# US 11,992,477 B2 · Pharmaceutical combination, composition, and combination preparation comprising glucokinase activator and SGLT-2 inhibitor and preparation methods and uses thereof

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- Number: US 11,992,477 B2
- Document ID: US11992477B2
- Status: Granted
- Kind: B2
- Application number: 17/058,883
- Filed: 2019-05-28
- Published: 2021-07-15
- Granted: 2024-05-28
- Earliest claimed: 2018-05-31
- Assignees: Hua Medicine (Shanghai) Ltd.
- Applicants: HUA Medicine (Shanghai) Ltd.
- Inventors: Li Chen; Yongguo Li; Gaosen Wang; Huisheng Gao
- Web page: https://patentgrep.com/patent/US11992477B2

## CPC

- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 9/1611: {Inorganic compounds}
- A61K 9/1617: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2086: {Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat (active cores with a complete drug-free outer coat A61K9/28)}
- A61K 9/2095: {Tabletting processes}
- A61K 9/2813: {Inorganic compounds}
- A61K 9/284: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone}
- A61K 9/2866: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 31/155: Amidines ([IMAGE cpc-sch-A61K-1029.gif]), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/451: having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/7034: attached to a carbocyclic compound, e.g. phloridzin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/50: for increasing or potentiating the activity of insulin
- A61P 9/12: Antihypertensives
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- C07D 231/38: Nitrogen atoms (nitro radicals C07D231/16)
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a pharmaceutical combination, comprising a glucokinase activator or a pharmaceutically acceptable salt, isotopic label, crystal form, hydrate, solvate, diastereomer, or enantiomer thereof and an SGLT-2 inhibitor. The present invention further relates to a pharmaceutical composition, a fixed-dose combination preparation, and preparation methods and uses thereof.

## Claims

### Claim 1

A fixed dose combination formulation, comprising:
(a) a glucokinase activator, which is a compound represented by the following formulae, or a pharmaceutically acceptable salt, an isotope labeled analogue, a crystalline form, a hydrate, a solvate, or a diastereomeric or enantiomeric form thereof,
(b) a SGLT-2 inhibitor; and
(c) one or more excipients.

### Claim 2 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the weight ratio of the glucokinase activator to the SGLT-2 inhibitor is about 30:1 to 1:30, about 20:1 to 1:12, about 0.75:1, about 1:2, about 1:1, about 1:4, about 1:6, about 1:12, about 2:1, about 2.5:1, about 3:1, about 5:1, about 6:1, about 7.5:1, about 10:1, about 15:1, or about 20:1.

### Claim 3 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the glucokinase activator is about 1-96% by weight; and the SGLT-2 inhibitor is about 0.1-80% by weight.

### Claim 4 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the glucokinase activator is the compound HMS5552 represented by the following formula, or an isotope labeled analogue or a pharmaceutically acceptable salt thereof,

### Claim 5 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the glucokinase activator is in the form of a solid dispersion containing a polymer carrier.

### Claim 6 (depends on 5)

The fixed dose combination formulation of claim 5, wherein the weight ratio of the glucokinase activator to the polymer carrier is about 1:10 to 10:1, about 1:9 to 9:1, about 1:4 to 4:1, about 3:7 to 7:3, about 2:3 to 3:2, about 3:4 to 4:3, about 4:5 to 5:4, about 5:6 to 6:5, about 1:1, about 2:3, about 3:4, about 4:5 or about 5:6.

### Claim 7 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the SGLT-2 inhibitor is selected from the group consisting of canagliflozin, canagliflozin hemihydrate, dapagliflozin, dapagliflozin propylene glycol monohydrate, empagliflozin, ipragliflozin, luseogliflozin and tofogliflozin, and a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the glucokinase activator is present in a dose ranging from about 1 mg to about 200 mg, from about 25 mg to about 100 mg, about 25 mg, about 50 mg, about 75 mg or about 100 mg.

### Claim 9 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the SGLT-2 inhibitor is present in a dose ranging from about 1 mg to 500 mg, from about 5 mg to about 300 mg, about 2.5 mg, about 5 mg, about 10 mg, about 12.5 mg, about 20 mg, about 25 mg, about 100 mg, about 200 mg or about 300 mg.

### Claim 10 (depends on 1)

The fixed dose combination formulation of any one of claim 1, wherein the one or more excipients are selected from the group consisting of binders, fillers, disintegrants, lubricants, glidants, surfactants, wetting agents, antioxidants, flavoring agents, sweetening agents, coloring agents and coating agents.

### Claim 11 (depends on 10)

The fixed dose combination formulation of claim 10, wherein the binder is selected from the group consisting of polyvinylpyrrolidone, hydroxypropyl cellulose and hydroxypropyl methyl cellulose; the filler is selected from the group consisting of microcrystalline cellulose, silicified microcrystalline cellulose, lactose, calcium dihydrogen phosphate, mannitol, corn starch and pregelatinized starch; the disintegrant is selected from the group consisting of croscarmellose sodium, crospovidone and sodium starch glycolate; the lubricant is selected from the group consisting of magnesium stearate and sodium stearyl fumarate; and the glidant is selected from the group consisting of colloidal silicon dioxide and talc.

### Claim 12 (depends on 1)

The fixed dose combination formulation of claim 1, which is a tablet.

### Claim 13 (depends on 12)

The fixed dose combination formulation of claim 12, which is a coated tablet.

### Claim 14 (depends on 13)

The fixed dose combination formulation of claim 13, wherein the coated tablet is a film-coated tablet, wherein the film-coating agent comprises:
film-coating substrate(s), which is hypromellose, hydroxypropyl methyl cellulose, or a mixture thereof;
optional plasticizer(s), which is polyvinyl alcohol, polyethylene glycol, propylene glycol, polysorbate, or a mixture thereof;
optional coloring agent(s), which is iron oxide red, iron oxide yellow, or a mixture thereof;
optional opacifier(s), which is titanium dioxide, and
optional glidant(s).

### Claim 15 (depends on 13)

The fixed dose combination formulation of claim 13, wherein the coated tablet is a film-coated tablet.

### Claim 16 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 1-96% of a solid dispersion containing HMS5552 and a polymer carrier;
about 0.1-80% of the SGLT-2 inhibitor;
about 0-80% of filler(s);
about 1-25% of binder(s);
about 0-15% of disintegrant(s);
about 0.1-10% of lubricant(s); and
about 0-3% of glidant(s).

### Claim 17 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 5 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 18 (depends on 1)

The fixed dose combination formulation of claim 1 comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 12.5 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 19 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 20 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 25 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 21 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 25 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 22 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 23 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 100 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 24 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 25 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 25 mg of empagliflozin;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 25 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 5.00 mg of empagliflozin, about 88.10 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 6.50 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate, and about 7.80 mg of a film-coating agent.

### Claim 26 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 12.50 mg of empagliflozin, about 99.30 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 7.00 mg of croscarmellose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of a film-coating agent.

### Claim 27 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 10.00 mg of empagliflozin, about 84.40 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate, and about 7.80 mg of a film-coating agent.

### Claim 28 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 25.00 mg of empagliflozin, about 88.20 mg of microcrystalline cellulose, about 8.40 mg of hydroxypropyl cellulose, about 5.60 mg of croscarmellose sodium, about 2.80 mg of magnesium stearate and about 8.40 mg of a film-coating agent.

### Claim 29 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 200 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 10.00 mg of empagliflozin, about 72.00 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.00 mg of croscarmellose sodium, about 3.00 mg of magnesium stearate, and about 9.00 mg of a film-coating agent.

### Claim 30 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 10.00 mg of empagliflozin, about 96.80 mg of microcrystalline cellulose, about 6.60 mg of Povidone, about 4.40 mg of croscarmellose sodium, about 2.20 mg of magnesium stearate, and about 6.60 mg of a film-coating agent.

### Claim 31 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 25.00 mg of empagliflozin, about 100.30 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.10 mg of croscarmellose sodium, about 2.40 mg of magnesium stearate, and about 7.20 mg of a film-coating agent.

### Claim 32 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 50 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 25.00 mg of empagliflozin, about 309.00 mg of microcrystalline cellulose, about 8.00 mg of croscarmellose sodium, about 4.00 mg of micronized silica gel, about 4.00 mg of magnesium stearate, and about 12.00 mg of a film-coating agent.

### Claim 33 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 34 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 35 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 36 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 37 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 100 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 5 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 38 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 25 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 10 mg of dapagliflozin or a corresponding amount of dapagliflozin propylene glycol monohydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-8% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 39 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 88.25 mg of microcrystalline cellulose, about 7.80 mg of hydroxypropyl cellulose, about 5.20 mg of croscarmellose sodium, about 2.60 mg of magnesium stearate and 7.80 mg of a film-coating agent.

### Claim 40 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 100.65 mg of microcrystalline cellulose, about 6.60 mg of hydroxypropyl cellulose, about 4.40 mg of croscarmellose sodium, about 2.20 mg of magnesium stearate and 6.60 mg of a film-coating agent.

### Claim 41 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 91.50 mg of microcrystalline cellulose, about 8.10 mg of hydroxypropyl cellulose, about 5.40 mg of croscarmellose sodium, about 2.70 mg of magnesium stearate and 8.10 mg of a film-coating agent.

### Claim 42 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 200 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 6.15 mg of dapagliflozin propylene glycol monohydrate, about 75.55 mg of microcrystalline cellulose, about 9.00 mg of hydroxypropyl cellulose, about 6.30 mg of croscarmellose sodium, about 3.00 mg of magnesium stearate and 9.00 mg of a film-coating agent.

### Claim 43 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 113.06 mg of microcrystalline cellulose, about 7.20 mg of hydroxypropyl cellulose, about 5.04 mg of croscarmellose sodium, about 2.40 mg of magnesium stearate and 7.20 mg of a film-coating agent.

### Claim 44 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 50 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 12.30 mg of dapagliflozin propylene glycol monohydrate, about 313.70 mg of microcrystalline cellulose, about 8.00 mg of hydroxypropyl cellulose, about 8.00 mg of croscarmellose sodium, about 4.00 mg of micronized silica gel, about 4.00 mg of magnesium stearate and 12.00 mg of a film-coating agent.

### Claim 45 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 46 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 47 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 100 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 100 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 48 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 75 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 49 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 50 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 50 (depends on 1)

The fixed dose combination formulation of claim 1, comprising by weight:
about 25 mg of HMS5552 in a solid dispersion containing about 1:1 of HMS5552 and methacrylic acid copolymer of type A;
about 300 mg of canagliflozin or a corresponding amount of canagliflozin hemihydrate;
about 0-70% of filler(s);
about 2-8% of binder(s);
about 1-5% of disintegrant(s);
about 0.5-3% of lubricant(s); and
about 0-0.5% of glidant(s).

### Claim 51 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 101.93 mg of canagliflozin hemihydrate, about 294.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate, and about 18.00 mg of a film-coating agent.

### Claim 52 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 101.93 mg of canagliflozin hemihydrate, about 344.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.00 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate, and about 18.00 mg of a film-coating agent.

### Claim 53 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 200 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 101.93 mg of canagliflozin hemihydrate, about 244.07 mg of microcrystalline cellulose, about 18.00 mg of hydroxypropyl cellulose, about 30.0 mg of croscarmellose sodium, about 6.00 mg of magnesium stearate, and about 18.00 mg of a film-coating agent.

### Claim 54 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 150 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 305.78 mg of canagliflozin hemihydrate, about 226.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate, and about 22.50 mg of a film-coating agent.

### Claim 55 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 100 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 305.78 mg of canagliflozin hemihydrate, about 276.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate, and about 22.50 mg of a film-coating agent.

### Claim 56 (depends on 1)

The fixed dose combination formulation of claim 1, comprising about 50 mg of a solid dispersion that contains about 1:1 of HMS5552 and methacrylic acid copolymer of type A, about 305.78 mg of canagliflozin hemihydrate, about 326.72 mg of microcrystalline cellulose, about 22.50 mg of hydroxypropyl cellulose, about 37.50 mg of croscarmellose sodium, about 7.50 mg of magnesium stearate, and about 22.50 mg of a film-coating agent.

### Claim 57 (depends on 1)

A method for preparing the fixed dose combination formulation of claim 1, comprising incorporating the active ingredients into one or more excipients for granulation, optionally further filling the obtained granule mixture into a vial, a sachet or a capsule, or compressing it into a tablet with a desired shape; and optionally further coating the obtained tablet.

### Claim 58 (depends on 1)

A method for slowing the progression delaying, or treating one or more metabolic disorders selected from the group consisting of: type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, hypertension, insulin resistance, diabetic nephropathy, decreased renal function and/or metabolic syndrome; or improving blood glucose control and/or reducing fasting plasma glucose, postprandial plasma glucose and/or glycosylated hemoglobin HbA1c, or preventing, slowing, delaying, or reversing complications of diabetes mellitus, comprising administering to a subject a therapeutically effective amount of the fix dose combination formulation of claim 1.

### Claim 59 (depends on 5)

The fixed dose combination formulation of claim 5, wherein the polymer carrier is a polyacrylic resin.

### Claim 60 (depends on 59)

The fixed dose combination formulation of claim 59, wherein the polymer carrier is methacrylic acid copolymer of type A.

### Claim 61 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the SGLT-2 inhibitor is empagliflozin.

### Claim 62 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the SGLT-2 inhibitor is dapagliflozin or dapagliflozin propylene glycol monohydrate.

### Claim 63 (depends on 1)

The fixed dose combination formulation of claim 1, wherein the SGLT-2 inhibitor is canagliflozin or canagliflozin hemihydrate.