CN110339176A - 包含吉格列汀和二甲双胍的组合药物及其制备方法 - Google Patents
包含吉格列汀和二甲双胍的组合药物及其制备方法 Download PDFInfo
- Publication number
- CN110339176A CN110339176A CN201910676778.7A CN201910676778A CN110339176A CN 110339176 A CN110339176 A CN 110339176A CN 201910676778 A CN201910676778 A CN 201910676778A CN 110339176 A CN110339176 A CN 110339176A
- Authority
- CN
- China
- Prior art keywords
- fland
- layer
- melbine
- composition
- medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 239000000203 mixture Substances 0.000 title claims abstract description 37
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 11
- 239000002245 particle Substances 0.000 claims description 12
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 11
- 229960003105 metformin Drugs 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 229940123208 Biguanide Drugs 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 5
- 150000004283 biguanides Chemical class 0.000 claims description 5
- 238000005253 cladding Methods 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
- 229920002125 Sokalan® Polymers 0.000 claims description 3
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001631 carbomer Drugs 0.000 claims description 3
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 3
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims 2
- 239000002131 composite material Substances 0.000 claims 1
- 229940057948 magnesium stearate Drugs 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 13
- 238000004090 dissolution Methods 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 11
- 201000010099 disease Diseases 0.000 abstract description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 description 14
- 230000000052 comparative effect Effects 0.000 description 7
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- 238000013268 sustained release Methods 0.000 description 5
- 239000012730 sustained-release form Substances 0.000 description 5
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- 239000000853 adhesive Substances 0.000 description 4
- 230000001070 adhesive effect Effects 0.000 description 4
- 230000003178 anti-diabetic effect Effects 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 229940095064 tartrate Drugs 0.000 description 4
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000003472 antidiabetic agent Substances 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 230000007246 mechanism Effects 0.000 description 3
- 229940127017 oral antidiabetic Drugs 0.000 description 3
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 208000013016 Hypoglycemia Diseases 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000002218 hypoglycaemic effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 208000037821 progressive disease Diseases 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 229910004298 SiO 2 Inorganic materials 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- -1 for example Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002458 gemigliptin Drugs 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- MGXWVYUBJRZYPE-YUGYIWNOSA-N incretin Chemical class C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)[C@@H](C)O)[C@@H](C)CC)C1=CC=C(O)C=C1 MGXWVYUBJRZYPE-YUGYIWNOSA-N 0.000 description 1
- 239000000859 incretin Substances 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(e)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 239000011885 synergistic combination Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及包含吉格列汀和二甲双胍的组合药物及其制备方法。本发明的由包含二甲双胍的第一层和包含吉格列汀的第二层组成的药物组合物对于预防和治疗糖尿病及其复杂疾病具有优异效果,并降低了每种组分的副作用。另外,本发明的组合物包含分离形式的吉格列汀和二甲双胍,以便保持这两种组分的固有溶出速率和改善患者顺应性。
Description
本申请是国际申请日2013年10月7日、国际申请号PCT/KR2013/008932于2015年4月8日进入中国国家阶段、申请号201380052265.X、发明名称“包含吉格列汀和二甲双胍的组合药物及其制备方法”的申请的分案申请。
技术领域
本发明涉及一种包含作为活性组分的吉格列汀(Gemigliptin)和二甲双胍的组合药物及其制备方法。
背景技术
糖尿病分成两种类型——即,胰岛素依赖性1型糖尿病和非胰岛素依赖性(胰岛素抵抗性)2型糖尿病,后者占糖尿病患者的90%以上。
2型糖尿病是来源于包括胰岛素抗性和胰岛素分泌病症的双重内分泌作用的复杂病态生理学的慢性进行性疾病。2型糖尿病的治疗通常从饮食和锻炼开始,并通向其中使用口服抗糖尿病药的单独药物疗法。尽管在某些患者中,在初期阶段可利用单独的常规药物疗法来控制血糖水平,但是在大多数患者中,在诊断后数年需要组合治疗,因为他们的血糖水平不能通过单独的药物疗法来控制。然而,因为2型糖尿病是一种进行性疾病,所以对常规组合治疗表现出良好的始初反应的大多数患者在长期维持稳定的血糖水平上遇到困难,并需要增加给药量或另外的治疗。虽然目前使用的组合治疗具有增强血糖控制的可能性,但是它们具有自身的局限性以及副作用,比如低血糖症、体重增加等。而且,两种或更多种口服抗糖尿病药的组合引起许多患者不适,并且可能导致患者不愿意遵循药物方案从而治疗失败。
吉格列汀是一种新开发的DPP-IV抑制剂,其活化肠促胰岛素,以表现出稳定的血糖水平下降。而且,吉格列汀不具有常规口服抗糖尿病药的缺点比如低血糖症和体重增加,且表现出低心血管病症风险,从而其已经超越磺酰脲类。
考虑上述,为了增强疗效、减轻副作用并改善患者顺应性,本发明人对于具有不同作用机制的两种或更多种抗糖尿病药的组合进行了深入研究。作为这种努力的结果,本发明人发现可以通过吉格列汀和二甲双胍的组合来实现这样的目的,因此完成了本发明。
发明内容
技术问题
本发明的目的是提供用于预防和治疗糖尿病的药物组合物,其包含作为活性组分的具有不同作用机制的抗糖尿病药。
本发明的另一个目的是提供制备用于预防和治疗糖尿病的药物组合物的方法,所述药物组合物包含作为活性组分的具有不同作用机制的抗糖尿病药。
解决问题的技术方案
因此,本发明提供药物组合物,其由包含二甲双胍的第一层和包含吉格列汀的第二层组成。
在本发明的药物组合物中,可以用包含吉格列汀的第二层包覆包含二甲双胍的第一层。
本发明的另一个目的是通过制备包含吉格列汀和二甲双胍的组合药物的方法实现的,所述方法包括以下步骤:
(a)将吉格列汀与药学可接受的赋形剂混合;
(b)将二甲双胍与药学可接受的赋形剂混合,并将混合物制粒;和
(c)将步骤(a)中制备的混合物与步骤(b)中制备的颗粒混合。
在本发明的方法中,步骤(c)优选地通过将包含吉格列汀的混合物和包含二甲双胍的颗粒压制成双层片剂来进行。或者,步骤(c)可以通过用包含吉格列汀的混合物包覆由包含二甲双胍的颗粒制成的片剂来进行。
根据本发明,由于组合了作为具有不同的作用机制的抗糖尿病药的DPP-IV抑制剂吉格列汀和二甲双胍,因此药物的协同作用增强了疗效、减轻了副作用,并且改善了患者顺应性。
而且,为了克服由于吉格列汀和二甲双胍的组合引起的问题并获得与单独药物相同的溶出度,本发明提供包含呈分离形式的吉格列汀和二甲双胍的组合药物。
因此,本发明的第一方面涉及药物组合物,其由包含二甲双胍的第一层和包含吉格列汀的第二层组成的双层。
本发明的另一方面涉及药物组合物,其中用包含吉格列汀的第二层包覆包含二甲双胍的第一层。
为了制备本发明的包含呈分离形式的吉格列汀和二甲双胍的组合药物,将吉格列汀制备成与赋形剂的混合物,将二甲双胍制粒,然后可以通过将二者混合来制备吉格列汀和二甲双胍的组合药物。
特别地,本发明的组合药物的制备方法包括以下步骤:
(a)将吉格列汀与药学可接受的赋形剂混合;
(b)将二甲双胍和药学可接受的赋形剂的混合物湿法制粒,并将颗粒干燥;和
(c)将步骤(a)中制备的包含吉格列汀的混合物与步骤(b)中制备的包含二甲双胍的颗粒混合。
在本发明的方法的一个实施方案中,分别制备包含吉格列汀的混合物和包含二甲双胍的颗粒,然后将其压制成由吉格列汀层和二甲双胍层组成的双层片剂。该组合药物表现出快速释放吉格列汀和持续释放二甲双胍的溶出模式,并且这两种溶出模式不会相互影响。
在本发明的另一个实施方案中,用吉格列汀层包覆包含二甲双胍的片剂。该包衣的组合药物可以通过将二甲双胍颗粒压制成片剂,将其进一步用与包衣基质混合的吉格列汀包覆来制备。
本发明的药物组合物可以包含药学可接受的载体或添加剂。在本发明的一个实施方案中,所述药物组合物可以包含药学可接受的赋形剂、崩解剂、粘合剂、润滑剂等。所述赋形剂可以包括但不限于微晶纤维素。所述崩解剂可以包括但不限于交联羧甲纤维素钠、交聚维酮、淀粉羟乙酸钠等。所述粘合剂可以包括但不限于聚乙烯吡咯烷酮、共聚维酮(copovidone)等。所述润滑剂可以包括但不限于胶态二氧化硅、水合二氧化硅(hydroussilicon dioxide)、硬脂酸镁、硬脂酰基富马酸钠山嵛酸甘油酯(Compritol)、硬脂酸钙、硬脂酸、滑石等。
在本发明的另一个实施方案中,包含吉格列汀的第二层可以不包含粘合剂。
另外,本发明的药物组合物可以是薄膜包衣的。薄膜包衣中可用的物质可以包括常规物质,比如羟丙基甲基纤维素、聚乙烯吡咯烷酮、共聚维酮、系列、系列,但不限于此。
在本发明的组合药物中,作为活性组分的吉格列汀可以吉格列汀酒石酸盐·1.5水合物的形式被包含,用量为基于吉格列汀层的总重量的10至80重量%,优选10至70重量%。作为另一活性组分的二甲双胍可以二甲双胍盐酸盐的形式被包含,用量为基于二甲双胍层总重量的40至80重量%,优选50至70重量%。
在本发明中,吉格列汀层可以包含20至90重量%的药学可接受的添加剂,并且二甲双胍层可以包括20至60重量%的药学可接受的添加剂。这样的比例适用于包括分离颗粒剂在内的本发明的所有制剂。如果制剂具有偏离上述范围的比例,则可能产生过大的片剂,因而降低给药便利性。为了给药便利性,吉格列汀层可以优选地为基于二甲双胍层的40重量%或更少,更优选30重量%或更少,最优选20重量%或更少。
在本发明中,二甲双胍层显示持续释放的溶出模式,并且可以使用用于该溶出模式的各种药学可接受的组分。最优选地,使用预胶化淀粉构建用于该目的的持续释放基质。所述持续释放基质组分以基于二甲双胍盐酸盐重量的40至80重量%,更优选50至70重量%,最优选55至65重量%的量被包含。
对于本发明的药物组合物而言,可以使用多种药学可接受的吉格列汀盐,其中吉格列汀酒石酸盐·1.5水合物是最优选的形式。吉格列汀酒石酸盐·1.5水合物的结构和制备方法公开在韩国专利第0776623号中,其公开内容援引加入本文。另外,对于本发明的药物组合物而言,可以使用多种药学可接受的二甲双胍盐,其中二甲双胍盐酸盐是最优选的形式。
发明的有益效果
由于具有不同作用机制的两种组分的协同组合,本发明的包含吉格列汀和二甲双胍的药物组合物对于预防和治疗糖尿病及其复杂疾病具有优异功效,并降低了每种组分的副作用。另外,本发明提供包含呈分离形式的吉格列汀和二甲双胍的组合药物,从而可以克服由于组合引起的问题,并且与单一组分的药物相比可以获得这两种组分的相同溶出速率。
附图简述
图1为显示与比较例1的单一组分药物相比,实施例1和2的组合药物的吉格列汀的溶出试验结果的图。
图2为显示与比较例1的单一组分药物相比,实施例1和2的组合药物的二甲双胍的溶出试验结果的图。
发明的实施方式
通过下述实施例更详细地解释本发明。然而,这些实施例仅用于例示本发明,而本发明的范围不限于此。
实施例1和2:制备包含吉格列汀和二甲双胍的双层片剂
在这些实施例中制备其中快速释放吉格列汀而不会影响持续释放二甲双胍的吉格列汀和二甲双胍的组合药物。
[表1]
通过使用聚乙烯吡咯烷酮作为粘合剂,将二甲双胍盐酸盐、微晶纤维素和预胶化淀粉的混合物制粒,将制备的颗粒干燥,并与卡波姆和硬脂酸镁混合,以制备二甲双胍层物质。制备包括吉格列汀酒石酸盐·1.5水合物的所有组分的简单混合物作为吉格列汀层物质。将二甲双胍层物质和吉格列汀层物质两者压制成双层片剂,并使用Opadry II对该片剂进行薄膜包衣。
比较例1:吉格列汀的单一组分药物和二甲双胍的单一组分药物
使用LG Life Sciences Ltd.生产的吉格列汀50mg片剂作为吉格列汀的单一组分药物,并且使用市售可获得的Glucophage XR 500mg片剂作为二甲双胍的单一组分药物。
试验例1:实施例和比较例的制剂的吉格列汀和二甲双胍的溶出试验
对于实施例1和2的双层片剂和比较例1的单一组分药物,在下述条件下进行溶出试验并比较。
[溶出条件]
洗出液:pH 1.2(900mL)
仪器:美国药典篮法(USP Basket Method),100rpm
温度:37℃
[结果]
图1和图2为显示与比较例1的单一组分药物相比,实施例1和2的组合药物的吉格列汀和二甲双胍的溶出试验结果的图。
如图1和图2所证实的,与比较例1的单一组分药物相比,实施例1和2中制备的包含吉格列汀和二甲双胍的包衣双层片剂表现出类似的溶出速率。
Claims (5)
1.用于预防或治疗糖尿病的组合药物,其由包含二甲双胍的第一层和包含吉格列汀的第二层组成,其中所述第一层还包含聚乙烯吡咯烷酮、微晶纤维素、预胶化淀粉、卡波姆和硬脂酸镁;所述第二层还包含微晶纤维素、交联羧甲纤维素钠和硬脂酰基富马酸钠;并且所述预胶化淀粉以基于二甲双胍盐酸盐重量的50至70重量%的量被包含。
2.根据权利要求1的组合药物,其中用所述包含吉格列汀的第二层包覆所述包含二甲双胍的第一层。
3.制备如权利要求1所定义的组合药物的方法,其包括以下步骤:
(a)将吉格列汀与药学可接受的赋形剂混合以获得第二层,所述赋形剂为微晶纤维素、交联羧甲纤维素钠和硬脂酰基富马酸钠;
(b)将二甲双胍与预胶化淀粉、聚乙烯吡咯烷酮、微晶纤维素、卡波姆和硬脂酸镁混合,并将混合物制粒以获得第一层,其中所述预胶化淀粉以基于二甲双胍盐酸盐重量的50至70重量%的量被包含;和
(c)将步骤(a)中制备的混合物与步骤(b)中制备的颗粒以分开的层混合,获得所述组合药物。
4.根据权利要求3的方法,其中步骤(c)是通过将步骤(a)中制备的包含吉格列汀的混合物和步骤(b)中制备的包含二甲双胍的颗粒压制成双层片剂来进行的。
5.根据权利要求3的方法,其中步骤(c)是通过用步骤(a)中制备的包含吉格列汀的混合物包覆由步骤(b)中制备的包含二甲双胍的颗粒制成的片剂来进行的。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2012-0111404 | 2012-10-08 | ||
KR20120111404 | 2012-10-08 | ||
CN201380052265.XA CN104884051A (zh) | 2012-10-08 | 2013-10-07 | 包含吉格列汀和二甲双胍的组合药物及其制备方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380052265.XA Division CN104884051A (zh) | 2012-10-08 | 2013-10-07 | 包含吉格列汀和二甲双胍的组合药物及其制备方法 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN110339176A true CN110339176A (zh) | 2019-10-18 |
Family
ID=50477605
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910676778.7A Pending CN110339176A (zh) | 2012-10-08 | 2013-10-07 | 包含吉格列汀和二甲双胍的组合药物及其制备方法 |
CN201380052265.XA Pending CN104884051A (zh) | 2012-10-08 | 2013-10-07 | 包含吉格列汀和二甲双胍的组合药物及其制备方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201380052265.XA Pending CN104884051A (zh) | 2012-10-08 | 2013-10-07 | 包含吉格列汀和二甲双胍的组合药物及其制备方法 |
Country Status (19)
Country | Link |
---|---|
EP (1) | EP2903602B1 (zh) |
KR (1) | KR101526553B1 (zh) |
CN (2) | CN110339176A (zh) |
AU (1) | AU2013330679B2 (zh) |
BR (1) | BR112015007360A8 (zh) |
CL (1) | CL2015000857A1 (zh) |
DO (1) | DOP2015000071A (zh) |
HK (1) | HK1211849A1 (zh) |
MX (1) | MX368184B (zh) |
MY (1) | MY174238A (zh) |
PE (1) | PE20150721A1 (zh) |
PH (1) | PH12015500653A1 (zh) |
RU (1) | RU2664422C2 (zh) |
SG (1) | SG11201502241XA (zh) |
TW (1) | TWI606848B (zh) |
UA (1) | UA114527C2 (zh) |
UY (1) | UY35065A (zh) |
WO (1) | WO2014058188A1 (zh) |
ZA (1) | ZA201501985B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112546013A (zh) * | 2020-12-29 | 2021-03-26 | 平光制药股份有限公司 | 一种沙格列汀二甲双胍双层片及其制备工艺 |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR102496851B1 (ko) | 2015-04-10 | 2023-02-08 | 제이더블유중외제약 주식회사 | 아나글립틴 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물 및 그의 제조 방법 |
WO2018093144A1 (ko) * | 2016-11-15 | 2018-05-24 | 주식회사 엘지화학 | 제2형 당뇨병 및 당뇨성 이상지질혈증 치료용 복합제제 |
WO2020091406A1 (ko) * | 2018-10-31 | 2020-05-07 | 주식회사 엘지화학 | 제2형 당뇨병 치료용 약제학적 조성물 |
KR102633770B1 (ko) | 2019-05-24 | 2024-02-02 | 주식회사 엘지화학 | 제2형 당뇨병 치료용 복합제제 |
CN112641776A (zh) * | 2019-10-12 | 2021-04-13 | 江苏晶立信医药科技有限公司 | 一种以二甲双胍或其可药用盐和澳格列汀或其可药用盐为活性成分的药用组合物 |
PE20231638A1 (es) * | 2020-08-14 | 2023-10-16 | Lg Chemical Ltd | Formulacion compuesta para tratamiento de diabetes mellitus tipo 2 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100074950A1 (en) * | 2008-03-14 | 2010-03-25 | Nectid Inc. | Anti-diabetic combinations |
WO2012090225A2 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of metformin with oleoylethanolamide as an effective anti-diabetic + anti- obesity agent |
CN102596191A (zh) * | 2009-10-02 | 2012-07-18 | 贝林格尔.英格海姆国际有限公司 | 包含bi-1356和二甲双胍的药物组合物 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR0112212A (pt) * | 2000-07-06 | 2003-12-30 | Metabasis Therapeutics Inc | Uma combinação de inibidores de fbpase e agentes antidiabéticos úteis para o tratamento de diabetes |
WO2005060942A1 (en) * | 2003-12-19 | 2005-07-07 | Aurobindo Pharma Ltd | Extended release pharmaceutical composition of metformin |
US20100323011A1 (en) * | 2008-03-04 | 2010-12-23 | Nazaneen Pourkavoos | Pharmaceutical compositions of a combination of metformin and a dipeptidyl peptidase-iv inhibitor |
AR071175A1 (es) * | 2008-04-03 | 2010-06-02 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un inhibidor de la dipeptidil-peptidasa-4 (dpp4) y un farmaco acompanante |
EP2356985A1 (en) | 2010-02-10 | 2011-08-17 | LEK Pharmaceuticals d.d. | Novel pharmaceutical compositions comprising a combination of metformin and sitagliptin |
WO2012049566A1 (en) * | 2010-10-14 | 2012-04-19 | Japan Tobacco Inc. | Combination therapy for use in treating diabetes |
EP2635268A1 (en) * | 2010-11-02 | 2013-09-11 | Boehringer Ingelheim International GmbH | Pharmaceutical combinations for the treatment of metabolic disorders |
AR085689A1 (es) * | 2011-03-07 | 2013-10-23 | Boehringer Ingelheim Int | Composiciones farmaceuticas de metformina, linagliptina y un inhibidor de sglt-2 |
-
2013
- 2013-10-04 UY UY0001035065A patent/UY35065A/es active IP Right Grant
- 2013-10-04 TW TW102135966A patent/TWI606848B/zh active
- 2013-10-07 UA UAA201504529A patent/UA114527C2/uk unknown
- 2013-10-07 SG SG11201502241XA patent/SG11201502241XA/en unknown
- 2013-10-07 MY MYPI2015700907A patent/MY174238A/en unknown
- 2013-10-07 RU RU2015117523A patent/RU2664422C2/ru active
- 2013-10-07 BR BR112015007360A patent/BR112015007360A8/pt not_active Application Discontinuation
- 2013-10-07 EP EP13844898.0A patent/EP2903602B1/en active Active
- 2013-10-07 MX MX2015004296A patent/MX368184B/es active IP Right Grant
- 2013-10-07 CN CN201910676778.7A patent/CN110339176A/zh active Pending
- 2013-10-07 KR KR1020130119059A patent/KR101526553B1/ko active IP Right Grant
- 2013-10-07 AU AU2013330679A patent/AU2013330679B2/en active Active
- 2013-10-07 PE PE2015000462A patent/PE20150721A1/es active IP Right Grant
- 2013-10-07 CN CN201380052265.XA patent/CN104884051A/zh active Pending
- 2013-10-07 WO PCT/KR2013/008932 patent/WO2014058188A1/en active Application Filing
-
2015
- 2015-03-23 DO DO2015000071A patent/DOP2015000071A/es unknown
- 2015-03-23 ZA ZA2015/01985A patent/ZA201501985B/en unknown
- 2015-03-24 PH PH12015500653A patent/PH12015500653A1/en unknown
- 2015-04-06 CL CL2015000857A patent/CL2015000857A1/es unknown
- 2015-12-28 HK HK15112746.5A patent/HK1211849A1/zh unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100074950A1 (en) * | 2008-03-14 | 2010-03-25 | Nectid Inc. | Anti-diabetic combinations |
CN102596191A (zh) * | 2009-10-02 | 2012-07-18 | 贝林格尔.英格海姆国际有限公司 | 包含bi-1356和二甲双胍的药物组合物 |
WO2012090225A2 (en) * | 2010-12-29 | 2012-07-05 | Nutracryst Therapeutics Private Limited | Novel cocrystals / molecular salts of metformin with oleoylethanolamide as an effective anti-diabetic + anti- obesity agent |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112546013A (zh) * | 2020-12-29 | 2021-03-26 | 平光制药股份有限公司 | 一种沙格列汀二甲双胍双层片及其制备工艺 |
CN112546013B (zh) * | 2020-12-29 | 2022-06-10 | 平光制药股份有限公司 | 一种沙格列汀二甲双胍双层片及其制备工艺 |
Also Published As
Publication number | Publication date |
---|---|
BR112015007360A8 (pt) | 2018-08-14 |
PE20150721A1 (es) | 2015-05-23 |
DOP2015000071A (es) | 2018-06-30 |
EP2903602A4 (en) | 2016-03-16 |
MY174238A (en) | 2020-04-01 |
KR101526553B1 (ko) | 2015-06-09 |
AU2013330679B2 (en) | 2016-10-06 |
WO2014058188A1 (en) | 2014-04-17 |
CN104884051A (zh) | 2015-09-02 |
SG11201502241XA (en) | 2015-04-29 |
KR20140045271A (ko) | 2014-04-16 |
MX368184B (es) | 2019-09-23 |
BR112015007360A2 (pt) | 2017-07-04 |
ZA201501985B (en) | 2016-01-27 |
PH12015500653B1 (en) | 2015-05-11 |
HK1211849A1 (zh) | 2016-06-03 |
AU2013330679A1 (en) | 2015-04-09 |
RU2015117523A (ru) | 2016-11-27 |
PH12015500653A1 (en) | 2015-05-11 |
UY35065A (es) | 2014-05-30 |
AU2013330679A8 (en) | 2015-04-16 |
MX2015004296A (es) | 2015-08-07 |
TWI606848B (zh) | 2017-12-01 |
RU2664422C2 (ru) | 2018-08-17 |
TW201416095A (zh) | 2014-05-01 |
UA114527C2 (uk) | 2017-06-26 |
EP2903602B1 (en) | 2019-09-18 |
CL2015000857A1 (es) | 2015-08-21 |
EP2903602A1 (en) | 2015-08-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN110339176A (zh) | 包含吉格列汀和二甲双胍的组合药物及其制备方法 | |
TW201206503A (en) | Controlled release compositions with reduced food effect | |
CN1561980A (zh) | 盐酸二甲双胍肠溶缓释制剂及其制备方法 | |
CN104586834A (zh) | 一种艾帕列净和二甲双胍的药物组合物及其制备方法 | |
AU2014207748B2 (en) | Combinations of a GLP1R agonist and metformin and use thereof for the treatment of type 2 diabetes and other disorders | |
KR101512386B1 (ko) | 미티글리나이드 및 메트포르민 복합제제 및 그의 제조방법 | |
CN102342940B (zh) | 制备抗结核病的组合的改良方法及由其制得的医药组合物 | |
CN102755310B (zh) | 一种含有左旋多巴的组合物药物制剂 | |
CN1331470C (zh) | 高溶出度的盐酸二甲双胍格列吡嗪胶囊的制备方法 | |
WO2005105109A1 (fr) | Pastilles a liberation orale modifiee et leur procede de preparation | |
JP4230524B2 (ja) | 2型糖尿病治療用の併用医薬 | |
KR102496851B1 (ko) | 아나글립틴 또는 이의 약학적으로 허용 가능한 염 및 메트포르민 또는 이의 약학적으로 허용 가능한 염을 포함하는 약제학적 조성물 및 그의 제조 방법 | |
CN102218062B (zh) | 一种治疗糖尿病的药物组合物 | |
TWI248815B (en) | The controlled release formulation of metformin HCl | |
WO2021130779A1 (en) | Pharmaceutical composition of casr modulators and methods and uses thereof | |
CN101756980A (zh) | 一种二甲双胍/米格列醇降糖口服制剂组合物及其制备 | |
CA2645318A1 (en) | Pharmaceutical formulations containing metformin | |
CN110812344A (zh) | 一种治疗糖尿病合并心绞痛的药物组合物及制备方法 | |
CN107951872A (zh) | 一种治疗糖尿病的口服药物组合物 | |
CN107648288A (zh) | 一种降糖药物组合物及用途 | |
KR20150039726A (ko) | 미티글리나이드 및 메트포르민 복합제제 및 그의 제조방법 | |
CN102423313A (zh) | 一种罗格列酮和盐酸二甲双胍的复方缓释制剂 | |
MX2008015171A (es) | Nueva combinacion farmaceutica empleasa en el tratamiento de la obesidad. |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
RJ01 | Rejection of invention patent application after publication | ||
RJ01 | Rejection of invention patent application after publication |
Application publication date: 20191018 |