WO2021109970A1 - Composition pharmaceutique dérivée de xanthine et son procédé de préparation - Google Patents

Composition pharmaceutique dérivée de xanthine et son procédé de préparation Download PDF

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Publication number
WO2021109970A1
WO2021109970A1 PCT/CN2020/132825 CN2020132825W WO2021109970A1 WO 2021109970 A1 WO2021109970 A1 WO 2021109970A1 CN 2020132825 W CN2020132825 W CN 2020132825W WO 2021109970 A1 WO2021109970 A1 WO 2021109970A1
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Prior art keywords
formula
compound
pharmaceutical composition
xanthine derivative
microcrystalline cellulose
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PCT/CN2020/132825
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English (en)
Chinese (zh)
Inventor
刘秀芝
陈艳
李章才
王颖
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成都苑东生物制药股份有限公司
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Priority to CN202080013251.7A priority Critical patent/CN113423404B/zh
Publication of WO2021109970A1 publication Critical patent/WO2021109970A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and specifically relates to a xanthine derivative pharmaceutical composition and a preparation method thereof and its use as a therapeutic drug, especially as a therapeutic dipeptidyl peptidase (DPP-IV) inhibitor.
  • DPP-IV therapeutic dipeptidyl peptidase
  • DPP-IV inhibitors reflect the current new direction of diabetes treatment, that is, from simply controlling glycated hemoglobin to improving ⁇ -cell function, stably controlling blood sugar and avoiding hypoglycemia.
  • no single-drug therapy can prevent the failure of ⁇ -cell function as the disease progresses.
  • it is particularly critical to choose the most reasonable drug combination and treatment timing, and the target of DPP-IV inhibitors is the basis.
  • the brand-new mechanism of medicine has become one of the choices and an important choice for the treatment of type 2 diabetes.
  • Dipeptidyl peptidase-IV (DPP-IV) inhibitors are used in the treatment of type 2 diabetes and have a strong selective inhibitory effect on DPP-IV.
  • DPP-IV Dipeptidyl peptidase-IV
  • GLP-1 glucagon-like peptide-1
  • GIP glycose-dependent insulinotropic polypeptide
  • the present invention provides a pharmaceutical composition of xanthine derivatives, specifically, a pharmaceutical composition of xanthine derivatives and a preparation method thereof as well as a therapeutic drug, especially as a therapeutic dipeptidyl peptidase ( DPP-IV) Use of inhibitors.
  • the present invention provides a xanthine derivative pharmaceutical composition, which contains 0.5-600 mg of a compound of formula I, wherein the compound of formula I has the following structure:
  • the pharmaceutical composition contains 1-400 mg of the compound of formula I.
  • the pharmaceutical composition contains 1-200 mg of the compound of formula I.
  • the pharmaceutical composition contains 1-100 mg of the compound of formula I.
  • the pharmaceutical composition contains 1-50 mg of the compound of formula I.
  • the pharmaceutical composition contains 1-25 mg of the compound of formula I.
  • the pharmaceutical composition contains 1-10 mg of the compound of formula I.
  • the pharmaceutical composition contains 1 to 5 mg of the compound of formula I.
  • the pharmaceutical composition contains 1 mg of the compound of formula I.
  • the pharmaceutical composition contains 2.5 mg of the compound of formula I.
  • the pharmaceutical composition contains 4 mg of the compound of formula I.
  • the pharmaceutical composition contains 5 mg of the compound of formula I.
  • the pharmaceutical composition contains 6 mg of the compound of formula I.
  • the pharmaceutical composition contains 7.5 mg of the compound of formula I.
  • the pharmaceutical composition contains 10 mg of the compound of formula I.
  • the pharmaceutical composition contains 25 mg of the compound of formula I.
  • the pharmaceutical composition contains 30 mg of the compound of formula I.
  • the pharmaceutical composition contains 50 mg of the compound of formula I.
  • the pharmaceutical composition contains 100 mg of the compound of formula I.
  • the pharmaceutical composition contains 200 mg of the compound of formula I.
  • the pharmaceutical composition contains 400 mg of the compound of formula I.
  • the pharmaceutical composition contains 600 mg of the compound of formula I.
  • the pharmaceutical composition contains 0.5-600 mg of the compound of formula I and one or more anti-diabetic drugs other than the compound of formula I, wherein the compound of formula I has the following structure
  • the pharmaceutical composition contains 1-100 mg of the compound of formula I and one or more anti-diabetic drugs other than the compound of formula I.
  • the anti-diabetic drug is selected from insulin sensitivity enhancers, compounds that affect abnormal regulation of hepatic glucose production, insulin signal transduction pathway regulators or insulin secretion promoters.
  • the anti-diabetic drugs are selected from the group consisting of non-sulfonylurea insulin secretagogues, sulfonylurea insulin secretagogues, biguanides, SGLT2 inhibitors, thiazolidinediones, ⁇ -glucosidase inhibitors , GPR40 agonist or hydroxymethylglutaryl-CoA reductase inhibitor.
  • the anti-diabetic drug is selected from repaglinide, nateglinide, mitiglinide, glimepiride, gliclapide, glibenclamide, glibenclamide, acetohexamide , Chlorpropamide, glibenclamide, tolbutamide, tolazamide, glipizide, sulfambutamide, gliquidone, glibenclamide, tolbutamide, tolazamide Urea, gliclazide, metformin, dapagliflozin, canagliflozin, empagliflozin, pioglitazone, rosiglitazone, acarbose, voglibose, miglitol, TAK875, furfur Glipizide, simvastatin, atorvastatin calcium, lovastatin, pravastatin or mevastatin or a pharmaceutically acceptable salt thereof.
  • the anti-diabetic drug is selected from one of repaglinide, glimepiride, metformin, canagliflozin, pioglitazone, voglibose, simvastatin, or a pharmaceutically acceptable one of repaglinide, glimepiride, metformin, canagliflozin, pioglitazone, voglibose, and simvastatin salt.
  • the compound of formula I in the pharmaceutical composition exists as a pharmaceutically acceptable salt or as a free base
  • the compound of formula I in the pharmaceutical composition exists as a free base.
  • the pharmaceutically acceptable salt is selected from hydrochloric acid, p-toluenesulfonic acid, tartaric acid, maleic acid, lactic acid, methanesulfonic acid, sulfuric acid, phosphoric acid, citric acid, acetic acid or trifluoroacetic acid.
  • the pharmaceutically acceptable salt is selected from p-toluenesulfonic acid, hydrochloric acid, tartaric acid or trifluoroacetic acid.
  • the pharmaceutical composition contains 0.5-600 mg of the compound of formula I, fillers and lubricants, wherein the compound of formula I has the following structure:
  • the pharmaceutical composition contains 1-400 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1-200 mg of the compound of formula I, fillers, and lubricants.
  • the pharmaceutical composition contains 1-100 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1-50 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1-25 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1-10 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1 to 5 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 600 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 400 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 200 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 100 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 50 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 30 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 25 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 10 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 5 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 2.5 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition contains 1 mg of the compound of formula I, a filler, and a lubricant.
  • the pharmaceutical composition also contains a binder selected from starch slurry, polyvinylpyrrolidone, polyethylene glycols, copovidone, hydroxypropyl cellulose, hypromellose, One or more of sodium carboxymethyl cellulose, methyl cellulose, and ethyl cellulose.
  • a binder selected from starch slurry, polyvinylpyrrolidone, polyethylene glycols, copovidone, hydroxypropyl cellulose, hypromellose, One or more of sodium carboxymethyl cellulose, methyl cellulose, and ethyl cellulose.
  • the adhesive in the pharmaceutical composition is copovidone.
  • the pharmaceutical composition also contains a disintegrant, and the disintegrant is selected from the group consisting of dry starch, alginic acid, sodium alginate, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose One or more of sodium cellulose, calcium carboxymethyl cellulose and sodium carboxymethyl starch.
  • the disintegrant in the pharmaceutical composition is low-substituted hydroxypropyl cellulose.
  • the filler in the pharmaceutical composition is selected from one or more of lactose, sugar alcohols, starch, pregelatinized starch, microcrystalline cellulose, sucrose, inorganic salts and dextrin.
  • the filler in the pharmaceutical composition is selected from one or two of pregelatinized starch and microcrystalline cellulose.
  • the lubricant is selected from colloidal silicon dioxide, magnesium stearate, talc, hydrogenated vegetable oil, polyethylene glycols, magnesium lauryl sulfate, sodium lauryl sulfate, One or more of sodium stearyl fumarate, stearic acid and calcium hydrogen phosphate.
  • the lubricant is selected from one or two of colloidal silicon dioxide or magnesium stearate.
  • the pharmaceutical composition contains 1-600 mg of the compound of formula I and fillers, lubricants, disintegrants and binders, wherein the compound of formula I has the following structure:
  • the pharmaceutical composition contains 600 mg of the compound of formula I, a filler, a lubricant, a disintegrant and a binder.
  • the pharmaceutical composition contains 400 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 200 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 100 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 50 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 25 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 10 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 5 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 2.5 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 1 mg of the compound of formula I and fillers, lubricants, disintegrants and binders.
  • the pharmaceutical composition contains 1-100 mg of the compound of formula I, 0.5-10.0 mg of colloidal silicon dioxide, 13.65-205.0 mg of microcrystalline cellulose, 11.22-230.0 mg of pregelatinized starch, and 1.2-10.0 of copovidone. mg, low-substituted hydroxypropyl cellulose 1.2-30.0mg, magnesium stearate 0.3-5.0mg.
  • the pharmaceutical composition contains 1 mg of compound of formula I, 0.5 mg of colloidal silicon dioxide, 13.65 mg of microcrystalline cellulose, 13.72 mg of pregelatinized starch, 1.5 mg of copovidone, and 1.5 mg of low-substituted hydroxypropyl cellulose. mg, magnesium stearate 0.38mg.
  • the pharmaceutical composition contains 2.5 mg of compound of formula I, 0.5 mg of colloidal silicon dioxide, 54.9 mg of microcrystalline cellulose, 13.72 mg of pregelatinized starch, 1.5 mg of copovidone, and low-substituted hydroxypropyl cellulose 1.5mg, 0.38mg of magnesium stearate.
  • the pharmaceutical composition contains 5.0 mg of the compound of formula I, 1.0 mg of colloidal silicon dioxide, 109.8 mg of microcrystalline cellulose, 27.45 mg of pregelatinized starch, 3.0 mg of copovidone, and low-substituted hydroxypropyl cellulose 3.0mg, 0.75mg magnesium stearate.
  • the pharmaceutical composition contains 100 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 120 mg of microcrystalline cellulose, 220 mg of pregelatinized starch, 10 mg of copovidone, 35 mg of low-substituted hydroxypropyl cellulose, and stearin Magnesium acid 2.5mg.
  • the pharmaceutical composition contains 25 mg of compound of formula I, 5 mg of colloidal silicon dioxide, 205 mg of microcrystalline cellulose, 51.3 mg of pregelatinized starch, 6 mg of copovidone, 6 mg of low-substituted hydroxypropyl cellulose, and stearin Magnesium acid 1.5mg.
  • the pharmaceutical composition contains 1 mg of compound of formula I, 0.2 mg of colloidal silicon dioxide, 44.8 mg of microcrystalline cellulose, 11.22 mg of pregelatinized starch, 1.2 mg of copovidone, and 1.2 mg of low-substituted hydroxypropyl cellulose. mg, magnesium stearate 0.3mg.
  • the compound of formula I in the pharmaceutical composition is a hydrate thereof, and has the following structure:
  • the pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms. Such as granules, capsules or tablets.
  • the present invention also provides a preparation method of the xanthine derivative pharmaceutical composition.
  • the preparation process of different dosage forms can be preferably the following preparation methods:
  • the preparation method of the granules the compound of formula I and pharmaceutically acceptable auxiliary materials are granulated and dried, then mixed with a lubricant and packaged.
  • the preparation method of the capsule mix the compound of formula I, hydrate or its pharmaceutically acceptable salt with pharmaceutically acceptable excipients, and then fill the capsule or mix the compound of formula I with pharmaceutically acceptable excipients, and add the viscous compound. After the mixture is granulated and dried, the lubricant is added, and the capsules are filled after mixing evenly.
  • Tablet preparation method mixing the compound of formula I, hydrate or pharmaceutically acceptable salt thereof with pharmaceutically acceptable excipients and then directly compressing the tablet, coating with a film coating premix aqueous solution; or applying the compound of formula I , Hydrate or its pharmaceutically acceptable salt is mixed with pharmaceutically acceptable excipients and then dry granulated, mixed with the remaining excipients and compressed into tablets, coated with a film coating premix aqueous solution; or the compound of formula I, hydrated
  • the compound or a pharmaceutically acceptable salt thereof is mixed with a pharmaceutically acceptable auxiliary material and then added to a binder, granulated and dried, then mixed with a lubricant, and then compressed into a tablet, and then coated with an aqueous solution of a film coating premix.
  • Another object of the present invention is to disclose the use of the pharmaceutical composition as a medicament for treating dipeptidyl peptidase IV related diseases; specifically, the use is to prepare a drug for treating type II diabetes or impaired glucose tolerance The use of drugs in the treatment of diseases.
  • the test of the influencing factors of the present invention shows that after being placed under high humidity (RH92.5%) conditions for 10 days, the properties, dissolution, related substances and content of the composition samples prepared in the examples of the present invention have no significant changes; After being placed under the conditions of °C and light (4500Lx ⁇ 500Lx) for 10 days, the properties, dissolution and content of the composition did not change significantly, and the related substances increased slightly. It shows that the pharmaceutical composition prepared by the embodiment of the present invention has good stability and excellent quality.
  • formula I compound and other anti-diabetic drugs such as metformin hydrochloride, pioglitazone hydrochloride, voglibose, etc. compose a compound formula
  • the oral glucose tolerance test (OGTT) test in normal mice shows that under the same conditions, the formula I compound of the present invention and Compared with a compound composed of anti-diabetic drugs and a positive control drug, it has a more significant hypoglycemic effect and is a significant improvement compared with a compound composed of the same anti-diabetic drugs.
  • the results show that a single administration of the compound of formula I tablets has good safety and tolerability in Chinese volunteers.
  • the maximum tolerated dose of the medicine is 400 mg.
  • the subject takes the compound of formula I tablets at a dose of more than 200 mg, one tablet per week, and the inhibitory rate of DPP-4 activity is maintained at more than 80% after taking multiple doses of DPP-4.
  • the inhibition rate of DDP-4 enzyme activity is maintained at 80% and above, which is expected to maintain a stable therapeutic effect.
  • 200mg-400mg once a week may be administered It is a clinically effective dose.
  • the filler mannitol 200SD, microcrystalline cellulose PH102, pregelatinized starch and the dihydrate of the compound of formula I were mixed in a certain proportion, and they were set to accelerate (40°C, RH75% ⁇ 5). %) closed and accelerated (40°C, RH75% ⁇ 5%) open conditions for 10 days and 30 days to investigate the properties and related substances.
  • the test results are shown in the following table.
  • the related substance detection adopts the related substance chromatographic conditions explored in the early stage of the API.
  • the specific chromatographic conditions are as follows:
  • Mobile phase mobile phase A: 0.02mol/L sodium dihydrogen phosphate (0.1% triethylamine, adjust the pH to 3.0 with phosphoric acid);
  • Example 1 Each 1000 tablets contains the following ingredients (0.5mg)
  • Preparation method 1.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and starch in a prescription amount into a mixing hopper to mix; press tablets; use Film coating premix aqueous solution coating, ready-to-have.
  • Example 2 Each 1000 tablets contains the following ingredients (1.5mg)
  • Example 3 Each 1000 tablets contains the following ingredients (4.0mg)
  • Preparation method 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and starch in a prescription amount into a mixing hopper to mix; press tablets; use Film coating premix aqueous solution coating, ready-to-have.
  • Example 4 Each 1000 tablets contains the following ingredients (6.0mg)
  • Example 5 Each 1000 tablets contains the following ingredients (1.0mg)
  • Preparation method 1.5g of film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and pregelatinized starch in a prescribed amount into a mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.
  • Example 6 Each 1000 tablets contains the following ingredients (2.0mg)
  • Preparation method 2.25g of film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound, colloidal silicon dioxide, microcrystalline cellulose, and pregelatinized starch in a prescribed amount into a mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.
  • Example 7 Each 1000 tablets contains the following ingredients (2.5mg)
  • Preparation method 2.25g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 8 Each 1000 tablets contains the following ingredients (5.0mg)
  • Preparation method 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 9 Each 1000 tablets contains the following ingredients (10.0mg)
  • Example 10 Example 11
  • Example 12 Example 13
  • Example 14 Compound of formula I 6.5g 7.5g 12.5g 15.0g 20.0g
  • Example 11 The preparation method of Example 11 is the same as that of Example 10.
  • Example 12 The preparation method of Example 12 is the same as that of Example 10.
  • Example 13 The preparation method of Example 13 is the same as that of Example 10.
  • Example 14 The preparation method of Example 14 is the same as that of Example 10.
  • Example 16 Compound of formula I 25.0g 30.0g Colloidal silica 5.0g 6.0g Microcrystalline cellulose 113.5g 108.7g starch 28.4g 27.2g
  • Example 15 Preparation method: 5.2g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound in the prescription amount and the microcrystalline cellulose, starch, and colloidal silicon dioxide in the prescription amount into the mixing hopper to mix; Tablets; coated with a film-coating premix aqueous solution, ready to be obtained.
  • Example 16 The preparation method of Example 16 is the same as that of Example 15.
  • Example 18 Compound of formula I 40.0g 50.0g 60.0g Colloidal silica 8.0g 10.0g 12.0g Microcrystalline cellulose 99.1g 120.1g 110.5g starch 24.8g 30.1g 27.7g
  • Example 18 The preparation method of Example 18 is the same as that of Example 17.
  • Example 19 The preparation method of Example 19 is the same as that of Example 17.
  • Example 20 contains the following ingredients per 1000 tablets (1.0mg)
  • 2.0g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 21 Each 1000 tablets contains the following ingredients (25.0mg)
  • film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 22 Each 1000 tablets contains the following ingredients (100.0mg)
  • 15.0g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound dihydrate, pregelatinized starch, copovidone, colloidal silicon dioxide, and internal addition in the prescribed amount Low-substituted hydroxypropyl cellulose and part of magnesium stearate are added to the mixing hopper and mixed to prepare a pre-mixed powder.
  • the pre-mixed powder is placed in a dry granulator to make dry granules; the dry granules are added in the prescribed amount
  • the microcrystalline cellulose, a part of low-substituted hydroxypropyl cellulose, and a part of magnesium stearate are added together; tableted; coated with an aqueous solution of film-coating premix agent to obtain.
  • Example 23 Each 1000 tablets contains the following ingredients (5.0mg)
  • Preparation method 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 24 Each 1000 tablets contains the following ingredients (10mg)
  • film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; add the p-toluenesulfonate, microcrystalline cellulose, pregelatinized starch, and magnesium stearate of the compound of formula I in the prescribed amount into the mixing hopper Medium mixing; tablet compression; coating with aqueous solution of film coating premix, ready to be obtained.
  • Example 25 Each 1000 tablets contains the following ingredients (10mg)
  • 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the formula I compound hydrochloride, mannitol, microcrystalline cellulose, and sodium stearyl fumarate into the mixing hopper Mixing; tableting; coating with a film-coating premix aqueous solution, ready to be obtained.
  • Example 26 Each 1000 tablets contains the following ingredients (10mg)
  • 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; add the formula I compound tartrate, microcrystalline cellulose, pregelatinized starch, and magnesium lauryl sulfate into a mixing hopper to mix ; Compressing tablets; Coating with a film-coating premix aqueous solution, ready to be obtained.
  • Example 27 Each 1000 tablets contains the following ingredients (10mg)
  • film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; combine the formula I compound trifluoroacetate with microcrystalline cellulose, pregelatinized starch, and sodium lauryl sulfate Add it to the mixing hopper to mix; compress tablets; use the film coating premix aqueous solution to coat, and it is ready.
  • Example 28 Example 29 Example 30
  • Example 31 Example 32
  • Example 33 Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Metformin Hydrochloride 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g 1000.0g Microcrystalline cellulose 139.3g 137g 134.0g 128.0g 110.0g 20.0g Polyvinylpyrrolidone 24.0g 24.0g 24.0g 24.0g 24.0g Sodium Stearyl Fumarate 12.0g 12.0g 12.0g 12.0g 12.0g 12.0g 12.0g
  • Example 29 The preparation method of Example 29 is the same as that of Example 28.
  • Example 30 The preparation method of Example 30 is the same as that of Example 28.
  • Example 31 The preparation method of Example 31 is the same as that of Example 28.
  • Example 32 The preparation method of Example 32 is the same as that of Example 28.
  • Example 33 The preparation method of Example 33 is the same as that of Example 28.
  • Example 34 Each 1000 bags contains the following components
  • Example 35 Example 36
  • Example 37 Example 38
  • Example 40 Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Pioglitazone hydrochloride 30.0g 30.0g 30.0g 30.0g 30.0g Colloidal silica 2.0g 3.0g 4.0g 5.0g 6.0g 10.0g Microcrystalline cellulose 157.84g 156.0g 153.6g 148.8g 134.4g 108.0g starch 39.46g 39.0g 38.4g 37.2g 33.6g 27.0g Hydroxypropyl cellulose 4.8g 4.8g 4.8g 4.8g 4.8g 4.8g 6.0g
  • Example 36 The preparation method of Example 36 is the same as that of Example 35.
  • Example 37 The preparation method of Example 37 is the same as that of Example 35.
  • Example 38 The preparation method of Example 38 is the same as that of Example 35.
  • Example 39 The preparation method of Example 39 is the same as that of Example 35.
  • Example 40 The preparation method of Example 40 is the same as that of Example 35.
  • Example 41 Each 1000 tablets contains the following components
  • Example 42 Example 43
  • Example 44 Implementation 45
  • Example 46 Example 47
  • Compound of formula I 0.5g 2.5g 5.0g 10.0g 25.0g 100.0g Voglibose 0.3g 0.3g 0.3g 0.3g 0.3g Microcrystalline cellulose 48.6g 111.4g 109.0g 104.2g 112.6g 283.8g sucrose 12.2g 27.8g 27.2g 26.0g 28.1g 70.9g Hypromellose 1.3g 3.0g 3.0g 3.0g 3.6g 10.0g
  • the prescription amount of hypromellose is made into a 5% (w/w) aqueous solution for use; 4.5g of film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; prepare the formula I compound, microcrystalline cellulose, sucrose, and voglibose in the prescribed amount to obtain a pre-mixed powder; place the pre-mixed powder In the granulator, add a prescription amount of hypromellose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of magnesium stearate and mix together; press tablets; use a film coating premix aqueous solution package Clothes, get it.
  • Example 48 Each 1000 tablets contains the following components
  • the prescription amount of ethyl cellulose is made into a 6% (w/w) aqueous solution for use; 1.95g of film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; add the trifluoroacetate, microcrystalline cellulose, dextrin, and voglibose of the compound of formula I in the prescribed amount into the mixing hopper Mix to obtain a pre-mixed powder; place the pre-mixed powder in a granulator, add a prescription amount of ethyl cellulose aqueous solution to make wet granules; dry the wet granules; add a prescription amount of stearic acid, and mix together; tableting ; Use film coating premix aqueous solution to coat, ready.
  • Example 50 Compound of formula I 25.0g 30.0g Colloidal silica 5.0g 6.0g Microcrystalline cellulose 113.5g 108.7g starch 28.4g 27.2g
  • Example 50 The preparation method of Example 50 is the same as that of Example 49.
  • Example 51 contains the following ingredients per 1000 tablets (5.0mg)
  • Component To Dihydrate of compound of formula I 5.0g Colloidal silica 1.0g Microcrystalline cellulose 68.2g Pregelatinized starch 68.2g Copovidone 3.0g Low-substituted hydroxypropyl cellulose 3.0g Magnesium stearate 1.5g
  • 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose, pregelatinized starch, the sieving material of the compound of formula I and magnesium stearate are added into a mixing hopper and mixed; compressed tablets; coated with an aqueous solution of a film-coating premix agent to obtain the product.
  • Example 52 Each 1000 tablets contains the following ingredients (5.0mg)
  • Example 52 The preparation method of Example 52 is the same as that of Example 51.
  • Examples 53 to 54 contain the following ingredients per 1000 tablets (2.5mg)
  • Example 54 Dihydrate of compound of formula I 2.5g 2.5g Colloidal silica 0.5g 0.5g Microcrystalline cellulose 34.1g 13.65 Pregelatinized starch 34.1g 54.6g Copovidone 1.5g 1.5g Low-substituted hydroxypropyl cellulose 1.5g 1.5g Magnesium stearate 0.75g 0.75g
  • Example 53 Preparation method: 2.25g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 54 The preparation method of Example 54 is the same as that of Example 53.
  • Examples 55-58 Contain the following ingredients per 1000 tablets (2.5mg)
  • Example 55 Example 56
  • Example 57 Example 58 Dihydrate of compound of formula I 2.5g 2.5g 2.5g 2.5g Colloidal silica 0.5g 0.5g 0.5g 0.5g Microcrystalline cellulose 54.6g 53.4g 52.2g 55.2g Pregelatinized starch 13.65g 13.35g 13.05g 13.8g Copovidone 1.5g 3g 4.5g 1.5g Low-substituted hydroxypropyl cellulose 1.5g 1.5g 1.5g 0.75g Magnesium stearate 0.75g 0.75g 0.75g 0.75g 0.75g 0.75g
  • Example 55 Preparation method: 2.25g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for later use; mix the formula I compound dihydrate, colloidal silicon dioxide, microcrystalline cellulose, copovidone, and low-substituted hydroxy Propyl cellulose and pregelatinized starch are added to the mixing hopper and mixed and then sieved, and then the sieved material of the above formula I compound and magnesium stearate are added to the mixing hopper and mixed; tableting; film coating premixing agent aqueous solution package Clothes, get it.
  • Example 56 The preparation method of Example 56 is the same as that of Example 55.
  • Example 57 The preparation method of Example 57 was the same as that of Example 55.
  • Example 58 The preparation method of Example 58 is the same as that of Example 55.
  • Example 59 Each 1000 tablets contains the following ingredients (5.0mg)
  • Example 59 The preparation method of Example 59 is the same as that of Example 51.
  • Example 60 Each 1000 tablets contains the following ingredients (5.0mg)
  • Example 60 The preparation method of Example 60 was the same as that of Example 51.
  • Example 61 Each 1000 tablets contains the following ingredients (2.5mg)
  • Example 61 The preparation method of Example 61 was the same as that of Example 55.
  • Example 62 A blank sample of 2.5 mg specification, every 1000 tablets contains the following ingredients.
  • Preparation method 2.25g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.
  • Example 63 A blank sample of 5 mg specification contains the following ingredients per 1000 tablets.
  • Colloidal silica 1.00g Microcrystalline cellulose 113.80g Pregelatinized starch 28.45g Copovidone 3.00g Low-substituted hydroxypropyl cellulose 3.00g Magnesium stearate 0.75g
  • Preparation method 4.5g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.
  • Example 64 A blank sample of 25 mg specifications contains the following ingredients per 1000 tablets.
  • Preparation method 9g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of colloidal silicon dioxide, microcrystalline cellulose, pregelatinized starch, copovidone, and low-substituted hydroxypropyl fiber Mixing vegetarian and magnesium stearate; compressing tablets; coating with aqueous solution of film coating premix, ready to be obtained.
  • Example 65 A blank sample of 100 mg specification contains the following ingredients per 1000 tablets.
  • Preparation method 15.0g film coating premix Prepare an aqueous suspension with a concentration of about 14% (w/w) for use; mix the prescription amount of pregelatinized starch, copovidone, colloidal silicon dioxide, internally added part of low-substituted hydroxypropyl cellulose, Add part of magnesium stearate into the mixing hopper and mix to prepare pre-mixed powder, then put the pre-mixed powder in a dry granulator to make dry granules; add prescription amount of microcrystalline cellulose and additional part to the dry granules Low-substituted hydroxypropyl cellulose and a part of magnesium stearate are mixed; tableting; coated with aqueous solution of film coating premix, ready to be obtained.
  • Dissolution testing method refer to the second method of appendix xC of the 2015 edition of the Chinese Pharmacopoeia.
  • Test Example 1 Study on tolerance, pharmacokinetics, and pharmacodynamics of a single dose in healthy humans
  • Formula I compound simulation tablets specifications: 2.5mg/tablet (prepared in reference example 62, no active ingredient), 5mg/tablet (prepared in reference example 63, no active ingredient), 25mg/tablet (prepared in reference example 64 Obtained, no active ingredient), 100mg/tablet (prepared in Example 65, no active ingredient)
  • Thermo Scientific TM 232F-AEC-TSC freezer refrigerator provided by Thermo Company;
  • Haier 2 ⁇ 8°C refrigerator provided by Haier Company
  • Eppendorf 5920R centrifuge provided by Eppendorf;
  • test groups and dosing schedule are shown in Table 5 below:
  • Group Dosage Route of administration Number of test group Number of control group test 1 2.5 oral 10 2 Tolerance, PK 2 5 oral 10 2 Tolerance, PK 3 10 oral 10 2 Tolerance, PK 4 25 oral 10 2 Tolerance, PK/PD 5 50 oral 10 2 Tolerance, PK/PD 6 100 oral 10 2 Tolerance, PK/PD 7 200 oral 10 2 Tolerance, PK/PD 8 400 oral 10 2 Tolerance, PK/PD 9 600 oral 6 2 Tolerance
  • Tests were performed at 2.5, 5, 10, 25, 50, 100, 200, 400 mg doses. Venous blood samples were collected before and after administration to detect the plasma concentration of eutagliptin.
  • Blood sample collection 2.5 ⁇ 10mg dose group before administration (-30min ⁇ 0min) and after administration 0.25h ⁇ 1min, 0.5h ⁇ 2min, 0.75h ⁇ 2min, 1h ⁇ 3min, 1.5h ⁇ 3min, 2h ⁇ 3min, 2.5h ⁇ 3min, 3h ⁇ 3min, 3.5h ⁇ 3min, 4h ⁇ 3min, 5h ⁇ 3min, 6h ⁇ 3min, 8h ⁇ 10min, 12h ⁇ 10min, 24h ⁇ 30min, 48h ⁇ 30min, 72h ⁇ 30min, 96h ⁇ 30min, Venous blood samples were collected 3.0mL at 120h ⁇ 30min; 5.0mL venous blood samples were collected before administration (-30min ⁇ 0min) in the 25mg dose group, and the other blood sampling time points and blood volume were the same as those in the 2.5 ⁇ 10mg group; the 50 ⁇ 400mg dose group was in the administration Collect 5.0mL venous blood sample before (-30min ⁇ 0min), 0.25h ⁇ 1min, 0.5h ⁇ 2min, 0.75h ⁇ 2
  • DPP-4 inhibition Rate 1-measured value/baseline value.
  • the safety analysis set was used to statistically describe and analyze the demographic data, physical examination and laboratory examination results, adverse events or/and adverse reactions.
  • the test group of each dose group and the placebo group were compared and analyzed.
  • the pharmacokinetic parameters were calculated using WinNonlin 8.1 software.
  • the non-compartmental model was used to calculate the pharmacokinetic parameters of each subject, and the WPS 2019 was used to calculate the mean and standard deviation of each parameter to evaluate the pharmacokinetic characteristics of the drug in the body.
  • the proportional relationship between pharmacokinetic parameters and dose will be analyzed by regression analysis and the 95% two-sided confidence interval (95% CI) of the slope will be calculated. .
  • a total of 104 subjects were enrolled in the tolerance test, and one subject withdrew from the test with a positive blood pregnancy test on day -1, and the rest did not fall off or were eliminated.
  • a total of 103 healthy volunteers completed 9 dose group trials with a single dose. The dose was increased from 2.5 mg to 600 mg in the dose group. None of the subjects could not tolerate it, and none of the subjects reached the criteria for stopping the trial.
  • a single administration of the compound of formula I tablets has good safety and tolerability in Chinese volunteers, and the maximum tolerated dose in a single oral administration is 600 mg.
  • the pharmacokinetic concentration analysis was performed on the subjects in the test group in the protocol set (PPS set).
  • PPS set included 88 subjects, of which 73 were in the test group and 15 were in the placebo group, so 73 subjects were used Perform pharmacokinetic parameter analysis.
  • the main pharmacokinetic parameters of the compounds of formula I are summarized in Table 6 below.
  • the inhibition rate of DPP-4 enzyme in each dose group of 25-400 mg was over 97% 24h after treatment, and the inhibition rate of DPP-4 enzyme was over 75.7% in the 200-400 mg dose group 168h after treatment.
  • the inhibitory rate of DPP-4 activity is maintained at about 80% within a 168-hour dosing interval.

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Abstract

L'invention concerne une composition pharmaceutique dérivée de xanthine, et plus particulièrement une composition pharmaceutique dérivée de xanthine, son procédé de préparation et son utilisation en tant que médicament thérapeutique, en particulier en tant qu'inhibiteur de dipeptidyl peptidase (DPP-IV) thérapeutique.
PCT/CN2020/132825 2019-12-02 2020-11-30 Composition pharmaceutique dérivée de xanthine et son procédé de préparation WO2021109970A1 (fr)

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