WO2018108128A1 - 葡萄糖激酶激活剂的口服制剂及其制备方法 - Google Patents

葡萄糖激酶激活剂的口服制剂及其制备方法 Download PDF

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WO2018108128A1
WO2018108128A1 PCT/CN2017/116209 CN2017116209W WO2018108128A1 WO 2018108128 A1 WO2018108128 A1 WO 2018108128A1 CN 2017116209 W CN2017116209 W CN 2017116209W WO 2018108128 A1 WO2018108128 A1 WO 2018108128A1
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Prior art keywords
solid dispersion
glucokinase activator
weight
tablet
group
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PCT/CN2017/116209
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English (en)
French (fr)
Inventor
陈力
李永国
王高森
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华领医药技术（上海）有限公司
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Priority to RU2019121695A priority Critical patent/RU2728824C1/ru
Application filed by 华领医药技术（上海）有限公司 filed Critical 华领医药技术（上海）有限公司
Priority to JP2019553613A priority patent/JP6913180B2/ja
Priority to AU2017376544A priority patent/AU2017376544C1/en
Priority to CA3046861A priority patent/CA3046861A1/en
Priority to EP17882225.0A priority patent/EP3556354A4/en
Priority to MX2019007119A priority patent/MX2019007119A/es
Priority to US16/470,291 priority patent/US11266630B2/en
Priority to KR1020197020462A priority patent/KR102265644B1/ko
Priority to BR112019011098A priority patent/BR112019011098A2/pt
Publication of WO2018108128A1 publication Critical patent/WO2018108128A1/zh
Priority to IL267312A priority patent/IL267312B2/en
Priority to ZA2019/04584A priority patent/ZA201904584B/en
Priority to US17/584,951 priority patent/US20220202779A1/en

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    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
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Definitions

  • the present invention relates to oral formulations of glucokinase activators, in particular oral modified release formulations, methods for their preparation and their use in the treatment of certain diseases.
  • the present invention relates to the regulation of the release behavior of an oral preparation of a glucokinase activator in a human body for the purpose of exerting a better therapeutic effect and reducing side effects.
  • the modulated release of the oral formulation of the glucokinase activator of the invention in the human body matches and matches the pharmacokinetic (PK) of the disease treatment with pharmacodynamics (PD) (PK/PD Correlation).
  • the modulated release comprises a modified release of an oral formulation comprising a glucokinase activator in the human gastrointestinal tract and a rapid release of an oral formulation comprising a glucokinase activator in the human small intestine.
  • the present invention relates to solid dispersions of glucokinase activators used in oral formulations of glucokinase activators, as well as compositions and methods of preparation of solid dispersions involving glucokinase activators and the types of polymeric carriers.
  • the invention also relates to a process for the preparation of an oral formulation of a glucokinase activator.
  • the present invention relates to the use of oral, solid dispersion and solid dispersion compositions of glucokinase activators for the treatment and/or prevention of selected diseases and medical conditions, in particular one or more selected from the group consisting of type I diabetes, Type II diabetes, impaired glucose tolerance, abnormal fasting blood glucose, and hyperglycemia. Furthermore, the present invention relates to a method of treating and/or preventing these diseases and medical conditions, which comprises administering to a patient in need thereof a therapeutically effective amount of an oral preparation of the present invention, including an oral modified release preparation.
  • Type II diabetes and glucokinase activator are Type II diabetes and glucokinase activator
  • Type II diabetes non-insulin dependent diabetes mellitus (NIDDM)
  • NIDDM non-insulin dependent diabetes mellitus
  • This is a hypermetemic chronic metabolic dysfunction disease caused by imbalance of blood glucose homeostasis caused by insulin secretion disorder and insulin resistance.
  • the blood sugar balance of the human body is mainly coordinated by insulin and glucagon.
  • GLP-1 glucagon-like peptide-1
  • Insulin and GLP-1 analogues have become important drugs for the treatment of diabetes.
  • Glucokinase is a hexokinase subtype IV (Colowick, SP, The hexokinase, in The Enzymes, 3 rd ed., Boyer, PD, Ed., Vol. 9, Academic Press, New York, 1973). , chap.1), whose activity is regulated by glucose concentration, can induce changes in glucose concentration in the body, regulate the metabolism of glucose metabolism hormones, including insulin, glucagon and GLP-1, and also take glucose after meal in the liver. Quickly convert to liver glycogen and maintain blood sugar balance. Glucose kinase therefore plays a central role in stabilizing the body's blood sugar balance.
  • Young type II (maturity-onset) diabetes (MODY-2) is a functional impairment caused by functional variability of the glucokinase gene, allowing mutations in glucokinase to be activated with higher concentrations of glucose.
  • Glucose-stimulated insulin secretion is impaired in islets, and hepatic glycogen synthesis is reduced, resulting in hyperglycemia.
  • Studies have shown that the expression and function of glucokinase in the liver and islets of patients with type 2 diabetes are significantly lower than those in healthy people. Therefore, up-regulating the activity of glucokinase in diabetic patients is beneficial for the treatment of hyperglycemia caused by impaired glucose tolerance and II.
  • Type 2 diabetes is a functional impairment caused by functional variability of the glucokinase gene, allowing mutations in glucokinase to be activated with higher concentrations of glucose.
  • Glucose-stimulated insulin secretion is impaired in islets, and hepatic glycogen
  • Glucose kinase is mainly distributed in the liver, which responds to elevated blood glucose and rapidly converts glucose into glycogen, for storage, while lowering the level of glucose in the blood.
  • Glucose kinase is expressed in both endocrine cells, alpha cells of islets, beta cells, and L cells in the gut, and is a major functional protein that regulates glucose-stimulated glucagon, insulin, and GLP-1 secretion.
  • Glucose kinase activators have been developed to characterize this target by improving the sensitivity of alpha, beta and L cells to changes in glucose concentration; improving glucose-regulated insulin, glucagon and GLP-1
  • the secretory function; the regulation of hepatic glucose export to promote hepatic glycogen synthesis and other synergistic mechanisms to systematically stabilize blood glucose levels in the body has become one of the hot targets for the development of new drugs for type 2 and type 2 diabetes (Matschinsky FM, Nat Rev Drug Discov. 2009, 8(5): 399-416).
  • HMS5552 Decreased expression and function of glucokinase causes early-phase insulin secretion disorders and hepatic glycogen production disorders. Diabetes drugs currently in clinical use, including insulin, cannot solve this problem, which is a clinical need that continues to be solved in the field of diabetes.
  • Oral hypoglycemic agents are clinically preferred for ease of use and portability, and are safe and easy to use.
  • innovative drugs for glucokinase activators are also suitable for oral preparations, especially oral solid preparations.
  • Oral preparations can be divided into oral solid preparations and oral liquid preparations, and oral solid preparations include tablets, capsules, granules, and dispersions. Agents, lozenges, pills, and the like.
  • the invention combines the characteristics of blood glucose fluctuations of diabetic patients throughout the day, including blood glucose regulation after fasting and postprandial, target and mechanism of glucokinase, distribution in human body, and function of blood glucose regulating sensor, etc., designing and inventing drugs Pharmacokinetics (PK) and Pharmacodynamics (PD) are suitable and matched (PK/PD Correlation), oral preparations suitable for glucokinase activators.
  • PK Pharmacokinetics
  • PD Pharmacodynamics
  • the present invention contemplates the achievement of the glucokinase activator to activate its target in each target organ in a timely or simultaneous manner, thereby ensuring the efficacy and safety of the drug.
  • the oral formulation of the glucokinase activator of the present invention is designed to: 1) appropriately reduce gastric release, rapid release in the small intestine; 2) utilize the intestinal pH environment to modulate the release and absorption of the glucokinase activator.
  • the rapid release of glucokinase activator in the human small intestine is beneficial to the timely or simultaneous arrival of drugs in the gut, islets and liver target organs, achieving a multi-point target, synergistic hypoglycemic clinical advantage, and playing a better therapeutic effect. Reduce the effects of toxic side effects.
  • one object of the invention is an oral formulation of a glucokinase activator, in particular an oral modified release formulation, and a process for the preparation thereof, comprising a solid dispersion of the glucokinase activator and an excipient.
  • Another object of the invention is a solid dispersion comprising a glucokinase activator, including the composition of the solid dispersion, the method of preparation, and the type of polymeric carrier.
  • Another object of the invention is a solid dispersion composition
  • a glucokinase activator comprising a solid dispersion of the invention and an excipient.
  • a further object of the invention is to treat and/or prevent one or more selected from the group consisting of type I diabetes, type II, with an oral preparation of the glucokinase activator comprising an oral modified release formulation, a solid dispersion or a solid dispersion composition.
  • an oral preparation of the glucokinase activator comprising an oral modified release formulation, a solid dispersion or a solid dispersion composition.
  • % by weight is expressed as a percentage of the total weight of the solid dispersion.
  • Solid dispersion refers to a solid dispersion formed by highly dispersing one or more pharmaceutically active ingredients into an inactive excipient or carrier.
  • the drug is present in the carrier in the form of molecules, colloidal, microcrystalline, amorphous or mixed forms (Naveen Dutt Dixit, Suneel Kumar Niranjan. A REVIEW: SOLID DISPERSION. WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES, 2014, Vol 3, Issue 9: 238-257.).
  • the type of the solid dispersion includes: a eutectic mixture; the solid solution includes a continuous solid solution and a discontinuous solid solution; a substitutional crystallization solution; a gap type crystallization solution; an amorphous solid solution; Glass solution and glass suspension, etc. (Shrawan Baghel, Helen Cathcart, Niall J. O'Reilly. Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. Journal of Pharmaceutical Sciences 105 (2016) 2527-2544.).
  • Solid dispersions can be prepared by solid hot melt extrusion, liquid spray drying, and melt-solvent methods (T.Vasconcelos, B.Sarmento, P.Costa, Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs). , Drug Disc. Today 12 (2007) 1068-1075.).
  • EUDRAGIT is the trade name for synthetic pharmaceutical excipients, which include methacrylic acid copolymers and methacrylate copolymers, commonly known as polyacrylic resins.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of an agent sufficient to provide a desired biological result.
  • the result can be a reduction and/or alleviation of the signs, symptoms or causes of the disease, or any other desired biological system changes.
  • an “effective amount” for therapeutic use refers to the amount of the composition required to clinically significantly reduce the disease of a compound that is an active ingredient of the present invention.
  • an appropriate “effective” amount can be determined by one of ordinary skill in the art using routine experimentation.
  • the expression “effective amount” generally refers to an amount when the active substance has a therapeutic effect.
  • treat or “treatment” and the term “prevention” are used herein.
  • Prevent is synonymous and is intended to mean delaying the progression of the disease, preventing the progression of the disease, and/or reducing the severity of the symptoms that will develop or are expected to develop.
  • these terms include improving the symptoms of existing diseases and preventing additional Symptoms, potential metabolic causes that ameliorate or prevent symptoms, inhibit disorders or diseases, for example, prevent the progression of a disorder or disease, alleviate a disorder or disease, cause a disorder or disease to regress, alleviate a condition caused by a disease or disorder, or cause a disease Or the symptoms of the disorder stop.
  • “Pharmaceutically” or “pharmaceutically acceptable” means a substance that is not biologically or otherwise substantially undesirable, that is, the substance can be administered to an individual without causing any undesirable The biological action does not interact in a detrimental manner with any of the components of the composition comprising the substance.
  • subject as used herein includes mammals and non-mammals.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates such as chimpanzees and other mites and monkeys; farm animals such as cattle, horses, sheep, goats, pigs; domestic animals such as rabbits, Dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-mammals include, but are not limited to, birds, fish, and the like.
  • the mammal is a human.
  • the compound which is an active ingredient in the solid dispersion of the glucokinase activator of the present invention can form a salt.
  • salt(s) refers to an acid salt formed with an inorganic and/or organic acid and a basic salt formed with an inorganic and/or organic base.
  • a zwitterion when having the compound containing a basic moiety such as, but not limited to, pyridine or imidazole, and an acidic moiety such as, but not limited to, a carboxylic acid, a zwitterion (“internal salt”) can be formed and the zwitterion (“Inner Salt”) is encompassed by the term “salt(s)" as used herein.
  • a basic moiety such as, but not limited to, pyridine or imidazole
  • an acidic moiety such as, but not limited to, a carboxylic acid
  • zwitterion Inner Salt
  • a salt having the compound can be formed, for example, by reacting the compound with an amount (e.g., an equivalent amount) of an acid or a base in a medium, such as a medium in which a salt precipitates or is aqueous Medium (freeze after reaction).
  • an amount e.g., an equivalent amount
  • an acid or a base in a medium, such as a medium in which a salt precipitates or is aqueous Medium (freeze after reaction).
  • alkyl refers to a branch of 1 to 20 carbon atoms, preferably 1 to 16 carbon atoms, more preferably 1 to 10 carbon atoms or A linear monovalent saturated aliphatic hydrocarbon group.
  • lower alkyl refers to a branched or straight-chain alkyl group of 1 to 9 carbon atoms, preferably 1 to 6 carbon atoms.
  • the term is further derived from groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 1-ethylpropyl, 3- Methyl butyl, n-hexyl, 2-ethylbutyl and the like are exemplified. Particularly preferred are methyl and ethyl.
  • lower alkenyl refers to a straight or branched chain hydrocarbon radical having from 1 to 9 carbon atoms, preferably from 1 to 6 carbon atoms, having an olefinic bond.
  • a preferred lower alkenyl group is 2-propenyl.
  • cycloalkyl refers to a monovalent mono- or polycarbocyclic group of 3 to 10 carbon atoms, preferably 3 to 7 carbon atoms, more preferably 4 to 6 carbon atoms. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, borneol, adamantyl, bicyclo [2.2.1] heptyl, decyl and the like. In a preferred embodiment, "cycloalkyl” refers to cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocyclyl denotes a mono- or polycyclic saturated ring wherein one, two or three of the carbon ring atoms are replaced by a hetero atom such as N, O or S.
  • heterocyclic groups include, but are not limited to, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dialkyl and the like.
  • Preferred heterocyclic groups are pyrrolidinyl, piperidinyl, morpholinyl or tetrahydropyranyl.
  • Heterocyclyl groups may be unsubstituted or substituted, and where appropriate, the linkage may be through their carbon framework or through one or more of their heteroatoms, it being understood that the substituents are not further substituted Unless otherwise indicated in the following examples or claims.
  • aryl refers to an aromatic mono- or polycarbocyclic group of 6 to 12 carbon atoms having at least one aromatic ring.
  • groups include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthalene, 1,2-dihydronaphthalene, indanyl, 1H-fluorenyl Wait.
  • Preferred aryl groups are phenyl or naphthyl, with phenyl being especially preferred.
  • heteroaryl refers to an aromatic mono- or polycyclic group of 5 to 12 atoms having at least one ring heteroatom containing one, two or three selected from N, O and S, and the remainder
  • the ring atom is the aromatic ring of C.
  • One or two ring carbon atoms in the heteroaryl group may be replaced by a carbonyl group.
  • Preferred heteroaryl rings are selected from the group consisting of pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, oxazolyl, isoxazolyl, thiadiazolyl, thiazolyl, furyl, thiophene , pyranyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, fluorenyl, isodecyl, oxazolyl, 7-azaindolyl, quinolinyl, isoquinolinyl, Porphyrin, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, quinoxalinyl, benzofuranyl, benzoxazinyl, benzothiazolyl, benzene And triazolyl, benzopyranyl, chromanyl, hetero
  • Preferred heteroaryl is selected from the group consisting of: 1H- Pyrazol-3-yl, thiazol-2-yl, [1,2,4]thiadiazol-5-yl,[1,3,4]thiadiazol-2-yl,pyridyl,pyrazinyl and Pyrimidinyl.
  • heteroaryl refers to an aromatic mono- or polycyclic group of 5 to 12 atoms having at least one ring heteroatom containing one, two or three selected from N, O and S, and the remainder
  • the ring atom is the aromatic ring of C.
  • One or two ring carbon atoms in the heteroaryl group may be replaced by a carbonyl group.
  • lower alkoxy refers to the group R'-O-, wherein R' is lower alkyl and the term “lower alkyl” has the meaning given above.
  • lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy, preferably methoxy and Ethoxy.
  • lower alkoxyalkyl refers to the group -R"-O-R', wherein R' represents a lower alkyl group as defined above, and R" represents a lower alkylene group such as methylene, ethylene or Propylene. Examples of lower alkoxyalkyl groups are methoxymethyl or 2-methoxy-ethyl.
  • halogen refers to a fluorine, chlorine, bromine or iodine group, preferably a fluorine, chlorine or bromine group, and more preferably a fluorine or chlorine group.
  • lower haloalkyl refers to a lower alkyl group as defined above wherein at least one hydrogen atom of the lower alkyl group is replaced by a halogen atom, preferably fluorine or chlorine, most preferably fluorine.
  • Preferred halogenated lower alkyl groups include trifluoromethyl, difluoromethyl, trifluoroethyl, 2,2-difluoroethyl, fluoromethyl and chloromethyl, of which trifluoromethyl is particularly preferred.
  • lower alkoxycarbonyl refers to the group -CO-OR' wherein R' is lower alkyl and the term “lower alkyl” has the meaning given above.
  • Preferred lower alkoxycarbonyl groups are methoxycarbonyl or ethoxycarbonyl.
  • Lower alkylthioalkyl refers to the group -R"-S-R', wherein R' represents a lower alkyl group as defined above, and R" represents a lower alkylene group such as methylene, ethylene or arylene. Propyl. Examples of lower alkoxyalkyl groups are methylthiomethyl or 2-methylthio-ethyl.
  • “Lower alkoxycarbonylamino” refers to the group -NH-CO-OR' wherein R' is lower alkyl.
  • lower alkenyloxycarbonyl refers to the group -CO-OR* wherein R* is lower alkenyl.
  • a preferred “lower alkenyloxycarbonyl” is 2-propen-1-yloxycarbonyl or allyloxycarbonyl.
  • lower alkanoyl denotes a group -CO-R', wherein R' is lower alkyl and the term “lower alkyl” has the meaning given above.
  • a preferred lower alkanoyl group is acetyl.
  • the compound as an active ingredient of the present invention may contain one or more asymmetric carbon atoms. And it may be in the form of an optically pure enantiomer, such as an enantiomer mixture of a racemate, an optically pure diastereomer, a mixture of diastereomers, a diastereomer. a mixture of racemates or racemates of diastereomers.
  • the optically active form can be obtained, for example, by resolution of the racemate, by asymmetric synthesis or by asymmetric chromatography (chromatography using a chiral adsorbent or eluent). The invention includes all of these forms.
  • the dosage of the compound as the active ingredient of the present invention depends on many factors such as the mode of administration, the age and weight of the subject, and the condition of the patient to be treated, and will ultimately be determined by the attending physician or veterinarian. Such amounts of active compound as determined by the attending physician or veterinarian are referred to herein and in the claims as "therapeutically effective amounts.”
  • the dosage of the compound will typically range from about 1 to about 1000 mg/day.
  • the therapeutically effective amount is an amount from about 1 mg to about 500 mg per day.
  • the solid dispersion is usually prepared by a melt method, a solvent method, a solvent-melting method, a spray drying method, a freeze drying method, a grinding method, or the like.
  • Melt method refers to mixing and melting a drug and a carrier material, and then rapidly cooling to a solid, and then placing the solid at a certain temperature to become a fragile substance, such as a dropping pill, which is suitable for a heat stable drug and poorly soluble in an organic solvent.
  • the solvent method with a low melting point carrier material such as PEG, citric acid, sugar or the like is also called coprecipitation method, which means that the drug and the carrier are co-dissolved in an organic solvent to evaporate the solvent, and the drug and the carrier material are simultaneously precipitated and dried. That is, a solid dispersion in which a drug and a carrier material are mixed is obtained, and the method is suitable for a drug and a carrier material which are volatile, thermally unstable, and easily soluble in an organic solvent.
  • Spray drying is a method in which fluidized technology is applied to the drying of liquid materials.
  • the basic principle is that the liquid material system (solution, suspension, emulsion, etc.) is atomized by gas in a drying tower (chamber), and in contact with hot air, moisture (solvent) is rapidly vaporized, that is, Dry powdered product.
  • the method can directly dry a solution, a suspension, an emulsion, etc. into a powdery or granular product, thereby eliminating the steps of evaporation and pulverization.
  • Spray drying methods include pressure spray drying, centrifugal spray drying, and air flow spray drying.
  • the disc is applied to the high-speed rotating disc in the horizontal direction to centrifugally force the solution to form a film, a filament or a droplet at a high speed, which is generated by the rotation of the disc due to the friction, obstruction and tear of the air.
  • the tangential acceleration and the radial acceleration generated by the centrifugal force the result is moving on the disc at a combined speed, and the trajectory is a spiral shape.
  • the droplets move at an average speed along the tangential direction of the disc, while the droplets are again sucked by the centripetal suction, due to the different sizes of the sprayed particles. Therefore, their flight distances are different, so particles falling at different distances form a cylinder that is symmetrical at the center of the rotation axis.
  • the wet material enters the dryer through the conveyor and the heated natural air at the same time. The two are fully mixed. Due to the large heat and mass exchange area, the evaporative drying is achieved in a short time.
  • Spray drying methods are widely used in the food industry (such as milk powder), pharmaceutical industry (dried Chinese medicine, solid dispersion preparation, particle size reduction, etc.), chemical industry, plastics industry and ceramics production.
  • Figure 1 is a graph of the distribution of glucokinase in vivo.
  • Figure 2 is a graph of blood concentration-time (half log) of HMS5552 tablets after a single oral administration of 50 mg in healthy subjects (HV) and type 2 diabetic patients (T2DM).
  • Figure 3 is a graph showing the mean dissolution and absorption profiles of simulated HMS5552 50 mg tablets in the human gut on an empty stomach.
  • Figure 4 is a graph showing the absorption profile of simulated HMS5552 50mg tablets in different parts of the human intestinal tract during fasting.
  • Example 5 is a dissolution profile of 75 mg tablets prepared in Example 13, Comparative Example 2, and Comparative Example 4 at pH 1.2, pH 4.5, and pH 6.8, respectively.
  • Figure 6 is a graph showing the dissolution profile of 75 mg of coated tablets prepared in Example 18 at pH 1.2, pH 4.5, and pH 6.8, respectively.
  • Fig. 7 is a bar graph showing the dissolution results of the 75 mg tablets prepared in Example 13, Comparative Example 2 and Comparative Example 4 at pH 1.2, respectively, for 30 minutes.
  • Fig. 8 is a bar graph showing the dissolution results of the 75 mg tablets prepared in Example 13, Comparative Example 2 and Comparative Example 4 at pH 4.5, respectively, for 30 minutes.
  • Fig. 9 is a bar graph showing the dissolution results of the 75 mg tablets prepared in Example 13, Comparative Example 2 and Comparative Example 4 at pH 6.8, respectively, for 30 minutes.
  • the present invention relates to a modified release technique of a glucokinase activator.
  • the invention relates to oral formulations for the design and preparation of glucokinase activators.
  • the oral preparation preferably an oral modified release preparation, further preferably an oral modified release solid preparation, is released in a small amount in gastric juice, is rapidly released in the intestinal tract, and is gradually absorbed in the intestinal tract, so that the pharmacokinetic-pharmacodynamic phase in the human body Suitable for (PK/PD Correlation), the in vivo blood concentration versus time curve (C ⁇ t curve) is inverted U-shaped.
  • the invention relates to a solid dispersion comprising a glucokinase activator or an isotopic marker thereof, or a pharmaceutically acceptable salt thereof and a polymeric carrier.
  • the invention relates to a solid dispersion, wherein said glucokinase activator is a compound of formula (Ia)
  • Z 1 , Z 2 , Z 3 are each independently hydrogen, lower alkyl, lower alkenyl, hydroxy, -NH 2 , halogen, lower alkoxy, -CF 3 , -OCF 3 , -S(CH 3 ), -S(O 2 )CH 3 , -CH 2 -aryl, heteroaryl, cyano, lower alkanoyl, -O-aryl, -O-CH 2 -aryl, -N(CH 3 ) 2 , a cycloalkyl group, a heterocyclic group, a -C(O)-heterocyclic group, or a lower alkyl group mono- or di-substituted with a hydroxy group;
  • R 2 is selected from the group consisting of lower alkyl, lower alkyl substituted by hydroxy, mono- or di-substituted, lower haloalkyl, lower alkoxyalkyl, lower alkylthioalkyl, lower alkoxy, cycloalkyl,
  • the cycloalkyl group is unsubstituted or independently mono- or di-substituted by halogen or lower alkyl, heterocyclic and aryl, said aryl being unsubstituted or independently mono- or halogen-- Two-substituted, and
  • R 3 is -lower alkyl-carbamoyl
  • the invention relates to a solid dispersion, wherein the glucokinase activator is selected from the group consisting of the following compounds, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof:
  • the invention relates to a solid dispersion wherein the glucokinase activator is the compound HMS5552, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a solid dispersion wherein said glucokinase activator is selected from the group consisting of:
  • the invention relates to a solid dispersion wherein the glucokinase activator is selected from the group consisting of TTP399, PF-04937319, RO4597014, and LY2608204, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof.
  • the invention relates to a solid dispersion wherein the polymeric carrier is a controlled release carrier.
  • the invention relates to a solid dispersion wherein the polymeric carrier is a polyacrylic resin based polymer.
  • the invention relates to a solid dispersion wherein the polymeric carrier is selected from the group consisting of methacrylic acid copolymers and methacrylate copolymers.
  • the present invention is directed to a solid dispersion wherein the polymeric carrier is selected from the group consisting of butyl methacrylate, a copolymer of dimethylaminoethyl methacrylate and methyl methacrylate, methacrylic acid and Copolymer of ethyl acrylate, copolymer of methacrylic acid and methyl methacrylate, copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate, ethyl acrylate and methyl a copolymer of methyl acrylate, a copolymer of methacrylic acid, methyl acrylate and methyl methacrylate, a copolymer of methacrylic acid and butyl acrylate.
  • the polymeric carrier is selected from the group consisting of butyl methacrylate, a copolymer of dimethylaminoethyl methacrylate and methyl methacrylate
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2) :1) Copolymer, copolymer of methacrylic acid and ethyl acrylate (1:1), copolymer of methacrylic acid and methyl methacrylate (1:2), ethyl acrylate, methyl methacrylate and methyl Copolymer of trimethylaminoethyl acrylate (1:2:0.2), ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate (1:2:0.1) copolymer, acrylic acid B Ester and methyl methacrylate (2:1) copolymer, methacrylic acid and butyl acrylate (35:65) copolymer, methacrylic acid and methyl methacrylate
  • the invention relates to a solid dispersion wherein the polymeric carrier is selected from Eudragit.
  • the invention relates to a solid dispersion wherein the polymeric carrier is selected from the group consisting of Eudragit E, Eudragit L, Eudragit S.
  • the invention relates to a solid dispersion, wherein the polymeric carrier is selected from the group consisting of Eudragit L100, Eudragit S 100, Eudragit E PO, Eudragit E 100, or Eudragit L 100-55.
  • the present invention is directed to a solid dispersion wherein the polymeric carrier is Eudragit L100, which is a methacrylic acid copolymer type A which is anionic copolymerization of methacrylic acid and methyl methacrylate (1:1). Things.
  • the invention relates to a solid dispersion wherein the weight ratio of glucokinase activator to polymeric carrier is from 1:10 to 10:1.
  • the invention relates to a solid dispersion wherein the weight ratio of glucokinase activator to polymeric carrier is from 1:9 to 9:1, 1:4 to 4:1, 3:7 to 7:3, 2:3 to 3:2, 3:4 to 4:3, 4:5 to 5:4 or 5:6 to 6:5.
  • the invention relates to a solid dispersion wherein the weight ratio of glucokinase activator to polymeric carrier is 1:1.
  • the invention relates to a solid dispersion wherein the glucokinase activator is present in an amount from 10% to 90% by weight of the solid dispersion.
  • the invention relates to a solid dispersion wherein the glucokinase activator is present in an amount from 30% to 80% by weight of the solid dispersion.
  • the invention relates to a solid dispersion in which a glucokinase activator The content is from 40% by weight to 80% by weight of the solid dispersion.
  • the invention relates to a solid dispersion wherein the glucokinase activator is present in an amount from 50% to 80% by weight of the solid dispersion.
  • the invention relates to a solid dispersion wherein the glucokinase activator is present in an amount of 50% by weight of the solid dispersion.
  • the invention relates to a solid dispersion wherein the polymeric carrier is present in an amount from 10% to 90% by weight of the solid dispersion.
  • the invention relates to a solid dispersion wherein the solid dispersion is obtained by spray drying.
  • the present invention is directed to a solid dispersion composition
  • a solid dispersion composition comprising the solid dispersion of the present invention and an excipient.
  • the present invention is directed to a solid dispersion composition wherein the excipient is selected from the group consisting of a diluent; a sweetener or flavoring agent; a surfactant; a filler; a binder; a disintegrant; Glidants/anti-adherents; release modifiers; stabilizers; coating agents; emulsifiers and/or solubilizers, and perfumes.
  • the excipient is selected from the group consisting of a diluent; a sweetener or flavoring agent; a surfactant; a filler; a binder; a disintegrant; Glidants/anti-adherents; release modifiers; stabilizers; coating agents; emulsifiers and/or solubilizers, and perfumes.
  • the invention relates to an oral formulation of a glucokinase activator comprising the solid dispersion or solid dispersion composition.
  • the invention relates to an oral formulation of a glucokinase activator which is an oral modified release formulation of a glucokinase activator.
  • the invention relates to an oral formulation of a glucokinase activator which is an oral modified release solid formulation of a glucokinase activator.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the oral modified release solid formulation of the glucokinase activator is selected from the group consisting of a tablet, a capsule, a granule, a powder, a lozenge, and a pill.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the oral modified release solid formulation of the glucokinase activator is a tablet.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the tablet comprises a solid dispersion, a filler, a binder, a disintegrant, and a lubricant of the invention.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion of the glucokinase activator in the tablet is present in an amount from 1% to 90% by weight and the filler is present in an amount of 1% by weight Up to 95% by weight, the content of the binder is from 0.5% by weight to 10% by weight, The content of the disintegrant is from 0.5% by weight to 7.5% by weight, and the content of the lubricant is from 0.25% by weight to 5% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the filler in the tablet is silicified microcrystalline cellulose or microcrystalline cellulose or lactose, the binder being hydroxypropyl Cellulose or hydroxypropylmethylcellulose or polyvinylpyrrolidone, said disintegrant is croscarmellose sodium or sodium carboxymethyl starch, and said lubricant is magnesium stearate Or sodium stearyl fumarate.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the tablet is a silicified microcrystalline cellulose, the binder is hydroxypropylcellulose, and the disintegrant is a cross-linking agent Sodium carboxymethylcellulose, and the lubricant is magnesium stearate.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the tablet is a coated tablet.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the coated tablet comprises a coating agent selected from the group consisting of sodium carboxymethylcellulose, cellulose acetate, acetic acid ophthalmic acid Cellulose phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymer , methyl cellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein and Opadry.
  • a coating agent selected from the group consisting of sodium carboxymethylcellulose, cellulose acetate, acetic acid ophthalmic acid Cellulose phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose
  • the invention relates to an oral formulation of a glucokinase activator, wherein the coating agent in the coated tablet is Opadry.
  • the oral preparation of the glucokinase activator of the present invention wherein the solid dispersion of the glucokinase activator in the coated tablet is from 1% to 90% by weight, and the filler is present in an amount of 1 From % by weight to 95% by weight, the content of the binder is from 0.5% by weight to 10% by weight, the content of the disintegrant is from 0.5% by weight to 7.5% by weight, and the content of the lubricant is from 0.25 % by weight to 5% by weight, coating The content of the agent is from 1% by weight to 10% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule is a gelatin capsule, a plant derived HPMC capsule, an enteric capsule or a soft capsule.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule comprises a solid dispersion, a filler, and/or a binder, and/or a disintegrant of the invention, and/ Or a lubricant.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the formulation in the capsule has a solid dispersion content of from 1% to 90% by weight and a filler content of from 5% to 95% by weight %, the content of the binder is from 0% by weight to 10% by weight, the content of the disintegrant is from 0.5% by weight to 7.5% by weight, and the content of the lubricant is from 0% by weight to 5% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion of the capsule is present in an amount from 1% to 90% by weight and the filler is present in an amount from 5% to 95% by weight
  • the binder is present in an amount of from 0.5% by weight to 10% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion of the capsule is present in an amount from 1% to 90% by weight, and the filler is present in an amount from 5% to 95% by weight, The content of the disintegrant is from 0.5% by weight to 7.5% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the filler in the capsule is silicified microcrystalline cellulose, the binder is hydroxypropylcellulose, and the disintegrant is The croscarmellose sodium and the lubricant are magnesium stearate.
  • the invention relates to an oral formulation of a glucokinase activator that elutes ⁇ 45% at pH 1.2-4.5 at 30 minutes, which elutes >85% at pH 6.0-7.0 for 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet elutes ⁇ 40% at pH 1.2-4.5 at 30 minutes and >85% at pH 6.0-7.0 at 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet dissolves ⁇ 30% at pH 1.2, dissolves at ⁇ 30% at pH 4.5, dissolves ⁇ 40% at 30 minutes, and at pH 6.8 , dissolution in 8 minutes >85%.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet is a coated tablet at a pH of 1.2, a dissolution of ⁇ 30% at 30 minutes, a pH of 4.5, a dissolution of ⁇ 40 at 30 minutes %, and pH 6.8, dissolution of >85% in 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule dissolves ⁇ 45% at pH 1.2, elutes ⁇ 45% at pH 4.5 for 30 minutes, and at pH 6.8 at pH 6.8 , dissolution in 8 minutes >85%.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in the unit formulation in an amount from about 1 mg to about 200 mg, and in one embodiment from about 2 mg to about 150 mg, in one In embodiments, from about 2.5 mg to about 150 mg, in one embodiment from about 5 mg to about 150 mg, and in one embodiment from about 5 mg to about 100 mg.
  • the invention relates to an oral formulation of a glucokinase activator, wherein The amount of the glucokinase activator in the tablet is from about 1 mg to about 200 mg, from about 2 mg to about 150 mg, from about 2.5 mg to about 150 mg, from about 5 mg to about 150 mg, or from about 5 mg to about 100 mg.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in the unit coated tablet in an amount from about 1 mg to about 200 mg, from about 2 mg to about 150 mg, from about 2.5 mg to about 150 mg, from about 5 mg to about 150 mg or from about 5 mg to about 100 mg.
  • the present invention relates to an oral formulation of the solid dispersion, solid dispersion composition or glucokinase activator prepared for the treatment and/or prevention of selected diseases and medical conditions, in particular one or Uses of a variety of drugs selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, and hyperglycemia.
  • the invention relates to an oral formulation of the solid dispersion, solid dispersion composition or glucokinase activator for treating and/or preventing a selected disease and medical condition, in particular one or more selected from the group consisting of A method of diabetes, type II diabetes, impaired glucose tolerance, impaired fasting blood glucose, and hyperglycemia, comprising administering to a patient a therapeutically effective amount of a solid dispersion, a solid dispersion composition, or a glucokinase activator of the present invention. preparation.
  • a process for preparing a solid dispersion of the present invention includes a melt process, a solvent process, a solvent-melt process, a spray drying process, a freeze drying process, and a milling process.
  • a method of making a solid dispersion of the invention comprises the steps of:
  • the solvent is anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene and toluene or a mixture thereof or a mixture thereof with water.
  • the inlet air temperature of the spray drying step is 90-150 ° C
  • the air inlet amount is 0.3-0.5 m 3 /min
  • the flow rate of the atomizing gas stream is 10-30 L/min
  • the solution spray speed is 5-200 mL/min.
  • the invention relates to an oral formulation of a glucokinase activator comprising a glucokinase activator solid dispersion or solid dispersion composition and an excipient.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator solid dispersion comprises a glucokinase activator, or an isotopic marker thereof, or a pharmaceutically acceptable salt thereof and a polymeric carrier .
  • the invention relates to an oral formulation of a glucokinase activator, wherein said glucokinase activator is a compound of formula (Ia)
  • Z 1 , Z 2 , Z 3 are each independently hydrogen, lower alkyl, lower alkenyl, hydroxy, -NH 2 , halogen, lower alkoxy, -CF 3 , -OCF 3 , -S(CH 3 ), -S(O 2 )CH 3 , -CH 2 -aryl, heteroaryl, cyano, lower alkanoyl, -O-aryl, -O-CH 2 -aryl, -N(CH 3 ) 2 , a cycloalkyl group, a heterocyclic group, a -C(O)-heterocyclic group, or a lower alkyl group mono- or di-substituted with a hydroxy group;
  • R 2 is selected from the group consisting of lower alkyl, lower alkyl substituted by hydroxy, mono- or di-substituted, lower haloalkyl, lower alkoxyalkyl, lower alkylthioalkyl, lower alkoxy, cycloalkyl,
  • the cycloalkyl group is unsubstituted or independently mono- or di-substituted by halogen or lower alkyl, heterocyclic and aryl, said aryl being unsubstituted or independently mono- or halogen-- Two-substituted, and
  • R 3 is -lower alkyl-carbamoyl
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is selected from the group consisting of the following compounds, or an isotopic marker thereof, or a pharmaceutically acceptable salt thereof:
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is the compound HMS5552, or an isotopic marker thereof, or a pharmaceutically acceptable salt thereof.
  • the invention relates to an oral formulation of a glucokinase activator, wherein said glucokinase activator is selected from the group consisting of:
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is selected from the group consisting of TTP399, PF-04937319, RO4597014 and LY2608204, or an isotopic label thereof, or a pharmaceutically acceptable salt thereof.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is a controlled release carrier.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is a polyacrylic resin based polymer.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of a methacrylic acid copolymer and a methacrylate copolymer.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of copolymers of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate, Copolymer of methacrylic acid and ethyl acrylate, copolymer of methacrylic acid and methyl methacrylate, copolymer of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate, acrylic acid a copolymer of an ester and methyl methacrylate, a copolymer of methacrylic acid, methyl acrylate and methyl methacrylate, a copolymer of methacrylic acid and butyl acrylate.
  • the polymeric carrier is selected from the group consisting of copolymers of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl me
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of butyl methacrylate, dimethylaminoethyl methacrylate, and methyl methacrylate (1:2) :1) Copolymer, copolymer of methacrylic acid and ethyl acrylate (1:1), copolymer of methacrylic acid and methyl methacrylate (1:2), ethyl acrylate, methyl methacrylate and methyl Copolymer of trimethylaminoethyl acrylate (1:2:0.2), ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate (1:2:0.1) copolymer, acrylic acid B Ester and methyl methacrylate (2:1) copolymer, methacrylic acid and butyl acrylate (35:65) copolymer, methacrylic acid and methyl methacrylate
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of Eudragit.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of Eudragit E, Eudragit L, Eudragit S.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is selected from the group consisting of Eudragit L100, Eudragit S100, Eudragit E PO, Eudragit E 100, or Eudragit L100-55.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the polymeric carrier is Eudragit L100, which is a methacrylic acid copolymer type A which is methacrylic acid and methyl methacrylate (1: 1) Anionic copolymer.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in an amount from 10% to 90% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in an amount from 30% to 80% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in an amount from 40% to 80% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in an amount from 50% to 80% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in an amount of 50% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator wherein the polymeric carrier is present in an amount from 10% to 90% by weight of the solid dispersion.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion is obtained by spray drying.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the excipient is selected from the group consisting of a diluent; a sweetener or flavoring agent; a surfactant; a filler; a binder; a disintegrant; One or more of a glidant/anti-adherent; a release modifier; a stabilizer; a coating agent; an emulsifier and/or a solubilizer, and a perfume.
  • the excipient is selected from the group consisting of a diluent; a sweetener or flavoring agent; a surfactant; a filler; a binder; a disintegrant; One or more of a glidant/anti-adherent; a release modifier; a stabilizer; a coating agent; an emulsifier and/or a solubilizer, and a perfume.
  • the invention relates to an oral formulation of a glucokinase activator which is an oral modified release formulation of a glucokinase activator.
  • the invention relates to an oral formulation of a glucokinase activator which is an oral modified release solid formulation of a glucokinase activator.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the oral modified release solid formulation of the glucokinase activator is selected from the group consisting of a tablet, a capsule, a granule, a powder, a lozenge, and a pill.
  • the invention relates to an oral formulation of a glucokinase activator comprising a solid dispersion of the invention, and/or a filler, and/or a binder, and/or a disintegrant, and/or lubrication Agent.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the oral modified release solid formulation of the glucokinase activator is a tablet.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the tablet comprises a solid dispersion, a filler, a binder, a disintegrant, and a lubricant of the invention.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion of the glucokinase activator in the tablet is present in an amount from 1% to 90% by weight and the filler is present in an amount of 1% by weight
  • the content of the binder is from 0.5% by weight to 10% by weight
  • the content of the disintegrant is from 0.5% by weight to 7.5% by weight
  • the content of the lubricant is from 0.25% by weight to 5% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the filler in the tablet is silicified microcrystalline cellulose or microcrystalline cellulose or lactose, the binder being hydroxypropyl Cellulose or hydroxypropylmethylcellulose or polyvinylpyrrolidone, said disintegrant is croscarmellose sodium or sodium carboxymethyl starch, and said lubricant is magnesium stearate Or sodium stearyl fumarate.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the filler in the tablet is silicified microcrystalline cellulose, the binder is hydroxypropylcellulose, and the disintegrant is The croscarmellose sodium, and the lubricant is magnesium stearate.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the tablet is a coated tablet.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the coated tablet comprises a coating agent selected from the group consisting of sodium carboxymethylcellulose, cellulose acetate, acetic acid Cellulose phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid copolymerization , methyl cellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose, titanium dioxide, carnauba wax, microcrystalline wax, zein and Opadry.
  • a coating agent selected from the group consisting of sodium carboxymethylcellulose, cellulose acetate, acetic acid Cellulose phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, methacrylic acid cop
  • the invention relates to an oral formulation of a glucokinase activator, wherein the coating agent in the coated tablet is Opadry.
  • the oral preparation of the glucokinase activator of the present invention wherein the solid dispersion of the glucokinase activator in the coated tablet is from 1% to 90% by weight, and the filler is present in an amount of 1 From % by weight to 95% by weight, the content of the binder is from 0.5% by weight to 10% by weight, the content of the disintegrant is from 0.5% by weight to 7.5% by weight, and the content of the lubricant is from 0.25 % by weight to 5% by weight, coating The content of the agent is from 1% by weight to 10% by weight.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule is a gelatin capsule, a plant derived HPMC capsule, an enteric capsule or a soft capsule.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule comprises a solid dispersion, a filler and/or a binder and/or a disintegrant and/or a lubricant of the invention.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the solid dispersion of the capsule is present in an amount from 1% to 90% by weight, and the filler is present in an amount of 5
  • the amount is from 95% by weight to 95% by weight, and/or the content of the binder is from 0% by weight to 10% by weight, and/or the content of the disintegrant is from 0.5% by weight to 7.5% by weight, and/or the content of the lubricant is 0%.
  • Weight% to 5% by weight is a glucokinase activator
  • the invention relates to an oral formulation of a glucokinase activator, wherein the filler in the capsule is silicified microcrystalline cellulose, the binder is hydroxypropylcellulose, and the disintegrant is The croscarmellose sodium and the lubricant are magnesium stearate.
  • the invention relates to an oral formulation of a glucokinase activator that elutes ⁇ 45% at pH 1.2-4.5 at 30 minutes, which elutes >85% at pH 6.0-7.0 for 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet elutes ⁇ 40% at pH 1.2-4.5 at 30 minutes and >85% at pH 6.0-7.0 at 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet dissolves ⁇ 30% at pH 1.2, dissolves at ⁇ 30% at pH 4.5, dissolves ⁇ 40% at 30 minutes, and at pH 6.8 , dissolution in 8 minutes >85%.
  • the invention relates to an oral formulation of a glucokinase activator wherein the tablet is a coated tablet at a pH of 1.2, a dissolution of ⁇ 30% at 30 minutes, a pH of 4.5, a dissolution of ⁇ 40 at 30 minutes %, and pH 6.8, dissolution of >85% in 30 minutes.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the capsule dissolves ⁇ 45% at pH 1.2, elutes ⁇ 45% at pH 4.5 for 30 minutes, and at pH 6.8 at pH 6.8 , dissolution in 8 minutes >85%.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in the unit formulation in an amount from about 1 mg to about 200 mg, and in one embodiment from about 2 mg to about 150 mg, in one In embodiments, from about 2.5 mg to about 150 mg, in one embodiment from about 5 mg to about 150 mg, and in one embodiment from about 5 mg to about 100 mg.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in a unit tablet in an amount from about 1 mg to about 200 mg, from about 2 mg to about 150 mg, from about 2.5 mg to about 150 mg, From about 5 mg to about 150 mg or from about 5 mg to about 100 mg.
  • the invention relates to an oral formulation of a glucokinase activator, wherein the glucokinase activator is present in the unit coated tablet in an amount from about 1 mg to about 200 mg, from about 2 mg to about 150 mg, from about 2.5 mg to about 150 mg, from about 5 mg to about 150 mg or from about 5 mg to about 100 mg.
  • the invention relates to an oral formulation of a glucokinase activator for use in the treatment and/or prevention of a selected disease and medical condition, in particular one or more selected from the group consisting of type I diabetes, Use in drugs for type 2 diabetes, impaired glucose tolerance, abnormal fasting blood glucose, and hyperglycemia.
  • the invention relates to an oral formulation of a glucokinase activator for the treatment and/or prevention of selected diseases and medical conditions, in particular one or more selected from the group consisting of type I diabetes, type II diabetes, impaired glucose tolerance, fasting blood glucose A method of abnormality and a disease of hyperglycemia comprising administering to the patient a therapeutically effective amount of an oral formulation of a glucokinase activator of the invention.
  • the invention relates to a method of preparing a solid dispersion comprising the steps of:
  • the solvent is anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene and toluene or a mixture thereof or a mixture thereof with water.
  • the inlet air temperature is, for example, 90 to 150 ° C
  • the inlet air amount is, for example, 0.3 to 0.5 m 3 /min
  • the flow rate of the atomizing gas stream is, for example, 10 to 30 L/min
  • the solution discharge speed is, for example, 5-200 mL/min.
  • the invention relates to a method of preparing an oral tablet of a glucokinase activator, comprising the steps of:
  • the invention relates to a method of preparing a glucokinase activator coated tablet comprising the steps of:
  • the invention also includes the glucokinase activator comprising an isotopically labeled glucokinase activator identical to those described herein, except for the fact that one or more atoms are atomic mass or mass The number is replaced by an atom of a different mass or mass of atoms usually found in nature.
  • isotopes that can be incorporated into the compound include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, for example, their isotopes are 2 H, 3 H, 13 C, 14 C, 15 N, 18, respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 C1.
  • Some isotopically labeled different compounds are used in compound and/or substrate tissue distribution assays.
  • Deuterated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred because of their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., H) may result in therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some cases. .
  • Isotopically labeled different compounds can generally be prepared by performing procedures similar to those disclosed in the Schemes below and/or in the Examples, wherein the non-isotopically labeled reagents are replaced with reagents labeled with appropriate isotopes.
  • the oral modified release formulations of the invention are oral solid formulations and oral liquid formulations.
  • the oral solid formulation is selected from the group consisting of a tablet, a capsule, a granule, a powder, a lozenge, and a pill.
  • the tablet is a coated tablet.
  • a further aspect of the invention relates to a solid dispersion composition of a glucokinase activator comprising a solid dispersion of glucokinase activator and an excipient selected from the group consisting of diluents such as tablets and/or capsules diluted Agent; sweetener or flavoring agent; antioxidant; surfactant; filler; binder; disintegrating agent such as tablet disintegrating agent; lubricant such as tablet and / or capsule lubricant; Anti-adherent; release modifier; stabilizer; coating agent; coloring agent; complexing agent; emulsifier and/or solubilizer; flavoring agent and perfume;
  • the solid dispersion composition of the glucokinase activator of the present invention can be used as it is, or can be manufactured into different dosage forms depending on the need for treatment or prevention.
  • the solid dispersion composition of the glucokinase activator of the present invention can be made into tablets and capsules.
  • Various dosage forms such as a granule, a granule, a powder, a tablet, and a pill can be produced by a known method.
  • the preparation may be prepared by a mixing step, a granulation process, a capsule filling, or a tableting and coating preparation step.
  • One embodiment of the present invention is a process for preparing a solid dispersion of a glucokinase activator of the present invention, which is selected from the group consisting of a spray drying method, a fluidized bed drying method, a solvent method, a melt extrusion method, and the like.
  • One embodiment of the invention is a solid dispersion of a glucokinase activator prepared by a spray drying process, the steps of which are:
  • Solvents used in the preparation of solid dispersions of glucokinase activators in embodiments of the invention include, but are not limited to, alkanols, esters, nitriles, cycloalkanes, aromatic hydrocarbons, ketones, and the like.
  • the solvent is selected from the group consisting of anhydrous ethanol, methanol, isopropanol, ethyl acetate, acetone, acetonitrile, isobutanol, n-hexane, benzene and toluene. It may be a single solvent, a mixed solvent, or a mixture of an organic solvent and water.
  • a further embodiment of the invention relates to the use of a solid dispersion or formulation of a glucokinase activator of the invention for the treatment and/or prophylaxis of selected diseases and medical conditions, in particular one or more selected from the group consisting of type I diabetes, type II diabetes, glucose A method of reducing tolerance, fasting blood glucose abnormalities, and hyperglycemia diseases, comprising administering to a patient a therapeutically effective amount of an oral preparation of a glucokinase activator of the present invention.
  • a further embodiment of the invention relates to a solid dispersion of a glucokinase activator of the invention or a formulation comprising the same for use in the preparation of a medicament for the treatment and/or prevention of a selected disease and a medical condition, in particular one or more selected from Use in drugs for type 1 diabetes, type 2 diabetes, decreased glucose tolerance, impaired fasting blood glucose, and hyperglycemia.
  • the amount of glucokinase activator used in the solid dispersion of the glucokinase activator of the invention may vary from about 1% to about 99% by weight, based on the total weight of the solid dispersion.
  • the glucokinase activator is present in an amount ranging from about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, or about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, about 15 wt%, about 16 wt%, about 17 wt%, about 18% by weight, About 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28%
  • the glucokinase activator is present in an amount ranging from about 1% to about 20% by weight. In another embodiment, the glucokinase activator is present in an amount ranging from about 2% to about 40% by weight. In a further embodiment, the glucokinase activator is present in an amount ranging from about 30% to about 60% by weight. In yet another embodiment, the glucokinase activator is present in an amount ranging from about 60% to about 80% by weight. In yet another embodiment, the glucokinase activator is present in an amount ranging from about 70% to about 90% by weight. In yet another embodiment, the amount of glucokinase activator ranges from about 80% to about 100% by weight.
  • the amount of polymeric carrier used in the solid dispersion of the glucokinase activator of the present invention may vary from about 1% to about 99% by weight, based on the total weight of the solid dispersion.
  • the polymeric carrier is present in an amount ranging from about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% % by weight, about 9% by weight, about 10% by weight, about 11% by weight, about 12% by weight, about 13% by weight, about 14% by weight, about 15% by weight, about 16% by weight, about 17% by weight, about 18% by weight % by weight, about 19% by weight, about 20% by weight, about 21% by weight, about 22% by weight, about 23% by weight, about 24% by weight, about 25% by weight, about 26% by weight, about 27% by weight, about 28% % by weight, about 29% by weight, About 30% by weight, about 3
  • the polymeric carrier is present in an amount ranging from about 1% to about 20% by weight. In another embodiment, the amount ranges from about 2% to about 40% by weight. In a further embodiment, the amount ranges from about 30% to about 60% by weight. In yet another embodiment, the amount ranges from about 60% to about 80% by weight. In yet another embodiment, the amount ranges from about 70% to about 90% by weight. In yet another embodiment, the amount ranges from about 80% to about 100% by weight.
  • the content of the glucokinase activator ranges from 30 to 60% by weight, and the content of the polymer carrier ranges from 40 to 70% by weight based on the total weight of the solid dispersion. .
  • the content of the glucokinase activator ranges from 40 to 60% by weight, and the content of the polymer carrier ranges from 40 to 60% by weight based on the total weight of the solid dispersion. %.
  • the polymeric carrier in the solid dispersion of the present invention is selected from the group consisting of polypropylene resin-based polymers which are composed of acrylic acid (or methacrylic acid and their esters such as methyl ester, ethyl ester, etc.). (a monomer) polymerized, or with methacrylic acid (or its ester such as methyl ester, ethyl ester, dimethylaminoethyl ester, etc.) in two monomers (binary) or in three monomers ( A ternary) polymer compound formed by copolymerization in a certain ratio.
  • polypropylene resin-based polymers which are composed of acrylic acid (or methacrylic acid and their esters such as methyl ester, ethyl ester, etc.).
  • methacrylic acid or its ester such as methyl ester, ethyl ester, dimethylaminoethyl ester, etc.
  • the polymeric carrier used in the solid dispersion of the invention is selected from the group consisting of butyl methacrylate, A Copolymer of dimethylaminoethyl acrylate and methyl methacrylate, copolymer of methacrylic acid and ethyl acrylate, copolymer of methacrylic acid and methyl methacrylate, ethyl acrylate, methacrylic acid a copolymer of an ester and trimethylaminoethyl methacrylate, a copolymer of ethyl acrylate and methyl methacrylate, a copolymer of methacrylic acid, methyl acrylate and methyl methacrylate, methacrylic acid and Copolymer of butyl acrylate.
  • the polymer carrier is selected from the group consisting of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1) copolymers, methacrylic acid and ethyl acrylate (1: 1) Copolymer, copolymer of methacrylic acid and methyl methacrylate (1:2), copolymerization of ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate (1:2:0.2) , ethyl acrylate, methyl methacrylate and trimethylaminoethyl methacrylate (1:2:0.1) copolymer, ethyl acrylate and methyl methacrylate (2:1) copolymer, Copolymer of acrylate and butyl acrylate (35:65), methacrylic acid and methyl methacrylate (1:1) polymer, methacrylic acid and methyl methacrylate (35:65),
  • polymeric carrier is selected from the group consisting of:
  • Eudragit E100 (Utchi E 100), which is a copolymer of butyl methacrylate, dimethylaminoethyl methacrylate and methyl methacrylate (1:2:1), including Eudragit E PO;
  • Eudragit L100 (Utchi L100) is a methacrylic acid copolymer type A which is an anionic copolymer of methacrylic acid and methyl methacrylate (1:1);
  • Eudragit S100 (Utech S 100), which is a copolymer of methacrylic acid and methyl methacrylate (1:2);
  • examples of solid dispersion compositions and other excipients used in the formulations of the glucokinase activators of the present invention include, but are not limited to, diluents such as tablets and/or capsules.
  • diluents such as tablets and/or capsules.
  • diluents suitable for use in the present invention include, but are not limited to, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose including silicified microcrystalline cellulose, sodium saccharin, glucose, and / or glycine.
  • the tablet and/or capsule diluent to which the present invention is applied includes, but is not limited to, calcium carbonate, calcium hydrogen phosphate, calcium phosphate, calcium sulfate, cellulose powder, glucan binding agent, fructose in addition to the above diluent. , kaolin, starch, pregelatinized starch, sugar for compressible sugars and confectionery, and combinations thereof.
  • sweeteners or flavoring agents suitable for use in the present invention include, but are not limited to, essential oils, water soluble extracts, sugars, monosaccharides, oligosaccharides, aldoses, ketoses, dextrose, maltose, lactose, glucose, Fructose, sucrose, mannitol, xylitol, D-sorbitol, erythritol, pentitol, hexitol, maltitol, acesulfame potassium, sweet protein, glycyrrhizin, sucralose, aspartame , saccharin, sodium saccharin, sodium cyclamate, syringyl aldehyde flavor, and combinations thereof.
  • antioxidants suitable for use in the present invention include, but are not limited to, alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, thioglycerol, potassium metabisulfite, propionic acid, propyl gallate, Sodium ascorbate, sodium bisulfite, sodium metabisulfite and sodium sulfite, and combinations thereof.
  • surfactants suitable for use in the present invention include, but are not limited to, but not limited to, salts of alkyl sulfates such as lauryl sulfate diethanol ammonium salt; alkyl aryl sulfonates such as dodecyl benzene sulfonic acid Calcium; alkylphenol-alkylene oxide addition product, such as nonylphenol-C18 ethoxylate; alcohol-oxyalkylene addition product, such as tridecyl alcohol-C16 ethoxylate; soap, such as stearin Sodium alkyl naphthalene-sulfonate, such as sodium dibutylnaphthalenesulfonate; dialkyl ester of sulfosuccinate, such as sodium bis(2-ethylhexyl)sulfosuccinate; sorbitol ester For example, sorbitol oleate; quaternary ammonium, such as lauryl methyl-
  • fillers suitable for use in the present invention include, but are not limited to, cellulose derivatives such as microcrystalline fibers.
  • Wort or wood cellulose including microcrystalline cellulose and silicified microcrystalline cellulose
  • lactose lactose, anhydrous or lactose monohydrate, sucrose, starch, pregelatinized starch, dextrose, mannitol (including mannitol Pearlitol SD) 200), fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/glucose binder, maltodextrin, compressible sugar And other known compatibilizers or fillers and/or mixtures of two or more thereof.
  • binders suitable for use in the present invention include, but are not limited to, carboxymethylcellulose (including sodium carboxymethylcellulose), hydroxypropylcellulose (including hydroxypropylcellulose EXF), corn starch, pregelatinization Starch, modified corn starch, polyvinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC) (including hydroxypropyl methylcellulose 2208), lactose, gum arabic, ethyl cellulose, cellulose acetate And wax binders such as carnauba wax, paraffin wax, cetyl wax, polyethylene or microcrystalline wax, and other conventional binders and/or mixtures of two or more thereof.
  • tablet adhesives suitable for use in the present invention include, but are not limited to, alginic acid, microcrystalline cellulose, dextrin, gelatin, liquid glucose, guar gum, methylcellulose, poly Ethylene oxide, povidone, and syrup, and combinations thereof.
  • disintegrants suitable for use in the present invention include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, glycolic acid starch Sodium, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.
  • croscarmellose sodium crospovidone
  • starch potato starch
  • corn starch sodium carboxymethyl starch
  • glycolic acid starch Sodium sodium carboxymethyl starch
  • microcrystalline cellulose low substituted hydroxypropyl cellulose
  • other known disintegrants include, but are not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium carboxymethyl starch, glycolic acid starch Sodium, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.
  • disintegrants include, but are not limited to,
  • any level of crospovidone can be used including, for example, crospovidone XL-10) and is selected from Kollidon Polyplasdone Kollidon Polyplasdone And Polyplasdone
  • the tablet disintegrating agent suitable for use in the present invention includes, but is not limited to, alginic acid, potassium podaklin, sodium starch glycolate, and pregelatinized starch, and combinations thereof in addition to the above disintegrating agents.
  • lubricants suitable for use in the present invention include, but are not limited to, magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, laurel Sodium sulphate, palmitic stearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats and other known lubricants and/or mixtures of two or more thereof.
  • the tablet and/or capsule lubricants suitable for use in the present invention include, but are not limited to, glyceryl behenate, light mineral oil, polyethylene glycol, hard purified stearic acid, and the like in addition to the lubricants described above. Their combination.
  • flow aids and/or anti-adherents suitable for use in the present invention include, but are not limited to, silica, colloidal silica, magnesium silicate, magnesium trisilicate, talc, and other forms of silica such as agglomerates. Silicate and hydrated silica gel.
  • release modifiers suitable for use in the present invention include, but are not limited to, hydroxypropyl methylcellulose, poly Vinyl alcohol (PVA), ethyl cellulose, methacrylic acid polymer, hydroxypropyl cellulose, starch, gum, cellulose ether, protein-derived substances, nylon, acrylic resin, polylactic acid, polychlorinated Ethylene, polyvinylpyrrolidone and cellulose acetate phthalate and combinations thereof.
  • Stabilizers suitable for use in the present invention include, but are not limited to, fatty acids such as oleic acid and its sodium salts, cholic acid and deoxycholic acid, cationic lipids such as stearamide, and anionic stabilizers such as phosphatidylethanolamine, phosphatidylserine , phosphatidic acid and phosphatidylglycerol, and combinations thereof.
  • the stabilizer is oleic acid.
  • Coating agents suitable for use in the present invention include, but are not limited to, sodium carboxymethylcellulose, cellulose acetate, cellulose acetate phthalate, ethyl cellulose, gelatin, medicinal glaze, hydroxypropyl cellulose, hydroxypropyl Methylcellulose, hydroxypropylmethylcellulose phthalate, methacrylic acid copolymer, methylcellulose, polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose Titanium dioxide, carnauba wax, microcrystalline wax, zein, and Opadry such as Opadry 03K12429 and combinations thereof.
  • Colorants suitable for use in the present invention include, but are not limited to, caramels, red colorants, yellow colorants, black colorants or blends, iron oxides, and combinations thereof.
  • complexing agents suitable for use in the present invention include, but are not limited to, ethylenediaminetetraacetic acid and salts (EDTA), edetic acid, gentisic acid amide, hydroxyquinoline sulfate, and combinations thereof.
  • EDTA ethylenediaminetetraacetic acid and salts
  • Emulsifiers and/or solubilizers suitable for use in the present invention include, but are not limited to, gum arabic, cholesterol, diethanolamine, glyceryl monostearate, lanolin alcohol, lecithin, mono- and di-glycerides, monoethanolamine, oils Acid, oleyl alcohol, poloxamer, polyoxyethylene 50 stearate, polyoxyethylene (35) castor oil, polyoxyethylene (40) hydrogenated castor oil, polyethylene glycol 10 oleyl ether, polyoxyethylene ( 20) Cetyl-octadecyl ether, polyoxyethylene (40) monostearate, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, propylene glycol Diacetate, propylene glycol monostearate, sodium lauryl sulfate, sodium stearate, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalate, dehydration Sorbitol monostearate, ste
  • Flavoring agents and perfumes suitable for use in the present invention include, but are not limited to, anethole, benzaldehyde, ethyl vanillin, menthol, methyl salicylate, monosodium glutamate, neroli, mint, peppermint oil, European Peppermint spirit, rose oil, thick rose water, thymol, toluene, vanilla, vanilla, vanillin, and combinations thereof.
  • Solvents suitable for use in the present invention include, but are not limited to, acetone, alcohol, absolute ethanol, dilute alcohol, hydrated pentane Alkene, benzyl benzoate, butanol, carbon tetrachloride, chloroform, corn oil, cottonseed oil, ethyl acetate, glycerin, hexanediol, isopropanol, methanol, dichloromethane, methyl isobutyl ketone, Mineral oil, peanut oil, polyethylene glycol, propylene carbonate, propylene glycol, sesame oil, water for injection, sterile water for injection, sterile rinse water, purified water, and combinations thereof.
  • the amount of active compound in a unit dosage formulation may vary or vary from about 1 mg to about 200 mg, preferably from about 2 mg to about 150 mg, more preferably from about 2.5 mg to about 150 mg, depending on the particular application.
  • the change or adjustment is more preferably varied or adjusted from about 5 mg to about 150 mg.
  • the amount of the glucokinase activator in the unit tablet of the present invention is from about 1 mg to about 200 mg, preferably from about 2 mg to about 150 mg, more preferably from about 5 mg to about 100 mg.
  • the chemicals used in the present invention are commercially available from companies such as Shin-Etsu Japan, Evonik Germany, J.T. Baker US, SCR China, Ashland US, FMC US, JRS Germany, Colorcon US, Capsugel, BASF, Rejuvenating Reagents and the like.
  • Production equipment and analytical test instruments and the like can be purchased from companies such as Sartorius, Nikon, Sympatec, Bruker, Gea Niro, Korsch, Erweka, Agilent, Quadro Engineering, Canada; Warters, US; TA, US; SOTAX, Switzerland; Mettler Toledo Instrument Newark, DE.
  • Example 1 weight ratio of active ingredient to polymer is 1:9)
  • Example 2 (weight ratio of active ingredient to polymer is 3:7)
  • Example 3 (weight ratio of active ingredient to polymer is 5:5)
  • Example 4 (weight ratio of active ingredient to polymer is 7:3)
  • Example 5 (weight ratio of active ingredient to polymer is 8:2)
  • Example 6 weight ratio of active ingredient to polymer is 9:1)
  • Example 7 (weight ratio of active ingredient to polymer is 6:4)
  • Example 8 (weight ratio of active ingredient to polymer is 4:6)
  • Example 9 weight ratio of active ingredient to polymer is 5:5)
  • Spray drying equipment suitable for use in the present invention includes, but is not limited to, spray drying equipment manufactured by Niro GEA Process Engineering Inc., Buchi Labortechnik AG, ProCept and SPX ANHYDROUS. Spray drying can be carried out by selecting a suitable drying gas inlet air temperature, intake air amount, feed rate and atomization pressure so that the droplets are sufficiently dried as they reach the device wall. This helps to ensure that the dried droplets are essentially solid, can form a fine powder, and do not stick to the wall, nor are they difficult to collect in the cyclone. The resulting powder is subjected to secondary drying to ensure that the product meets quality requirements.
  • the solid dispersion was prepared by spray drying the solution prepared in the above Examples 1-8, wherein the spray dryer was set to have an inlet air temperature of 90-150 ° C, and the inlet air flow rate was set to 0.3-0.5 m 3 /min. The flow rate was 15-30 L/min, the above solution was sprayed at a rate of 5-7 mL/min, and spray dried to obtain a solid dispersion 1-8.
  • the solid solution was prepared by spray drying the solution prepared in the above Example 9, wherein the spray dryer was set to have an inlet air temperature of 90-150 ° C, the inlet air flow rate was set to 20-30 kg/h, and the flow rate of the gas stream was 3- At 30 kg/h, the above solution was sprayed at a rate of 5 to 200 mL/min, and spray-dried to obtain a solid dispersion 9.
  • Solid dispersions 1-9 were prepared as described above, wherein:
  • the mass fraction of the compound HMS5552 in the solid dispersion 1 is 10%; the mass fraction of the compound HMS5552 in the solid dispersion 2 is 30%; the mass fraction of the compound HMS5552 in the solid dispersion 3 is 50%; and the compound HMS5552 in the solid dispersion 4
  • the mass fraction is 70%; solid
  • the mass fraction of the compound HMS5552 in the bulk dispersion 5 is 80%; the mass fraction of the compound HMS5552 in the solid dispersion 6 is 90%; the mass fraction of the compound HMS5552 in the solid dispersion 7 is 60%; and the compound of the solid dispersion 8 in the HMS5552
  • the mass fraction was 40%; the mass fraction of the compound HMS5552 in the solid dispersion 9 was 50%.
  • the coated tablets may be formulated as described above in the "Preparation of Glucose Kinase Activator Tablets" or as separate formulations.
  • the function of the coating film mainly increases the hardness, facilitates moisture resistance, increases the aesthetic appearance, facilitates swallowing, and the like. Preparation steps of glucokinase activator coated tablets:
  • a glucokinase activator tablet is prepared, and the formulation and preparation process of the tablet are the same as above.
  • Coating take the core of the tablet and weigh it into the coating pan. After the temperature of the bed reaches 30-60 °C, the coating starts. The weight gain of the target coating is 2% by weight to 4% by weight, and the weight gain is achieved. After the target is stopped, the coating liquid is stopped, and the sheet is cooled to 25-30 ° C and then discharged.
  • glucokinase activator coated tablets were prepared according to this procedure. The prescriptions for these coated tablets are listed below.
  • Example 10 A 5 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 5 mg.
  • Prescription composition Unit prescription / g %(w/w) Solid dispersion 9 10.0 3.1 Silicified microcrystalline cellulose 297.5 93.0 Hydroxypropyl cellulose 7.5 2.3 Croscone sodium 2.5 0.78 Magnesium stearate 2.5 0.78 total 320.0 100
  • Example 11 100 mg tablet formulation (in 1000 tablets), ie the amount of active ingredient therein is
  • Prescription composition Unit prescription / g %(w/w)
  • Solid dispersion 9 200.0 81.6 Silicified microcrystalline cellulose 32.5 13.3 Hydroxypropyl cellulose 7.5 3.1 Croscone sodium 2.5 1.02 Magnesium stearate 2.5 1.02 total 245.0 100
  • Example 12 A 25 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 25 mg.
  • Example 13 A 75 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 75 mg.
  • Prescription composition Unit prescription / g %(w/w) Solid dispersion 9 150.0 54.5 Silicified microcrystalline cellulose 112.5 40.9 Hydroxypropyl cellulose 7.5 2.7 Croscone sodium 2.5 0.91 Magnesium stearate 2.5 0.91 total 275.0 100
  • Example 14 A 25 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 25 mg.
  • Example 15 A 50 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 50 mg.
  • Example 16 A 100 mg tablet formulation (in 1000 tablets), i.e., wherein the amount of active ingredient is 100 mg.
  • the coated tablets may be formulated as described above in the "Preparation of Glucose Kinase Activator Tablets" or as separate formulations.
  • the function of the coating film mainly increases the hardness, facilitates moisture resistance, increases the aesthetic appearance, facilitates swallowing, and the like. Preparation steps of glucokinase activator coated tablets:
  • a glucokinase activator tablet is prepared, and the formulation and preparation process of the tablet are the same as above.
  • Coating take the core of the tablet and weigh it into the coating pan. After the temperature of the bed reaches 30-60 °C, start. The coating has a target coating weight gain of 2% by weight to 4% by weight. After the weight gain target is reached, the spray coating liquid is stopped, and the sheet bed is cooled to 25-30 ° C and then discharged.
  • glucokinase activator coated tablets were prepared according to this procedure. The prescriptions for these coated tablets are listed below.
  • Example 17 A 50 mg coated tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 50 mg.
  • Example 18 A 75 mg coated tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 75 mg.
  • the pure water is weighed and subjected to wet granulation. After discharging, it is wet-granulated by a mill, dried to a particle size of 2-3 wt%, and then subjected to dry granulation by a mill.
  • Capsule filling the capsules are filled with capsules.
  • Capsule shell types suitable for use in the present invention are: gelatin capsules of animal origin, HPMC capsules of plant origin, enteric capsules, soft capsules, and the like.
  • Example 19 50 mg capsule formulation (based on 1000 tablets), wherein the amount of active ingredient is 50 mg
  • Capsule filling The mixed powder is directly filled into capsules.
  • Capsule shell types suitable for use in the present invention are gelatin capsules of animal origin, HPMC capsules of plant origin, enteric capsules, and the like.
  • Example 20 A 50 mg capsule formulation (based on 1000 tablets), i.e., the amount of the active ingredient was 50 mg.
  • Example 21 A 25 mg capsule formulation (based on 1000 tablets), i.e., the amount of active ingredient was 25 mg.
  • Comparative Example 1 A 25 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 25 mg.
  • Comparative Example 2 A 75 mg tablet formulation (in 1000 tablets), i.e., the amount of the active ingredient was 75 mg.
  • Example 12 and Example 13 were replaced with the compound HMS5552 API powder and Eudragit L100 (Utchi L100), respectively, while maintaining the other compositions and ratios, and prepared using the above glucokinase activator tablets.
  • Comparative Example 3 and Comparative Example 4 were prepared.
  • Comparative Example 3 A 25 mg tablet formulation (in 1000 tablets), i.e., the amount of the active ingredient was 25 mg.
  • Comparative Example 4 A 75 mg tablet formulation (in 1000 tablets), i.e., the amount of active ingredient was 75 mg.
  • glucokinase activator tablets can be prepared in the same manner.
  • Tablets prepared using the above examples were prepared or in the same manner as in the above preparation examples.
  • SAD single-dose hill-climbing
  • Tablets prepared using the above examples were prepared or in the same manner as in the above preparation examples.
  • multi-dose climb (MAD) test patients with type 2 diabetes (T2DM) received a single oral dose of 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg of the active ingredient, and the plasma concentration increased rapidly with an average peak time of 1.5. - 2 hours, followed by a steady decline, terminal elimination half-life of about 6.8-8.6 hours, no significant difference compared with healthy subjects; 25 mg, 50 mg, 100 mg, 150 mg, 200 mg twice daily, continuous oral administration for 5.5 days After steady state, the average plasma concentration peak time is 1.5-3 hours, and the terminal elimination half-life is about 7.7-10.3 hours.
  • the plasma exposure is basically no accumulation compared with the single administration of T2DM patients (the accumulation ratio ranges from 1-1.8). .
  • the compound HMS5552 tablet prepared in Example 12 was administered in healthy subjects (HV) and T2DM patients (T2DM) with an active ingredient specification of 50 mg, ie two tablets having an active ingredient size of 25 mg, for single oral administration.
  • the post-blood concentration-time curve is shown in Figure 2.
  • PBPK model simulates the absorption of oral glucokinase activator in human intestinal tract
  • the PBPK model was established by using Simcyp software to simulate the absorption degree and main absorption site of compound HMS5552 in human intestinal tract after oral administration of 50 mg of HMS5552 tablet in healthy individuals in fasting state.
  • Figure 3 is a graph showing the mean dissolution and absorption profiles of glucokinase activator oral formulations in the intestine when a 50 mg single dose of fasting administration of a healthy person simulated by the PBPK model.
  • the oral preparation of glucokinase activator rapidly dissolves in the intestine, and the dissolution rate is over 90% in 30 minutes; compared with dissolution, the glucokinase activator absorbs completely, but the absorption rate is slightly slower, about The absorption plateau was reached 2-3 hours after administration, which is consistent with the clinically observed plasma peak time of glucokinase activators in humans, indicating that the model can well predict the dissolution of glucokinase activators in humans. absorb.
  • Figure 4 shows the PBPK model of a healthy human 50mg single-dose fasting glucose
  • the absorption fraction of the kinase activator in different parts of the human intestinal tract can be seen that after a single administration of HMS5552 tablets in the human body, the main absorption site is located in the duodenum, the jejunum I segment and the jejunum segment II at the front end of the intestine, three The total absorption score is 0.8, accounting for 87% of the total absorption rate (0.92).
  • the dissolution of tablets and capsules is the paddle method of the Chinese Pharmacopoeia (2010 edition), which is tested for dissolution in three different dissolution media at pH 1.2 and/or pH 4.5 and/or pH 6.8, respectively. At 5 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes, 5 ml were sampled separately for HPLC analysis.
  • the oral preparation prepared by the solid dispersion technique of the present invention has a significant difference in dissolution under different pH conditions; and tablets prepared by conventional means do not have this feature.
  • the tablet preparation process and formulation composition are the same or similar, the different forms of the compound HMS5552 result in different dissolution characteristics of the active ingredient compound HMS5552 in the oral preparation, namely pure HMS5552 powder (Comparative Example 2), HMS5552+Eudragit L100 simple mixture (Comparative Example 4) or solid dispersion form (Example 13).
  • the dissolution of the tablet prepared by the solid dispersion technique of the present invention is pH-dependent, that is, at a pH of 1.2 to 4.5, the dissolution rate is not higher than 45% at 30 minutes, and at a pH of 6.0 to 7.0, 30.
  • the dissolution rate in minutes is not less than 85% (Table 1-10).
  • the tablets prepared in Comparative Example 2 and Comparative Example 4 had similar dissolution results at pH 1.2, pH 4.5, and pH 6.8 for 30 minutes.
  • the dissolution ratio at 30 minutes was 16.2%, 24.6%, and 88.6% at pH 1.2, pH 4.5, and pH 6.8, respectively.

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Abstract

本发明涉及固体分散体及其制备方法，其中，所述固体分散体包含葡萄糖激酶激活剂、其同位素标记物或其可药用盐和聚合物载体。本发明进一步涉及包含所述固体分散体和赋形剂的固体分散体组合物。本发明还涉及葡萄糖激酶激活剂的口服制剂，其包含所述固体分散体或固体分散体组合物。本发明还进一步涉及葡萄糖激酶激活剂的片剂和胶囊剂及它们的制备方法。另外，本发明还涉及固体分散体、固体分散体组合物和口服制剂包括片剂和胶囊剂的用途，其用于治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病。

Description

葡萄糖激酶激活剂的口服制剂及其制备方法 技术领域
本发明涉及葡萄糖激酶激活剂的口服制剂，具体地口服调节释放制剂(oral modified release formulation)，其制备方法及其治疗某些疾病的用途。
在更详细方面中，本发明涉及调节葡萄糖激酶激活剂的口服制剂在人体内的释放行为以达到发挥更好的疗效和降低副作用的目的。本发明的葡萄糖激酶激活剂的口服制剂在人体内的调节释放使疾病治疗的药物代谢动力学(PK)与药效动力学(PD)相适合和相匹配(PK/PD Correlation)。所述调节释放包括葡萄糖激酶激活剂的口服制剂在人体胃肠道中的调节释放和包括葡萄糖激酶激活剂的口服制剂在人体小肠中的快速释放。本发明涉及在葡萄糖激酶激活剂的口服制剂中使用葡萄糖激酶激活剂的固体分散体，以及涉及葡萄糖激酶激活剂的固体分散体的组成和制备方法以及聚合物载体的种类。本发明还涉及葡萄糖激酶激活剂的口服制剂的制备方法。
本发明涉及葡萄糖激酶激活剂的口服制剂、固体分散体和固体分散体组合物的用途，其用于治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病。此外，本发明涉及治疗和/或预防这些疾病及医学病症的方法，其中包括向有需要的患者给予治疗有效量的本发明的口服制剂，包括口服调节释放制剂。
背景技术
II型糖尿病与葡萄糖激酶激活剂
糖尿病已成为世界范围的普遍性疾病，其全球患者数量现为4.15亿，而中国患者人数高达1.1亿(International Diabetes Federation,Diabetes Atlas,2015)。II型糖尿病即非胰岛素依赖型糖尿病(non-insulin dependent diabetes mellitus，NIDDM)，占糖尿病患者的90％以上。这是一种由于胰岛素分泌障碍和胰岛素抵抗引起的人体血糖稳态平衡失调而导致的高血糖慢性代谢功能紊乱性疾病。人体血糖平衡主要是由胰岛素、胰高糖素两个控糖激素协调完成。GLP-1(胰高血糖素样肽-1)能够参与胰岛素的分泌调节，也是一 个在人体血糖平衡中起到重要作用的分子因子和糖尿病治疗药物。胰岛素和GLP-1类似物已经成为治疗糖尿病的重要药物。
葡萄糖激酶(Glucokinase，简称GK)是己糖激酶亚型IV(Colowick,S.P.,The hexokinase,in The Enzymes,3rd ed.,Boyer,P.D.,Ed.,Vol.9,Academic Press,New York,1973,chap.1)，其活性变化受葡萄糖浓度调节，可感应体内葡萄糖浓度的变化，调节糖代谢激素，包括胰岛素、胰高糖素和GLP-1的分泌，同时在肝脏将餐后摄取的葡萄糖快速转变成肝糖原，维护血糖平衡。葡萄糖激酶因此在稳定人体血糖平衡方面起到核心作用。青年的II型(青春发生型(maturity-onset))糖尿病(MODY-2)是由于葡萄糖激酶基因的功能变异引起的功能损伤，使变异的葡萄糖激酶激活需要更高浓度的葡萄糖才能实现，造成患者胰岛中葡萄糖刺激的胰岛素分泌功能受损，肝糖原合成能力降低，造成高血糖症。研究表明，II型糖尿病患者的肝脏和胰岛中的葡萄糖激酶的表达和功能均比健康人群明显降低，因此，上调糖尿病患者葡糖激酶的活性有益于治疗糖耐量受损引起的高血糖症和II型糖尿病。
葡萄糖激酶主要分布在肝脏，其应对血糖升高而快速地将葡萄糖转化为肝糖原进行储备，同时降低血液中葡萄糖的水平。葡萄糖激酶同时在内分泌细胞、胰岛的α细胞、β细胞和肠道中的L细胞中有所表达，是调控葡萄糖刺激的胰高糖素、胰岛素和GLP-1分泌的主要功能蛋白。葡萄糖激酶激活剂是针对这一靶点的特征进行开发的，其能够通过提高α细胞、β细胞和L细胞对葡萄糖浓度变化的敏感性；改善葡萄糖调控的胰岛素、胰高血糖素和GLP-1的分泌功能；调节肝糖输出促进肝糖原合成等协同机制来系统性地稳定体内血糖水平，已成为2型II型糖尿病新型药物研发的热门靶点之一(Matschinsky FM,Nat Rev Drug Discov.2009,8(5):399-416)。
葡萄糖激酶的表达和功能降低会造成胰岛素类早相分泌失调和肝糖原生成障碍。目前临床使用的糖尿病药品，包括胰岛素都无法解决该问题，这是糖尿病领域继续需要解决的临床需求。(S)-2-[4-(2-氯-苯氧基)-2-氧代-2,5-二氢-吡咯-1-基]-4-甲基-戊酸[1-((R)-2,3-二羟基-丙基)-1H-吡唑-3-基]-酰胺(下文中称作HMS5552)是目前最有希望解决以上临床需求的糖尿病治疗药物。口服降糖药物因服用和携带方便且安全易用是临床上的首选，葡萄糖激酶激活剂的创新药也适用口服制剂，尤其是口服固体制剂。口服制剂可分为口服固体制剂和口服液体制剂，口服固体制剂有片剂，胶囊剂，颗粒剂，散 剂，锭剂，丸剂等。
发明内容
本发明结合糖尿病病人的全天血糖波动特征，包括空腹和餐后的血糖调节、葡萄糖激酶的靶点与作用机制、在人体中的分布以及血糖调节敏感器的功能等，设计和发明了使药物代谢动力学(Pharmacokinetics,PK)与药效动力学(Pharmacodynamics,PD)相适合和相匹配(PK/PD Correlation)的、适合葡萄糖激酶激活剂的口服制剂。
鉴于葡萄糖激酶的主要靶向器官分布在肝脏、胰腺和肠道，本发明关注实现葡萄糖激酶激活剂在各个靶器官中及时或同时激活其靶标，从而保证药品的有效性和安全性。
本发明葡萄糖激酶激活剂的口服制剂的设计思路为:1)适当减少胃中释放，在小肠中快速释放；2)利用小肠pH环境调节葡萄糖激酶激活剂的释放和吸收。葡萄糖激酶激活剂在人体小肠中快速释放，有益于药物及时或同时到达在肠道，胰岛和肝脏靶点器官，实现一靶多点，协同降糖的临床优势，起到发挥更好的疗效和降低毒副作用的效果。
因此，本发明的一个目的是葡萄糖激酶激活剂的口服制剂，具体地口服调节释放制剂及其制备方法，所述制剂包含所述葡萄糖激酶激活剂的固体分散体和赋形剂。
本发明的另一目的是含葡萄糖激酶激活剂的固体分散体，包括该固体分散体的组成、制备方法及聚合物载体的种类。
本发明的另一目的是含葡萄糖激酶激活剂的固体分散体组合物，包括本发明的固体分散体和赋形剂。
本发明的又一目的是用所述葡萄糖激酶激活剂的口服制剂包括口服调节释放制剂、固体分散体或固体分散体组合物治疗和/或预防一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法和用途。
本领域技术人员通过上下文说明以及通过实施例可明了本发明的其他目的。
定义
如本文所用，术语“约”是指±5％可修正的值。
重量％(wt％)表示为占固体分散体的总重量的百分比。
固体分散体(solid dispersion,SD)是指将一种或多种药物活性成分高度分散到无活性的辅料或载体所形成的固体分散体系。在固体分散体中，药物在载体中存在形式为分子、胶态、微晶、无定型或混合方式等(Naveen Dutt Dixit,Suneel Kumar Niranjan.A REVIEW:SOLID DISPERSION.WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES,2014,Vol 3,Issue 9:238-257.)。根据药物分子在固体载体中的分布，固体分散体的类型包括：共融混合物；固体溶液包括连续的固体溶液和不连续的固体溶液；替位型结晶溶液；间隙型结晶溶液；无定形固体溶液；玻璃溶液和玻璃悬浮液等(Shrawan Baghel,Helen Cathcart,Niall J.O'Reilly.Polymeric Amorphous Solid Dispersions:A Review of Amorphization,Crystallization,Stabilization,Solid-State Characterization,and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs.Journal of Pharmaceutical Sciences 105(2016)2527-2544.)。固体分散体可以通过固体热熔挤出，液体喷雾干燥，以及融化-溶剂法等方法进行制备(T.Vasconcelos,B.Sarmento,P.Costa,Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs,Drug Disc.Today 12(2007)1068-1075.)。
EUDRAGIT(尤特奇)是合成药用辅料的商品名，它包括甲基丙烯酸共聚物和甲基丙烯酸酯共聚物，通称为聚丙烯酸树脂。聚丙烯酸树脂类辅料按其构成、比例及聚合度不同而分为不同的型号。其中，Eudragit E为甲基丙烯酸二甲胺基乙酯与甲基丙烯酸酯的聚合物；Eudragit L为甲基丙烯酸与甲基丙烯酸甲酯的聚合物，游离羧基:酯＝1:1，Eudragit S为甲基丙烯酸与甲基丙烯酸甲酯的聚合物，游离羧基:酯＝1:2。
术语“有效量”或“治疗有效量”是指足以提供希望的生物结果的试剂的量。该结果可为疾病的征兆、症状或原因的减少和/或减轻，或任何其它希望的生物系统的变化。例如，治疗用途的“有效量”是指包含作为本发明活性成分的化合物的临床上显著减少疾病所需要的组合物的量。在任何个案中，适当的“有效”量可由本领域普通技术人员使用常规实验来测定。因此，表达方式“有效量”通常是指活性物质具有治疗效果时的量。
本申请使用的术语“治疗(treat)”或“处置(treatment)”与术语“预防 (prevent)”同义，意在表示推迟疾病发展、防止疾病发展和/或降低将会发展或预期会发展的所述症状的严重性。因此，这些术语包括改善已有的疾病症状、预防另外的症状、改善或预防症状的潜在的代谢原因、抑制障碍或疾病，例如，阻止障碍或疾病的发展、减轻障碍或疾病、使障碍或疾病退行、减轻由疾病或障碍导致的病症，或使疾病或障碍的症状停止。
“药用的”或“药理上可接受的”是指并非在生物学上或其它方面实质上不希望的物质，即，可将所述物质给药于个体，而不会导致任何不希望的生物作用或不会以有害的方式与包含这种物质的组合物的任何组分相互作用。
本申请使用的术语“受试者”包括哺乳动物和非哺乳动物。哺乳动物的实例包括但不限于哺乳动物纲的任何成员：人、非人灵长类如黑猩猩及其它猿类和猴类；农场动物如牛、马、绵羊、山羊、猪；家养动物如兔、狗和猫；实验室动物，包括啮齿类动物如大鼠、小鼠和豚鼠等。非哺乳动物的实例包括但不限于鸟、鱼等。在本发明一个实施方案中，哺乳动物为人。
作为本发明的葡萄糖激酶激活剂固体分散体中的活性成分的化合物可形成盐。除非另有说明，当提及本申请中具有所述化合物时，应理解为其包括对其盐的提及。本申请使用的术语“盐(一种或多种)”是指与无机和/或有机酸形成的酸式盐及与无机和/或有机碱形成的碱式盐。另外，当具有所述化合物含有碱性部分(例如但不限于，吡啶或咪唑)和酸性部分(例如但不限于，羧酸)时，可形成两性离子(“内盐”)且所述两性离子(“内盐”)包含在本申请使用的术语“盐(一种或多种)”中。优选为药用(即，无毒的，生理学上可接受的)盐，但其它盐也是有用的。具有所述化合物的盐可例如通过以下方法形成：在介质中使具有所述化合物与一定量的(例如等量的)酸或碱反应，所述介质为例如盐在其中析出的介质或为含水介质(反应后冻干)。
不同化合物及不同化合物的盐、溶剂化物、酯和前药的多晶型形式意在包括在本发明中。
应当理解本文采用的术语用于描述具体实施方案的目的，而不意在进行限制。此外，尽管在本发明的实践或试验中可以使用与本文描述的那些类似或等价的任何方法、装置和材料，但是现在描述优选的方法、装置和材料。
如本文中使用的，术语“烷基”，单独或与其它基团组合地，是指1至20个碳原子，优选1至16个碳原子，更优选1至10个碳原子的支链或直链一价饱和脂族烃基。
术语“低级烷基”，单独或与其它基团组合地，是指1至9个碳原子，优选1至6个碳原子的支链或直链烷基。此术语进一步由基团如甲基，乙基，正丙基，异丙基，正丁基，仲丁基，异丁基，叔丁基，正戊基，1-乙基丙基，3-甲基丁基，正己基，2-乙基丁基等示例。特别优选的是甲基和乙基。
如本文中使用的，术语“低级烯基”，单独或与其它基团组合地，是指具有烯键的1至9个碳原子，优选1至6个碳原子的直链或支链烃基。优选的低级烯基是2-丙烯基。
术语“环烷基”是指3至10个碳原子，优选3至7个碳原子，更优选4至6个碳原子的一价单或多碳环基团。此术语进一步由基团如环丙基，环丁基，环戊基，环己基，环庚基，冰片基，金刚烷基，双环[2.2.1]庚基，茚基等示例。在一个优选的实施方案中，“环烷基”是指环丁基，环戊基或环己基。
术语“杂环基”表示单或多环饱和环，其中碳环原子中的一、二或三个被杂原子如N，O或S代替。杂环基的实例包括但不限于，吗啉基，硫代吗啉基，哌嗪基，哌啶基，吡咯烷基，四氢吡喃基，四氢呋喃基，1,3-二烷基等。优选的杂环基是吡咯烷基，哌啶基，吗啉基或四氢吡喃基。杂环基可以是未取代的或取代的，并且适宜时，连接可以通过它们的碳框架(frame)或通过它们的一个或多个杂原子，理解的是所述的取代基没有进而另外被取代，除非在下面的实施例或权利要求中另外指出。
术语“芳基”是指具有至少一个芳族环的6至12个碳原子的芳族单或多碳环基团。这样的基团的实例包括但不限于，苯基，萘基，1,2,3,4-四氢萘，1,2-二氢萘，2,3-二氢化茚基，1H-茚基等。优选的芳基是苯基或萘基，其中特别优选苯基。
术语“杂芳基”是指5至12个原子的芳族单或多环基团，其具有至少一个含有一、二或三个选自N，O和S中的环杂原子，并且余下的环原子是C的芳环。杂芳基中的一个或两个环碳原子可以被羰基代替。优选的杂芳基环选自：吡咯基，吡唑基，咪唑基，三唑基，四唑基，唑基，二唑基，异唑基，噻二唑基，噻唑基，呋喃基，噻吩基，吡喃基，吡啶基，吡嗪基，嘧啶基，哒嗪基，吲哚基，异吲哚基，吲唑基，7-氮杂吲哚基，喹啉基，异喹啉基，噌啉基，吡唑并[1,5-a]吡啶基，咪唑并[1,2-a]吡啶基，喹喔啉基，苯并呋喃基，苯并嗪基，苯并噻唑基，苯并三唑基，苯并吡喃基，苯并二氢吡喃基，异色满基，香豆素基，异香豆素基和苯并吡喃基。优选的杂芳基选自：1H- 吡唑-3-基，噻唑-2-基，[1,2,4]噻二唑-5-基，[1,3,4]噻二唑-2-基，吡啶基，吡嗪基和嘧啶基。
术语“杂芳基”是指5至12个原子的芳族单或多环基团，其具有至少一个含有一、二或三个选自N，O和S中的环杂原子，并且余下的环原子是C的芳环。杂芳基中的一个或两个环碳原子可以被羰基代替。
如本文中使用的，术语“低级烷氧基”是指基团R’-O-，其中R’是低级烷基并且术语“低级烷基”具有上面给出的含义。低级烷氧基的实例是甲氧基，乙氧基，正丙氧基，异丙氧基，正丁氧基，异丁氧基，仲丁氧基和叔丁氧基，优选甲氧基和乙氧基。
术语“低级烷氧基烷基”是指基团-R”-O-R’，其中R’表示如上定义的低级烷基，并且R”表示低级亚烷基如亚甲基，亚乙基或亚丙基。低级烷氧基烷基的实例是甲氧基甲基或2-甲氧基-乙基。
如本文中使用的，术语“卤素”是指氟，氯，溴或碘基团，优选氟，氯或溴基团，并且更优选氟或氯基团。
术语“低级卤代烷基”是指如上定义的低级烷基，其中低级烷基的至少一个氢原子被卤素原子，优选氟或氯，最优选氟代替。优选的卤代低级烷基中有三氟甲基，二氟甲基，三氟乙基，2,2-二氟乙基，氟甲基和氯甲基，其中特别优选三氟甲基。
术语“羧基”是指基团-COOH，而术语“氨基羰基”是指基团-CO-NH2。
术语“低级烷氧基羰基”是指基团-CO-OR’，其中R’是低级烷基，并且术语“低级烷基”具有上面给出的含义。优选的低级烷氧基羰基是甲氧基羰基或乙氧基羰基。
“低级烷硫基烷基”是指基团-R”-S-R’，其中R’表示如上定义的低级烷基，并且R”表示低级亚烷基如亚甲基，亚乙基或亚丙基。低级烷氧基烷基的实例是甲硫基甲基或2-甲硫基-乙基。
“低级烷氧基羰基氨基”是指基团-NH-CO-OR’，其中R’是低级烷基。
术语“低级烯氧基羰基”是指基团-CO-OR*，其中R*是低级烯基。一种优选的“低级烯氧基羰基”是2-丙烯-1-基氧基羰基或烯丙氧基羰基。
如本文中使用的，术语“低级烷酰基”表示基团-CO-R’，其中R’是低级烷基，并且术语“低级烷基”具有上面给出的含义。优选的低级烷酰基是乙酰基。
作为本发明的活性成分的化合物可以含有一个或多个不对称碳原子， 并且其存在形式可以是旋光纯对映异构体、例如外消旋物的对映异构体混合物、旋光纯非对映异构体、非对映异构体混合物、非对映异构体的外消旋物或非对映异构体的外消旋物的混合物。可以通过例如外消旋物的拆分，通过不对称合成或不对称色谱法(使用手性吸附剂或洗脱剂的色谱法)，获得旋光活性形式。本发明包括所有这些形式。
作为本发明的活性成分的化合物的剂量取决于许多因素，例如给药方式、受试者的年龄和体重以及待治疗的患者的情况，并且最终将由主治医生或兽医确定。活性化合物由主治的医生或兽医确定的这样的量在本文中并且在权利要求书中称作“治疗有效量”。例如，所述化合物的剂量典型地在约1至约1000mg/天的范围内。优选地，治疗有效量为约1mg至约500mg/天的量。
固体分散体，制备常用的方法包含熔融法、溶剂法、溶剂-熔融法、喷雾干燥法、冷冻干燥法、研磨法等。熔融法系指将药物与载体材料混合熔融后迅速冷却成固体，再将该固体在一定温度下放置使成为易碎物，例如滴丸，该法适合对热稳定的药物和难溶于有机溶剂、熔点低的载体材料如PEG、枸橼酸、糖等溶剂法亦称为共沉淀法，系指将药物和载体共溶于有机溶剂中挥干溶剂，使药物与载体材料同时析出，经干燥即得到药物与载体材料混合成的固体分散体，该法适合于易挥发、热不稳定、易溶于有机溶剂的药物和载体材料。
喷雾干燥是流化技术应用于液态物料干燥的一种方法。基本原理通过气体于干燥塔(室)中将液态物料体系(溶液、混悬液、乳浊液，等)经雾化后，在与热空气的接触中，水分(溶剂)迅速汽化，即得到干燥粉末状产品。该法能直接使溶液、混悬液、乳浊液等快速干燥成粉状或颗粒状制品，可省去蒸发、粉碎等工序。
喷雾干燥方法包括压力喷雾干燥法、离心喷雾干燥法和气流式喷雾干燥法。
(1)压力喷雾干燥法：
①原理：利用高压泵，以70～200大气压的压力，将物料通过雾化器(喷枪)，聚化成10～200的雾状微粒与热空气直接接触，进行热交换，短时间完成干燥。
(2)离心喷雾干燥法：
①原理：利用水平方向作高速旋转的圆盘给予溶液以离心力，使其以高速甩出，形成薄膜、细丝或液滴，由于空气的摩擦、阻碍、撕裂的作用，随圆盘旋转产生的切向加速度与离心力产生的径向加速度，结果以一合速度在圆盘上运动，其轨迹为一螺旋形，液体沿着此螺旋线自圆盘上抛出后，就分散成很微小的液滴以平均速度沿着圆盘切径方向运动，同时液滴又受到地心吸力而下落，由于喷洒出的微粒大小不同。因而它们飞行距离也就不同，因此在不同的距离落下的微粒形成一个以转轴中心对称的圆柱体。
(3)气流式喷雾干燥法：
①原理：湿物料经输送机与加热后的自然空气同时进入干燥器，二者充分混合，由于热质交换面积大，从而在很短的时间内达到蒸发干燥的目的。
喷雾干燥方法广泛应用于食品工业(譬如奶粉)、制药行业(中药干燥、固体分散体制备、减小粒径等)、化工行业、塑料工业和陶瓷生产中。
附图说明
图1为葡萄糖激酶在体内的分布的图。
图2为HMS5552片剂在健康受试者(HV)和2型糖尿病患者(T2DM)中以50mg单次口服给药后的血药浓度-时间曲线图(半对数)。
图3为模拟的HMS5552 50mg片剂空腹时在人体肠道中的平均溶出和吸收曲线图。
图4为模拟的HMS5552 50mg片剂空腹时在人体肠道中不同部位的吸收分布图。
图5为实施例13、对比实施例2和对比实施例4制备的75mg片剂分别在pH1.2、pH4.5和pH6.8时的溶出曲线图。
图6为实施例18制备的75mg包衣片剂分别在pH1.2、pH4.5和pH6.8时的溶出曲线图。
图7为实施例13、对比实施例2和对比实施例4制备的75mg片剂分别在pH1.2时，30分钟的溶出结果柱状图。
图8为实施例13、对比实施例2和对比实施例4制备的75mg片剂分别在pH4.5时，30分钟的溶出结果柱状图。
图9为实施例13、对比实施例2和对比实施例4制备的75mg片剂分别在pH6.8时，30分钟的溶出结果柱状图。
具体实施方式
本发明涉及葡萄糖激酶激活剂的调节释放技术。具体地，本发明涉及设计和制备葡萄糖激酶激活剂的口服制剂。该口服制剂，优选为口服调节释放制剂，进一步优选为口服调节释放固体制剂，在胃液中少量释放，在肠道中快速释放，在肠道内逐步吸收，使得人体中的药动学-药效学相适合(PK/PD Correlation)，体内血药浓度对时间曲线(C～t曲线)呈现倒U字形。
在一个实施方案中，本发明涉及固体分散体，其包含葡萄糖激酶激活剂或其同位素标记物，或其可药用盐和聚合物载体。
在一个实施方案中，本发明涉及固体分散体，其中所述的葡萄糖激酶激活剂为式(Ia)的化合物
Figure PCTCN2017116209-appb-000001
其中：
Z1，Z2，Z3相互独立地是氢，低级烷基，低级烯基，羟基，-NH2，卤素，低级烷氧基，-CF3，-OCF3，-S(CH3)，-S(O2)CH3，-CH2-芳基，杂芳基，氰基，低级烷酰基，-O-芳基，-O-CH2-芳基，-N(CH3)2，环烷基，杂环基，-C(O)-杂环基，或被羟基单-或二-取代的低级烷基；
R2选自：低级烷基，被羟基单-或二-取代的低级烷基，低级卤代烷基，低级烷氧基烷基，低级烷硫基烷基，低级烷氧基，环烷基，所述环烷基是未取代的或是独立地被卤素或低级烷基单-或二-取代的，杂环基和芳基，所述芳基是未取代的或是独立地被卤素单-或二-取代的，并且
R3是-低级烷基-氨基甲酰基，或
通过环碳原子连接到所示的胺基上的未取代或取代的杂芳基，其中一个杂原子是氮，该氮与所述连接环碳原子相邻，所述取代的杂芳基在除了与所述连接碳原子相邻的位置之外的位置独立地被选自以下基团的基团所取代：
低级烷基，卤素，低级烷氧基羰基，氰基，羧基，环烷基，芳基，2-氧 代-唑烷-5-基甲基，-N(低级烷基)2,2,2-二甲基-[1,3]二氧戊环-4-基，-CH2-二甲基-[1,3]二氧戊环，叔丁基-二甲基-硅氧基乙基，未取代的-CH2-芳基，被氰基或烷氧基取代的-CH2-芳基，杂环基，-CH2-杂环基，-6-(CH2)-2，2-二甲基-[1,3]二烷-4-基-乙酸叔丁酯，和独立地被以下基团单-、二-或三-取代的低级烷基：羟基，卤素，烷氧基，-N(低级烷基)2，-NH2，低级烷酰基，低级烷氧基羰基，低级烯氧基羰基，羧基，氨基羰基或低级烷氧基羰基氨基；其同位素标记物或其可药用盐。
在一个实施方案中，本发明涉及固体分散体，其中所述的葡萄糖激酶激活剂选自以下化合物，或其同位素标记物，或其可药用盐：
Figure PCTCN2017116209-appb-000002
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂为化合物HMS5552，或其同位素标记物，或其可药用盐。
Figure PCTCN2017116209-appb-000003
在一个实施方案中，本发明涉及固体分散体，其中所述的葡萄糖激酶激活剂选自：
Figure PCTCN2017116209-appb-000004
Figure PCTCN2017116209-appb-000005
或其同位素标记物，或其可药用盐。
在一个实施方案中，本发明涉及固体分散体，其中所述的葡萄糖激酶激活剂选自TTP399、PF-04937319、RO4597014和LY2608204，或其同位素标记物，或其可药用盐。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体为控释性载体。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体为聚丙烯酸树脂类聚合物。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体选自甲基丙烯酸共聚物和甲基丙烯酸酯共聚物。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸和丙烯酸乙酯的共聚物，甲基丙烯酸和甲基丙烯酸甲酯的共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯的共聚物，丙烯酸乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸与丙烯酸丁酯的共聚物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，甲基丙烯酸和丙烯酸乙酯(1:1)共聚物，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯和甲基丙烯酸甲酯(2:1)共聚物，甲基丙烯酸与丙烯酸丁酯(35:65)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(35:65)共聚物。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体选自Eudragit。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体选自Eudragit E、Eudragit L、Eudragit S。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体选自Eudragit L100、Eudragit S 100、Eudragit E PO、Eudragit E 100、或Eudragit L 100-55。
在一个实施方案中，本发明涉及固体分散体，其中所述聚合物载体为Eudragit L100，是甲基丙烯酸共聚物A型，其为甲基丙烯酸和甲基丙烯酸甲酯(1:1)阴离子共聚物。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂与聚合物载体的重量比为1:10至10:1。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂与聚合物载体的重量比为1:9至9:1、1:4至4:1、3:7至7:3、2:3至3:2、3:4至4:3、4:5至5:4或5:6至6:5。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂与聚合物载体的重量比为1:1。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂的含量占所述固体分散体的10重量％至90重量％。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂的含量占所述固体分散体的30重量％至80重量％。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂的 含量占所述固体分散体的40重量％至80重量％。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂的含量占所述固体分散体的50重量％至80重量％。
在一个实施方案中，本发明涉及固体分散体，其中葡萄糖激酶激活剂的含量占所述固体分散体的50重量％。
在一个实施方案中，本发明涉及固体分散体，其中聚合物载体的含量占所述固体分散体的10重量％至90重量％。
在一个实施方案中，本发明涉及固体分散体，其中通过喷雾干燥获得该固体分散体。
在一个实施方案中，本发明涉及固体分散体组合物，其包含本发明的固体分散体和赋形剂。
在一个实施方案中，本发明涉及固体分散体组合物，其中的赋形剂选自稀释剂；甜味剂或调味剂；表面活性剂；填充剂；粘合剂；崩解剂；润滑剂；助流剂/抗粘附剂；释放改性剂；稳定剂；包衣剂；乳化剂和/或增溶剂，和香料中的一种或多种。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其包含所述的固体分散体或固体分散体组合物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其为葡萄糖激酶激活剂的口服调节释放制剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其为葡萄糖激酶激活剂的口服调节释放固体制剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述葡萄糖激酶激活剂的口服调节释放固体制剂选自片剂、胶囊剂、颗粒剂、散剂、锭剂和丸剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述葡萄糖激酶激活剂的口服调节释放固体制剂为片剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述片剂包含本发明的固体分散体、填充剂、粘合剂、崩解剂和润滑剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂中所述葡萄糖激酶激活剂的固体分散体的含量为1重量％至90重量％，填充剂的含量为1重量％至95重量％，粘合剂的含量为0.5重量％至10重量％， 崩解剂的含量为0.5重量％至7.5重量％，润滑剂的含量为0.25重量％至5重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂中所述填充剂为硅化微晶纤维素或，微晶纤维素或，乳糖，所述粘合剂为羟丙基纤维素或，羟丙基甲基纤维素或，聚乙烯基吡咯烷酮，所述崩解剂为交联羧甲基纤维素钠或，羧甲基淀粉钠，和所述润滑剂为硬脂酸镁或硬脂酰富马酸钠。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂所述填充剂为硅化微晶纤维素，所述粘合剂为羟丙基纤维素，所述崩解剂为交联羧甲基纤维素钠，和所述润滑剂为硬脂酸镁。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述片剂为包衣片剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述包衣片剂包含包衣剂，所述包衣剂选自：羧甲基纤维素钠、醋酸纤维素、醋酸邻苯二甲酸纤维素、乙基纤维素、明胶、药用釉料、羟丙纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸共聚物、甲基纤维素、聚乙二醇、聚醋酸乙烯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米醇溶蛋白和欧巴代。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述包衣片剂中的包衣剂为欧巴代。
在一个实施方案中，本发明的葡萄糖激酶激活剂的口服制剂，其中包衣片剂中所述葡萄糖激酶激活剂的固体分散体的含量为1重量％至90重量％，填充剂的含量为1重量％至95重量％，粘合剂的含量为0.5重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，润滑剂的含量为0.25重量％至5重量％，包衣剂的含量为1重量％至10重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述胶囊剂为明胶胶囊剂，植物来源的HPMC胶囊剂，肠溶胶囊剂或软胶囊剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述胶囊剂包含本发明的的固体分散体、填充剂、和/或粘合剂、和/或崩解剂，和/或润滑剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中制剂，所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，粘合剂的含量为0重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，和润滑剂的含量为0重量％至5重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中，所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，粘合剂的含量为0.5重量％至10重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，崩解剂的含量为0.5重量％至7.5重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中所述填充剂为硅化微晶纤维素，所述粘合剂为羟丙基纤维素，所述崩解剂为交联羧甲基纤维素钠和所述润滑剂为硬脂酸镁。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其在pH1.2～4.5时，30分钟溶出<45％，其在pH6.0～7.0时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂在pH1.2～4.5时，30分钟溶出<40％，在pH6.0～7.0时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂为包衣片剂时，在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂在pH1.2时，30分钟溶出<45％，pH4.5时，30分钟溶出<45％，和pH6.8时，30分钟溶出>85％。在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单位制剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg，在一个实施方案中为约2mg至约150mg，在一个实施方案中为约2.5mg至约150mg，在一个实施方案中为约5mg至约150mg，和在一个实施方案中为约5mg至约100mg。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单 位片剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单位包衣片剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
在一个实施方案中，本发明涉及所述的固体分散体、固体分散体组合物或葡萄糖激酶激活剂的口服制剂，在制备用于治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的药物中的用途。
在一个实施方案中，本发明涉及所述的固体分散体、固体分散体组合物或葡萄糖激酶激活剂的口服制剂治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法，包括向患者给予治疗有效量的本发明的固体分散体、固体分散体组合物或葡萄糖激酶激活剂的口服制剂。
在一个实施方案中，涉及一种制备本发明固体分散体的方法，包括熔融法、溶剂法、溶剂-熔融法、喷雾干燥法、冷冻干燥法、研磨法。
在一个实施方案中，涉及一种制备本发明固体分散体的方法，包括以下步骤：
(1)配制喷雾干燥液，包括将聚合物载体和葡萄糖激酶激活剂溶于溶剂中；
(2)喷雾干燥；
其中，所述溶剂为无水乙醇、甲醇、异丙醇、乙酸乙酯、丙酮、乙腈、异丁醇、正己烷、苯和甲苯或它们的混合物或它们与水的混合物。
具体地，在一个实施方案中，所述制备固体分散体的方法中，喷雾干燥步骤的进风温度为90-150℃，进风量范围为0.3-0.5m3/min，雾化气流的流速为10-30L/min，溶液喷液速度为5-200mL/min。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其包含葡萄糖激酶激活剂固体分散体或固体分散体组合物和赋形剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的葡萄糖激酶激活剂固体分散体包含葡萄糖激酶激活剂，或其同位素标记物，或其可药用盐和聚合物载体。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的葡萄糖激酶激活剂为式(Ia)的化合物
Figure PCTCN2017116209-appb-000006
其中：
Z1，Z2，Z3相互独立地是氢，低级烷基，低级烯基，羟基，-NH2，卤素，低级烷氧基，-CF3，-OCF3，-S(CH3)，-S(O2)CH3，-CH2-芳基，杂芳基，氰基，低级烷酰基，-O-芳基，-O-CH2-芳基，-N(CH3)2，环烷基，杂环基，-C(O)-杂环基，或被羟基单-或二-取代的低级烷基；
R2选自：低级烷基，被羟基单-或二-取代的低级烷基，低级卤代烷基，低级烷氧基烷基，低级烷硫基烷基，低级烷氧基，环烷基，所述环烷基是未取代的或是独立地被卤素或低级烷基单-或二-取代的，杂环基和芳基，所述芳基是未取代的或是独立地被卤素单-或二-取代的，并且
R3是-低级烷基-氨基甲酰基，或
通过环碳原子连接到所示的胺基上的未取代或取代的杂芳基，其中一个杂原子是氮，该氮与所述连接环碳原子相邻，所述取代的杂芳基在除了与所述连接碳原子相邻的位置之外的位置独立地被选自以下基团的基团所取代：
低级烷基，卤素，低级烷氧基羰基，氰基，羧基，环烷基，芳基，2-氧代-唑烷-5-基甲基，-N(低级烷基)2,2,2-二甲基-[1,3]二氧戊环-4-基，-CH2-二甲基-[1,3]二氧戊环，叔丁基-二甲基-硅氧基乙基，未取代的-CH2-芳基，被氰基或烷氧基取代的-CH2-芳基，杂环基，-CH2-杂环基，-6-(CH2)-2，2-二甲基-[1,3]二烷-4-基-乙酸叔丁酯，和独立地被以下基团单-、二-或三-取代的低级烷基：羟基，卤素，烷氧基，-N(低级烷基)2，-NH2，低级烷酰基，低级烷氧基羰基，低级烯氧基羰基，羧基，氨基羰基或低级烷氧基羰基氨基；或其同位素标记物，或其可药用盐。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的葡萄糖激酶激活剂选自以下化合物，或其同位素标记物，或其可药用盐：
Figure PCTCN2017116209-appb-000007
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂为化合物HMS5552，或其同位素标记物，或其可药用盐。
Figure PCTCN2017116209-appb-000008
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的葡萄糖激酶激活剂选自：
Figure PCTCN2017116209-appb-000009
Figure PCTCN2017116209-appb-000010
或其同位素标记物，或其可药用盐。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的葡萄糖激酶激活剂选自TTP399，PF-04937319，RO4597014和LY2608204，或其同位素标记物，或其可药用盐。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体为控释性载体。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体为聚丙烯酸树脂类聚合物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自甲基丙烯酸共聚物和甲基丙烯酸酯共聚物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸和丙烯酸乙酯的共聚物，甲基丙烯酸和甲基丙烯酸甲酯的共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯的共聚物，丙烯酸乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸与丙烯酸丁酯的共聚物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，甲基丙烯酸和丙烯酸乙酯(1:1)共聚物，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯和甲基丙烯酸甲酯(2:1)共聚物，甲基丙烯酸与丙烯酸丁酯(35:65)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(35:65)共聚物。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自Eudragit。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自Eudragit E、Eudragit L、Eudragit S。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体选自Eudragit L100、Eudragit S100、Eudragit E PO、Eudragit E 100、或Eudragit L100-55。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述聚合物载体为Eudragit L100，是甲基丙烯酸共聚物A型，其为甲基丙烯酸和甲基丙烯酸甲酯(1:1)阴离子共聚物。在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂的含量占所述固体分散体的10重量％至90重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂的含量占所述固体分散体的30重量％至80重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂的含量占所述固体分散体的40重量％至80重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂的含量占所述固体分散体的50重量％至80重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中葡萄糖激酶激活剂的含量占所述固体分散体的50重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中聚合物载体的含量占所述固体分散体的10重量％至90重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中通过喷雾干燥获得该固体分散体。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中的赋形剂选自稀释剂；甜味剂或调味剂；表面活性剂；填充剂；粘合剂；崩解剂；润滑剂；助流剂/抗粘附剂；释放改性剂；稳定剂；包衣剂；乳化剂和/或增溶剂，和香料中的一种或多种。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其为葡萄糖激酶激活剂的口服调节释放制剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其为葡萄糖激酶激活剂的口服调节释放固体制剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述葡萄糖激酶激活剂的口服调节释放固体制剂选自片剂，胶囊剂，颗粒剂，散剂，锭剂和丸剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其包含本发明的固体分散体，和/或填充剂，和/或粘合剂，和/或崩解剂，和/或润滑剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述葡萄糖激酶激活剂的口服调节释放固体制剂为片剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述片剂包含本发明的固体分散体、填充剂、粘合剂、崩解剂和润滑剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂中所述葡萄糖激酶激活剂的固体分散体的含量为1重量％至90重量％，填充剂的含量为1重量％至95重量％，粘合剂的含量为0.5重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，润滑剂的含量为0.25重量％至5重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂中所述填充剂为硅化微晶纤维素或，微晶纤维素或，乳糖，所述粘合剂为羟丙基纤维素或，羟丙基甲基纤维素或，聚乙烯基吡咯烷酮，所述崩解剂为交联羧甲基纤维素钠或，羧甲基淀粉钠，和所述润滑剂为硬脂酸镁或硬脂酰富马酸钠。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂中所述填充剂为硅化微晶纤维素，所述粘合剂为羟丙基纤维素，所述崩解剂为交联羧甲基纤维素钠，和所述润滑剂为硬脂酸镁。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中的片剂为包衣片剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述的包衣片剂包含包衣剂，所述包衣剂选自：羧甲基纤维素钠、醋酸纤维素、醋酸邻苯二甲酸纤维素、乙基纤维素、明胶、药用釉料、羟丙纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸共聚物、甲基纤维素、聚乙二醇、聚醋酸乙烯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米醇溶蛋白和欧巴代。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述包衣片剂中的包衣剂为欧巴代。
在一个实施方案中，本发明的葡萄糖激酶激活剂的口服制剂，其中包衣片剂中所述葡萄糖激酶激活剂的固体分散体的含量为1重量％至90重量％，填充剂的含量为1重量％至95重量％，粘合剂的含量为0.5重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，润滑剂的含量为0.25重量％至5重量％，包衣剂的含量为1重量％至10重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述胶囊剂为明胶胶囊剂，植物来源的HPMC胶囊剂，肠溶胶囊剂或软胶囊剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中所述胶囊剂包含本发明的固体分散体、填充剂和/或粘合剂和/或崩解剂和/或润滑剂。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重 量％至95重量％，和/或粘合剂的含量为0重量％至10重量％，和/或崩解剂的含量为0.5重量％至7.5重量％，和/或润滑剂的含量为0重量％至5重量％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂中所述填充剂为硅化微晶纤维素，所述粘合剂为羟丙基纤维素，所述崩解剂为交联羧甲基纤维素钠和所述润滑剂为硬脂酸镁。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其在pH1.2～4.5时，30分钟溶出<45％，其在pH6.0～7.0时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂在pH1.2～4.5时，30分钟溶出<40％，在pH6.0～7.0时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中片剂为包衣片剂时，在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中胶囊剂在pH1.2时，30分钟溶出<45％，pH4.5时，30分钟溶出<45％，和pH6.8时，30分钟溶出>85％。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单位制剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg，在一个实施方案中为约2mg至约150mg，在一个实施方案中为约2.5mg至约150mg，在一个实施方案中为约5mg至约150mg，和在一个实施方案中为约5mg至约100mg。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单位片剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，其中单位包衣片剂中所述葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂，在制备用于治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、 II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的的药物中的用途。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服制剂治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法，包括向患者给予治疗有效量的本发明葡萄糖激酶激活剂的口服制剂。
在一个实施方案中，本发明涉及一种制备固体分散体的方法，包括以下步骤：
(1)配制喷雾干燥液，包括将聚合物载体和葡萄糖激酶激活剂溶于溶剂中；
(2)喷雾干燥；
其中，所述溶剂为无水乙醇、甲醇、异丙醇、乙酸乙酯、丙酮、乙腈、异丁醇、正己烷、苯和甲苯或它们的混合物或它们与水的混合物。
具体地，在喷雾干燥时，进风温度为例如90-150℃，进风量范围为例如0.3-0.5m3/min，雾化气流的流速为例如10-30L/min，溶液喷液速度为例如5-200mL/min。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂的口服片剂的制备方法，其中包括以下步骤：
(1)称量与过筛：称量处方量的各组分，其中润滑剂过筛备用；
(2)制粒：a.将内加的填充剂、固体分散体与粘合剂放入湿法制粒机，按设定参数预混合，加入称量好的纯水进行湿法制粒，出料后用磨粉机进行湿法整粒，然后干燥(箱式或者流化床干燥)，再用磨粉机进行干法整粒；或b.将内加的填充剂、固体分散体放入湿法制粒机，按设定参数预混合，加入配好的粘合剂溶液进行湿法制粒，出料后用磨粉机进行湿法整粒，然后干燥(箱式或者流化床干燥)，再用磨粉机进行干法整粒；
(3)混合：称量实际得到的颗粒量，按比例称量外加的填充剂，崩解剂及润滑剂，混合；
(4)压片：将混合的颗粒装入旋转压片机，开始压片。
在一个实施方案中，本发明涉及葡萄糖激酶激活剂包衣片剂的制备方法，包括以下步骤：
(1)制备葡萄糖激酶激活剂片剂；
(2)配制包衣液：在均匀搅拌的条件下配制包衣混悬液；
(3)包衣：称量葡萄糖激酶激活剂片剂，放入包衣锅内，喷包衣液进行包衣，出片。
本发明还包括包含同位素标记的所述葡萄糖激酶激活剂，所述同位素标记的葡萄糖激酶激活剂与本申请描述的那些葡萄糖激酶激活剂相同，除了以下事实：一个或多个原子被原子质量或质量数与通常在自然界中发现的原子质量或质量数不同的原子代替。可结合至所述化合物中的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，例如它们的同位素分别为2H、3H、13C、14C、15N、18O、17O、31P、32P、35S、18F和36C1。
一些同位素标记的不同化合物(例如用3H和14C标记的那些化合物)用在化合物和/或底物组织分布测定中。由于氚代(即，3H)和碳-14(即，14C)同位素易于制备和可检测性，因此它们是特别优选的。另外，用较重同位素如氘(即，H)取代可得到由于较大代谢稳定性(例如提高的体内半衰期或降低的剂量要求)而带来的治疗优势并因此在一些情况中可为优选的。同位素标记的不同化合物大体上可通过执行与本申请下文在方案中和/或在实施例中公开的操作相似的操作来制备，其中用适当同位素标记的试剂代替非同位素标记的试剂。
在一个实施方案中，本发明的口服调节释放制剂为口服固体制剂和口服液体制剂。
在一个实施方案中，所述口服固体制剂选自片剂、胶囊剂、颗粒剂、散剂、锭剂和丸剂。
在另一个实施方案中，所述片剂为包衣片剂。
本发明又一个方面涉及葡萄糖激酶激活剂的固体分散体组合物，其中包括葡萄糖激酶激活剂的固体分散体和赋形剂，该赋形剂选自：稀释剂例如片剂和/或胶囊剂稀释剂；甜味剂或调味剂；抗氧化剂；表面活性剂；填充剂；粘合剂；崩解剂例如片剂崩解剂；润滑剂例如片剂和/或胶囊剂润滑剂；助流剂/抗粘附剂；释放改性剂；稳定剂；包衣剂；着色剂；络合剂；乳化剂和/或增溶剂；矫味剂和香料；聚合物载体。
本发明的葡萄糖激酶激活剂的固体分散体组合物可以直接使用，或者根据治疗或预防的需要制造成不同的剂型。
本发明的葡萄糖激酶激活剂的固体分散体组合物可以制成片剂、胶囊 剂、颗粒剂、散剂、锭剂和丸剂等各种剂型，可以采用公知方法制造。例如，可以经过混合、造粒加工、胶囊充填或压片和包衣等制剂步骤，来制备制剂。
本发明一个实施方案为一种制备本发明的葡萄糖激酶激活剂的固体分散体的方法，所述方法选自喷雾干燥法，流化床干燥法，溶剂法，熔融挤出法等。
本发明一个实施方案为通过喷雾干燥法制备葡萄糖激酶激活剂的固体分散体，步骤为：
(1)配制喷雾干燥溶液，包括将聚合物载体和葡萄糖激酶激活剂溶于溶剂中；
(2)喷雾干燥，控制进风温度，进风量，雾化气流的流速和压力，和溶液的喷液速度等。
本发明实施方案中葡萄糖激酶激活剂的固体分散体制备中所使用的溶剂包括但不限于链烷醇、酯、腈、环烷烃、芳烃、酮等。具体地，所述溶剂选自以下溶剂：无水乙醇，甲醇，异丙醇，乙酸乙酯，丙酮，乙腈，异丁醇，正己烷，苯和甲苯。可以是单一溶剂，也可以是混合溶剂，或者是有机溶剂和水的混合物。
本发明又一个实施方案涉及使用本发明的葡萄糖激酶激活剂的固体分散体或制剂治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法，包括向患者给予治疗有效量的本发明的葡萄糖激酶激活剂的口服制剂。
本发明又一个实施方案涉及本发明的葡萄糖激酶激活剂的固体分散体或包含该组合物的制剂，其用于制备治疗和/或预防所选疾病及医学病症，尤其一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的药物中的用途。
本发明中的葡萄糖激酶激活剂的固体分散体中使用的葡萄糖激酶激活剂的量，以固体分散体的总重量计，可以在约1重量％至约99重量％之间变化。在一个实施方案中，葡萄糖激酶激活剂的含量范围为约1重量％，约2重量％，约3重量％，约4重量％，约5重量％，约6重量％，约7重量％，约8重量％，约9重量％，约10重量％，约11重量％，约12重量％，约13重量％，约14重量％，约15重量％，约16重量％，约17重量％，约18重量％， 约19重量％，约20重量％，约21重量％，约22重量％，约23重量％，约24重量％，约25重量％，约26重量％，约27重量％，约28重量％，约29重量％，约30重量％，约31重量％，约32重量％，约33重量％，约34重量％，约35重量％，约36重量％，约37重量％，约38重量％，约39重量％，约40重量％，约41重量％，约42重量％，约43重量％，约44重量％，约45重量％，约46重量％，约47重量％，约48重量％，约49重量％，约50重量％，约51重量％，约52重量％，约53重量％，约54重量％，约55重量％，约56重量％，约57重量％，约58重量％，约59重量％，约60重量％，约61重量％，约62重量％，约63重量％，约64重量％，约65重量％，约66重量％，约67重量％，约68重量％，约69重量％，约70重量％，约71重量％，约72重量％，约73重量％，约74重量％，约75重量％，约76重量％，约77重量％，约78重量％，约79重量％，约80重量％，约81重量％，约82重量％，约83重量％，约84重量％，约85重量％，约86重量％，约87重量％，约88重量％，约89重量％，约90重量％，约91重量％，约92重量％，约93重量％，约94重量％，约95重量％，约96重量％，约97重量％，约98重量％，或约99重量％，或其间的任意范围。在一个实施方案中，葡萄糖激酶激活剂的含量范围为约1重量％至约20重量％。在另一个实施方案中，葡萄糖激酶激活剂的含量范围为约2重量％至约40重量％。在进一步的实施方案中，葡萄糖激酶激活剂的含量范围为约30重量％至约60重量％。在又一实施方案中，葡萄糖激酶激活剂的含量范围为约60重量％至约80重量％。在又一实施方案中，葡萄糖激酶激活剂的含量范围为约70重量％至约90重量％。在又一实施方案中，葡萄糖激酶激活剂的含量范围为约80重量％至约100重量％。
本发明中的葡萄糖激酶激活剂的固体分散体中使用的聚合物载体的量，以固体分散体的总重量计，可以在约1重量％至约99重量％之间变化。在一个实施方案中，聚合物载体的含量范围为约1重量％，约2重量％，约3重量％，约4重量％，约5重量％，约6重量％，约7重量％，约8重量％，约9重量％，约10重量％，约11重量％，约12重量％，约13重量％，约14重量％，约15重量％，约16重量％，约17重量％，约18重量％，约19重量％，约20重量％，约21重量％，约22重量％，约23重量％，约24重量％，约25重量％，约26重量％，约27重量％，约28重量％，约29重量％， 约30重量％，约31重量％，约32重量％，约33重量％，约34重量％，约35重量％，约36重量％，约37重量％，约38重量％，约39重量％，约40重量％，约41重量％，约42重量％，约43重量％，约44重量％，约45重量％，约46重量％，约47重量％，约48重量％，约49重量％，约50重量％，约51重量％，约52重量％，约53重量％，约54重量％，约55重量％，约56重量％，约57重量％，约58重量％，约59重量％，约60重量％，约61重量％，约62重量％，约63重量％，约64重量％，约65重量％，约66重量％，约67重量％，约68重量％，约69重量％，约70重量％，约71重量％，约72重量％，约73重量％，约74重量％，约75重量％，约76重量％，约77重量％，约78重量％，约79重量％，约80重量％，约81重量％，约82重量％，约83重量％，约84重量％，约85重量％，约86重量％，约87重量％，约88重量％，约89重量％，约90重量％，约91重量％，约92重量％，约93重量％，约94重量％，约95重量％，约96重量％，约97重量％，约98重量％，或约99重量％，或其间的任意范围。在一个实施方案中，聚合物载体的含量范围为约1重量％至约20重量％。在另一个实施方案中，含量范围为约2重量％至约40重量％。在进一步的实施方案中，含量范围为约30重量％至约60重量％。在又一实施方案中，含量范围为约60重量％至约80重量％。在又一实施方案中，含量范围为约70重量％至约90重量％。在又一实施方案中，含量范围为约80重量％至约100重量％。
优选的，本发明的葡萄糖激酶激活剂固体分散体中，以固体分散体的总重量计，葡萄糖激酶激活剂的含量范围为30-60重量％，聚合物载体的含量范围为40-70重量％。
更优选的，本发明的葡萄糖激酶激活剂固体分散体中，以固体分散体的总重量计，葡萄糖激酶激活剂的含量范围为40-60重量％，聚合物载体的含量范围为40-60重量％。
在一个实施方案中，本发明的固体分散体中的聚合物载体选自聚丙烯树脂类聚合物，其是由丙烯酸(或甲基丙烯酸及它们的酯如：甲酯、乙酯等)以本体(一种单体)聚合，或者与甲基丙烯酸(或它的酯如：甲酯、乙酯、二甲胺基乙酯等)以二种单体(二元)或以三种单体(三元)按一定比例共聚而形成的高分子化合物。
在本发明固体分散体中使用的所述聚合物载体选自甲基丙烯酸丁酯、甲 基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸和丙烯酸乙酯的共聚物，甲基丙烯酸和甲基丙烯酸甲酯的共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯的共聚物，丙烯酸乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸与丙烯酸丁酯的共聚物。
进一步，所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，甲基丙烯酸和丙烯酸乙酯(1:1)共聚物，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯和甲基丙烯酸甲酯(2:1)共聚物，甲基丙烯酸与丙烯酸丁酯(35:65)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(35:65)共聚物。
进一步，所述聚合物载体为Eudragit(尤特奇)，包括Eudragit E、Eudragit L、Eudragit S、Eudragit RL和Eudragit RS，其中Eudragit E是以二甲胺基甲基丙烯酸酯和其他中性甲基丙烯酸酯类共聚而成，包括甲基丙烯酸二甲胺基乙酯与甲基丙烯酸酯的聚合物；Eudragit L和Eudragit S是以甲基丙烯酸与不同比例甲基丙烯酸酯类共聚而成，包括甲基丙烯酸与甲基丙烯酸甲酯，游离羧基：酯＝1:1或甲基丙烯酸与甲基丙烯酸甲酯，游离羧基：酯＝1:2；Eudragit RL和Eudragit RS型为含有某些季胺基因的丙烯酸和甲基丙烯酸酯的共聚物，包括含有10％季胺基团的丙烯酸与甲基丙烯酸酯的共聚物和含有5％季胺基团的丙烯酸与甲基丙烯酸酯的共聚物。
进一步，所述聚合物载体选自：
Eudragit E100(尤特奇E 100)，其为甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，包括尤特奇E PO；
Eudragit L100(尤特奇L100)，是甲基丙烯酸共聚物A型，其为甲基丙烯酸和甲基丙烯酸甲酯(1:1)阴离子共聚物；
Eudragit S100(尤特奇S 100)，其为甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物；
另外，可理解的是，本发明的葡萄糖激酶激活剂的固体分散体组合物和制剂中使用的其他赋形剂的实例包括但不限于：稀释剂例如片剂和/或胶囊剂 稀释剂；甜味剂或调味剂；抗氧化剂；表面活性剂；填充剂；粘合剂；崩解剂例如片剂崩解剂；润滑剂例如片剂和/或胶囊剂润滑剂；助流剂/抗粘附剂；释放改性剂；稳定剂；包衣剂；着色剂；络合剂；乳化剂和/或增溶剂；矫味剂和香料。
适用于本发明的稀释剂的实例包括但不限于ω-3脂肪酸或其衍生物、乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素包括硅化微晶纤维素、糖精钠、葡萄糖和/或甘氨酸。进一步，适用本于发明的片剂和/或胶囊剂稀释剂除上述稀释剂外还包括但不限于碳酸钙、磷酸氢钙、磷酸钙、硫酸钙、纤维素粉、葡聚糖结合剂、果糖、高岭土、淀粉、预胶化淀粉、可压缩糖和糖果用的糖以及它们的组合。
适用于本发明的甜味剂或调味剂的实例包括但不限于香精油、水溶性提取物、糖、单糖、低聚糖、醛糖、酮糖、右旋糖、麦芽糖、乳糖、葡萄糖、果糖、蔗糖、甘露糖醇、木糖醇、D-山梨醇、赤藓醇、戊糖醇、己糖醇、麦芽糖醇、丁磺氨钾、甜蛋白、甘草素、三氯蔗糖、天冬甜素、糖精、糖精钠、环己氨基磺酸钠、甲酸丁香酯醛调味剂以及它们的组合。
适用于本发明的抗氧化剂的实例包括但不限于α生育酚、抗坏血酸、抗坏血酸棕榈酸酯、丁羟茴醚、丁羟甲苯、硫代甘油、焦亚硫酸钾、丙酸、没食子酸丙酯、抗坏血酸钠、亚硫酸氢钠、偏亚硫酸氢钠和亚硫酸钠以及它们的组合。
适用于本发明的表面活性剂的实例包括但不限于但不限于硫酸烷基酯的盐，例如硫酸月桂基酯二乙醇铵盐；烷基芳基磺酸盐，例如十二烷基苯磺酸钙；烷基苯酚-氧化烯加合产物，例如壬基苯酚-C18乙氧基化物；醇-氧化烯加合产物，例如十三烷基醇-C16乙氧基化物；皂类，例如硬脂酸钠；烷基萘-磺酸盐，例如二丁基萘磺酸钠；磺基琥珀酸盐的二烷基酯，例如二(2-乙基己基)磺基琥珀酸钠；山梨糖醇酯，例如山梨糖醇油酸酯；季铵，如月桂基甲基-氯化铵；脂肪酸的聚乙二醇酯，如聚乙二醇硬脂酸酯；环氧乙烷和环氧丙烷的嵌段共聚物；磷酸单烷基酯的盐和磷酸二烷基酯的盐；植物油，如大豆油、菜籽油、橄榄油、蓖麻油、葵花子油、椰子油、玉米油、棉籽油、亚麻子油、棕榈油、花生油、红花油、麻油、桐油等；以及上述植物油的酯以及它们的组合。
适用于本发明的填充剂的实例包括但不限于纤维素衍生物诸如微晶纤 维素或木纤维素(包括微晶纤维素和硅化微晶纤维素)、乳糖、无水或一水乳糖、蔗糖、淀粉、预胶化淀粉、右旋糖、甘露醇(包括甘露醇Pearlitol SD 200)、果糖、木糖醇、山梨醇、玉米淀粉、改性玉米淀粉、无机盐诸如碳酸钙、磷酸钙、磷酸二钙、硫酸钙、糊精/葡萄糖结合剂、麦芽糊精、可压缩糖及其它已知的增容剂或填充剂和/或它们中两种或更多种的混合物。
适用于本发明的粘合剂的实例包括但不限于羧甲基纤维素(包括羧甲基纤维素钠)、羟丙基纤维素(包括羟丙基纤维素EXF)、玉米淀粉、预胶化淀粉、改性玉米淀粉、聚乙烯基吡咯烷酮(PVP)、羟丙基甲基纤维素(HPMC)(包括羟丙基甲基纤维素2208)、乳糖、阿拉伯胶、乙基纤维素、乙酸纤维素及蜡粘合剂诸如巴西棕榈蜡、石蜡、鲸蜡、聚乙烯类或微晶蜡及其它常规粘合剂和/或它们中两种或更多种的混合物。进一步，除了上述粘合剂外，适用于本发明的片剂粘合剂还包括但不限于海藻酸、微晶纤维素、糊精、明胶、液体葡萄糖、瓜尔胶、甲基纤维素、聚氧化乙烯、聚维酮和糖浆以及它们的组合。
适用于本发明的崩解剂的实例包括但不限于交联羧甲基纤维素钠、交聚维酮、淀粉、马铃薯淀粉、预胶化淀粉、玉米淀粉、羧甲基淀粉钠、羟基乙酸淀粉钠、微晶纤维素、低取代的羟丙基纤维素及其它已知的崩解剂。几种具体类型的崩解剂适用于本申请所述制剂。例如，可使用任何级别的交聚维酮包括例如交聚维酮XL-10)且选自Kollidon
Figure PCTCN2017116209-appb-000011
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Figure PCTCN2017116209-appb-000012
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Figure PCTCN2017116209-appb-000013
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Figure PCTCN2017116209-appb-000014
和Polyplasdone
Figure PCTCN2017116209-appb-000015
进一步，适用于本发明的片剂崩解剂除了上述崩解剂外还包括但不限于海藻酸、波拉克林钾、淀粉羟乙酸钠和预胶化淀粉以及它们的组合。
适用于本发明的润滑剂的实例包括但不限于硬脂酸镁、硬脂酸锌、硬脂酸钙、滑石、巴西棕榈蜡、硬脂酸、棕榈酸、硬脂基富马酸钠、月桂基硫酸钠、棕榈酸硬脂酸甘油酯、棕榈酸、豆蔻酸及氢化植物油和脂肪及其它已知的润滑剂和/或它们中两种或更多种的混合物。进一步，适用于本发明的片剂和/或胶囊剂润滑剂除了上述润滑剂外还包括但不限于甘油二十二烷酸酯、轻质矿物油、聚乙二醇、硬纯化硬脂酸以及它们的组合。
适用于本发明的助流剂和/或抗粘附剂的实例包括但不限于二氧化硅、胶态二氧化硅、硅酸镁、三硅酸镁、滑石及其它形式的二氧化硅诸如聚集的硅酸盐和水化硅胶。
适用于本发明的释放改性剂的实例包括但不限于羟丙基甲基纤维素、聚 乙烯醇(PVA)、乙基纤维素、甲基丙烯酸(酯)聚合物、羟丙基纤维素、淀粉、树胶、纤维素醚、源于蛋白质的物质、尼龙、丙烯酸树脂、聚乳酸、聚氯乙烯、聚乙烯基吡咯烷酮和乙酸邻苯二甲酸纤维素以及它们的组合。
适用于本发明的稳定剂包括，但不限于，脂肪酸如油酸和它的钠盐，胆酸及脱氧胆酸，阳离子脂质如硬脂酰胺，和阴离子稳定剂如磷脂酰乙醇胺，磷脂酰丝氨酸，磷脂酸和磷脂酰甘油以及它们的组合。在一个实施方案中，稳定剂是油酸。
适用于本发明的包衣剂包括但不限于羧甲基纤维素钠、醋酸纤维素、醋酸邻苯二甲酸纤维素、乙基纤维素、明胶、药用釉料、羟丙纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸共聚物、甲基纤维素、聚乙二醇、聚醋酸乙烯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米醇溶蛋白和欧巴代例如欧巴代03K12429以及它们的组合。
适用于本发明的着色剂包括但不限于焦糖、红着色剂、黄着色剂、黑着色剂或共混物、氧化铁以及它们的组合。
适用于本发明的络合剂的实例包括但不限于乙二胺四乙酸和盐(EDTA)、依地酸、龙胆酸乙醇酰胺、硫酸羟喹啉以及它们的组合。
适用于本发明的乳化剂和/或增溶剂包括但不限于阿拉伯胶、胆固醇、二乙醇胺、单硬脂酸甘油酯、羊毛脂醇、卵磷脂、单-和二-甘油酯、单乙醇胺、油酸、油醇、泊洛沙姆、聚氧乙烯50硬脂酸酯、聚氧乙烯(35)蓖麻油、聚氧乙烯(40)氢化蓖麻油、聚乙二醇10油醚、聚氧乙烯(20)十六烷基-十八烷基醚、聚氧乙烯(40)单硬脂酸酯、聚山梨酯20(polysorbate 20)、聚山梨酯40、聚山梨酯60、聚山梨酯80、丙二醇二乙酸酯、丙二醇单硬脂酸酯、月桂基硫酸钠、硬脂酸钠、脱水山梨糖醇单月桂酸酯、脱水山梨糖醇单油酸酯、脱水山梨糖醇单棕酸酯、脱水山梨糖醇单硬脂酸酯、硬脂酸、三乙醇胺、乳化蜡以及它们的组合。
适用于本发明的矫味剂和香料包括但不限于茴香脑、苯甲醛、乙基香草醛、薄荷脑、水杨酸甲酯、谷氨酸一钠、橙花油、薄荷、薄荷油、欧薄荷醑(peppermint spirit)、玫瑰花油、浓玫瑰水、麝香草酚、妥卢香脂酊、香草、香草酊、香草醛以及它们的组合。
适用于本发明的溶剂包括但不限于丙酮、醇、无水乙醇、稀醇、水合戊 烯、苯甲酸苄酯、丁醇、四氯化碳、氯仿、玉米油、棉籽油、乙酸乙酯、甘油、己二醇、异丙醇、甲醇、二氯甲烷、甲基异丁基酮、矿物油、花生油、聚乙二醇、碳酸丙烯酯、丙二醇、芝麻油、注射用水、无菌注射用水、无菌冲洗用水、纯净水以及它们的组合。
根据具体应用，单位剂量制剂中的活性化合物的量可在从约1mg至约200mg内变化或调整，优选在从约2mg至约150mg内变化或调整，更优选在从约2.5mg至约150mg内变化或调整，更加优选在从约5mg至约150mg内变化或调整。
具体地，本发明单位片剂中葡萄糖激酶激活剂的含量为约1mg至约200mg，优选为约2mg至约150mg，更优选为约5mg至约100mg。
下面结合附图和具体实施例对本发明作进一步说明，但本发明并不局限于实施例，在本发明的技术基础上做出的若干修改和替换均属于本发明的保护范围。
实施例
葡萄糖激酶激活剂的固体分散体的制备
本发明使用的化学品可以购自公司如Shin-Etsu Japan，Evonik Germany,J.T.Baker US,SCR China,Ashland US,FMC US,JRS Germany,Colorcon US,Capsugel,BASF，振兴试剂等。生产设备和分析测试仪器等可以购自这样的公司如Sartorius，Nikon，Sympatec，Bruker，Gea Niro，Korsch，Erweka，Agilent，Quadro Engineering,Canada；Warters,US；TA,US；SOTAX,Switzerland；Mettler Toledo Instrument Newark，DE。
I.葡萄糖激酶激活剂的固体分散体的制备
1.1固体分散体喷雾干燥前溶液的制备
实施例1(活性成分与聚合物的重量比为1:9)
称取Eudragit L100(优特奇L100，Evonik Germany)6.75克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入0.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例2(活性成分与聚合物的重量比为3:7)
称取Eudragit L100(优特奇L100，Evonik Germany)5.25克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入2.25克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例3(活性成分与聚合物的重量比为5:5)
称取Eudragit L100(优特奇L100，Evonik Germany)3.75克，在搅拌条件下加入无水乙醇(J.T.Baker/)中，至完全溶解后加入3.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例4(活性成分与聚合物的重量比为7:3)
称取Eudragit L100(优特奇L100，Evonik Germany)2.25克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入5.25克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例5(活性成分与聚合物的重量比为8:2)
称取Eudragit L100(优特奇L100，Evonik Germany)1.5克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入6克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例6(活性成分与聚合物的重量比为9:1)
称取Eudragit L100(优特奇L100，Evonik Germany)0.75克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入6.75克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例7(活性成分与聚合物的重量比为6:4)
称取Eudragit L100(优特奇L100，Evonik Germany)3.0克，在搅拌条件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入4.5克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例8(活性成分与聚合物的重量比为4:6)
称取Eudragit L100(优特奇L100，Evonik Germany)4.5克，在搅拌条 件下加入无水乙醇(J.T.Baker)中，至完全溶解后加入3.0克化合物HMS5552，加足量无水乙醇后继续搅拌得到50ml黄色至橙色溶液。
实施例9(活性成分与聚合物的重量比为5:5)
称取Eudragit L100(优特奇L100，Evonik Germany)187.5克，在搅拌条件下加入无水乙醇(振兴试剂)中，至完全溶解后加入187.5克化合物HMS5552，继续搅拌得到2500ml黄色至橙色溶液。
1.2葡萄糖激酶激活剂的固体分散体的制备
针对上述制备的溶液进行喷雾干燥，来制备葡萄糖激酶激活剂固体分散体。所得固体分散体的编号与上面实施例的编号对应。适用于本发明喷雾干燥设备包括但不限于Niro GEA Process Engineering Inc.,Buchi Labortechnik AG，ProCept和SPX ANHYDROUS公司制作的喷雾干燥设备。可以通过选择合适的干燥气体进风温度、进风量、进液速度和雾化压力进行喷雾干燥，以便液滴在其到达装置壁时被充分干燥。这有助于确保干燥的液滴基本上是固体，可以形成细粉末，并且不会粘壁，也不至于难以在旋风器中收集。所得粉末进行二次干燥，确保产品符合质量要求。
喷雾干燥法制备葡萄糖激酶激活剂固体分散体生产工艺流程描述
对上述实施例1-8中制备的溶液通过喷雾干燥来制备固体分散体，其中喷雾干燥机设置的进风温度为90-150℃，进风流速设置为0.3-0.5m3/min，气流的流速为15-30L/min，上述溶液的喷液速度为5-7mL/min，喷雾干燥得到固体分散体1-8。
对上述实施例9中制备的溶液通过喷雾干燥来制备固体分散体，其中喷雾干燥机设置的进风温度为90-150℃，进风流速设置为20-30kg/h，气流的流速为3-30kg/h，上述溶液的喷液速度为5-200mL/min，喷雾干燥得到固体分散体9。
按照上述方式，分别制备了固体分散体1-9，其中：
固体分散体1中化合物HMS5552的质量分数为10％；固体分散体2中化合物HMS5552的质量分数为30％；固体分散体3中化合物HMS5552的质量分数为50％；固体分散体4中化合物HMS5552的质量分数为70％；固 体分散体5中化合物HMS5552的质量分数为80％；固体分散体6中化合物HMS5552的质量分数为90％；固体分散体7中化合物HMS5552的质量分数为60％；固体分散体8中化合物HMS5552的质量分数为40％；固体分散体9中化合物HMS5552的质量分数为50％。
II.葡萄糖激酶激活剂片剂的制备
包衣片可以用上面“葡萄糖激酶激活剂片剂的制备”中所述的处方，或者单独的处方。包衣膜的功能，主要有增加硬度，便于防潮，增加外观美感，便于吞咽，等等。葡萄糖激酶激活剂包衣片剂的制备步骤：
(1)制备葡萄糖激酶激活剂片剂，片剂的处方和制备工艺同上。
(2)包衣液的配制：在搅拌条件下配制含固量为15重量％的包衣混悬液，并搅拌均匀。
(3)包衣：取片芯称重，放入包衣锅内，待片床温度达到30-60℃后开始包衣，目标包衣增重为2重量％-4重量％，达到增重目标后停止喷包衣液，冷却片床至25-30℃后出片。
按照该方法制备了以下剂量的葡萄糖激酶激活剂包衣片剂。这些包衣片剂的处方见下列表。
实施例10 5mg片剂处方(按1000片计)，即其中活性成分的量为5mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 10.0 3.1
硅化微晶纤维素 297.5 93.0
羟丙基纤维素 7.5 2.3
交联羧甲基纤维素钠 2.5 0.78
硬脂酸镁 2.5 0.78
总计 320.0 100
实施例11 100mg片剂处方(按1000片计)，即其中活性成分的量为
100mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 200.0 81.6
硅化微晶纤维素 32.5 13.3
羟丙基纤维素 7.5 3.1
交联羧甲基纤维素钠 2.5 1.02
硬脂酸镁 2.5 1.02
总计 245.0 100
实施例12 25mg片剂处方(按1000片计)，即其中活性成分的量为25mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 50.0 15.6
硅化微晶纤维素 257.5 80.5
羟丙基纤维素 7.5 2.3
交联羧甲基纤维素钠 2.5 0.78
硬脂酸镁 2.5 0.78
总计 320.0 100
实施例13 75mg片剂处方(按1000片计)，即其中活性成分的量为75mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 150.0 54.5
硅化微晶纤维素 112.5 40.9
羟丙基纤维素 7.5 2.7
交联羧甲基纤维素钠 2.5 0.91
硬脂酸镁 2.5 0.91
总计 275.0 100
实施例14 25mg片剂处方(按1000片计)，即其中活性成分的量为25mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 50.0 15.6
硅化微晶纤维素 239.6 74.9
羟丙基甲基纤维素 16.0 5.0
羟基乙酸淀粉钠 11.2 3.5
硬脂酸镁 3.2 1.0
总计 320.0 100
实施例15 50mg片剂处方(按1000片计)，即其中活性成分的量为50mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 100.0 33.3
微晶纤维素 183.5 61.2
羟丙基纤维素 7.5 2.5
交联羧甲基纤维素钠 6.0 2.0
硬脂酸镁 3.0 1.0
总计 300.0 100
实施例16 100mg片剂处方(按1000片计)，即其中活性成分的量为100mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 200.0 80.0
一水乳糖 27.5 11.0
聚乙烯吡咯烷酮 12.5 5.0
交联羧甲基纤维素钠 5.0 2.0
硬脂酰富马酸钠 5.0 2.0
总计 250.0 100
III.葡萄糖激酶激活剂包衣片剂的制备
包衣片可以用上面“葡萄糖激酶激活剂片剂的制备”中所述的处方，或者单独的处方。包衣膜的功能，主要有增加硬度，便于防潮，增加外观美感，便于吞咽，等等。葡萄糖激酶激活剂包衣片剂的制备步骤：
(1)制备葡萄糖激酶激活剂片剂，片剂的处方和制备工艺同上。
(2)包衣液的配制：在搅拌条件下配制含固量为15重量％的包衣混悬液，并搅拌均匀。
(3)包衣：取片芯称重，放入包衣锅内，待片床温度达到30-60℃后开始 包衣，目标包衣增重为2重量％-4重量％，达到增重目标后停止喷包衣液，冷却片床至25-30℃后出片。
按照该方法制备了以下剂量的葡萄糖激酶激活剂包衣片剂。这些包衣片剂的处方见下列表。
实施例17 50mg包衣片剂处方(按1000片计)，即其中活性成分的量为50mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 100.0 33.3
硅化微晶纤维素 187.5 62.5
羟丙基纤维素 7.5 2.5
交联羧甲基纤维素钠 2.5 0.83
硬脂酸镁 2.5 0.83
总计 300.0 100
欧巴代 9.0 3.0
实施例18 75mg包衣片剂处方(按1000片计)，即其中活性成分的量为75mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 150.0 54.5
硅化微晶纤维素 112.5 40.9
羟丙基纤维素 7.5 2.7
交联羧甲基纤维素钠 2.5 0.91
硬脂酸镁 2.5 0.91
总计 275.0 100
欧巴代 8.25 3.0
IV.葡萄糖激酶激活剂胶囊的制备
胶囊制备方法一：
(1)称量与过筛：称量处方量的各组分，过筛备用。
(2)制粒：将内加的微晶纤维素、固体分散体(上述制备得到的固体分散体9)与羟丙基纤维素放入湿法制粒机，按设定好参数预混合，加入称量好的纯水进行湿法制粒，出料后用磨粉机进行湿法整粒，干燥至颗粒的LOD为2-3重量％，再用磨粉机进行干法整粒。
(3)胶囊灌装：将颗粒囊灌胶囊。适用于本发明的胶囊壳类型有：动物来源的明胶胶囊，植物来源的HPMC胶囊，肠溶胶囊，软胶囊，等。
实施例19 50mg胶囊处方(按1000粒计)，即其中活性成分的量为50mg
处方组成 单位处方/g ％(w/w)
固体分散体9 100.0 36.04
硅化微晶纤维素 170.0 61.26
羟丙基纤维素 7.5 2.70
总计 277.5 100.0
胶囊制备方法二：
(1)称量与混合：称量处方量的各组分，混合备用。
(2)胶囊灌装：将混好的粉末直接灌装胶囊。适用于本发明的胶囊壳类型有，动物来源的明胶胶囊，植物来源的HPMC胶囊，肠溶胶囊，等。
实施例20 50mg胶囊处方(按1000粒计)，即其中活性成分的量为50mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 100.0 33.33
硅化微晶纤维素 192.5 64.17
交联羧甲基纤维素钠 7.5 2.50
总计 300.0 100
实施例21 25mg胶囊处方(按1000粒计)，即其中活性成分的量为25mg。
处方组成 单位处方/g ％(w/w)
固体分散体9 50 16.67
硅化微晶纤维素 247.5 82.5
交联羧甲基纤维素钠 2.5 0.83
总计 300.0 100
V.对比实施例
分别将实施例12和实施例13中的固体分散体9替换为化合物HMS5552的原料药粉末，调整处方中微晶纤维素的量，并保持其它的组成和配比不变，采用上述葡萄糖激酶激活剂片剂制备工艺，制备得到对比实施例1和对比实施例2。
对比实施例1 25mg片剂处方(按1000片计)，即其中活性成分的量为25mg。
处方组成 单位处方/g ％(w/w)
化合物HMS5552原料药粉末 25 7.8
硅化微晶纤维素 282.5 88.3
羟丙基纤维素 7.5 2.3
交联羧甲基纤维素钠 2.5 0.78
硬脂酸镁 2.5 0.78
总计 320.0 100
对比实施例2 75mg片剂处方(按1000片计)，即其中活性成分的量为75mg。
处方组成 单位处方/g ％(w/w)
化合物HMS5552原料药粉末 75.0 27.3
硅化微晶纤维素 187.5 68.2
羟丙基纤维素 7.5 2.7
交联羧甲基纤维素钠 2.5 0.91
硬脂酸镁 2.5 0.91
总计 275.0 100
分别将实施例12和实施例13中的固体分散体9替换为化合物HMS5552原料药粉末和Eudragit L100(尤特奇L100)，保持其它组成和配比不变，采用上述葡萄糖激酶激活剂片剂制备工艺，制备得到对比实施例3和对比实施例4。
对比实施例3 25mg片剂处方(按1000片计)，即其中活性成分的量为25mg。
处方组成 单位处方/g ％(w/w)
化合物HMS5552原料药粉末 25.0 7.8
Eudragit L100(尤特奇L100) 25.0 7.8
硅化微晶纤维素 257.5 80.5
羟丙基纤维素 7.5 2.3
交联羧甲基纤维素钠 2.5 0.78
硬脂酸镁 2.5 0.78
总计 320.0 100
对比实施例4 75mg片剂处方(按1000片计)，即其中活性成分的量为75mg。
处方组成 单位处方/g ％(w/w)
化合物HMS5552原料药粉末 75.0 27.3
Eudragit L100(尤特奇L100) 75.0 27.3
硅化微晶纤维素 112.5 40.9
羟丙基纤维素 7.5 2.7
交联羧甲基纤维素钠 2.5 0.91
硬脂酸镁 2.5 0.91
总计 275.0 100
可以按照相同的方式制备其它剂量或规格的葡萄糖激酶激活剂片剂。
VI.测试
1.葡萄糖激酶激活剂的口服制剂在人体内的药代动力学
使用上述实施例制备的片剂或者按照与上述制备实施例相同的方式制备片剂。在单剂量爬坡(SAD)试验中，健康受试者分别以活性成分规格为5mg、10mg、15mg、25mg、35mg和50mg单次口服给药后，血浆浓度迅速上升，平均达峰时间为1.25-2.5小时，随后平稳下降，末端消除半衰期约为4.5-7.5小时。
使用上述实施例制备的片剂或者按照与上述制备实施例相同的方式制备片剂。在多剂量爬坡(MAD)试验中，2型糖尿病(T2DM)患者以活性成分规格为25mg、50mg、100mg、150mg和200mg单次口服给药后，血浆浓度迅速上升，平均达峰时间为1.5-2小时，随后平稳下降，末端消除半衰期约为6.8-8.6小时，与健康受试者相比无显著差别；以25mg、50mg、100mg、150mg、200mg每天两次、连续口服给药5.5天达稳态后，血浆浓度平均达峰时间为1.5-3小时，末端消除半衰期约为7.7-10.3小时，血浆暴露量与T2DM患者单次给药相比基本无蓄积(蓄积比范围为1-1.8)。
使用实施例12制备的化合物HMS5552片剂在健康受试者(HV)和T2DM患者(T2DM)中以活性成分规格为50mg，即两片、活性成分规格为25mg的片剂，单次口服给药后的血药浓度-时间曲线见图2。
2.PBPK模型法模拟葡萄糖激酶激活剂口服制剂在人体肠道中的吸收
采用Simcyp软件建立了PBPK模型，模拟空腹状态下健康人单剂量口服50mg的HMS5552片剂后，化合物HMS5552在人体肠道内的吸收程度及主要吸收部位。
图3为PBPK模型模拟的健康人50mg单剂量空腹给药时葡萄糖激酶激活剂口服制剂在肠道中的平均溶出和吸收曲线图。从图中可以看出，葡萄糖激酶激活剂的口服制剂在肠道中迅速溶出，在30分钟内溶出率达90％以上；与溶出相比，葡萄糖激酶激活剂吸收完全，但吸收速度略慢，约在给药后2-3小时达到吸收平台期，这与临床观察到的葡萄糖激酶激活剂在人体中的血浆达峰时间一致，表明模型可以很好的预测葡萄糖激酶激活剂在人体内的溶出和吸收。
图4显示的是PBPK模型模拟的健康人50mg单剂量空腹给药时葡萄糖 激酶激活剂在人体肠道中不同部位的吸收分数，可以看出HMS5552片剂在人体中单次给药后，主要吸收部位位于肠道前端的十二指肠、空肠I段和空肠II段，三者的吸收分数总和为0.8，占总吸收率(0.92)的87％。
3.体外溶出度测试
片剂和胶囊的溶出度是采用《中国药典》(2010年版)的桨法，分别测试在pH1.2和/或pH4.5和/或pH6.8三种不同溶出介质中的溶出，在5分钟，10分钟，20分钟，30分钟，45分钟和60分钟时，分别取样5ml，进行HPLC分析。
按照上述测试方法，测量上述5种剂量规格的片剂和胶囊，其溶出度结果如下。
表1：实施例12制备的25mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 57 83 92 95 96 97
pH4.5 8.7 13.7 18.6 21.6 24.8 27.3
pH1.2 8.4 12.8 16.6 18.7 20.6 22.0
表2：实施例10制备的5mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 57.8 81 91.1 94.1 95.9 96.7
pH4.5 17.1 25.1 32.4 36.8 41.6 45.3
pH1.2 13.4 18.4 22.1 24.0 25.9 27.3
表3：实施例17制备的50mg包衣片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 51.3 73.4 85.6 92.1 97.2 99.8
pH4.5 8.2 11.7 15.7 18.1 20.8 22.8
pH1.2 7.1 9.8 12.7 14.5 16.1 17.2
表4：实施例18制备的75mg包衣片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 96.9 100 100.1 100.8 101.0 101.0
pH4.5 10.0 15.7 20.3 23.6 26.8 28.9
pH1.2 8.1 11.7 14.7 16.5 18.0 19.1
表5：实施例11制备的100mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 60 85.2 95.2 99.3 100.7 101.2
pH4.5 6.0 9.5 14.1 17.2 20.5 23.8
pH1.2 4.9 7.6 10.6 12.3 14.4 15.8
表6：实施例21制备的25mg胶囊溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 65.83 89.35 95.24 95.97 96.89 97.64
pH4.5 25.9 37.24 40.6 43.96 46.38 47.65
pH1.2 31.8 36.43 39.37 40.69 42.81 44.29
表7：实施例13制备的75mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 64.5 79.7 86.3 88.6 90.8 92.0
pH4.5 13.4 16.9 21.5 24.6 28.4 31.3
pH1.2 8.4 11.5 14.3 16.2 18.1 19.4
表8：实施例14制备的25mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 41.7 71.6 88.9 95.8 99.3 103.1
pH4.5 18.7 24.0 29.1 33.2 38.1 41.6
pH1.2 9.1 13.4 17.6 20.1 22.3 23.5
表9：实施例15制备的50mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 81.3 92.4 95.1 95.8 96.1 96.3
pH4.5 16.6 22.9 29.1 32.9 36.9 40.0
pH1.2 14.4 19.3 22.6 24.7 26.7 27.9
表10：实施例16制备的100mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 49.4 74.7 88.7 93.6 96.4 97.3
pH4.5 7.9 12.8 18.3 21.9 25.8 28.3
pH1.2 1.5 3.3 8.1 11.3 14.9 16.8
表11：对比实施例1制备的25mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 43.1 61.9 83.2 91.4 97.4 99.9
pH4.5 38.5 57.5 77.8 84.7 92.9 96.8
pH1.2 41.3 60.9 79.8 87.9 94.0 97.1
表12：对比实施例2制备的75mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 25.6 40.8 56.9 65.3 73.6 79.8
pH4.5 24.4 40.7 57.8 67.2 76.3 82.0
pH1.2 36.5 46.9 58.9 68.5 80.2 85.7
表13：对比实施例3制备的25mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 53.3 73.9 89.9 95.4 98.6 99.3
pH4.5 50.9 68.4 84.7 91.1 95.0 96.3
pH1.2 43.8 66.0 83.9 91.1 95.4 97.5
表14：对比实施例4制备的75mg片剂溶出结果
pH值/时间点 5 10 20 30 45 60
pH6.8 24.7 40.4 58.6 68.7 78.7 85.2
pH4.5 30.9 41.7 58.8 68.1 77.0 82.6
pH1.2 30.6 46.6 62.5 72.3 80.9 85.8
结论：
采用本发明固体分散体技术制备的口服制剂在不同pH条件下，溶出度具有显著的差异；而采用常规手段制备的片剂，不具有该特征。如图5所示，尽管片剂制备工艺及处方组成相同或相似，化合物HMS5552的不同存在形式导致口服制剂中的有效成分化合物HMS5552有不同的溶出特征，即纯HMS5552粉末(对比实施例2)、HMS5552+Eudragit L100简单混合物(对比实施例4)或固体分散体形式(实施例13)。
上述差异表明，采用本发明固体分散体技术制备的片剂的溶出为pH依赖型，即在pH1.2～4.5时，30分钟溶出度不高于45％，在pH6.0～7.0时，30分钟溶出度不低于85％(表1-10)。
更进一步，如图7-9所示，对比实施例2和对比实施例4制备的片剂在pH1.2、pH4.5和pH6.8时，30分钟溶出结果相近。而采用本发明的固体分散体技术制备的片剂实施例13，30分钟溶出比例在pH1.2、pH4.5、和pH6.8时分别为16.2％、24.6％、和88.6％。

Claims (75)

  1. 固体分散体，其包含葡萄糖激酶激活剂，或其同位素标记物，或其可药用盐和聚合物载体。
  2. 如权利要求1的固体分散体，其中所述的葡萄糖激酶激活剂为式(Ia)的化合物
    Figure PCTCN2017116209-appb-100001
    其中：
    Z1，Z2，Z3相互独立地是氢，低级烷基，低级烯基，羟基，-NH2，卤素，低级烷氧基，-CF3，-OCF3，-S(CH3)，-S(O2)CH3，-CH2-芳基，杂芳基，氰基，低级烷酰基，-O-芳基，-O-CH2-芳基，-N(CH3)2，环烷基，杂环基，-C(O)-杂环基，或被羟基单-或二-取代的低级烷基；
    R2选自：低级烷基，被羟基单-或二-取代的低级烷基，低级卤代烷基，低级烷氧基烷基，低级烷硫基烷基，低级烷氧基，环烷基，所述环烷基是未取代的或是独立地被卤素或低级烷基单-或二-取代的，杂环基和芳基，所述芳基是未取代的或是独立地被卤素单-或二-取代的，并且
    R3是-低级烷基-氨基甲酰基，或
    通过环碳原子连接到所示的胺基上的未取代或取代的杂芳基，其中一个杂原子是氮，该氮与所述连接环碳原子相邻，所述取代的杂芳基在除了与所述连接碳原子相邻的位置之外的位置独立地被选自以下基团的基团所取代：
    低级烷基，卤素，低级烷氧基羰基，氰基，羧基，环烷基，芳基，2-氧代-唑烷-5-基甲基，-N(低级烷基)2,2,2-二甲基-[1,3]二氧戊环-4-基，-CH2-二甲基-[1,3]二氧戊环，叔丁基-二甲基-硅氧基乙基，未取代的-CH2-芳基，被氰基或烷氧基取代的-CH2-芳基，杂环基，-CH2-杂环基，-6-(CH2)-2，2-二甲基-[1,3]二烷-4-基-乙酸叔丁酯，和独立地被以下基团单-、二-或三-取代的低级烷基：羟基，卤素，烷氧基，-N(低级烷基)2，-NH2，低级烷酰基，低级烷 氧基羰基，低级烯氧基羰基，羧基，氨基羰基或低级烷氧基羰基氨基；或其同位素标记物，或其可药用盐。
  3. 如权利要求1或2的固体分散体，其中所述的葡萄糖激酶激活剂选自以下化合物，或其同位素标记物，或其可药用盐：
    Figure PCTCN2017116209-appb-100002
  4. 如权利要求1-3中任意一项的固体分散体，其中葡萄糖激酶激活剂为化合物HMS5552，或其同位素标记物，或其可药用盐，
    Figure PCTCN2017116209-appb-100003
  5. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体为控释性载体。
  6. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体为聚丙烯酸树脂类聚合物。
  7. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体选自甲基丙烯酸共聚物和甲基丙烯酸酯共聚物。
  8. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸和丙烯酸乙酯的共聚物，甲基丙烯酸和甲基丙烯酸甲酯的共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯的共聚物，丙烯酸乙酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸、丙烯酸甲酯和甲基丙烯酸甲酯的共聚物，甲基丙烯酸与丙烯酸丁酯的共聚物。
  9. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体选自甲基丙烯酸丁酯、甲基丙烯酸二甲胺基乙酯和甲基丙烯酸甲酯(1:2:1)共聚物，甲基丙烯酸和丙烯酸乙酯(1:1)共聚物，甲基丙烯酸和甲基丙烯酸甲酯(1:2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.2)共聚物，丙烯酸乙酯、甲基丙烯酸甲酯和甲基丙烯酸氯化三甲胺基乙酯(1:2:0.1)共聚物，丙烯酸乙酯和甲基丙烯酸甲酯(2:1)共聚物，甲基丙烯酸与丙烯酸丁酯(35:65)共聚物，甲基丙烯酸与甲基丙烯酸甲酯(1:1)聚合物，甲基丙烯酸与甲基丙烯酸甲酯(35:65)共聚物。
  10. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体为Eudragit。
  11. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体选自Eudragit E、Eudragit L、Eudragit S。
  12. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体选自Eudragit L 100、Eudragit S 100、Eudragit E PO、Eudragit E 100、或Eudragit L 100-55。
  13. 如权利要求1-4中任意一项的固体分散体，其中所述聚合物载体为甲基丙烯酸共聚物A型(甲基丙烯酸与甲基丙烯酸甲酯(1:1)的阴离子共聚物)。
  14. 如权利要求1-4中任一项的固体分散体，其中所述聚合物载体为Eudragit L 100。
  15. 如权利要求1-14中任意一项的固体分散体，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为1:10至10:1。
  16. 如权利要求1-14中任意一项的固体分散体，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为1:9至9:1、1:4至4:1、3:7至7:3、2:3至3:2、3:4至4:3、4:5至5:4或5:6至6:5。
  17. 如权利要求1-14中任意一项的固体分散体，其中所述葡萄糖激酶激活剂与聚合物载体的重量比为1:1。
  18. 如权利要求1-17中任意一项的固体分散体，其为通过熔融法，或溶剂法，或溶剂-熔融法，或喷雾干燥法，或冷冻干燥法，或研磨法，或热熔挤出法制备的混合物。
  19. 如权利要求1-18中任意一项的固体分散体，其为通过喷雾干燥制备获得的混合物。
  20. 固体分散体组合物，其包含如权利要求1-19中任意一项所述的固体分散体和赋形剂。
  21. 如权利要求20的固体分散体组合物，其中所述的赋形剂选自稀释剂；甜味剂或调味剂；表面活性剂；填充剂；粘合剂；崩解剂；润滑剂；助流剂/抗粘附剂；释放改性剂；稳定剂；包衣剂；乳化剂和/或增溶剂，和香料中的一种或多种。
  22. 葡萄糖激酶激活剂的口服制剂，其包含权利要求1-19中任意一项的固体分散体或权利要求20或21的固体分散体组合物，所述葡萄糖激酶激活剂的口服制剂为葡萄糖激酶激活剂的口服调节释放制剂。
  23. 如权利要求22的葡萄糖激酶激活剂的口服制剂，其为葡萄糖激酶激活剂的口服调节释放固体制剂。
  24. 如权利要求23的葡萄糖激酶激活剂的口服制剂，其中所述葡萄糖激酶激活剂的口服调节释放固体制剂选自片剂，胶囊剂，颗粒剂，散剂，锭剂和丸剂。
  25. 葡萄糖激酶激活剂的片剂，其中所述片剂包含权利要求1-19中任意一项的固体分散体和选自以下的一种或多种：填充剂、粘合剂、崩解剂和润滑剂。
  26. 如权利要求25所述的葡萄糖激酶激活剂的片剂，其中所述片剂中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为1重量％至95重量％，粘合剂的含量为0.5重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，和润滑剂的含量为0.25重量％至5重量％。
  27. 如权利要求25或26所述的葡萄糖激酶激活剂的片剂，所述片剂中所述填充剂为硅化微晶纤维素、微晶纤维素或乳糖，所述粘合剂为羟丙基纤维素、羟丙基甲基纤维素或聚乙烯基吡咯烷酮，所述崩解剂为交联羧甲基纤维素钠、羟基乙酸淀粉钠或羧甲基淀粉钠，和所述润滑剂为硬脂酸镁或硬脂酰富马酸钠。
  28. 如权利要求27所述的葡萄糖激酶激活剂的片剂，其中所述片剂中所述填充剂为硅化微晶纤维素，所述粘合剂为羟丙基纤维素，所述崩解剂为交联羧甲基纤维素钠，和所述润滑剂为硬脂酸镁。
  29. 如权利要求25-28中任意一项所述的葡萄糖激酶激活剂的片剂，其中单位片剂中葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
  30. 如权利要求中25所述的葡萄糖激酶激活剂的片剂，所述片剂包含120mg至180mg的化合物HMS5552固体分散体，33.1mg至151.6mg硅化微晶纤维素，1.4mg至27.5mg羟丙基纤维素，1.4mg至20.6mg交联羧甲基纤维素钠和0.7mg至13.8mg硬脂酸镁，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  31. 如权利要求30所述的葡糖糖激酶激活剂的片剂，其包含150mg的化合物HMS5552固体分散体,112.5mg硅化微晶纤维素，7.5mg羟丙基纤维素，2.5mg交联羧甲基纤维素钠和2.5mg硬脂酸镁，其中所述化合物HMS5552固体分散体包含75mg的化合物HMS5552。
  32. 如权利要求25所述的葡糖糖激酶激活剂的片剂，所述片剂包含170mg至230mg的化合物HMS5552固体分散体，2.5mg至71.9mg硅化微晶纤维素，1.2mg至24.5mg羟丙基纤维素，1.2mg至18.4mg交联羧甲基纤维素钠和0.6mg至12.3mg硬脂酸镁，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  33. 如权利要求32所述的葡糖糖激酶激活剂的片剂，其包含200mg的化合物HMS5552固体分散体，32.5mg硅化微晶纤维素，7.5mg羟丙基纤维素，2.5mg交联羧甲基纤维素钠和2.5mg硬脂酸镁，其中所述化合物HMS5552固体分散体包含100mg的化合物HMS5552。
  34. 如权利要求25所述的葡糖糖激酶激活剂的片剂，所述片剂包含40mg至60mg的化合物HMS5552固体分散体,188.0mg至276.0mg硅化微晶纤维素， 1.6mg至32.0mg羟丙基纤维素，1.6mg至24.0mg交联羧甲基纤维素钠和0.8mg至16.0mg硬脂酸镁，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  35. 如权利要求34所述的葡糖糖激酶激活剂的片剂，其包含50mg的化合物HMS5552固体分散体,257.5mg硅化微晶纤维素，7.5mg羟丙基纤维素，2.5mg交联羧甲基纤维素钠和2.5mg硬脂酸镁，其中所述化合物HMS5552固体分散体包含25mg的化合物HMS5552。
  36. 如权利要求25所述的葡糖糖激酶激活剂的片剂，所述片剂包含40mg至60mg的化合物HMS5552固体分散体,188.0mg至276.0mg硅化微晶纤维素，1.6mg至32.0mg羟丙基甲基纤维素，1.6mg至24.0mg羟基乙酸淀粉钠和0.8mg至16.0mg硬脂酸镁，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  37. 如权利要求36所述的葡糖糖激酶激活剂的口服制剂，所述片剂包含50mg的化合物HMS5552固体分散体,239.6mg硅化微晶纤维素，16.0mg羟丙基甲基纤维素，11.2mg羟基乙酸淀粉钠和3.2mg硬脂酸镁，其中所述化合物HMS5552固体分散体包含25mg的化合物HMS5552。
  38. 如权利要求25所述的葡糖糖激酶激活剂的片剂，所述片剂包含170mg至230mg的化合物HMS5552固体分散体,2.5mg至71.9mg一水乳糖，1.2mg至24.5mg聚乙烯吡咯烷酮，1.2mg至18.4mg交联羧甲基纤维素钠和0.6mg至12.3mg硬脂酰富马酸钠，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  39. 如权利要求38所述的葡糖糖激酶激活剂的片剂，所述片剂包含200mg的化合物HMS5552固体分散体,27.5mg一水乳糖，12.5mg聚乙烯吡咯烷酮，5.0mg交联羧甲基纤维素钠和5.0mg硬脂酰富马酸钠，其中所述化合物HMS5552固体分散体包含100mg的化合物HMS5552。
  40. 如权利要求25所述的葡萄糖激酶激活剂的片剂，其为包衣片剂。
  41. 如权利要求40的葡萄糖激酶激活剂的片剂，其中所述的包衣片剂包含包衣剂，所述包衣剂选自：羧甲基纤维素钠、醋酸纤维素、醋酸邻苯二甲酸纤维素、乙基纤维素、明胶、药用釉料、羟丙纤维素、羟丙基甲基纤维素、羟丙基甲基纤维素邻苯二甲酸酯、甲基丙烯酸共聚物、甲基纤维素、聚乙二 醇、聚醋酸乙烯邻苯二甲酸酯、虫胶、蔗糖、二氧化钛、巴西棕榈蜡、微晶蜡、玉米醇溶蛋白和欧巴代。
  42. 如权利要求41的葡萄糖激酶激活剂的片剂，其中的包衣剂为欧巴代。
  43. 如权利要求40所述的葡萄糖激酶激活剂的片剂，所述包衣片剂包含80mg至120mg的化合物HMS5552的固体分散体，112.5mg至216.3mg硅化微晶纤维素，1.5mg至30.0mg羟丙基纤维素，1.5mg至22.5mg交联羧甲基纤维素钠，0.8mg至15.0mg硬脂酸镁和3.0mg至30.0mg欧巴代，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  44. 如权利要求43所述的葡萄糖激酶激活剂的片剂，其包含100mg的化合物HMS5552的固体分散体，187.5mg硅化微晶纤维素，7.5mg羟丙基纤维素，2.5mg交联羧甲基纤维素钠，2.5mg硬脂酸镁和9mg欧巴代，其中所述化合物HMS5552固体分散体包含50mg的化合物HMS5552。
  45. 如权利要求40所述的葡萄糖激酶激活剂的片剂，所述包衣片剂包含120mg至180mg的化合物HMS5552的固体分散体，33.1mg至151.6mg硅化微晶纤维素，1.4mg至27.5mg羟丙基纤维素，1.4mg至20.6mg交联羧甲基纤维素钠，0.7mg至13.8mg硬脂酸镁和2.75mg至27.5mg欧巴代，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  46. 如权利要求45所述的葡萄糖激酶激活剂的片剂，其包含150mg的化合物HMS5552的固体分散体，112.5mg硅化微晶纤维素，7.5mg羟丙基纤维素，2.5mg交联羧甲基纤维素钠，2.5mg硬脂酸镁和8.25mg欧巴代，其中所述化合物HMS5552固体分散体包含75mg的化合物HMS5552。
  47. 葡萄糖激酶激活剂的胶囊剂，其中所述胶囊剂包含权利要求1-19中任一项的固体分散体和选自以下的一种或多种：填充剂、粘合剂、崩解剂和润滑剂。
  48. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，其中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，粘合剂的含量为0重量％至10重量％，崩解剂的含量为0.5重量％至7.5重量％，和润滑剂的含量为0重量％至5重量％。
  49. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，其中所述胶囊剂包含固体分散体、填充剂和粘合剂。
  50. 如权利要求49所述的葡萄糖激酶激活剂的胶囊剂，其中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，粘合剂的含量为0.5重量％至10重量％。
  51. 如权利要求49或50所述的葡萄糖激酶激活剂的胶囊剂，其中所述固体分散体为化合物HMS5552的固体分散体，所述填充剂为硅化微晶纤维素、微晶纤维素或乳糖，所述粘合剂为羟丙基纤维素、羟丙基甲基纤维素或聚乙烯基吡咯烷酮。
  52. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，其中所述胶囊剂包含固体分散体、填充剂和崩解剂。
  53. 如权利要求52所述的葡萄糖激酶激活剂的胶囊剂，其中所述固体分散体的含量为1重量％至90重量％，填充剂的含量为5重量％至95重量％，和崩解剂的含量为0.5重量％至7.5重量％。
  54. 如权利要求52或53所述的葡萄糖激酶激活剂的胶囊剂，其中所述固体分散体为化合物HMS5552的固体分散体，填充剂为硅化微晶纤维素、微晶纤维素或乳糖，和所述崩解剂为交联羧甲基纤维素钠或羧甲基淀粉钠。
  55. 如权利要求54所述的葡萄糖激酶激活剂的胶囊剂，其中所述填充剂为硅化微晶纤维素，和所述崩解剂为交联羧甲基纤维素钠。
  56. 如权利要求47-55中任意一项所述的葡萄糖激酶激活剂的胶囊剂，其中单位制剂中葡萄糖激酶激活剂的含量为约1mg至约200mg、约2mg至约150mg、约2.5mg至约150mg、约5mg至约150mg或约5mg至约100mg。
  57. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，所述胶囊剂包含80mg至120mg的化合物HMS5552固体分散体，150.0mg至218.5mg硅化微晶纤维素，1.5mg至22.5mg交联羧甲基纤维素钠，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  58. 如权利要求57所述的葡萄糖激酶激活剂的胶囊剂，其包含100mg的化合物HMS5552固体分散体，150mg硅化微晶纤维素，7.5mg羟丙基纤维素，其中所述化合物HMS5552固体分散体包含50mg的化合物HMS5552。
  59. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，所述胶囊剂包含80mg至120mg的HMS5552固体分散体，129.8mg至196.1mg硅化微晶纤维素，1.4mg至27.8mg羟丙基纤维素，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  60. 如权利要求59所述的葡萄糖激酶激活剂的胶囊剂，所述胶囊剂包含100mg的化合物HMS5552固体分散体，192.5mg硅化微晶纤维素，7.5mg交联羧甲基纤维素钠，其中所述化合物HMS5552固体分散体包含50mg的化合物HMS5552。
  61. 如权利要求47所述的葡萄糖激酶激活剂的胶囊剂，所述胶囊剂包含40mg至60mg的化合物HMS5552固体分散体，217.5mg至258.5mg硅化微晶纤维素，1.5mg至22.5mg交联羧甲基纤维素钠，其中在所述固体分散体中，所述化合物HMS5552与聚合物载体的比例为1:1。
  62. 如权利要求61所述的葡萄糖激酶激活剂的胶囊剂，其包含50mg的化合物HMS5552固体分散体，247.5mg硅化微晶纤维素，2.5mg交联羧甲基纤维素钠，其中所述化合物HMS5552固体分散体包含25mg的化合物HMS5552。
  63. 权利要求22-24中任意一项所述的葡萄糖激酶激活剂的口服制剂、权利要求25-46中任意一项所述的片剂或权利要求47-62中任意一项所述的胶囊剂，其在pH1.2～4.5时，30分钟溶出<45％，其在pH6.0～7.0时，30分钟溶出>85％。
  64. 如权利要求63所述的葡萄糖激酶激活剂的口服制剂、片剂或胶囊剂，其中片剂在pH1.2～4.5时，30分钟溶出<40％，在pH6.0～7.0时，30分钟溶出>85％。
  65. 如权利要求63所述的葡萄糖激酶激活剂的口服制剂、片剂或胶囊剂，其中片剂在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
  66. 如权利要求63所述的葡萄糖激酶激活剂的口服制剂、片剂或胶囊剂，其中片剂为包衣片剂时，在pH1.2时，30分钟溶出<30％，pH4.5时，30分钟溶出<40％，和pH6.8时，30分钟溶出>85％。
  67. 如权利要求63所述的葡萄糖激酶激活剂的口服制剂、片剂或胶囊剂，其中胶囊剂在pH1.2时，30分钟溶出<45％，pH4.5时，30分钟溶出<45％，和pH6.8时，30分钟溶出>85％。
  68. 权利要求1-19中任意一项所述的固体分散体、如权利要求20或21所述的固体分散体组合物、如权利要求22-24中任意一项所述的葡萄糖激酶激活剂的口服制剂、如权利要求25-46中任意一项所述的片剂或如权利要求47-62中任意一项所述的胶囊剂在制备用于治疗或预防一种或多种选自I型糖 尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的药物中的用途。
  69. 治疗或预防一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常以及高血糖症的疾病的方法，包括向患者给予治疗有效量的权利要求1-19中任意一项所述的固体分散体、如权利要求20或21所述的固体分散体组合物、如权利要求22-24中任意一项所述的葡萄糖激酶激活剂的口服制剂、如权利要求25-46中任意一项所述的片剂或如权利要求47-62中任意一项所述的胶囊剂。
  70. 如权利要求1-19中任意一项所述的固体分散体、如权利要求20或21所述的固体分散体组合物、如权利要求22-24中任意一项所述的葡萄糖激酶激活剂的口服制剂、如权利要求25-46中任意一项所述的片剂或如权利要求47-62中任意一项所述的胶囊剂，其用于治疗或预防一种或多种选自I型糖尿病、II型糖尿病、葡萄糖耐量降低、空腹血糖异常和高血糖症的疾病。
  71. 一种制备如权利要求1-19中任意一项的固体分散体的方法，包括熔融法、溶剂法、溶剂-熔融法、喷雾干燥法、冷冻干燥法、研磨法。
  72. 一种制备如权利要求1-19中任意一项所述的固体分散体的方法，包括以下步骤：
    (1)配制喷雾干燥液，包括将所述聚合物载体和葡萄糖激酶激活剂溶于溶剂中；
    (2)喷雾干燥，
    其中，所述溶剂为无水乙醇、甲醇、异丙醇、乙酸乙酯、丙酮、乙腈、异丁醇、正己烷、苯和甲苯或它们的混合物或它们与水的混合物。
  73. 一种制备权利要求22-24中任意一项的葡萄糖激酶激活剂的口服制剂的方法，包括通过湿法制粒或干法制粒。
  74. 如权利要求73所述的方法，其中通过湿法制粒制备所述口服制剂。
  75. 一种制备如权利要求40-46任意一项所述的葡萄糖激酶激活剂片剂的方法，包括以下步骤：
    (1)制备葡萄糖激酶激活剂的片剂；
    (2)配制包衣液；
    (3)包衣。
PCT/CN2017/116209 2016-12-15 2017-12-14 葡萄糖激酶激活剂的口服制剂及其制备方法 WO2018108128A1 (zh)

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