi-4-(β-ϋ-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene a coating formulation comprising 1-gas-4-(PD-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)·benzene Methyl]-benzene, a film coating agent (such as hydroxypropyl methylcellulose, such as Hymromellose 2910, Methocel E5, or Methocel E15), a plasticizer (such as polyethylene glycol, such as Macrogol 400, 6000 or 8000, Or propylene glycol) and optional slip agents (such as talc). Representatively contains 1-gas-4-(p_D-glucosyl-1-yl)-2-[4-((S)-tetrazide -3-yloxy The composition of the film coating of -benzoyl]-benzene is as follows: 1- gas-4-(pD-glucopyran-1-yl)-2-[4-((S)-tetra-argon Indole-3-yloxy)-phenylhydrazinyl]-benzene, for example 5 mg, 10 mg, 12.5 mg or 25 mg; - optionally L-arginine, for example from about 5 mg to about 25 mg; Propyl methylcellulose (eg, Methocel E5, Methocel E15, or 卩1^1:11^〇〇31 603 or 606), for example from about 25 11^ to about 40 11^ (especially 34.5 mg to 38 mg, or 34.5 Mg); - polyethylene glycol (eg Macrogol 400, 6000 or 8000), for example from about 12 to about 12 mg; - propylene glycol 'for example from about 〇 mg to about 15 mg (especially 9 mg); and - talc' such as 〇 From mg to about 15 mg (especially 9 mg). For different doses and different arginine content, the arginine content can be replaced by propylmethylcellulose (HPMC). In one embodiment, polyethylene glycol and Propylene glycol is mutually exclusive in the above composition, ie, 'propylene glycol is absent in the presence of polyethylene glycol, or polyethylene glycol is absent if 162339.doc •16·201249480 is present in propylene glycol. Representatively contains 1 _ gas _4_(β_β-Grape "Bottomose-1-yltetrahydrogen. The composition of the film-coating suspension of -3-yloxy)-phenylphenylbenzene further comprises water, e.g., from about 240 mg to about 1440 mg', especially in the range of from 904 mg to 1440 mg. The total solids concentration of the suspension was about 4 〇/. Up to about 12·5°/〇w/w, especially 4% to 6% w/w » 1-gas-4-(β-Π)_glucopyranose_丨_yl)_2_[4_((s) The total solids of the coating suspension of _tetrahydrofuran-3-yloxy)-benzyl]-stup is from about mg to about 12 mg. For example, the total solids are at 12 5 mg helium _4_(p_D_glucopyran-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)benzoyl]-benzene The film coating suspension is 60 mg solids, and is 25 mg 1- gas·4-(β_Ε)_glucopiperidin-1-yl)-2-[4-((8)_tetrahydrofuran+yloxy The film coating suspension of phenyl)-phenylhydrazinyl]-benzene was 120 mg total solids. Therefore, for the same enthalpy of 丨-gas _4_(β-ϋ-glucopyran-1-yl)_2_[4_((8)_tetra-argon-?3-yloxybenzyl]-benzene And double coating time (ie double coating of the coating suspension) 'can be prepared for the high dose range of the car ^ gas winter (four) · grape (four) sugar small base) -2- [4- called tetrahydrobite asthma _3 _ yloxy) phenylmethyl] benzene. Therefore, different dose strengths can be achieved by varying the coating (spray) time. L-arginine is preferably required for the stability of statin. Alternatively, a seal coat can be applied between the metformin XR core and the film coating containing linali; In one embodiment, the 'sealing coating' is present between the metformin core and the film coating containing the lining (if necessary, further comprising L_arginine). In another embodiment, the 'sealing coating' is not present between the metformin core and the film coating containing the lira (preferably further comprising L-arginine). 162339.doc 201249480 For compound "A", arginine is preferably not required. For compound "A", the seal coat of the two-twist XR core is optional. In one embodiment, a seal coat is present between the diterpene XR core and the film coating containing Compound "A". In another embodiment, the seal coat is not present between the metformin XR core and the film coating containing compound "A". Alternatively, for a film coating containing API (linagliptin or compound "A"), a mixture comprising hydroxypropylcellulose and hydroxypropylmethylcellulose or polyvinyl alcohol (PVA) and polyethylene can be used. Film coating of a mixture of diols (PEG); or commercially available film coatings such as Opadry®, Opadry II® or other Opardy IR film coatings, which are prepared powder blends supplied by Colorcon. With an API coating based on Opadry II or PVA, a greater solids concentration and a shorter coating duration can be achieved, so it operates at a solids concentration ranging from 10 to 30%, especially 20%. This greater solids concentration (e. g., 20%) generally results in a shorter coating time, such as 2 to 5 hours. For example, other variants of the API-containing film coating composition comprising one or more of the following ingredients of Table 1 or 2 can be provided, for example, from Table 1 or 2: Table 1 of linaliride on a diterpene XR core Exemplary formulation of API coating (% w/w) PEG-containing variant (eg 2.5 mg API) PEG-containing variant (reduced arginine) (eg 5 mg API) PG-containing variant (low DL) (eg 2.5 mg API) variants containing PG (high DL) (eg 2.5 mg API) other variants (eg 2.5 mg API) other variants (eg 5 mg API) linagliptin 4.20 4.39 4.55 5.29 4.16 4.16 HPMC (eg Pharmacoat615 ) * 67.23 70.18 72.73 70.55 - - HPMC (eg Methocel E5) - - - - 57.5 57.5 Polyethylene glycol (eg PEG 6000) 20.17 21.05 - - 15 15 162339.doc • 18 - 201249480 Propylene glycol - - 3.64 3.53 - - L - arginine 8.40 4.39 9.09 10.58 8.33 8.33 talc - - 10.00 10.05 15 15 pure water** ** ** «this ** total 100.00 100.00 100.00 100.00 100.00 100.00 solids content of suspension (%) 5.95 5.70 5.50 5.67 4.0 4.0 * or Methocel E15 ** solvent is a volatile component, it is not guaranteed Remaining in the final product In one embodiment of the API coating of the present invention, the film coating agent used is extremely viscous. In another embodiment of the API coating of the present invention, the film coating agent used is less viscous. Table 2 Other exemplary formulations of the API coating of linagliptin on the diterpene XR core. PEG-containing variants PEG-containing variants PG-containing variants PG-containing variant composition (% w/w) (eg 2.5 Mg (reduced arginine) (low DL) (eg (high DL) (eg API) (eg 5 mg API) 2.5 mg API) 2.5 mg API) Lily lamp 4.20 4.39 4.55 5.29 HPMC (eg Pharmacoat 615) 67.23 70.18 72.73 70.55 Polyethylene glycol (eg PEG 6000) 20.17 21.05 - - Propylene glycol - - 3.64 3.53 L-arginine 8.40 4.39 9.09 10.58 Talc - - 10.00 10.05 Purified water** This φ ** ♦* Total 100.00 100.00 100.00 100.00 Solids content (%) of the suspension 5.95 5.70 5.50 5.67 ** Solvent is a volatile component which does not remain in the final product. Film coating suspension of the API according to the invention (linagliptin or compound "A") The liquid/solution can be prepared by a conventional method such as the following: a film coating agent hydroxypropyl decyl cellulose (HPMC), a plasticizer polyethylene glycol (PEG) (for example, Macrogol 400, 6000 or 8000) or as Alternative plasticizers for propylene glycol (PG) and water dissolution and by suitable mixers • 19- 162339.doc 201249480 e.g. by a propeller mixer) to produce a coating solution free of API. If necessary, add a slip agent talc suspended in water and a suspension obtained by homogenization. Use talc as needed. Dissolve or suspend the API (linagliptin or compound "A") and (preferably in the case of linagliptin) the stabilizer L-arginine in water and add to HPMC, PEG or PG and optionally The aqueous solution of talc is dispersed and provided by a suitable mixer (e.g., by a propeller mixer) to provide an API coating suspension. Alternatively, the film coating agent hydroxypropyl methylcellulose (HPMC) and water are dissolved and mixed by a suitable mixer (e.g., by Ultraturrax). Stabilizer L-arginine (which is present in the case of linagliptin and may be absent in the case of compound "A"), plasticizer polyethylene glycol (PEG) (eg Macrogol 400, 6000 or 8000) Or propylene glycol (PG), optionally talc and water, for example by means of Ultrk turrax, are dispersed by homogenization. After degassing the HPMC solution (or directly after manufacture of the HPMC solution), an aqueous suspension of PEG or PG, optionally L-arginine and optionally talc, is added to the HPMC aqueous solution and mixed/homogenized. The API (linagliptin or compound "A") is dissolved or suspended in water and added to an aqueous solution of HPMC, PEG or PG, optionally L-arginine and optionally talc to provide an API coating suspension. The film coating operation is carried out in a conventional film coater. The API (linagliptin or compound "A") coating suspension/solution was coated on the metformin XR core via a coating treatment. Initial preheating of the core is necessary because the balance of the core water is required. 0 162339.doc •20· 201249480 The spray rate and air flow through the coating pan are adjusted to produce a uniform coating of the overall width of the tablet bed. And coverage. The amount of coating suspension can be controlled by an increase in the weight percent of the tablet core and is generally in the range of from about 4 to about 12.5%. In a single way, this range resulted in a linalistatin drug content analysis approaching the required 25 mg or 5 mg in a content homogeneity analysis of linagliptin, with a standard deviation of about 2 to 4%. The duration of the coating step is about 4 to 1 hour. The duration of the coating step depends on the batch size, processing parameters such as the spray rate of the coating suspension, and the solids concentration. In another aspect, the range results in a compound "A" in the content homogeneity analysis, the compound "A" drug analysis is close to the required 5 mg, 125 mg, 10 mg or 25 mg, with a standard deviation of about 2 to 4%. The duration of the coating step is from about 4 to 10 hours. The duration of the coating step depends on the batch size, processing parameters such as the spray rate of the coating suspension, and the solids concentration. The API coating suspension is applied to the core of the core comprising the diterpene bismuth xr formulation and the solids deposited in the API film layer are controlled to achieve the desired dosage. The weight of the core and film coated tablets can be controlled by an increase in the weight percentage during the coating process. Instead of or in addition to the weight gain method, a PAT method, such as an in-line leg or Raman method for endpoint detection of API analysis, and a membrane coating with API can be used to prepare a coating suspension optional seal coating. Open the two-inch double XR core. In general, for the manufacture of film-coated tablets 162339.doc • 21 - 201249480 and the core of the tablet can be coated with a sealed coating suspension using a standard film coater. The film coating solvent is a volatile component that does not remain in the final product. A typical sealant coating comprises a film coating, a plasticizer and optionally a slip aid, one or more pigments and/or colorants. The monomethyl hydrazine XR core can utilize a seal coater (and a plasticizer), such as a mixture of propylcellulose and (tetra)methylcellulose, polyethylene glycol (PVA), and polyethylene glycol (PEG). The mixture, hydroxypropyl methylcellulose and a mixture of polyethylene glycol (PEG) or propylene glycol (PG), or any other suitable immediate release film coating agent, is hermetically coated. One commercially available film coating is 〇padry 8, Opadry II® or other 〇pardy IR film coating, which is a blend of powders provided by c〇i〇rc〇n. The seal coat may further include a slip agent as needed. The final pharmaceutical composition of the invention is a keying agent. Such a binder may be further coated by a final film overcoat film such as hydroxypropylcellulose and hydroxypropylmethylcellulose comprising titanium dioxide and/or other colorants such as iron oxides, dyes and color ingots. a mixture of polyvinyl alcohol (pVA) and polyethylene glycol (PEG) comprising titanium dioxide and/or other colorants (such as iron oxides, dyes and lakes); comprising titanium dioxide and/or other colorants ( a mixture of hydroxypropyl decyl cellulose such as iron oxides, dyes and lakes and polyethylene glycol (PEG) or propylene glycol (pg); or any other suitable immediate release film coating agent. The final tablet provides a taste mask and additional stability. One commercially available film coating is Opadry®, Opadry II® or other Opardy IR(R) coatings which are prepared powder blends supplied by Colorcon. 162339.doc • 22- 201249480 Preferably, for the manufacture of a film-coated lozenge, a coating suspension is prepared and a tablet coating is applied from the coating suspension using a standard film coating machine. In general, for API-free outer coatings, the weight increase is about 4%, preferably about 3%. The film coating solvent is a volatile component which is not retained in the final product. Typical film coatings include film coatings, plasticizers and optional slip agents, one or more pigments and/or colorants. For example, the coating may include hydroxypropyl methylcellulose (HPMC), propylene glycol or polyethylene glycol, talc, and optionally titanium dioxide and/or iron oxide (e.g., iron oxide yellow and/or iron oxide red). The pharmaceutical lozenge compositions of the present invention may also comprise one or more additional formulation ingredients selected from a wide range of excipients known in the art of pharmaceutical formulation. Depending on the desired properties of the pharmaceutical formulation, any number of ingredients may be selected individually or in combination based on its use in the manufacture of the rotatory composition. Such ingredients include, but are not limited to, diluents, compression aids, slip agents, disintegrants, lubricants, perfumes, flavoring agents, sweeteners, and preservatives. The term "key agent" is intended to encompass a compressed medical dosage formulation of various shapes and sizes. The present invention also provides: 1# from a combination of a fixed dose combination of a subject in need of such treatment, and eight: with a therapeutically effective amount of the subject of the invention being a human H. In the embodiment, the treatment is required Dosage form. Including fixed-dose combination group: the system is a key agent _), - twice a day (BID), - day _ ^ music can be - once a day manufacturing and polymorphic two-person (TID) or four times a day投I62339.doc •23· 201249480 The term "linagliptin" as used herein refers to linagliptin, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a polymorph thereof. The crystal form is described in WO 2007/128721. Preferred crystalline forms are the polymorphs A and B described therein. In particular, linagliptin is the free base methyl-quinazoline·2-yl)indolyl]-3-methyl)_8_(3_(R)amine-based mother-bited small base)- In the case of linagliptin or a pharmaceutically acceptable salt thereof, linagliptin is preferred. Processes for the preparation of linagliptin are described, for example, in the patent applications WO 2004/018468 and WO 2006/048427. 1-[(4-Methyl-quinazolin-2-yl)methyl]_3_methyl_7·(2-butyne-I.yl)- 8-(3-(R)-amino-based啶_丨_基)_黄嘌呤(Lilaride):

According to the invention, it is understood that the SGLT2 inhibitor (specifically, qi, · (D D-glucopyranose _ 卜基卜 2_[4_((s)·tetrahydrofuran·3 yloxy)-benzyl) The definition of benzene (compound "A")) also includes hydrates, solvates and polymorphs thereof, and prodrugs thereof. The preferred gas-' (dipenal-glucopyran-1-yl) In the case of -2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl bromide, the advantageous crystalline form This crystal form has a preferred solubility which provides excellent bioavailability of the SGLT2 inhibitor. Further, the crystal form is physiologically stable and thus provides excellent shelf life stability of the pharmaceutical composition. 162339.doc •24· 201249480 1-Gas-4-(β-ϋ-glucopyran-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-phenylhydrazine ]-Benzene (compound "A"):

Methods of preparing SGLT2 inhibitors and prodrugs thereof in accordance with the present invention are known to those skilled in the art. Advantageously, the compounds according to the invention can be prepared using synthetic methods as described in the literature (including the above-referenced patent application). In particular, a preferred method for preparing 1-chloro-4-yl (p_D-glucopyranose)-[4-((S)_tetrahydrofuran-3-yloxy)-benzylbenzene is described in WO 2006/120208. To avoid any doubt, the disclosures of the above-referenced references to the specifics of the specifics of the above-mentioned articles are specifically incorporated herein by reference. Indications As described herein, by administering a pharmaceutical composition according to the present invention, a therapeutic effect can be achieved which makes it useful for the treatment and/or prevention of certain diseases, conditions or conditions, such as those described herein. Therefore, the treatment or prevention according to the present invention is advantageously suitable for the patients in need of such treatment or prevention, loading + post-inflammation + 々α «up and down to one or more selected from overweight and obesity (specifically, class I obesity) , τ τ face obesity, in class obesity, visceral obesity and abdominal obesity) composed of a group of eve, by ten, sputum. Furthermore, the treatment or prevention according to the invention is advantageously suitable for such patients whose musk is not directly increased. Compared to the monotherapy of 162339.doc -25-201249480, the pharmaceutical compositions and methods of the present invention allow a reduction in the HbAlc value to a desired target for a greater number of patients and longer treatments, for example &lt; 7❶/〇 and better <6.5%. The pharmaceutical composition according to the present invention and, in particular, the active ingredient thereof, are not excellent in terms of blood glucose control, in particular in view of reducing fasting blood sugar, postprandial blood glucose and/or glycated hemoglobin (HbAlc). The reduction of HbAlc by the administration of the pharmaceutical composition of the present invention is preferably equal to or greater than 5%, more preferably equal to or greater than 1%. /. And the reduction is especially in 1_〇. /0 to 2.0% range. Moreover, the method and/or use according to the present invention can be advantageously applied to such patients exhibiting one, two or more of the following conditions: (a) Fasting blood glucose or serum glucose concentration greater than 11 〇 mg/dL, in particular More than 125 mg/dL; (b) Postprandial blood glucose equal to or greater than 14〇mg/dL; (c) HbAlc value equal to or greater than 6.5%, specifically equal to or greater than 7.0%, especially equal to or greater than 7.5%, more specific It is equal to or greater than 8.0 〇 / 〇. The invention also discloses the use of the pharmaceutical composition for improving glycemic control in a patient having type 2 diabetes or a first condition exhibiting pre-diabetes. Therefore, the present invention also includes diabetes prevention. Therefore, as long as one of the above symptoms of pre-diabetes occurs, the pharmaceutical composition according to the present invention can be used to improve glycemic control, the occurrence of indium-type diabetes can be delayed or prevented. Moreover, the pharmaceutical composition according to the invention is particularly suitable for the treatment of patients having islet dependence 162339.doc -26-201249480, ie using insulin or insulin derivatives or insulin substitutes or including insulin or its derivatives or alternatives thereof A formulation that is otherwise treated or otherwise treated by a patient. Such patients include type 2 diabetes patients and type 1 diabetes patients. Thus, in accordance with a preferred embodiment of the present invention, there is provided a method of improving glycemic control and/or reducing fasting blood glucose, postprandial blood glucose and/or glycosylated hemoglobin HbAl c in a patient in need thereof, the patient being diagnosed as glucose resistant Poorly acquired (IGT), impaired fasting glucose (IFG), insulin resistance and metabolic syndrome and/or type 2 diabetes and type 1 diabetes, the method is characterized by administering a pharmaceutical composition as defined above and below The patient. According to another preferred embodiment of the present invention, there is provided a method of improving glycemic control in a patient suffering from type 2 diabetes (specifically, an adult patient) as an aid to diet and exercise. Thus, the method and/or use according to the present invention can be advantageously applied to such patients exhibiting one, two or more of the following conditions: (a) inadequate glycemic control by diet and exercise; (b) Regardless of the oral monotherapy with metformin, the oral monotherapy with metformin at the maximum tolerated dose is not adequately controlled for glycemic control; (c) regardless of oral monotherapy with another antidiabetic drug, specific In spite of the oral monotherapy of other antidiabetic drugs at the maximum tolerated dose, insufficient glycemic control is still available. The blood glucose concentration is lowered to insulin-independent by administration of the pharmaceutical composition according to the present invention. Therefore, the pharmaceutical composition according to the present invention is particularly suitable for treating patients diagnosed as having one or more of the following conditions: - Tensenmycin resistance, sorghum, and - pre-diabetes, - Type 2 diabetes, especially with advanced type 2 diabetes, type 1 diabetes. Moreover, the pharmaceutical compositions according to the invention are especially suitable for the treatment of patients diagnosed with one or more of the following conditions: (a) obesity (including I, π and/or sputum obesity), visceral obesity and/or abdominal obesity, (b) Triglyceride blood concentration &gt; 15 〇 mg / dL, (c) HDL-cholesterol blood concentration &lt; 4 〇 mg / dL (female patient) and &lt; 5 〇 mg / dL (male patient), ( d) systolic blood pressure 2130 mm Hg and diastolic blood pressure 85 mm Hg, (e) fasting blood glucose concentration mg/dL. It is hypothesized that patients diagnosed with impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and/or metabolic syndrome have developed cardiovascular disease, such as myocardial infarction, coronary heart disease, cardiac insufficiency, High wind I of the uterus embolism event I can reduce cardiovascular risk according to the ▲ sugar control of the present invention. The pharmaceutical compositions according to the present invention exhibit excellent safety characteristics. Thus, the treatment or prophylaxis according to the present invention may be advantageously used to ban the monosaccharide method of another anti-sugar heart and/or intolerance to a therapeutic dose of such a drug. In particular, the treatment or prevention according to the present invention may be beneficial to soil 162339.doc • 28· 201249480 for the display of one or more of the following abnormalities or the increased risk of one or more of the following abnormalities: renal insufficiency or nephropathy , metabolic status and/or risk of heart disease, heart failure, liver disease, lung disease, lactic acidosis, or female patients who are pregnant or breastfeeding. It can be seen that the administration of the pharmaceutical composition according to the present invention does not pose a risk of low glucose or a low risk of causing hypoglycemia. Therefore, the treatment or prevention according to the present invention can also be advantageously used for such patients exhibiting hypoglycemia or an increased risk of hypoglycemia.医药 The pharmaceutical composition according to the present invention is particularly suitable for long-term treatment or prevention of diseases and/or conditions as described above and below, in particular for long-term glycemic control in patients with type 2 diabetes. The term "long-term" as used above and hereinafter means the treatment or administration of a patient over a period of longer than 12 weeks, preferably a longer than 25 weeks, particularly preferably longer than one year. Therefore, a particularly preferred embodiment of the present invention provides a treatment (preferably oral treatment) to improve (especially long-term improvement) type 2 diabetic patients (especially patients with advanced type 2 diabetes), in which case the additional material is overweight, Methods of blood glucose control in obesity (including work, π and/or m obesity), visceral obesity, and/or abdominal obesity. According to another aspect of the present invention, there is provided a method of preventing, slowing, delaying or treating a condition selected from the group consisting of: a complication of diabetes, such as cataracts and microangiopathy, and a large number of patients in need thereof. s disease (such as blood abnormalities), kidney disease, retinopathy, neuropathy, tissue bureau.卩Ischemia, diabetic foot, arteriosclerosis, myocardial infarction, acute crown 162339.doc -29- 201249480 sinus syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, Arrhythmia and vascular restenosis, the method is characterized by administering a pharmaceutical composition according to the present invention to the patient. In particular, one or more aspects of diabetic nephropathy (such as hyperperfusion, proteinuria, and albuminuria) can be treated, delaying progression, or delaying or preventing its onset. The term "tissue ischemia" includes, inter alia, diabetic lesions, diabetic microvascular lesions, poor wound healing, and diabetic ulcers. The terms "microvascular disease and macrovascular disease" & "microvascular and macrovascular complications" are used interchangeably in this application. According to another aspect of the present invention, there is provided a method for preventing or delaying the prevention or slowing of a patient in need thereof by a metabolic method selected from the group consisting of: type 2 diabetes, poor glucose tolerance, fasting blood, and often IFG), blood glucose, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, surrogate diabetes, and diabetes associated with cystic fibrosis, the method characterized by administering the pharmaceutical composition according to the present invention to the patient. According to another aspect of the present invention, there is provided a method of improving control and/or reducing fasting blood glucose 'postprandial blood glucose and/or glycated hemoglobin=bAlc for a patient in need thereof, the method being characterized by being according to the present invention The pharmaceutical composition is administered to the patient. The pharmaceutical composition according to the present invention also has advantageous disease-modulating properties for diseases or conditions which are poor in glucose tolerance, fasting blood glucose abnormality (IFG), muslin resistance, and 7 or metabolic syndrome. According to another aspect of the present invention, it is provided that a patient is required to pre-slow, delay glucose tolerance (IGT), fasting blood glucose abnormality 162339.doc 201249480 =FG) A method of metabolic syndrome to type 2 diabetes or reversing its progression, characterized in that the pharmaceutical composition according to the present invention is administered to the patient. As a result of the use of the pharmaceutical composition according to the present invention, an improvement in the control of the desired sugar can be obtained and the condition and/or disease associated with or caused by the increase in the concentration of the sugar can be treated. By virtue of the pharmaceutical composition according to the invention, the excess blood glucose concentration is not changed to an insoluble living form (such as fat), but is discharged through the urine of the patient. It can be seen that the loss of fat is the main cause of the observed weight loss, and no significant change in the body's water or protein content is observed. Therefore, the result is no weight gain or even weight loss. According to another aspect of the present invention, there is provided a method of reducing a body: and/or body fat or avoiding an increase in body weight and/or body fat or promoting body weight and/or salt y to a patient in need thereof, the method being characterized by The pharmaceutical composition according to the invention is administered to the patient. By the administration of the combination or pharmaceutical composition according to the present invention, the abnormal accumulation of ectopic fat (of the liver of the s) can be reduced or suppressed. Thus, according to another aspect of the present invention, there is provided a method for preventing, delaying, delaying or treating a ectopic fat attributed to a patient in need thereof: accumulation of a disease or condition caused by accumulation The method of the method is characterized in that the pharmaceutical composition according to the invention is administered to the patient. The disease or condition caused by the abnormal accumulation of liver fat is especially selected from the group consisting of general fatty liver, non-alcoholic fatty liver (NAFL), nonalcoholic fatty hepatitis (NASH), hypertrophic fatty liver, diabetes. Fatty liver, alcohol-induced fatty liver or toxicity I62339.doc •31· 201249480 Group of fatty liver. Another aspect of the invention provides a method of maintaining and/or improving sensitization to and/or treating or preventing hyperinsulinemia and/or sputum resistance in a patient in need thereof, the method being characterized by The pharmaceutical composition according to the invention is administered to the patient. According to another aspect of the present invention, there is provided a method of preventing, delaying progression, delaying or treating new-onset diabetes (N〇DAT) and/or post-transplant metabolic syndrome (PTMS) in a patient in need thereof, the method It is characterized by administering a pharmaceutical composition according to the invention to the patient. According to another aspect of the present invention, there is provided a method of preventing and reducing complications associated with NODAT and/or PTMS, including microvascular and macrovascular diseases and events, transplant rejection, infection, and death, in a patient in need thereof, » The method of hai is characterized in that a pharmaceutical composition according to the present invention is administered to the patient. The pharmaceutical composition according to the present invention can promote a decrease in the serum total urate concentration of a patient. Thus, in accordance with another aspect of the present invention, a method of treating a condition in which blood uric acid is too high and associated with hyperuricemia, such as gout, hypertension, and renal failure, is provided to a patient in need thereof, the method being characterized by The pharmaceutical composition according to the invention is administered to the patient. The administration of pharmaceutical compositions increases the urinary excretion of glucose. This increase in osmotic excretion and drainage and a decrease in urate concentration are advantageous in treating or preventing renal knots. Accordingly, in another aspect of the present invention, there is provided a method of treating or preventing f stones in a patient having a characteristic, which is characterized in that a pharmaceutical composition according to the present invention is administered to the patient. The invention is also directed to a pharmaceutical composition according to the invention for use in the methods described above and below. The invention also relates to the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for use in the methods described above and below. Definitions The term "active ingredient" according to the pharmaceutical composition of the present invention means an SGLT2 inhibitor, a DPP-4 inhibitor and/or metformin according to the present invention. The term "body mass index" or "face" of a human patient is defined as the weight expressed in kilograms divided by the square of the height in meters, such that bmi has units of kg/m2. The term "overweight" is defined as a condition in which an individual has a BMI greater than 25 kg/m2 and less than 3 〇 kg/m2. The terms "overweight" and "pre-obesity" are interoperable. The term "obesity" is defined as an individual having a condition equal to or greater than 3 〇 kg/m2. According to the U of the WHO, the obesity can be classified as follows: The term "type I obesity" is a condition with a BMI equal to or greater than 30 kg/m2 but less than 35 kg/m2; m "π-type obesity" is equal to or greater than 35 kg. A condition of /m2 but less than 40 kg/m2; the term "obese" is a condition in which bmi is greater than 4 〇kg/m2. Intraoperative visceral obesity is a condition in which the waist and hip* of greater than or equal to 1 男性 (male) and 〇·8 (female) are measured. It determines the risk of resistance to geranium and the formation of pre-diabetes. The term "abdominal obesity" is generally defined as a condition of waist circumference &gt; 4 inches or 1 〇 2 em (male | ±) and 35 inches or 94 cm (female). For the sake of the nationality or Japanese 162339.doc -33. 201249480, abdominal obesity can be defined as waist circumference 285 cm (male) and 290 cm (female) (see for example, investigating committee for the diagnosis of metabolic syndrome in Japan) o The term "normal blood glucose" is defined as a condition in which an individual has a fasting blood glucose concentration within a normal range (greater than 70 mg/dL (3.89 mmol/L) and less than 100 mg/dL (5.6 mmol/L)). The word "fasting" has the usual meaning as a medical term. The term "hyperglycemia" is defined as a condition in which an individual has a fasting blood glucose concentration above a normal range (greater than 100 mg/dL (5.6 mmol/L)). The word "empty belly" has the usual meaning as a medical term. The term "hypoglycemia" is defined as a condition in which an individual has a blood glucose concentration below the normal range (specifically below 70 mg/dL (3.89 mmol/L) or even below 60 mg/dL). The term "postprandial hyperglycemia" is defined as a condition in which an individual has a 2-hour postprandial blood glucose or serum glucose concentration greater than 200 mg/dL (11.1 mmol/L). The term "fasting blood glucose abnormality" or "IFG" is defined as an individual having between 100 and 125 mg/dL (ie, 5.6 to 6.9 mmol/L), specifically greater than 110 mg/dL and less than 126 mg/ciL (7.00 mmol/). A condition of fasting blood glucose concentration or fasting serum glucose concentration in the range of L). Individuals with "normal fasting glucose" have a ventral glucose concentration of less than 100 mg/dL (i.e., less than 5.6 mmol/L). The term "bad glucose tolerance" or "IGT" is defined as 162339.doc ·34· 201249480 2 hours for individuals with 140 mg/dL (7.8 mmol/L) and less than 200 mg/dL (ll.ll mmol/L). A condition of postprandial blood glucose or serum glucose concentration. Glucose tolerance abnormality, ie, 2 hours postprandial blood glucose or serum glucose concentration can be measured as blood glucose expressed in mg glucose/dL plasma 2 hours after taking 75 g of glucose on an empty stomach: agronomic degree has "normal glucose tolerance" The individual has a 2-hour postprandial blood glucose or serum glucose concentration of less than 14 mg/dL (7,8 mmol/L). The term "hyperinsulinemia" is defined as a condition in which an individual with insulin resistance, with or without normal blood glucose, has an increased fasting or postprandial serum or plasma insulin concentration above normal concentration, and is not thin with insulin resistance. The individual has a waist-to-hip ratio of &lt;1.〇 (male) or &lt;0.8 (female). The terms "insulin sensitization", "insulin resistance improvement" or "insulin resistance reduction" are synonymous and interoperable. The term "insulin resistance" is defined as the state in which a circulating insulin concentration that exceeds the normal response to glucose load is required to maintain a normal blood glucose state (Ford ES et al. JAMA. (2002) 287:356-9). One method for determining insulin resistance is the normal glucoemia-hyperinsulinemia tongs test. The ratio of insulin to glucose is determined within the range of the combined lycopene (4) sugar infusion technique. If the glucose is absorbed by less than 25% of the background population studied, it can be seen as methadone resistance (WHO definition). In comparison to the slenderness test, the lesser and least laborious is the so-called minimum model '#, during the intravenous glucose tolerance test, the concentration of the sugar in the blood is measured at fixed time intervals and the insulin resistance is calculated therefrom. With this method, it is impossible to distinguish between liver and peripheral insulin resistance. Moreover, the response to treatment, insulin sensitivity, and hyperinsulinemia in patients with resistance to tamsin and resistance to tamsin can be assessed by evaluating the steady-state model of resistance to insulin 162339.doc •35·201249480 (HOMA-IR) score (a reliable indicator of insulin resistance) and quantified (Katsuki A et al., Diabetes Care 2001. 24. 362-5). Other references are methods for determining the HOMA-index of insulin sensitivity (Matthews et al., Diabetologia 1985, 28: 412-19), and methods for determining the ratio of intact pro-prime prostaglandins to temsin (For st et al., Diabetes) 2003, 52 (Supplement 1): A459) and a study of normal blood glucose clamps. In addition, plasma adiponectin concentrations can be monitored as a potential replacement for tamper sensitivity. The insulin resistance was assessed by the steady-state assessment model (HOMA)-IR score as follows (Galvin P et al, Diabet Med 1992; 9: 921-8): HOMA-IR = [fasting serum insulin (μυ/ιηί )] χ [fasting blood glucose (mm 〇 1 / L) / 22 5] Usually 'other parameters are used in daily clinical practice to evaluate phosphine resistance. Preferably, for example, the patient's triglyceride concentration is used as an increased concentration of triglyceride which is significantly associated with the presence of resistance to temsin. Patients with a predisposition to develop IGT or IFG or type 2 diabetes are those with normal insulin and those with hyperinsulinemia and defined as insulin resistant. A typical patient with insulin resistance is usually overweight or obese, but this is not always the case. If insulin resistance can be detected, it is a strong indication of the presence of pre-diabetes..., it can be used to maintain glucose homeostasis, and individuals take 2 to 3 times more endogenous insulin products than healthy individuals (for example). Cause any clinical symptoms. The method for studying the function of islet β cells is similar to the above method for insulin sensitivity, hyperinsulinemia or insulin resistance: (4) The improvement of cell function can be determined, for example, by measuring the function of β-cells. Matthews et al., Diabet0l0gia 1985, 28: 412 19), intact before 162339.doc • 36 - 201249480 Proinsulin to insulin ratio (Forst et al, Diabetes 2〇〇3, u (Suppl·υ: A459), in oral Insulin/c-like secretion after glucose tolerance test or dietary tolerance test, or sexual test after frequent sampling of intravenous glucose 'by applying high blood sugar clamp research and / or minimal model. (StumvoH et al' Eur J Clin Wst 2〇〇1,3i: 38〇81). The term “pre-diabetes” is a condition in which individuals tend to develop type 2 diabetes. Pre-diabetes extends the definition of glucose intolerance to include having 2100 mg Individuals with a higher normal range of /dL (JB Meigs et al, Diabetes 2003; 52: 1475-1484) and fasting hyperinsulinemia (increased plasma insulin concentration). The scientific and medical basis for the identification of urinary diseases as a serious health threat is presented in the joint publication of the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases. The Prevention or Delay of Type 2 Diabetes position statement (Diabetes Care 2002; 25: 742-749). Individuals who may have insulin resistance are those who have two or more of the following attributes: «1:1) are overweight or obese, 2) Hypertension, 3) Hyperlipidemia, 4) One or more Class 1 disorders associated with the diagnosis of iGT or IFG or Type 2 diabetes. Insulin resistance can be confirmed in such individuals by calculating the H0MA-IR score. For the purposes of the present invention, insulin resistance is defined as an individual having a HOMA-IR score of &gt; 4.0 or a clinical condition greater than the upper limit of the criteria defined by the laboratory performing glucose and insulin assays. 162339.doc -37- 201249480 The term "type 1 diabetes" is defined as the individual's fasting or serum glucose greater than 125 mg/dL (6.94 mmol/L) in the presence of autoimmunity to islet beta cells or insulin. The concentration of the disease. If glucose tolerance test is performed, the blood glucose concentration of diabetic patients will exceed 200 mg glucose/dL in the presence of autoimmunity against islet β cells or insulin for 2 hours after taking 7 5 g of glucose in the empty stomach. Mmmol/L) plasma. In the glucose tolerance test, 75 g of glucose was orally administered to the patient being tested and the blood glucose concentration was recorded immediately before and 1 and 2 hours after taking the glucose, 10 to 12 hours after the fasting. The autoimmune presence of pancreatic β-cells can be observed by detecting circulating islet cell autoantibodies ["1 糖尿病 type j diabetes]], ie at least one of the following: G AD6 5 [glutamate degrading enzyme 65], ICA [islet cell cytoplasm], IA-2 [cytoplasmic cytoplasmic domain IA-2], ZnT8 [zinc transporter-8] or anti-insulin; or autoimmune in the absence of general circulating autoantibodies Other symptoms of sexuality [type 1 diabetes], as detected by pancreatic biopsy or imaging. There is usually a genetic predisposition (such as HLA, INS VNTR and PTPNU), but this is not always the case. The term "type 2 diabetes" Defined as an individual having a fasting blood glucose or serum glucose concentration greater than 125 mg/dL (6.94 mmol/L). Measurement of blood glucose values is a standard step in routine medical analysis. If glucose tolerance test is performed, the blood glucose concentration of diabetic patients will exceed 200 mg glucose/dL (1.1 mmol/L) blood stasis after taking air glucose for 75 hours for 2 hours. In the glucose test, 1 to 5 hours after fasting, 7 5 g of glucose was orally administered to the patient being tested, and before taking glucose 162339.doc • 38 · 201249480 with 1 and 2 Blood glucose levels were recorded immediately after hours. In healthy individuals, the blood glucose before taking glucose is between 60 and 110 mg/dL, compared with less than 200 mg/dL after 1 hour of glucose and less than 14〇mg/dLe after 2 hours. Between 140 and 220 mg' is considered to be abnormal glucose tolerance. The term "late type 2 diabetes" includes patients with secondary drug failure, indications for insulin therapy, and progression to microvascular and macrovascular complications such as diabetic nephropathy, or coronary heart disease (CHD). The term "HbAlc" denotes the product of the non-enzymatic glycosylation reaction of the hemoglobin b chain. The determination is known to those skilled in the art. HbAlc values are especially important in monitoring the treatment of diabetes. Since its production is basically dependent on the blood sugar concentration and the life of the red blood cells, HbAk with the meaning of "blood sugar memory" reflects the blood glucose concentration of the previous 4 to 6 weeks. Diabetic patients who have consistently better adjusted HbAic values by intensive urinary tract treatment (i.e., &lt;6.5% of total hemoglobin in the sample) are significantly protected by anti-diabetic microangiopathy. For example, 'metformin alone can achieve an average improvement in the value of diabetic patients. In order to reach &lt;65% and better said &lt;6% of the money. In all diabetic patients requiring the target «, the reduction in HbAlc value is insufficient. The term "insufficient blood glucose control" within the scope of the present invention means "insufficient blood glucose control" means that the patient exhibits a value of more than 65%, especially more than 7%, especially more than 7.5%, especially more than 8%. Illness. "metabolic syndrome" (also known as "Symptom X" (when it is used in the form of Metabolic Abnormalities) - also known as "abnormal metabolic syndrome") and Tengdaosu anti-162339.doc •39- 201249480 The main characteristic compound syndrome (Laaksonen DE et al, Am J Epidemiol 2002; 156:1070-7) » According to the ATP III/NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection , Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) JAMA: Journal of the American Medical Association (2001) 285: 2486-2497), when three or more of the following risk factors exist, metabolism can be made Diagnosis of Syndrome: 1. Abdominal obesity, defined as waist circumference > 40 inches or 102 cm (male) and > 35 inches or 94 cm (female); or as a national or sputum patient, defined as waist circumference 285 Cm (male) and 290 cm (female); 2. triglyceride &gt; 15 mg/dL; 3. HDL-cholesterol &lt; 40 mg/dL (male); 4. blood pressure 2130/85 mm Hg (SBP&gt;;130 or DBP 85); 5. Fasting blood glucose tlOOmg/dL. The NCEP definition has been validated (Laaksonen DE et al, Am J Epidemiol. (2002) 156: 1070-7). Triglycerides and HDL cholesterol in the blood can also be determined and described by standard methods in medical analysis, for example, in Thomas L (editor): "1^1?〇1&gt;1111"0丨3811〇36_],1 '11-Books Verlagsgesellschaft mbH, Frankfurt/Main, 2000 0 According to the usual definition, if the systolic blood pressure (SBP) exceeds the value of 140 mm Hg and the diastolic blood pressure (DBP) exceeds the value of 90 mm Hg, it can be diagnosed as hypertension. If the patient suffers from phenotypic diabetes, it is currently recommended to reduce systolic blood pressure to levels below 162339.doc -40 - 201249480 130 mm Hg and diastolic blood pressure to below 80 mm Hg. NODAT (new diabetes after transplantation) and PTMS (post-transplant metabolic syndrome) are defined in accordance with the American Diabetes Association Diagnostic Criteria for Type 2 Diabetes and the International Diabetes Federation (IDF) and the American Heart Association (IDC) American Heart Association) / Definition of the National Heart, Lung, and Blood Institute. NODAT and/or PTMS are associated with increased risk of microvascular and macrovascular disease and events, transplant rejection, infection, and death. A number of predictors have been identified as potential risk factors associated with NODAT and/or PTMS, including older transplants, males, pre-implantation body mass index, pre-transplant diabetes, and immunosuppression. The term "gestational diabetes" (pregnancy diabetes) refers to a form of diabetes that develops during pregnancy and usually disappears after birth. Gestational diabetes is diagnosed by a screening test between Week 24 and Week 28 of pregnancy. It is usually a simple test in which the blood glucose concentration is measured 1 hour after administration of 5 g of glucose solution. If the 1 h concentration is higher than 14 〇 mg/dL, then suspected gestational diabetes is "final diagnosis can be obtained by standard glucose tolerance test, for example using 75 g of glucose. The term "hyperuricemia is too high" means a condition of high serum total urate concentration. The American Medical Association (American Medical Ass〇ciati〇n) treats uric acid concentrations between 3.6 mg/dL (about 214 hunger) and 83 mg/dL (about 494 (four) 〇i/l) in human blood. It is normal. High serum total urate concentrations, or hyperuricemia, are often associated with several diseases. For example, a high serum total urate concentration can cause an arthritis called gout in the joint. Gout is a condition caused by the accumulation of monosodium urate or uric acid crystals in the articular cartilage, tendon and surrounding tissues of the joint due to the increase in the total urate level in the bloodstream 162339.doc 201249480. Ureate or uric acid accumulation on such tissues stimulates the inflammatory response of such tissues. When uric acid or urate crystallizes in the kidney, uric acid at a saturated level in the urine causes the formation of kidney stones. In addition, high serum total urate is usually associated with metabolic syndrome called cardiovascular disease and hypertension. The term "hypoxicemia" means a condition in the presence or absence of a positive balance of sodium-deficient water, which is recognized when blood sodium is below 135 mml/L. Hypospadia is a condition that can occur in an individual who is excessively depleted of water; however, it is more common that hyponatremia is a drug or a complication caused by other underlying medical conditions that can lead to reduced drainage. Too low a blood lead can result in water intoxication, which occurs when the normal permeability of the extracellular fluid is below the safety limit due to the retention of excess water. Water poisoning is a potentially fatal disturbance of brain function. Typical symptoms of water poisoning include nausea, vomiting, headache, and discomfort. The term "treatment" includes treatment of a patient who already has such a condition (specifically, a phenotype). Treatment may be symptomatic treatment to alleviate the symptoms or cause of a particular indication to reverse or partially reverse the indication. Or stop or slow the progression of the disease. Thus, the compositions and methods of the present invention are useful, for example, in the treatment of a period of time and in the treatment of chronic conditions. The terms "prophylactic treatment" and "prevention" are used interchangeably and include treating a patient having the risk of developing a condition as described above&apos; thus reducing the risk. 162339.doc -42·

Claims (1)

201249480 VII. Scope of application: 1. A pharmaceutical composition comprising a) an internal sustained release core comprising metformin (especially monomethyl guanidine) and one or more excipients; b) optional intermediate a seal coat; and c) an external immediate release coating comprising at least one active pharmaceutical ingredient selected from the group consisting of DPP-4 inhibitors (preferred Hnagliptin) and SGLT-2 inhibitors (preferably 1_Chloro-4_(0_1)_glucopyranose_丨_yl[4-((5)-tetrahydrofuran-3(yloxy)-benzylbendyl); and one or more excipients. 2. The pharmaceutical composition of claim 1, wherein the internal sustained release core &amp;) is a formulation comprising diterpene guanidine hydrochloride, a swellable and/or sustained release polymer, and/or a plurality of other excipients. 3. A pharmaceutical composition according to item 1 or 2, wherein the external immediate release coating comprises linalistatin, arginine as a stabilizer, a film coating agent, a plasticizer, and optionally A film coating formulation of a slip agent. &quot; 4. The pharmaceutical composition of claim 3 wherein the weight ratio of physico-arginine to linagliptin is in the range of from about 2:1 to about 1:1, or up to about 〇2:1. 5. The pharmaceutical composition of claim M2, wherein the external immediate release coating c) comprises 1-gas-4 ((β·0-glucopyranose·κ)_2_[4_(〇s). A film coating formulation of argon biting _ 3_ yloxy)-benzyl] benzene, a film coating agent, a plasticizer, and optionally a slip agent. &amp; The pharmaceutical composition of claim 3 or 5, wherein the film coating agent is propyl 162339.doc 201249480 methylcellulose. 7. The pharmaceutical composition of claim 6, wherein the hydroxypropyl decyl cellulose is Hypromellose 2910, Methocel® 5 or Methocel®15. 8. The pharmaceutical composition of claim 3 or 5, wherein the plasticizer is polyethylene glycol. 9. The pharmaceutical composition of claim 8, wherein the polyethylene glycol is Macr(R) i 400, 6000 or 8000. 10. The pharmaceutical composition of claim 3 or 5, wherein the plasticizer is propylene glycol β. 11. The pharmaceutical composition according to claim 3 or 5, wherein the optional slip agent is talc. 12. Or a pharmaceutical composition of 2 in which the seal coat is present. 13. The pharmaceutical composition of claim 12, wherein the seal coat comprises a film coating, a plasticizer, and optionally a slip agent, one or more pigments and/or colorants. 14. The pharmaceutical composition of claim 1 or 2, wherein the seal coat is absent. 15. The pharmaceutical composition of claim 1 or 2, wherein the diterpene dihydrochloride is present in a unit dosage strength of 500, 750, 850, 1000 or 1500 mg. 16. The pharmaceutical composition of claim 1 or 2, wherein the linagliptin is present in a unit dose strength of 〇 5, 1, 2.5 or 5 mg. 17. The pharmaceutical composition according to claim 1 or 2, wherein the grape pentose-1·yl)-2-[4-((S)-tetrahydrofuran_3_yloxy)phenyl fluorenyl]_ The benzene is present at a unit dose strength of 5, 10, 12.5 or 25 mg. 18. The pharmaceutical composition of claim 1 or 2 which is a lozenge administered orally. 19. The lozenge of claim 18, further comprising an outer film topcoat. 20. The tablet of claim 19, wherein the outer film topcoat comprises a film coating agent, a plasticizer, and optionally a slip agent, one or more pigments and/or colorants. 21. The pharmaceutical composition of claim 1 or 2 which is used for the treatment and/or prevention of metabolic diseases, slows progression and/or delays onset. 22. The pharmaceutical composition of claim 21, wherein the metabolic disease is type 2 diabetes and a condition associated therewith. The pharmaceutical composition of claim 22, wherein the metabolic disease is diabetes complications. 24. The pharmaceutical composition of claim 21, wherein the patient is a type 2 diabetic patient not previously treated with an anti-hyperglycemic agent, or although one or two are selected from the group consisting of metformin, continually brewing gland, and sputum Conventional ketones (eg, pioglitazone), ginines, alpha-glucosidase blockers, GLP-1 or GLP-1 analogs, and insulin or insulin analogs Type 2 diabetic patients who are treated with antihyperglycemic agents but are still not adequately glycemic. 162339.doc 201249480 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: (none) 162339.doc