WO2024027752A1 - 包含杂环化合物的药物组合物及其制备方法和应用 - Google Patents
包含杂环化合物的药物组合物及其制备方法和应用 Download PDFInfo
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- 229940033123 tannic acid Drugs 0.000 description 1
- 229920002258 tannic acid Polymers 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention relates to a pharmaceutical composition containing a heterocyclic compound and its preparation method and application.
- Cation channels such as transient receptor potential (TRP) cation channel subfamily C, member 5 (TRPC5), regulate the flow of calcium and sodium ions across cell membranes.
- TRP transient receptor potential
- TRPC5 transient receptor potential cation channel subfamily C, member 5
- Voltage-dependent events include, but are not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contractions, cardiac muscle contractions, and skeletal muscle contractions.
- Non-selective cation channels such as TRPC5
- Calcium influx through activation of non-selective cation channels such as TRPC5 also alters intracellular free calcium concentration.
- Calcium is a ubiquitous second messenger molecule in cells, and changes in intracellular calcium levels have profound effects on signaling and gene expression. Therefore, activation of non-selective cation channels such as TRPC5 can lead to changes in gene expression and cellular phenotypes.
- Gene expression events include, but are not limited to, the production of mRNA encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability in that cell.
- TRPC5 forms homomeric multi-subunit structures such as tetramers (i.e. TRPC5 homomultimers) and heteromeric multi-subunit structures such as tetramers (i.e. TRPC5-TRPC1 heteromultimers).
- TRPC5 when the term TRPC5 is used herein (e.g., when identifying modulators of TRPC5, such as TRPC5 antagonists), the term TRPC5 is used generically to include TRPC5 homomultimers or heteromultimers (e.g. TRPC5-TPRC1 or TRPC5-TRPC4 heteromultimers) or both.
- Modulating the function of the TRPC5 protein provides methods for modulating calcium homeostasis, sodium homeostasis, membrane polarization and/or intracellular calcium levels, and compounds that modulate the function of TRPC5 can be used in many ways, including but not limited to maintaining calcium homeostasis, regulating Intracellular calcium levels, modulating membrane polarization, and treating or preventing diseases, disorders or conditions associated with calcium and/or sodium homeostasis or physiological disorders (dyshomeostasis).
- TRPC5-containing ion channels are, for example, suitable for use in the modulation of TRPC5-containing ion channels, which can be in homomultimeric and heteromultimeric forms with other ion channels such as TRPC1 or TRPC3 (i.e., TRPC5-TRPC1 and TRPC1-TRPC3-
- TRPC5-TRPC1 and TRPC1-TRPC3- The activity of transient receptor potential cation channel subfamily C, member 5 (TRPC5) exists to treat diseases.
- TRPC5 is associated with diseases such as FSGS and diabetic nephropathy (J. Clin. Invest., 2013 Dec 2; 123(12): 5298-5309, Zhou et al., Science 358, 1332-1336(2017).
- Focal node Segmental glomerulosclerosis (FSGS) is a clinicopathological syndrome, clinically manifested as massive proteinuria or nephrotic syndrome, pathologically characterized by focal segmental distribution of glomerulosclerotic lesions and foot process fusion caused by podocyte degeneration. Or disappear.
- FSGS accounts for about 5% to 10% of adult nephrotic syndrome in my country, and patients are more common in young and middle-aged men. More than 50% of patients with persistent nephrotic syndrome progress to end-stage renal disease within 5 to 10 years.
- TRPC5 is sequestered in the cytoplasm, maintaining normal filtration barriers.
- podocyte damage activates RAC1, causing TRPC5 to move from the cytoplasm to the cell membrane, which promotes AT1 receptor-induced TRPC5 channel calcium ions flow, further promoting RAC1 activity.
- RAC1 activation induces actin reorganization and detachment of podocytes from the glomerulus; the loss of podocytes destroys the filtration barrier, allowing serum proteins to leak into the urine.
- the drugs used clinically to treat FSGS are mainly hormones, immunosuppressants, CNIs and alkylating agents, all of which have serious toxic and side effects, and many need to be used in combination with other drugs to be effective and prone to recurrence. Therefore, the development of new TRPC5 inhibitor drugs is of positive significance for the treatment of the above diseases.
- the development of pharmaceutical preparations containing these compounds that are suitable for pharmaceutical use, such as preparation forms with stability and safety, so as to achieve good results in the pharmaceutical and medication stages has become an urgent technical problem to be solved.
- the technical problem to be solved by the present invention is the lack of preparations of heterocyclic compounds represented by formula I in the prior art.
- the present invention provides a pharmaceutical composition containing a heterocyclic compound and its preparation method and application.
- the composition has good stability and can achieve rapid dissolution in phosphate buffer; and the preparation method of the pharmaceutical composition is simple and suitable for industrial production.
- the invention provides a pharmaceutical composition Q, which contains substance X and pharmaceutical excipients;
- the substance X is a compound represented by formula I, a pharmaceutically acceptable salt thereof, a solvate of a compound represented by formula I, or a solvate of a pharmaceutically acceptable salt thereof;
- the pharmaceutical excipients are selected from the group consisting of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption accelerators, surfactants, adsorption carriers, lubricants and glidants. Kind or variety.
- the pharmaceutical excipients are selected from one or more of disintegrants, fillers, lubricants and glidants.
- the substance X is the only active ingredient.
- the dosage of substance X is a therapeutically effective amount.
- the solvate of the compound represented by Formula I is a conventional solvate in the art, and the solvate includes but is not limited to the hydrate of the compound represented by Formula I, the hydrate of the compound represented by Formula I, and the solvate of the compound represented by Formula I.
- the compound represented by Formula I is in crystalline form.
- the solvate of the compound represented by Formula I is in crystalline form.
- the substance The diffraction pattern is at 8.95 ⁇ 0.20°, 12.92 ⁇ 0.20°, 16.39 ⁇ 0.20°, 17.00 ⁇ 0.20°, 17.44 ⁇ 0.20°, 17.76 ⁇ 0.20°, 18.08 ⁇ 0.20°, 19.02 ⁇ 0.20°, 21.95 ⁇ 0.20°, 22.20 ⁇
- the X-ray powder diffraction pattern of the compound represented by formula I using Cu-K ⁇ radiation and expressed in 2 ⁇ angle also has a diffraction peak at one or more of the following places: 10.63 ⁇ 0.20° , 11.69 ⁇ 0.20°, 13.52 ⁇ 0.20°, 14.49 ⁇ 0.20°, 14.74 ⁇ 0.20°, 15.83 ⁇ 0.20°, 18.81 ⁇ 0.20°, 19.72 ⁇ 0.20°, 21.27 ⁇ 0.20°, 22.62 ⁇ 0.20°, 22.99 ⁇ 0.20° ,25.41 ⁇ 0.20°, 25.74 ⁇ 0.20°, 26.18 ⁇ 0.20°, 26.58 ⁇ 0.20°, 27.85 ⁇ 0.20°, 28.23 ⁇ 0.20°, 28.70 ⁇ 0.20°, 29.16 ⁇ 0.20°, 30.17 ⁇ 0.20°, 30.51 ⁇ 0.20°, 31.20 ⁇ 0.20°, 32.16 ⁇ 0.20°, 32.52 ⁇ 0.20°, 32.74 ⁇ 0.20°, 32.89 ⁇ 0.20°,
- the crystal form B of the compound represented by Formula I has an X-ray powder diffraction pattern expressed at 2 ⁇ angle using Cu-K ⁇ radiation at 8.95 ⁇ 0.20°, 10.63 ⁇ 0.20°, 11.69 ⁇ 0.20°, 12.92 ⁇ 0.20°, 13.52 ⁇ 0.20°, 14.49 ⁇ 0.20°, 14.74 ⁇ 0.20°, 15.83 ⁇ 0.20°, 16.39 ⁇ 0.20°, 17.00 ⁇ 0.20°, 17.44 ⁇ 0.20°, 17.76 ⁇ 0.20°, 18.08 ⁇ 0.20°, 18.81 ⁇ 0.20°, 19.02 ⁇ 0.20°, 19.72 ⁇ 0.20°, 21.27 ⁇ 0.20°, 21.95 ⁇ 0.20°, 22.20 ⁇ 0.20°, 22.62 ⁇ 0.20°, 22.99 ⁇ 0.20°, 23.49 ⁇ 0.20°, 24.15 ⁇ 0.20°, 24.92 ⁇ 0.20°, 25.41 ⁇ 0.20°, 25.74 ⁇ 0.20°, 25.94 ⁇ 0.20°, 26.18 ⁇ 0.20°, 26.58 ⁇ 0.20°
- the X-ray powder diffraction pattern of the compound represented by formula I using Cu-K ⁇ radiation and expressed at a 2 ⁇ angle has the diffraction peak shown in Table 1.
- the crystal form B of the compound represented by formula I uses Cu-K ⁇ radiation, and its X-ray powder diffraction (XRPD) pattern is as shown in Figure 8.
- the differential scanning calorimetry (DSC) curve of the crystal form B of the compound represented by formula I has an endothermic peak at 247.7°C ⁇ 3°C.
- thermogravimetric analysis (TGA) curve of the crystal form B of the compound represented by formula I loses 1.0% in the temperature range from 35°C ⁇ 3°C to 220°C ⁇ 3°C.
- thermogravimetric analysis curve of crystal form B of the compound represented by formula I is shown in Figure 10.
- the crystalline form B of the compound represented by formula I is an unsolvated compound.
- the crystal form B of the compound represented by Formula I is an ansolvate
- the solvent includes water, trifluoroacetic acid, and dichloromethane; for example, the solvent includes water, trifluoroacetic acid, and dichloromethane.
- the solvent includes water, trifluoroacetic acid, and dichloromethane.
- the filler is conventional in the art.
- the filler is one or more of lactose, lactose monohydrate, mannitol and microcrystalline cellulose.
- the microcrystalline cellulose is, for example, microcrystalline cellulose PH102
- the lactose monohydrate is, for example, lactose monohydrate GRANULAC200
- the mannitol is, for example, mannitol 200SD
- the lactose is, for example, lactose Flowlac100.
- the filler is any one of the following groups:
- the filler is a mixture of microcrystalline cellulose and lactose monohydrate, such as a mixture of microcrystalline cellulose PH102 and lactose monohydrate GRANULAC200;
- the filler is a mixture of microcrystalline cellulose and lactose, such as a mixture of microcrystalline cellulose PH102 and lactose Flowlac100;
- the filler is a mixture of microcrystalline cellulose and mannitol, such as a mixture of microcrystalline cellulose PH102 and mannitol 200SD;
- the filler is mannitol, for example, mannitol 200SD.
- the disintegrant is conventional in this field.
- the disintegrant is cross-linked carboxylic acid.
- the glidant is a conventional glidant in this field, for example, the glidant is silicon dioxide.
- the lubricant is a conventional lubricant in this field, for example, the lubricant is magnesium stearate.
- the pharmaceutical composition Q consists of the substance X and the pharmaceutical excipients.
- the pharmaceutical composition Q consists of the substance X, the disintegrant, the filler, the lubricant and the glidant.
- the content of the substance X can be 5% to 15% by weight of the total weight of the pharmaceutical composition, for example, 10%.
- the content of the filler by weight can be 70% to 90% of the total weight of the pharmaceutical composition, preferably 80% to 90%, such as 85%. or 88%.
- the filler in the pharmaceutical composition Q, is a mixture of microcrystalline cellulose and lactose monohydrate, a mixture of microcrystalline cellulose and lactose, or a mixture of microcrystalline cellulose and mannitol, and the content of the filler is It can be 70% to 90% by weight of the total weight of the pharmaceutical composition, preferably 80% to 90%, such as 85% or 88%.
- the filler in the pharmaceutical composition Q, is mannitol, and the content of the filler by weight can be 80% to 90% of the total weight of the pharmaceutical composition, for example, 85%. or 88%.
- the filler is a mixture of microcrystalline cellulose and lactose monohydrate, and the mass ratio of the lactose monohydrate to the microcrystalline cellulose can be 50:35 to 70: 15, preferably 56:29 to 64:21, such as 56:29 or 64:21.
- the filler is a mixture of microcrystalline cellulose and lactose, and the mass ratio of the lactose to the microcrystalline cellulose can be 60:25 to 68:17, for example, 64 :twenty one.
- the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the mannitol to the microcrystalline cellulose can be 60:25 to 68:17, for example 64:21.
- the disintegrant content may be 2% to 5% by weight of the total weight of the pharmaceutical composition, such as 3%.
- the disintegrant is croscarmellose sodium
- the content of the croscarmellose sodium by weight can be the total weight of the pharmaceutical composition. 2% to 5%, such as 3%.
- the content of the glidant in the pharmaceutical composition Q, can be 1% to 5% by weight of the total weight of the pharmaceutical composition, such as 1%.
- the lubricant content may be 1% to 5% by weight of the total weight of the pharmaceutical composition, such as 1%.
- the mass ratio of the glidant to the lubricant can be 0.5:1.5 to 1.5:0.5, such as 1:1.
- the pharmaceutical composition Q consists of 5% to 15% of the substance X, 80% to 90% of the filler, 2% to 5% of the disintegrant, 1% to 5% % of the lubricant and 1% to 5% of the glidant.
- the pharmaceutical composition consists of 10% of the substance
- the disintegrant is composed of 1% of the lubricant and 1% of the glidant.
- the pharmaceutical composition is composed of 10% of the crystal form B of the compound represented by formula I and 85% of the The filler, 3% of the cross-linked carboxymethyl It is composed of sodium cellulose, 1% of the magnesium stearate and 1% of the silicon dioxide, and the percentage is the mass ratio of the pharmaceutical composition.
- the pharmaceutical composition Q is selected from any of the following groups:
- composition 1 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide and 1% magnesium stearate;
- composition 2 10% substance X, 64% lactose monohydrate, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide and 1% magnesium stearate;
- composition 3 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide and 1% magnesium stearate;
- composition 4 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide and 1% magnesium stearate;
- composition 5 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide and 1% magnesium stearate;
- the percentage is the mass ratio of the pharmaceutical composition.
- the pharmaceutical composition Q is selected from any of the following groups:
- composition 6 10% crystal form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1% magnesium stearate;
- composition 7 10% crystal form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1% magnesium stearate;
- composition 8 10% crystal form B of the compound represented by formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1 %Magnesium stearate;
- composition 9 10% crystal form B of the compound represented by formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1% Magnesium stearate;
- composition 10 10% crystal form B of the compound represented by formula I, 85% mannitol 200SD, 3% croscarmellose sodium SD711, 1% silicon dioxide and 1% magnesium stearate; described Percentage is the mass ratio of the pharmaceutical composition.
- the pharmaceutical composition Q is administered orally.
- the pharmaceutical composition Q has a specification of 10 mg/portion or 40 mg/portion.
- the pharmaceutical composition Q can be a solid preparation, such as a solid oral preparation.
- the pharmaceutical composition Q may be a tablet or capsule, such as a capsule.
- the pharmaceutical composition Q is a pharmaceutical composition for treating and/or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases.
- the psychiatric, neurological or neurodegenerative disorder may be selected from: disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder , dysthymia, dysthymia and postpartum depression, and bipolar disorder), anxiety- and fear-related conditions (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder disease, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia syndrome, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Wehr-Coeli syndrome), and impaired impulses Control and addiction-related disorders, Parkinson'
- the kidney disease may be focal segmental glomerulosclerosis, minimal change nephropathy, diabetic nephropathy, Allport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, Idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangial hyperplasia glomerulonephritis, amyloid nephropathy (preferably primary amyloid nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephropathy Sclerosis, primary glomerular disease (preferably IgA nephropathy).
- the present invention provides a pharmaceutical composition R, which includes the above-mentioned pharmaceutical composition Q and a capsule shell, and the pharmaceutical composition Q is filled in the capsule shell.
- the capsule shell is a conventional capsule shell in this field.
- the capsule shell is, for example, an HPMC capsule shell or a gelatin capsule shell, preferably an HPMC capsule shell.
- the pharmaceutical composition R consists of the above-mentioned pharmaceutical composition Q and a capsule shell, and the pharmaceutical composition Q is filled in the capsule shell.
- the pharmaceutical composition R is selected from any of the following groups:
- composition 1 10% substance X, 56% lactose monohydrate, 29% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;
- composition 2 10% substance ;
- composition 3 10% substance X, 64% mannitol, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;
- composition 4 10% substance X, 64% lactose, 21% microcrystalline cellulose, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;
- composition 5 10% substance X, 85% mannitol, 3% croscarmellose sodium, 1% silicon dioxide, 1% magnesium stearate and the capsule shell;
- the percentage is the mass ratio of the pharmaceutical composition.
- the pharmaceutical composition R is selected from any of the following groups:
- composition 6 10% crystal form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide , 1% magnesium stearate and the HPMC capsule shell;
- composition 7 10% crystal form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC200, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the HPMC capsule shell;
- composition 8 10% crystal form B of the compound represented by formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1 % magnesium stearate and the HPMC capsule shell;
- composition 9 10% crystal form B of the compound represented by formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% Magnesium stearate and the HPMC capsule shell;
- composition 10 10% crystal form B of the compound represented by formula I, 85% mannitol 200SD, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the above HPMC capsule shell;
- composition 11 10% crystal form B of the compound represented by formula I, 56% lactose monohydrate GRANULAC200, 29% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide , 1% magnesium stearate and the gelatin capsule shell;
- composition 12 10% crystal form B of the compound represented by formula I, 64% lactose monohydrate GRANULAC 200, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the gelatin capsule shell;
- composition 13 10% crystal form B of the compound represented by formula I, 64% mannitol 200SD, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1 % magnesium stearate and the gelatin capsule shell;
- composition 14 10% crystal form B of the compound represented by formula I, 64% lactose Flowlac100, 21% microcrystalline cellulose PH102, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% Magnesium stearate and the gelatin capsule shell;
- composition 15 10% crystal form B of the compound represented by formula I, 85% mannitol 200SD, 3% croscarmellose sodium SD711, 1% silicon dioxide, 1% magnesium stearate and the above Gelatin capsule shell; the percentage is the mass ratio of the pharmaceutical composition.
- the pharmaceutical composition R is administered orally.
- the pharmaceutical composition R has a specification of 10 mg/pellet or 40 mg/pellet.
- the pharmaceutical composition R can be a solid preparation, such as a solid oral preparation.
- the pharmaceutical composition R can be a capsule.
- the pharmaceutical composition R is a pharmaceutical composition for treating and/or preventing psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases.
- the psychiatric, neurological or neurodegenerative disorder may be selected from: disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depression, such as major depressive disorder, major depressive disorder , dysthymia, dysthymia and postpartum depression, and bipolar disorder), anxiety- and fear-related conditions (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder disease, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia syndrome, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Wehr-Coeli syndrome), and impaired impulses Control and addiction-related conditions, Alzheimer'
- kidney diseases described are focal segmental glomerulosclerosis, minimal change nephropathy, diabetic nephropathy, Allport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, special nephropathy, Idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangioproliferative Glomerulonephritis, amyloid nephropathy (preferably primary amyloid nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis , Primary glomerular disease (preferably IgA),
- the present invention provides a preparation method of the above-mentioned pharmaceutical composition Q.
- the preparation method of the pharmaceutical composition preferably includes the following steps:
- the type and content of the substance X, the disintegrant and the filler are as described in any one of the present invention; the silicon dioxide is a glidant, and the magnesium stearate is a lubricant.
- the mass ratio of the filler and the substance X may be 3:1.
- the filler in the preparation method of the pharmaceutical composition, in the step (a), may be one or more of the lactose, the lactose monohydrate and the mannitol.
- the disintegrant in the preparation method of the pharmaceutical composition, in the step (b), may be croscarmellose sodium.
- the substance X or the filler in the preparation method of the pharmaceutical composition, in the step (a), can be the substance X of 30 mesh or the filler of 30 mesh.
- the filler, the disintegrant or the silica in the preparation method of the pharmaceutical composition, in the step (b), can be the filler of 30 mesh, the disintegrant of 30 mesh Or 30 mesh silica.
- the mixing conditions may be stirring at 20 rpm for 10-60 min, for example, stirring at 20 rpm for 20 min.
- the magnesium stearate may be 60 mesh magnesium stearate.
- the adding condition may be stirring at 20 rpm for 2 to 10 minutes, for example, 3 minutes.
- the preparation method of the pharmaceutical composition preferably includes the following steps: adding 3 times the mass of the substance Mix the mannitol (mannitol 200SD) described in the purpose with the substance For example, stir at 20 rpm for 20 minutes); add the magnesium stearate of 60 mesh and mix (for example, stir at 20 rpm for 3 minutes) to obtain the pharmaceutical composition Q.
- the present invention provides a preparation method of pharmaceutical composition R, which involves capsule filling of the above pharmaceutical composition Q.
- the capsule can be a conventional capsule in the art.
- the capsule is, for example, an HPMC capsule shell or a gelatin capsule shell, preferably an HPMC capsule shell.
- the filling can be carried out by using a fully automatic capsule filling machine.
- the fully automatic capsule filling machine model is In-Cap XL.
- the present invention provides an application of substance Y in the preparation of medicines.
- the substance Y is the above-mentioned pharmaceutical composition Q or pharmaceutical composition R; the medicine is a medicine for treating and/or preventing TRPC5-mediated diseases. .
- the TRPC5-mediated disease may be a psychiatric disorder, a neurological disorder, a neurodegenerative disorder or renal disease.
- the psychiatric, neurological or neurodegenerative disorder may be selected from: disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depressive disorders such as major depressive disorder, major depressive disorder, psychotic disorder, dysthymia and postpartum depression and bipolar disorder), anxiety- and fear-related conditions (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder, panic disorder, social anxiety disorder , obsessive-compulsive disorder and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociative amnesia, fugue amnesia , Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Wehr-Coeli syndrome), associated with impaired impulse control and addiction disorders, Parkinson's disease, amyotrophic lateral
- kidney diseases described are focal segmental glomerulosclerosis, minimal change nephropathy, diabetic nephropathy, Allport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, special nephropathy, Idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangioproliferative Glomerulonephritis, amyloid nephropathy (preferably primary amyloid nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis , Primary glomerular disease (preferably IgA),
- the present invention provides an application of substance Y in the preparation of medicines, and the substance Y is the above-mentioned pharmaceutical composition Q or pharmaceutical composition R, the drug is a drug used to treat and/or prevent psychiatric disorders, neurological disorders, neurodegenerative disorders or renal diseases.
- the psychiatric, neurological or neurodegenerative disorder may be selected from: disorders associated with dysregulated emotional processing (e.g., borderline personality disorder or depressive disorders such as major depressive disorder, severe depressive disorders, dysthymia, dysthymia and postpartum depression, and bipolar disorder), anxiety- and fear-related conditions (e.g., post-traumatic stress disorder, panic disorder, agoraphobia, social phobia, generalized anxiety disorder , panic disorder, social anxiety disorder, obsessive-compulsive disorder, and separation anxiety), memory disorders (e.g., Alzheimer's disease, amnesia, aphasia, brain injury, brain tumors, chronic fatigue syndrome, Creutzfeldt-Jakob disease, dissociation amnesia, fugue amnesia, Huntington's disease, learning disabilities, sleep disorders, multiple personality disorder, pain, post-traumatic stress disorder, schizophrenia, sports injuries, stroke and Wehr-Coeli syndrome), and impairment Impulse control and addiction-related disorders, Alzheimer's, borderline
- kidney diseases described are focal segmental glomerulosclerosis, minimal change nephropathy, diabetic nephropathy, Allport syndrome, hypertensive nephropathy, nephrotic syndrome, steroid-resistant nephrotic syndrome, membranous nephropathy, special nephropathy, Idiopathic membranous nephropathy, membranoproliferative glomerulonephritis, immune complex-mediated MPGN, complement-mediated MPGN, lupus nephritis, post-infectious glomerulonephritis, thin basement membrane disease, mesangioproliferative Glomerulonephritis, amyloid nephropathy (preferably primary amyloid nephropathy), C1q nephropathy, rapidly progressive glomerulonephritis, anti-glomerular basement membrane disease, C3 glomerulonephritis, hypertensive nephrosclerosis or primary glomerular disease (preferably IgA n
- fillers also known as “diluent” refers to a class of excipients used in a scientific context to increase the volume and weight of a pharmaceutical composition product dosage form.
- fillers may be, for example: calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethylcellulose, fructose, lactose, lactose monohydrate, lactitol, maltose, maltodextrin, maltitol , mannitol, microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, corn starch, dextrin, sucrose, trehalose and xylitol.
- disintegrant refers to a class of excipients used in a scientific context to promote the breakup of pharmaceutical composition product dosage forms into smaller fragments in an aqueous environment.
- the disintegrant may be, for example: alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, colloidal silica, croscarmellose sodium, crospovidone, carboxymethylcellulose Sodium starch, low substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, carboxymethyl cellulose Sodium cellulose, sodium starch glycolate and starch.
- lubricant refers to a class of excipients used in a scientific context to improve the processing of pharmaceutical composition product dosage forms.
- the lubricant may be, for example: calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, benzene Sodium formate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate.
- glidant refers to a type of auxiliary material that reduces the friction between particles and improves the fluidity of powders. Therefore, the glidant can be, for example: silica, micronized silica gel.
- pharmaceutically acceptable salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
- base addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable base in pure solution or a suitable inert solvent.
- Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts.
- acid addition can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in pure solution or a suitable inert solvent.
- a salt included in The pharmaceutically acceptable acid, and the Inorganic acids include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc.
- the pharmaceutically acceptable acids include organic acids, and the organic acids include but are not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartaric acid, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
- solvate refers to a substance formed by combining a compound of the invention with a stoichiometric or non-stoichiometric amount of solvent.
- the solvent molecules in a solvate may exist in an ordered or unordered arrangement.
- the solvents include but are not limited to: water, methanol, ethanol, etc.
- pharmaceutically acceptable salt and “solvate” in the term “pharmaceutically acceptable salt solvate” are as described above and refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid. Or a substance prepared from a base and combined with a stoichiometric or non-stoichiometric solvent.
- pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and preparation of prescriptions, which are all substances included in pharmaceutical preparations except active ingredients. See the Pharmacopoeia of the People's Republic of China (2020 Edition), Part Four, or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition).
- treatment refers to therapeutic therapy.
- treatment means: (1) alleviating the disease or one or more biological manifestations of the condition, (2) interfering with (a) one or more points in the biological cascade that causes or causes the condition or (b) ) one or more biological manifestations of a condition, (3) amelioration of one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment, or (4) slow the progression of a condition or one or more biological manifestations of a condition.
- prevention refers to the reduction of the risk of acquiring or developing a disease or disorder.
- patient refers to any animal, preferably a mammal, to which a compound or composition is or has been administered in accordance with embodiments of the present invention.
- mammal includes any mammal. Examples of mammals include, but are not limited to, cattle, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being preferred.
- terapéuticaally effective amount refers to an amount of a compound that, when administered to a patient, is sufficient to effectively treat the disease or condition described herein.
- the “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, and can be adjusted as necessary by one skilled in the art.
- the reagents and raw materials used in the present invention are all commercially available.
- the positive and progressive effect of the present invention is that: the pharmaceutical composition provided by the present invention has good stability and good dissolution performance; the pharmaceutical composition has a simple preparation method and is suitable for industrial production.
- Figure 1 shows the XRPD spectrum of Form A.
- Figure 2 shows the DSC spectrum of Form A.
- Figure 3 shows the TGA spectrum of Form A.
- Figure 4 is the 1 H-NMR spectrum of Form A (DMSO-d 6 );
- Figure 5 is the 1 H-NMR spectrum (D 2 O) of Form A.
- Figure 6 is the PLM spectrum of Form A.
- Figure 7 is the FT-IR spectrum of Form A.
- Figure 8 is the XRPD spectrum of crystal form B of the compound represented by formula I.
- Figure 9 is a DSC spectrum of crystal form B of the compound represented by formula I.
- Figure 10 is a TGA spectrum of crystal form B of the compound represented by formula I.
- Figure 11 is a 1 H-NMR spectrum of crystal form B of the compound represented by formula I.
- Figure 12 is a PLM spectrum of crystal form B of the compound represented by formula I.
- Figure 13 is the FT-IR spectrum of crystal form B of the compound represented by formula I.
- Figure 14 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of prescription 1.
- Figure 15 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of prescription 2.
- Figure 16 shows the dissolution curves of 10 mg and 40 mg HPMC capsules and 40 mg gelatin capsules of prescription 3.
- Figure 17 shows the dissolution curves of 40 mg HPMC capsules and gelatin capsules of prescription 4.
- Figure 18 shows the dissolution curves of 10 mg and 40 mg HPMC capsules of prescription 5.
- Figure 19 shows the dissolution curves of 10 mg and 40 mg gelatin capsules of prescription 5.
- Figure 20 is the stability dissolution curve of the 10 mg HPMC capsule of prescription 5 under the conditions of 25°C/60% RH.
- Figure 21 is the stability dissolution curve of the 40 mg HPMC capsule of prescription 5 under the conditions of 25°C/60% RH.
- Figure 22 shows the stability dissolution curve of the 10 mg HPMC capsule of prescription 5 under the conditions of 40°C/75%RH.
- Figure 23 shows the stability dissolution curve of the 40 mg HPMC capsule of prescription 5 under the conditions of 40°C/75% RH.
- Figure 24 is the XRPD comparison chart of the 10 mg HPMC capsule of prescription 5 under the conditions of 40°C/75% RH for 0 days and 2 months.
- Figure 25 is the XRPD comparison chart of the 40 mg HPMC capsule of prescription 5 under the conditions of 40°C/75% RH for 0 days and 2 months.
- Figure 26 shows the stability dissolution curve of the 10 mg gelatin capsule of prescription 5 under the conditions of 40°C/75%RH.
- Figure 27 is the stability dissolution curve of the 40 mg gelatin capsule of prescription 5 under the conditions of 40°C/75% RH.
- Figure 28 is the XRPD comparison chart of the 10 mg gelatin capsule of prescription 5 under the conditions of 40°C/75% RH for 0 days and 1 month.
- Figure 29 is the XRPD comparison chart of the 40 mg gelatin capsule of prescription 5 under the conditions of 40°C/75% RH for 0 days and 1 month.
- Figure 30 shows the stability dissolution curve of the 40 mg gelatin capsule of prescription 5 under high temperature conditions of 60°C.
- Figure 31 is an XRPD overlay of crystal form B of the compound represented by formula I before and after pressure and grinding tests.
- ACN acetonitrile
- API active pharmaceutical ingredient
- DMSO dimethyl sulfoxide
- DSC differential scanning calorimetry
- DVS dynamic moisture adsorption
- FT-IR Fourier transform infrared spectroscopy
- HPLC high performance liquid chromatography
- PLM Polarizing microscope
- RH relative humidity
- SD standard deviation
- TGA thermogravimetric analysis
- T onset initial temperature/start temperature
- XRPD X-ray powder diffraction.
- DSC Differential scanning calorimetry
- TGA Thermogravimetric analysis
- PLM Polarized light microscopy
- the packaged materials are canned using a fully automatic capsule filling machine (model: In-Cap XL).
- the canning parameters are as follows:
- Compound 1-1 was prepared according to the method described in WO2022/001767A1.
- Example 2 Weigh about 30 mg of the crystal form A obtained in Example 1 and add 0.3 mL of water to ensure that a suspension with appropriate concentration is obtained. The suspension was stirred at 50°C to 5°C for 10 cycles at a temperature increase and decrease rate of 0.1°C/min. After the cycle is completed, the obtained solid is centrifuged with a 0.45 ⁇ m filter membrane at 5°C for 5 minutes, and the obtained solid is used as the seed crystal for the next step;
- composition information of the obtained prescription 1 is shown in the following table:
- the preparation method of Recipe 2 is the same as Recipe 1, except that the 10 mg specification uses the No. 5 dosage plate.
- the composition information of Recipe 2 is shown in the table below, and its dissolution data is shown in Figure 15.
- composition information of the obtained prescription 2 is shown in the following table:
- composition information of the 10 mg HPMC capsules and 40 mg HPMC capsules and gelatin capsules of the obtained prescription 3 is shown in the table below, and the dissolution data is shown in Figure 16; the 10 mg specification of the obtained prescription 4
- the composition information of HPMC capsules and 40mg HPMC capsules and gelatin capsules is shown in the table below, and its dissolution data is shown in Figure 17.
- composition of HPMC capsules in Prescription 3 is shown in the table below:
- composition of the gelatin capsule of prescription 3 is shown in the table below:
- the dissolution data of the two capsules of prescription 3 are shown in the table below:
- composition of HPMC capsules in Prescription 4 is shown in the table below:
- composition of the gelatin capsule of prescription 4 is shown in the table below:
- the dissolution data of the two capsules of prescription 4 are shown in the table below:
- composition of HPMC capsules in Prescription 5 is shown in the table below:
- composition of the gelatin capsule of prescription 5 is shown in the table below:
- the dissolution data of gelatin capsules of prescription 5 are shown in the table below:
- HPMC capsule product of prescription 5 obtained in method 1 of Example 6 was packaged for stability testing, and the HPMC capsules of 10 mg and 40 mg specifications were placed under the conditions of 25°C ( ⁇ 2°C)/60% ( ⁇ 5%) RH. Leave it for 0 days and 3 months for stability testing; at the same time, place 10mg and 40mg HPMC capsules under 40°C ( ⁇ 2°C)/75% ( ⁇ 5%) RH conditions for 0 days, 1 month, and 2 Conduct stability inspections at 1 and 3 months.
- the packaging container is a medicinal high-density polyethylene bottle + oral solid medicinal polypropylene child-safe combination bottle cap;
- Packaging specifications 7 capsules/bottle
- the properties of 10 mg HPMC capsules are stable for 0 days, 1 month, 2 months, and 3 months.
- the properties of 40 mg HPMC capsules are stable for 0 days, 1 month, 2 months, and 3 months.
- Monthly properties are stable.
- the gelatin capsule product of prescription 5 obtained in method 2 of Example 6 was placed under the conditions of 40°C ( ⁇ 2°C)/75% ( ⁇ 5%) RH for 0 days, 2 weeks and 1 month for stability investigation.
- the 40 mg gelatin capsule sample was placed out for 0 days and 2 weeks under the influence of high temperature factors of 60°C ( ⁇ 2°C) to examine its stability.
- the packaging container is a 45mL oral solid medicinal high-density polyethylene bottle + oral solid medicinal polypropylene child-safe combination bottle cap;
- Packaging specifications 10 capsules/bottle.
- the stability data of the gelatin capsule sample under 40°C/75%RH conditions showed that after being placed under accelerated conditions for 2 weeks, the dissolution results in pH 4.5 acetate buffer were not significantly different from those of the 0-day sample, and the content and moisture There is no significant difference from the 0-day sample, and the impurity results are good. After the capsule sample was placed for 4 weeks (i.e. 1 month), there was no significant difference in content and moisture from the 0-day sample, and the impurity results were good.
- TRPC5 is a type of non-selective cation channel that is permeable to calcium ions. Therefore, TRPC5 agonist Englerin A (EA) and TRPC5 inhibitor Pico145 were used as positive controls in this experiment. Fluo-4AM fluorescent dye was used to detect the effect of compounds on TRPC5- The effect of Ca 2+ in HEK 293 cells indirectly reflects the effect of compounds on TRPC5 channels.
- Pico145 MCE, batch number 31245;
- DMEM high sugar Gibco, batch number 2230805;
- FBS Gibco, batch number 1981614;
- HEPES Sigma, batch number WXBD0664V;
- Blasticidin Gibco, batch number 1737347;
- Hygromycine Yeasen, batch number H18010;
- Doxycycline Sigma, batch number BCBL6540V;
- Fluo-4AM Molecular Devices, batch number 1231041;
- Poly-D-Lysine Sigma, lot number SLBQ9797V.
- Resuscitation solution 100% DMEM (Dulbecco's Modified Eagle Medium) high sugar
- Selection medium DMEM high sugar + 10% FBS (Phosphate Buffered Saline, phosphate buffered saline) + 1% P/S (Penicillin-Streptomycin Solution, penicillin-streptomycin solution) + 1% HEPES (4-hydroxyethyl) Piperazine ethanesulfonic acid)+Blasticidin (5 ⁇ g/mL)+Hygromycine (50 ⁇ g/mL)
- Induction medium DMEM high sugar+10% FBS+1% P/S+1% HEPES+doxycycline (1 ⁇ g/mL)
- Recovery process Take out the liquid nitrogen tank, transfer it to a water bath in an ice box, make a circle to dissolve until it contains a small piece of ice, transfer the frozen solution to the recovery solution, centrifuge at 1000 rpm for 5 minutes, discard the supernatant, and transfer to selective culture
- the culture medium was expanded in a CO 2 incubator (5% CO 2 , 95% humidity, 37°C).
- TRPC5 calcium signal detection external solution 4.0908g NaCl, 0.1864g KCl, 0.111g CaCl 2 , 0.0476g MgCl 2 , 0.9g Glucose (glucose), 1.1915g HEPES (4-hydroxyethylpiperazinethanesulfonic acid).
- the external solution for TRPC5 calcium signal detection contains a final concentration of 4 ⁇ M Fluo-4 (containing 0.5% BSA)
- Concentration of the compound to be tested conventional preparation, use DMSO to prepare a solution that is 8 times the final concentration of the test (the final concentration of the test is: 1nM, 3nM, 10nM, 30nM, 100nM, 300nM and 1000nM), each bottom plate well 60 ⁇ L.
- the Flipr test fluorescence value is subtracted from the value of the unstained (dye) cell well (i.e., the background fluorescence value).
- Graphpad Prism 6.0 software is used for statistics and data processing. The trajectory chart is normalized by removing the baseline. Chemical processing, ratio display, dose-effect diagram to calculate AUC (area under the curve formed by calcium flow signal) collected data and log value of compound concentration, use log[Inhibitor] vs. response-Variable slope to calculate IC 50 value.
- the compound represented by formula I has no inhibitory activity on TRPC5 channel
- Rats SD rats, SPF grade, 3 males, weight range 180-200g (Source: Beijing Vitong Lihua Experimental Animal Technology Co., Ltd., certificate number: 110011201109106028);
- Dispensing After accurately weighing the compound shown in PO group formula I, first add the required volume of 5% solutol (5% polyethylene glycol (15)-hydroxystearate, Beijing Fengli Jingqiu Pharmaceutical Co., Ltd., Batch No. 1760094G0), vortex and mix for 2 minutes, ultrasonic for 30 minutes, stir for 2 hours until no particles are visible to the naked eye, administer while stirring, and take the middle layer of the drug for administration.
- solutol 5% polyethylene glycol (15)-hydroxystearate, Beijing Fengli Jingqiu Pharmaceutical Co., Ltd., Batch No. 1760094G0
- Rats SD rats, SPF grade, 3 males, weight range 220-300g (Source: Beijing Speiful Biotechnology Co., Ltd., certificate number: 110324200103216838);
- the rats were randomly divided into 3 groups according to their body weight.
- the specific grouping and administration conditions are as follows:
- the blood collection time points of the PO group were 0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours.
- the blood collection time points of the PO group were 0.167, 0.5, 1, 2, 3, 4, 6, 9, 12 and 24 hours.
- Ion source Ion Electrospray (ESI)
- Ionization mode Positive ion mode (Positive)
- Detection mode (Mode): Multiple reaction monitoring (MRM)
- Sample pretreatment process Take 3 ⁇ L of working solution, add 57 ⁇ L of blank matrix (rat blank plasma) into a 1.5 mL centrifuge tube, add 240 ⁇ L of acetonitrile containing 200 ng/mL tolbutamide and 0.1% FA (formic acid) to precipitate protein, vortex Vortex for 1 minute to mix, and centrifuge the sample at 13,000 rpm for 15 minutes at 4°C. Take 100 ⁇ L of the supernatant in another 96-deep well plate, add 100 ⁇ L of methanol:water (1:3, v:v) solution containing 0.1% FA, oscillate and mix for 1 minute, and centrifuge at 3500 rpm in a 96-well plate centrifuge. Inject the sample directly after 5 minutes.
- Ion source Ion Electrospray (ESI)
- Ionization mode Positive ion mode (Positive)
- Detection mode (Mode): Multiple reaction monitoring (MRM)
- Sample pretreatment process Take 30 ⁇ L of sample, add 120 ⁇ L of acetonitrile containing 0.1% FA and 200 ng/mL mixed standard solution to precipitate protein, vortex to mix evenly, and centrifuge the sample at 13000 rpm for 10 minutes in a centrifuge at 4°C. Take 100 ⁇ L of the supernatant in another 96-deep well plate, add 100 ⁇ L of methanol:water (1:3, v:v) solution, and oscillate and mix for 10 minutes.
- the data will be analyzed through the non-compartmental model using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA) to obtain PK parameters (C max , T max , AUC last , AUC inf , T 1/2 , selected according to different administration routes, MRT and other parameters).
- PK parameters C max , T max , AUC last , AUC inf , T 1/2 , selected according to different administration routes, MRT and other parameters.
- the specific results are shown in the table below.
- the analyte of the data listed in the table is compound 1-1.
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Abstract
提供了包含杂环化合物的药物组合物及其制备方法和应用。还提供了一种药物组合物Q,其包含物质X和药用辅料,所述的物质X为式I所示化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物。该药物组合物具有如下一个或多个优点:稳定性良好,溶出性能好,制备方法简单,适合工业化生产;
Description
本申请要求申请日为2022年08月05日的中国专利申请202210938921.7的优先权。本申请引用上述中国专利申请的全文。
本发明涉及一种包含杂环化合物的药物组合物及其制备方法和应用。
阳离子通道(诸如瞬时型感受器电位(TRP)阳离子通道亚家族C,成员5(TRPC5))调节钙和钠离子通过细胞膜的流动。钠和钙的内流导致细胞的去极化。这增加了电压门控离子通道会达到对于激活所需的阈值的可能性。因此,非选择性阳离子通道的激活可增加电兴奋性,并增加电压依赖性事件的频率。电压依赖性事件包括但不限于神经元的动作电位、心动作电位、平滑肌收缩、心肌收缩和骨骼肌收缩。
通过非选择性阳离子通道(诸如TRPC5)的激活引起的钙内流还改变细胞内游离钙浓度。钙是细胞中普遍存在的第二信使分子,细胞内钙水平的改变对信号传导和基因表达具有深远的影响。因此,非选择性阳离子通道(诸如TRPC5)的激活可导致基因表达和细胞表型的变化。基因表达事件包括但不限于编码细胞表面受体、离子通道和激酶的mRNA的产生。基因表达中的这些变化可导致该细胞中的超兴奋性。
同聚TRPC5离子通道是主要在神经元中表达的信号传导门控、Ca2+可通过通道。TRPC5形成同聚多亚基结构(诸如四聚体(即TRPC5同源多聚体))和异聚多亚基结构(诸如四聚体(即TRPC5-TRPC1异源多聚体))。除非明确另外说明,当在本文中使用术语TRPC5时(例如当鉴定TRPC5的调节剂,诸如TRPC5拮抗剂),术语TRPC5是一般性地使用,以包括TRPC5同源多聚体或异源多聚体(例如TRPC5-TPRC1或TRPC5-TRPC4异源多聚体)中之一或二者。
调节TRPC5蛋白的功能提供调节钙稳态、钠稳态、膜极化和/或细胞内钙水平的方法,并且可调节TRPC5功能的化合物可用于许多方面,包括但不限于维持钙稳态、调节细胞内钙水平、调节膜极化,以及治疗或预防与钙和/或钠稳态或生理紊乱(dyshomeostasis)相关的疾病、病症或病况。
抑制含有离子通道的TRPC5的化合物例如适用于通过调节可呈同源多聚体形式及与其他离子通道(诸如TRPC1或TRPC3)呈异源多聚体形式(即,TRPC5-TRPC1及TRPC1-TRPC3-TRPC5)存在的瞬时型感受器电位阳离子通道亚家族C,成员5(TRPC5)的活性以治疗病症。
TRPC5与FSGS和糖尿病肾病等疾病相关(J.Clin.Invest.,2013年12月2日;123(12):5298-5309,Zhou等人,Science 358,1332-1336(2017)。局灶节段性肾小球硬化(FSGS)是一种临床病理综合征,临床表现为大量蛋白尿或肾病综合征,病理以局灶节段分布的肾小球硬化病变及足细胞变性所致足突融合或消失为特征。FSGS约占我国成人肾病综合征的5%~10%,患者以青壮年男性多见。持续肾病综合征的患者,5~10年内50%以上进展至终末期肾病。
在健康肾小球中,TRPC5被隔离在细胞质中,维持正常过滤障碍,当足细胞损伤后,足细胞损伤激活RAC1,引起TRPC5从胞浆转移至细胞膜,这促进了AT1受体诱导的通过TRPC5通道钙离子内
流,进一步促进RAC1活性,RAC1激活诱导肌动蛋白重组和足细胞从肾小球上脱离;足细胞的损失破坏了过滤屏障,使得血清蛋白漏到尿液里面。
目前临床使用的FSGS治疗药物主要为激素、免疫抑制剂、CNIs和烷化剂,都存在严重毒副作用,并且很多需要与其他药联合使用才有效,容易复发。因此,开发新的TRPC5抑制剂药物,对于上述疾病的治疗具有积极意义。同时,研发包含这些化合物的适于成药的药物制剂,例如具有稳定性和安全性的制剂形式,从而在制药及用药阶段取得良好效果,成为亟待解决的技术问题。
发明内容
本发明所要解决的技术问题是现有技术中的式I所示杂环化合物的制剂缺乏,为此,本发明提供了一种包含杂环化合物的药物组合物及其制备方法和应用,该药物组合物稳定性良好,磷酸盐缓冲液中可实现快速溶出;并且该药物组合物制备方法简单,适合工业化生产。
本发明提供了一种药物组合物Q,其包含物质X和药用辅料;
其中,所述的物质X为式I所示化合物、其药学上可接受的盐、式I所示化合物的溶剂合物或其药学上可接受的盐的溶剂合物;
所述的药用辅料选自稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂和助流剂中的一种或多种。
某一方案中,所述药用辅料选自崩解剂、填充剂、润滑剂和助流剂中的一种或多种。
某一方案中,所述的物质X为唯一活性成分。
某一方案中,所述的物质X的用量为治疗有效量。
某一方案中,所述的式I所示化合物的溶剂合物为本领域常规的溶剂合物,所述溶剂合物包括但不限于式I所示化合物的水合物、式I所示化合物的乙腈合物或式I所示化合物的N-甲基吡咯烷酮合物。
某一方案中,所述的式I所示化合物为晶型。
某一方案中,所述的式I所示化合物的溶剂合物为晶型。
某一方案中,所述的物质X为式I所示化合物的晶型B,其中,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图在8.95±0.20°、12.92±0.20°、16.39±0.20°、17.00±0.20°、17.44±0.20°、17.76±0.20°、18.08±0.20°、19.02±0.20°、21.95±0.20°、22.20±0.20°、23.49±0.20°、24.15±0.20°、24.92±0.20°、25.94±0.20°、27.14±0.20°和29.68±0.20°处有衍射峰。
某一方案中,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图还在以下一处或多处有衍射峰:10.63±0.20°、11.69±0.20°、13.52±0.20°、14.49±0.20°、14.74±0.20°、15.83±0.20°、18.81±0.20°、19.72±0.20°、21.27±0.20°、22.62±0.20°、22.99±0.20°、25.41±0.20°、25.74±0.20°、
26.18±0.20°、26.58±0.20°、27.85±0.20°、28.23±0.20°、28.70±0.20°、29.16±0.20°、30.17±0.20°、30.51±0.20°、31.20±0.20°、32.16±0.20°、32.52±0.20°、32.74±0.20°、32.89±0.20°、34.36±0.20°、35.45±0.20°、35.98±0.20°、36.65±0.20°、37.00±0.20°、37.45±0.20°、37.73±0.20°、38.04±0.20°、38.36±0.20°和39.11±0.20°。
某一方案中,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图在8.95±0.20°、10.63±0.20°、11.69±0.20°、12.92±0.20°、13.52±0.20°、14.49±0.20°、14.74±0.20°、15.83±0.20°、16.39±0.20°、17.00±0.20°、17.44±0.20°、17.76±0.20°、18.08±0.20°、18.81±0.20°、19.02±0.20°、19.72±0.20°、21.27±0.20°、21.95±0.20°、22.20±0.20°、22.62±0.20°、22.99±0.20°、23.49±0.20°、24.15±0.20°、24.92±0.20°、25.41±0.20°、25.74±0.20°、25.94±0.20°、26.18±0.20°、26.58±0.20°、27.14±0.20°、27.85±0.20°、28.23±0.20°、28.70±0.20°、29.16±0.20°、29.68±0.20°、30.17±0.20°、30.51±0.20°、31.20±0.20°、32.16±0.20°、32.52±0.20°、32.74±0.20°、32.89±0.20°、34.36±0.20°、35.45±0.20°、35.98±0.20°、36.65±0.20°、37.00±0.20°、37.45±0.20°、37.73±0.20°、38.04±0.20°、38.36±0.20°和39.11±0.20°处有衍射峰。
某一方案中,所述的式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图具有如表1所示的衍射峰。
某一方案中,所述的式I所示化合物的晶型B,其使用Cu-Kα辐射,其X射线粉末衍射(XRPD)图谱如图8所示。
某一方案中,所述的式I所示化合物的晶型B,其差示扫描量热(DSC)曲线在247.7℃±3℃处具有吸热峰。
某一方案中,所述的式I所示化合物的晶型B,其差示扫描量热曲线如图9所示。
某一方案中,所述的式I所示化合物的晶型B,其热重分析曲线(TGA)在35℃±3℃至220℃±3℃温度范围内失重1.0%。
某一方案中,所述的式I所示化合物的晶型B,其热重分析曲线如图10所示。
某一方案中,所述的式I所示化合物的晶型B为无溶剂合物。
某一方案中,所述的式I所示化合物的晶型B为无溶剂合物,所述溶剂包括水、三氟乙酸、二氯甲烷;例如所述溶剂包括水、三氟乙酸、二氯甲烷的一种或多种。
某一方案中,所述药物组合物Q中,所述填充剂为本领域常规,较佳地,所述填充剂为乳糖、一水乳糖、甘露醇和微晶纤维素中的一种或多种,所述微晶纤维素例如为微晶纤维素PH102,所述一水乳糖例如为一水乳糖GRANULAC200,所述甘露醇例如为甘露醇200SD,所述乳糖例如为乳糖Flowlac100。
某一方案中,所述药物组合物Q中,所述填充剂为如下任一组:
(a)所述填充剂为微晶纤维素和一水乳糖混合物,例如为微晶纤维素PH102和一水乳糖GRANULAC200混合物;
(b)所述填充剂为微晶纤维素和乳糖混合物,例如为微晶纤维素PH102和乳糖Flowlac100混合物;
(c)所述填充剂为微晶纤维素和甘露醇混合物,例如为微晶纤维素PH102和甘露醇200SD混合物;
(d)所述填充剂为甘露醇,例如为甘露醇200SD。
某一方案中,所述药物组合物Q中,所述崩解剂为本领域常规的,较佳地,所述崩解剂为交联羧
甲基纤维素钠,例如为交联羧甲基纤维素钠SD711。
某一方案中,所述药物组合物Q中,所述助流剂为本领域常规的助流剂,例如所述助流剂为二氧化硅。
某一方案中,所述药物组合物Q中,所述润滑剂为本领域常规的润滑剂,例如所述润滑剂为硬脂酸镁。
某一方案中,所述药物组合物Q由所述物质X和所述药用辅料组成。
某一方案中,所述药物组合物Q由所述物质X、所述崩解剂、所述填充剂、所述润滑剂和所述助流剂组成。
某一方案中,所述药物组合物Q中,所述物质X含量以重量计可为所述的药物组合物总重量的5%~15%,例如为10%。
某一方案中,所述药物组合物Q中,所述填充剂含量以重量计可为所述的药物组合物总重量的70%~90%,优选为80%~90%,例如为85%或88%。
某一方案中,所述药物组合物Q中,所述填充剂为微晶纤维素和一水乳糖混合物、微晶纤维素和乳糖混合物或微晶纤维素和甘露醇混合物,所述填充剂含量以重量计可为所述的药物组合物总重量的70%~90%,优选为80%~90%,例如为85%或88%。
某一方案中,所述药物组合物Q中,所述填充剂为甘露醇,所述填充剂含量以重量计可为所述的药物组合物总重量的80%~90%,例如为85%或88%。
某一方案中,所述药物组合物Q中,所述填充剂为微晶纤维素和一水乳糖混合物,所述一水乳糖和所述微晶纤维素质量比可为50:35至70:15,优选为56:29至64:21,例如56:29或64:21。
某一方案中,所述药物组合物Q中,所述填充剂为微晶纤维素和乳糖混合物,所述乳糖和所述微晶纤维素质量比可为60:25至68:17,例如64:21。
某一方案中,所述药物组合物Q中,所述填充剂为微晶纤维素和甘露醇混合物,所述甘露醇和所述微晶纤维素质量比可为60:25至68:17,例如64:21。
所述药物组合物Q中,所述崩解剂含量以重量计可为所述的药物组合物总重量的2%~5%,例如3%。
某一方案中,所述药物组合物Q中,所述崩解剂为交联羧甲纤维素钠,所述交联羧甲纤维素钠含量以重量计可为所述的药物组合物总重量的2%~5%,例如3%。
某一方案中,所述药物组合物Q中,所述助流剂含量以重量计可为所述的药物组合物总重量的1%~5%,例如1%。
某一方案中,所述药物组合物Q中,所述润滑剂含量以重量计可为所述的药物组合物总重量的1%~5%,例如1%。
某一方案中,所述药物组合物Q中,所述助流剂与所述润滑剂质量比可为0.5:1.5至1.5:0.5,例如1:1。
某一方案中,所述药物组合物Q由5%~15%的所述物质X、80%~90%的所述填充剂、2%~5%的所述崩解剂、1%~5%的所述润滑剂与1%~5%的所述助流剂组成,较佳地,所述药物组合物由10%的所述物质X、85%的所述填充剂、3%的所述崩解剂1%的所述润滑剂与1%的所述助流剂组成,进一步地,所述药物组合物由10%的所述式I所示化合物的晶型B、85%的所述填充剂、3%的所述交联羧甲
纤维素钠、1%的所述硬脂酸镁与1%的所述二氧化硅组成,所述百分比为占所述药物组合物的质量比。
某一方案中,所述药物组合物Q选自如下任一组:
药物组合物1:10%物质X、56%一水乳糖、29%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;
药物组合物2:10%物质X、64%一水乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;
药物组合物3:10%物质X、64%甘露醇、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;
药物组合物4:10%物质X、64%乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;
药物组合物5:10%物质X、85%甘露醇、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;
所述百分比为占所述药物组合物的质量比。
某一方案中,所述药物组合物Q选自如下任一组:
药物组合物6:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;
药物组合物7:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC200、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;
药物组合物8:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;
药物组合物9:10%式I所示化合物的晶型B、64%乳糖Flowlac100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;
药物组合物10:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;所述百分比为占所述药物组合物的质量比。
某一方案中,所述药物组合物Q通过口服使用。
某一方案中,所述药物组合物Q为10mg/份或40mg/份规格。
某一方案中,所述药物组合物Q可以为固体制剂,例如固体口服制剂。
某一方案中,所述药物组合物Q可以为片剂或者胶囊剂,例如胶囊剂。
某一方案中,所述药物组合物Q为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物组合物。
某一方案中,所述的精神病症、神经病症或神经退行性病症可选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症。
所述的肾病可为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选IgA肾病)。
本发明提供了一种药物组合物R,其包含上述药物组合物Q和胶囊外壳,所述的药物组合物Q装填于所述的胶囊外壳中。
某一方案中,所述药物组合物R中,所述胶囊外壳为本领域常规的胶囊外壳,所述胶囊外壳例如为HPMC胶囊外壳或明胶胶囊外壳,优选为HPMC胶囊外壳。
某一方案中,所述药物组合物R由上述药物组合物Q和胶囊外壳组成,所述的药物组合物Q装填于所述的胶囊壳中。
某一方案中,所述药物组合物R选自如下任一组:
药物组合物1:10%物质X、56%一水乳糖、29%的微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;
药物组合物2:10%物质X、64%一水乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;
药物组合物3:10%物质X、64%甘露醇、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;
药物组合物4:10%物质X、64%乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;
药物组合物5:10%物质X、85%甘露醇、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;
所述百分比为占所述药物组合物的质量比。
某一方案中,所述药物组合物R选自如下任一组:
药物组合物6:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;
药物组合物7:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC200、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;
药物组合物8:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;
药物组合物9:10%式I所示化合物的晶型B、64%乳糖Flowlac100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;
药物组合物10:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;
药物组合物11:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;
药物组合物12:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC200、21%微晶纤维素
PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;
药物组合物13:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;
药物组合物14:10%式I所示化合物的晶型B、64%乳糖Flowlac100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;
药物组合物15:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;所述百分比为占所述药物组合物的质量比。
某一方案中,所述药物组合物R通过口服使用。
某一方案中,所述药物组合物R为10mg/粒或40mg/粒规格。
某一方案中,所述药物组合物R可为固体制剂,例如固体口服制剂。
某一方案中,所述药物组合物R可为胶囊剂。
某一方案中,所述药物组合物R为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物组合物。
某一方案中,所述的精神病症、神经病症或神经退行性病症可选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症。
所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选IgA肾病)。
本发明提供了一种上述药物组合物Q的制备方法,所述药物组合物的制备方法优选包含以下步骤:
(a)将所述物质X和部分所述填充剂混合得混合物M;
(b)将剩余所述填充剂、所述崩解剂、所述二氧化硅与所得混合物M混合,加入硬脂酸镁,得所述药物组合物Q;
其中,所述物质X、所述崩解剂和所述填充剂的种类和含量如本发明任一项所述;所述二氧化硅为助流剂、所述硬脂酸镁为润滑剂。
所述药物组合物的制备方法中,所述步骤(a)中,所述填充剂和所述物质X的质量比可为3:1。
所述药物组合物的制备方法中,所述步骤(a)中,所述填充剂可为所述乳糖、所述一水乳糖和所述甘露醇中的一种或多种
所述药物组合物的制备方法中,所述步骤(b)中,所述崩解剂可为交联羧甲纤维素钠。
所述药物组合物的制备方法中,所述步骤(a)中,所述物质X或所述填充剂可为30目的所述物质X或30目的所述填充剂。
所述药物组合物的制备方法中,所述步骤(b)中,所述填充剂、所述崩解剂或所述二氧化硅可为30目的所述填充剂、30目的所述崩解剂或30目的所述二氧化硅。
所述药物组合物的制备方法中,所述步骤(b)中,所述混合条件可为20rpm搅拌10~60min,例如为20rpm搅拌20min。
所述药物组合物的制备方法中,所述步骤(b)中,所述硬脂酸镁可为60目的硬脂酸镁。
所述药物组合物的制备方法中,所述步骤(b)中,所述加入条件可为20rpm搅拌2~10min,例如为3min。
所述药物组合物的制备方法优选包含如下步骤:将3倍于所述物质X质量的30目的所述乳糖(例如乳糖Flowlac100)、30目的所述一水乳糖(例如一水乳糖GRANULAC200)或30目的所述甘露醇(甘露醇200SD)与30目的所述物质X混合得混合物M;将30目的所述填充剂、30目的所述崩解剂与30目的所述二氧化硅与混合物M混合(例如,20rpm搅拌20min);加入60目的所述硬脂酸镁混合(例如,20rpm搅拌3min),得所述药物组合物Q。
本发明提供了一种药物组合物R的制备方法,其为将上述药物组合物Q进行胶囊灌装,即可。
所述药物组合物R的制备方法中,所述胶囊可为本领域常规的胶囊,所述胶囊例如为HPMC胶囊外壳或明胶胶囊外壳,优选为HPMC胶囊外壳。
所述药物组合物R的制备方法中,所述灌装可利用全自动胶囊灌装机进行胶囊灌装,例如所述全自动胶囊灌装机型号为In-Cap XL。
本发明提供了一种物质Y在制备药物中的应用,所述物质Y为上述药物组合物Q或药物组合物R;所述的药物为用于治疗和/或预防TRPC5介导的疾病的药物。
在所述的应用中,所述的TRPC5介导的疾病可为精神病症、神经病症、神经退行性病症或肾病。
所述的精神病症、神经病症或神经退行性病症可选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症。
所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选IgA肾病)。
本发明提供了一种物质Y在制备药物中的应用,所述物质Y为上述药物组合物Q或药物组合物
R,所述的药物为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物。
在所述的应用中,所述的精神病症、神经病症或神经退行性病症可选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、阿尔茨海默病、帕金森病、亨廷顿病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症。
所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化或原发性肾小球疾病(优选IgA肾病)。
术语解释:
术语“填充剂”,也称“稀释剂”,是指在科学的背景下用于增加药物组合物产品剂型的体积和重量的一类辅料。因此,填充剂可以是,例如:碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、乙酸纤维素、乙基纤维素、果糖、乳糖、一水乳糖、乳糖醇、麦芽糖、麦芽糊精、麦芽糖醇、甘露醇、微晶纤维素、聚右旋糖、聚乙二醇、碳酸氢钠、碳酸钠、氯化钠、山梨糖醇、玉米淀粉、糊精、蔗糖、海藻糖和木糖醇。
术语“崩解剂”,是指在科学的背景下用于促进药物组合物产品剂型在水环境中破裂成更小的碎片的一类辅料。因此,崩解剂可以是,例如:海藻酸、海藻酸钙、羧甲基纤维素钙、壳聚糖、胶体二氧化硅、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、羟丙甲纤维素、甘氨酸、瓜尔胶、羟丙基纤维素、硅酸铝镁、甲基纤维素、聚维酮、海藻酸钠、羧甲基纤维素钠、羟基乙酸淀粉钠和淀粉。
术语“润滑剂”,是指在科学的背景下用于改善药物组合物产品剂型加工过程的一类辅料。因此,润滑剂可以是,例如:硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌。
术语“助流剂”,是指降低颗粒间摩擦力,改善粉末流动性的一类辅料。因此,助流剂可以是,例如:二氧化硅、微粉硅胶。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述
无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述,是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的,与化学计量或非化学计量的溶剂结合形成的物质。
本文所用术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2020年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009 Sixth Edition)。
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)缓解疾病或者病症的一种或多种生物学表现,(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,(3)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用,或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“患者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为优。
术语“治疗有效量”是指在给予患者时,足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,可由本领域技术人员根据需要进行调整。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明所提供的药物组合物稳定性良好,溶出性能好;该药物组合物制备方法简单,适合工业化生产。
图1为晶型A的XRPD谱图。
图2为晶型A的DSC谱图。
图3为晶型A的TGA谱图。
图4为晶型A的1H-NMR谱图(DMSO-d6);
图5为晶型A的1H-NMR谱图(D2O)。
图6为晶型A的PLM谱图。
图7为晶型A的FT-IR谱图。
图8为式I所示化合物晶型B的XRPD谱图。
图9为式I所示化合物晶型B的DSC谱图。
图10为式I所示化合物晶型B的TGA谱图。
图11为式I所示化合物晶型B的1H-NMR谱图。
图12为式I所示化合物晶型B的PLM谱图。
图13为式I所示化合物晶型B的FT-IR谱图。
图14为处方1的10mg和40mg规格的HPMC胶囊的溶出曲线。
图15为处方2的10mg和40mg规格的HPMC胶囊的溶出曲线。
图16为处方3的10mg和40mg规格的HPMC胶囊和40mg规格的明胶胶囊的溶出曲线。
图17为处方4的40mg规格的HPMC胶囊和明胶胶囊的溶出曲线。
图18为处方5的10mg和40mg规格的HPMC胶囊的溶出曲线。
图19为处方5的10mg和40mg规格的明胶胶囊的溶出曲线。
图20为处方5的10mg规格HPMC胶囊25℃/60%RH条件下的稳定性溶出曲线。
图21为处方5的40mg规格HPMC胶囊25℃/60%RH条件下的稳定性溶出曲线。
图22为处方5的10mg规格HPMC胶囊40℃/75%RH条件下的稳定性溶出曲线。
图23为处方5的40mg规格HPMC胶囊40℃/75%RH条件下的稳定性溶出曲线。
图24为处方5的10mg规格HPMC胶囊40℃/75%RH条件下0天和放置2个月的XRPD对比图。
图25为处方5的40mg规格HPMC胶囊40℃/75%RH条件下0天和放置2个月的XRPD对比图。
图26为处方5的10mg规格明胶胶囊40℃/75%RH条件下的稳定性溶出曲线。
图27为处方5的40mg规格明胶胶囊40℃/75%RH条件下的稳定性溶出曲线。
图28为处方5的10mg规格明胶胶囊40℃/75%RH条件下0天和放置1个月的XRPD对比图。
图29为处方5的40mg规格明胶胶囊40℃/75%RH条件下0天和放置1个月的XRPD对比图。
图30为处方5的40mg规格明胶胶囊在60℃高温条件下的稳定性溶出曲线。
图31为式I所示化合物晶型B在压力和研磨测试前后晶型B的XRPD叠图。
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
缩写词:
ACN:乙腈;API:活性药物成分;DMSO:二甲亚砜;DSC:差式扫描量热法;DVS:动态水分吸附;FT-IR:傅立叶转换红外光谱;HPLC:高效液相色谱;PLM:偏光显微镜;RH:相对湿度;SD:标准偏差;TGA:热失重分析;Tonset:初始温度/起始温度;XRPD:X-射线粉末衍射。
仪器方法:
1.X-射线衍射(XRPD),方法如下表所示:
2.差示扫描量热(DSC)分析,方法如下表所示:
3.热失重分析(TGA),方法如下表所示:
4.核磁共振(1H-NMR),方法如下表所示:
5.傅里叶转换红外光谱(FT-IR),方法如下表所示:
6.Karl Fisher,方法如下表所示:
7.偏光显微镜(PLM),方法如下表所示:
8.实验中使用的辅料信息见下表:
9.胶囊溶出方法,见下表:
10.胶囊溶出液相关参数,见下表:
11.胶囊罐装:
将分装物料采用全自动胶囊灌装机(型号:In-Cap XL)进行罐装,罐装参数如下:
制备实施例
依照WO2022/001767A1记载方法制备化合物1-1。
实施例1晶型A的制备
合成路线:
1.1化合物1-2的制备
向反应瓶中加入化合物1-1(100g,0.23mol),碘化钠(37.3g,0.25mmol)和四氢呋喃(1L),搅拌溶解,冰浴降温至0℃左右,向反应液中滴加叔丁醇锂(1M的四氢呋喃溶液,271.6mL,0.28mol),滴加完毕,随后向反应液中加入氯甲基磷酸二叔丁酯(87.8g,0.34mol),反应液升温至室温(约18℃)反应12小时。反应液加水淬灭,控温25℃以下浓缩除去四氢呋喃,向浓缩后的体系中加入乙酸乙酯(1L×2)萃取,有机相用饱和食盐水(1L)洗涤,用无水硫酸钠干燥后,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化得化合物1-2(55g)。LC-MS[M+H]+=664.2。
1.2晶型A的制备
将化合物1-2(55g,83mmol)溶于二氯甲烷(500mL)中,搅拌下向反应液中滴加三氟乙酸(100mL),混合物在25℃下搅拌1小时。反应完毕(LCMS显示纯度80%),混合物减压浓缩后得到油状的式I所示化合物的粗产品,向粗产品中加入乙腈(50mL)分散,有固体析出,向体系中缓慢滴加乙醇(400mL),有大量固体析出,室温(约17℃)搅拌1小时,抽滤,滤饼使用乙腈和水的混合溶剂(300mL,5/1(v/v))室温(约17℃)打浆,多次重复该操作直至化合物的纯度为98%以上,将所得固体冻干,得到晶型A为白色固体,其XRPD谱图解析数据见下表。
LC-MS[M+H]+=552.0;1H NMR(400MHz,DMSO-d6):δ8.14(s,1H),7.84(dd,J=9.2,2.8Hz,1H),7.79(dd,J=8.4,5.6Hz,1H),7.68(td,J=8.4,2.6Hz,1H),7.36(s,1H),5.68(d,J=7.6Hz,2H),4.91(s,2H),4.54(t,J=5.6Hz,2H),3.98(t,J=5.6Hz,2H)。
晶型A的表征数据如下表所示:
晶型A的XRPD图谱解析数据见下表:
实施例2式I所示化合物的晶型B的制备
称取约30mg实施例1所得的晶型A加入0.3mL的水,确保得到浓度合适的悬浮液。以0.1℃/min的升降温速率,将悬浮液于50℃至5℃下搅拌10个循环。循环结束后,将所得固体用0.45μm滤膜在5℃下离心5min,得到的固体作为下一步的晶种;
称取400mg的晶型A置于8mL玻璃瓶中。加入4mL水,在50℃搅拌30min,得到混悬液。将约5mg的上述制备得到的晶种加入到上述混悬液中。将该样品放入升降温循环机上,以0.1℃/min的升降温速率,将悬浮液于50℃至5℃下搅拌6个循环。离心过滤,收集固体。固体在50℃真空干燥2h后得到了333.0mg类白色的晶型B,收率是83.3%。其XRPD谱图解析数据见下表1。式I所示化合物的晶型B即为以下处方中的API。
式I所示化合物晶型B的表征数据,见下表:
表1.晶型B的XRPD图谱解析数据
实施例3处方1的制备
将3倍API(式I所示化合物的晶型B)量的一水乳糖(填充剂)与API混合过30目筛,然后依次将剩余一水乳糖、处方量微晶纤维素PH102、交联羧甲纤维素钠SD711以及二氧化硅过30目筛洗筛。将过筛后的物料转移至3L混合桶中,20rpm混合20min,将硬脂酸镁过60目筛,加入混合桶中继续20rpm混合3min,使用全自动胶囊灌装机进行胶囊灌装。其中10mg规格使用4号HPMC胶囊壳,4号剂量盘;40mg规格使用0号HPMC胶囊壳,1号剂量盘。其溶出数据如图14所示。
所得处方1的组成信息如下表所示:
其溶出数据如下表所示:
实施例4处方2的制备
处方2制备方法同处方1,只是其中10mg规格使用的是5号剂量盘,所得处方2的组成信息如下表所示,其溶出数据如图15所示。
所得处方2的组成信息如下表所示:
其溶出数据如下表所示:
实施例5处方3和处方4的制备
将3倍API量的填充剂与API混合过30目筛,然后依次将剩余填充剂、交联羧甲纤维素钠SD711以及二氧化硅过30目筛。将过筛后的物料转移至3L混合桶中,20rpm混合20min,将硬脂酸镁过60目筛,加入混合桶中继续20rpm混合3min,使用全自动胶囊灌装机进行胶囊灌装。其中10mg规格胶囊使用5号剂量盘进行灌装,使用4号HPMC胶囊壳;40mg规格使用0号剂量盘,0号HPMC胶囊壳和0号明胶胶囊壳制备两个类型的胶囊(除胶囊壳外,内容物、工艺完全相同),所得处方3的10mg规格的HPMC胶囊和40mg规格的HPMC胶囊和明胶胶囊的组成信息如下表所示,其溶出数据如图16所示;所得处方4的10mg规格的HPMC胶囊和40mg规格的HPMC胶囊和明胶胶囊的组成信息如下表所示,其溶出数据如图17所示。
处方3的HPMC胶囊的组成见下表:
处方3的明胶胶囊的组成,见下表:
处方3两种胶囊的溶出数据,见下表:
处方4的HPMC胶囊的组成,见下表:
处方4的明胶胶囊的组成,见下表:
处方4的两种胶囊的溶出数据,见下表:
实施例6处方5的制备
方法1:处方5的HPMC胶囊的制备
将3倍API量的甘露醇200SD与API混合过30目筛,然后依次将剩余填充剂、交联羧甲纤维素钠SD711以及二氧化硅过30目筛。将过筛后的物料转移至3L混合桶中,20rpm混合20min,将硬脂酸镁过60目筛,加入混合桶中继续20rpm混合3min,使用全自动胶囊灌装机进行胶囊灌装。其中10mg规格胶囊使用5号剂量盘进行灌装,使用4号HPMC胶囊壳;40mg规格使用0号剂量盘,0号HPMC胶囊壳。所得处方5的HPMC胶囊的组成信息如下表示,其溶出数据如图18所示。
处方5的HPMC胶囊的组成,见下表:
处方5的HPMC胶囊的溶出数据,见下表:
方法2:处方5的明胶胶囊的制备
将3倍API量的甘露醇200SD与API混合过30目筛,然后依次将剩余填充剂、交联羧甲纤维素钠SD711以及二氧化硅过30目筛。将过筛后的物料转移至3L混合桶中,在20rpm混合25min后,将混合桶中物料取出称重,折算所需硬脂酸镁量,称取折算后的过60目筛的硬脂酸镁,加入混合桶中继续20rpm混合3min,总混粉末使用全自动胶囊灌装机进行胶囊灌装。其中10mg规格胶囊使用5号剂量盘进行灌装,使用4号胶囊壳;40mg规格使用0号剂量盘,0号胶囊壳。所得处方5的明胶胶囊的处方组成如下表所示,其溶出数据如图19所示。
处方5的明胶胶囊的组成,见下表:
处方5的明胶胶囊的溶出数据,见下表:
实施例7制剂处方的稳定性研究
7.1处方5的HPMC胶囊的稳定性研究
将实施例6方法1中所得处方5的HPMC胶囊产品经包装后进行稳定性考察,将10mg和40mg规格的HPMC胶囊放在25℃(±2℃)/60%(±5%)RH条件下放置0天和3个月进行稳定性考察;同时将10mg和40mg规格HPMC胶囊放在40℃(±2℃)/75%(±5%)RH条件下放置0天、1个月、2个月和3个月进行稳定性考察。
包装信息:包装容器为药用高密度聚乙烯瓶+口服固体药用聚丙烯儿童安全组合瓶盖;
包装规格:7粒/瓶
7.1.1 25℃/60%RH条件下的稳定性结果
HPMC胶囊在25℃/60%RH条件下的稳定性数据如下表以及图20和图21所示。
10mg规格HPMC胶囊25℃/60%RH条件下的稳定性溶出数据,见下表:
40mg规格HPMC胶囊25℃/60%RH条件下的稳定性溶出数据,见下表:
10mg和40mg规格HPMC胶囊25℃/60%RH条件下放置0天和3个月,其API含量、有关物质、水分数据变化情况汇总,结果见下表:
7.1.2 40℃/75%RH条件下的稳定性结果
HPMC胶囊在40℃/75%RH条件下的稳定性数据如下表和图22、图23、图24与图25所示。
10mg规格HPMC胶囊40℃/75%RH条件下的稳定性溶出数据,见下表:
40mg规格HPMC胶囊40℃/75%RH条件下的稳定性溶出数据,见下表:
10mg规格HPMC胶囊40℃/75%RH条件下的API含量、有关物质、水分数据变化情况汇总,结果见下表:
40mg规格HPMC胶囊40℃/75%RH条件下的API含量、有关物质、水分数据变化情况汇总,相关结果见下表:
如图22、图23所示,10mg HPMC胶囊放置0天、1个月、2个月、3个月性状稳定,同样的,40mg HPMC胶囊放置0天、1个月、2个月、3个月性状稳定。
10mg和40mg规格的HPMC胶囊在25℃(±2℃)/60%(±5%)RH和40℃(±2℃)/75%(±5%)RH条件下的稳定性研究中,在3个月内外观、鉴别、含量、溶出、有关物质和水分均无明显变化,稳定性较好。
7.2处方5的明胶胶囊的稳定性研究
将实施例6方法2中所得处方5的明胶胶囊产品经包装后在40℃(±2℃)/75%(±5%)RH条件下放置0天、2周和1个月进行稳定性考察。同时将其中40mg规格的明胶胶囊样品在60℃(±2℃)高温影响因素条件下放样0天和2周考察其稳定性情况。
包装信息:包装容器为45mL口服固体药用高密度聚乙烯瓶+口服固体药用聚丙烯儿童安全组合瓶盖;
包装规格:10粒/瓶。
7.2.1 40℃/75%RH条件下的稳定性结果
明胶胶囊在40℃/75%RH条件下的稳定性数据如下表所示和图26、图27、图28和图29所示。
如图26所示,10mg规格明胶胶囊40℃/75%RH条件下放置0天、2周、4周(即1个月)的稳
定性溶出数据,见下表:
如图27所示,40mg规格明胶胶囊40℃/75%RH条件下放置0天、2周、4周(即1个月)的稳定性溶出数据,见下表:
10mg及40mg规格明胶胶囊40℃/75%RH条件下放置0天、2周、1个月的API含量、有关物质、水分数据变化情况汇总,相关结果见下表:
该明胶胶囊样品在40℃/75%RH条件下的稳定性数据显示,加速条件下放置2周后,在pH 4.5醋酸盐缓冲液中的溶出结果与0天样品无明显差异,含量、水分与0天样品无明显差异,杂质结果良好。胶囊样品放置4周(即1个月)后,含量、水分与0天样品无明显差异,杂质结果良好。
7.2.2 60℃高温下稳定性结果
40mg规格的胶囊在60℃高温条件下0天和2周的稳定性结果如下表和图30所示。
如图30所示,40mg规格明胶胶囊60℃高温条件下放样0天和2周的稳定性溶出数据,见下表:
实施例8式I所示化合物的晶型B(API成分)制剂可行性评估
8.1压力下转晶行为研究
称取约10mg式I所示化合物的晶型B,用小型压片机以10MPa压力压片5分钟,并通过XRPD表征研究晶型转变以及结晶度的变化情况,结果显示,式I所示化合物的晶型B在此压力下结晶度无明显变化,见图31。
8.2模拟干法研磨实验
称取约10mg式I所示化合物的晶型B,用研钵研磨3min,并通过XRPD表征研究晶型转变以及结晶度的变化情况,结果显示,式I所示化合物的晶型B在此实验中结晶度无明显变化,见图31。
8.3模拟湿法研磨实验
称取约10mg式I所示化合物晶型B,分别加入20μL水或乙醇,之后用研钵研磨3min,并通过XRPD表征研究晶型转变以及结晶度的变化情况,结果显示,式I所示化合物的晶型B在水或乙醇中研磨,其结晶度无明显变化,见图31。
效果实施例:
生物学活性测试试验
效果实施例1
TRPC5是一类非选择性阳离子通道,对钙离子具有通透性,因此本实验选用TRPC5激动剂Englerin A(EA)、TRPC5抑制剂Pico145作为阳性对照,使用Fluo-4AM荧光染料检测化合物对TRPC5-HEK 293细胞内Ca2+的影响来间接反映化合物对TRPC5通道的影响。
Pico145:MCE,批号31245;
DMEM高糖:Gibco,批号2230805;
FBS:Gibco,批号1981614;
P/S:Gibco,批号2289326;
HEPES:Sigma,批号WXBD0664V;
Blasticidin:Gibco,批号1737347;
Hygromycine:Yeasen,批号H18010;
Doxycycline:Sigma,批号BCBL6540V;
Fluo-4AM:Molecular Devices,批号1231041;
Poly-D-Lysine:Sigma,批号SLBQ9797V。
1.细胞培养
1.1 TRPC5-HEK 293细胞复苏
复苏液:100%DMEM(Dulbecco's Modified Eagle Medium)高糖
选择培养基:DMEM高糖+10%FBS(Phosphate Buffered Saline,磷酸盐缓冲液)+1%P/S(Penicillin-Streptomycin Solution,青霉素-链霉素溶液)+1%HEPES(4-羟乙基哌嗪乙磺酸)+稻瘟散(Blasticidin,5μg/mL)+潮霉素(Hygromycine,50μg/mL)
诱导培养基:DMEM高糖+10%FBS+1%P/S+1%HEPES+多西环素(Doxycycline,1μg/mL)
复苏过程:液氮罐中取出,于冰盒中转移至水浴锅,划圈溶解至含一小块冰时转移冻存液至复苏液中,1000rpm离心5min,弃去上清,转移至选择培养基中,CO2培养箱中(5%CO2,95%湿度,37℃)扩培。
1.2 TRPC5-HEK 293细胞接板
实时荧光实验前14h,用PBS清洗细胞,用含EDTA的胰蛋白酶(TRYPSIN-EDTA)消化细胞,诱导培养基稀释细胞至20万细胞/mL,接至已包被多聚赖氨酸(PDL,Poly-D-Lysine)(母液10mg/mL,终浓度10μg/mL)的96孔黑壁底透板中,100μL/孔即2万细胞/孔。
2.缓冲液配制
500mL TRPC5钙信号检测用外液:4.0908g NaCl,0.1864g KCl,0.111g CaCl2,0.0476g MgCl2,0.9g Glucose(葡萄糖),1.1915g HEPES(4-羟乙基哌嗪乙磺酸)。
钙荧光染料:TRPC5钙信号检测用外液含终浓度4μM Fluo-4(含0.5%BSA)
3.化合物的配制
激动剂:Englerin A(EA)
激动剂浓度:由于EA激活TRPC5的EC50大约在0.35nM,使用0.3nM EA
阳性抑制剂:Pico145(HC608)
阳性抑制剂浓度:100nM
待测化合物:化合物1-1和式I所示化合物
待测化合物浓度:常规配制,用DMSO进行配制,配制为8倍于检测终浓度的药液(检测终浓度分别为:1nM、3nM、10nM、30nM、100nM、300nM和1000nM),每个底板孔60μL。
4.数据处理
Flipr测试荧光值减去未进行染色(dye)的细胞孔的值(即本底荧光值),采用Graphpad Prism 6.0软件进行统计和数据处理,轨迹图采用去除基线(remove baseline)的方式进行归一化处理,比值型显示,量效图求取AUC(钙流信号形成的曲线下面积)收集数据与化合物浓度的log值,采用log[Inhibitor]vs.response—Variable slope计算IC50值。
结果见下表:
式I所示化合物对TRPC5通道无抑制活性
效果实施例2化合物单次灌胃(以5%Solutol为溶媒)给药雄性SD大鼠PK研究
1.实验目的:
探索本发明式I所示化合物(125mg/kg)及化合物1-1(100mg/kg)单次灌胃给药后雄性大鼠血浆中该化合物的时间-血药浓度曲线,获得本发明式I所示化合物及化合物1-1单次给药大鼠的PK参数(Cmax,Tmax,AUClast,AUCinf,T1/2、MRT等)。
2.实验方案
2.1实验仪器
实验仪器见下表:
2.2实验准备
2.2.1式I所示化合物的实验准备
大鼠:SD大鼠,SPF级,3只雄性,体重范围180-200g(来源:北京维通利华实验动物技术有限公司,合格证号:110011201109106028);
饲养条件:普通级动物房饲养,自由饮食饮水,3只/笼饲养,12/12小时明/暗周期调节(7:00am/7:00pm),温度23±1℃。
配药:PO组式I所示化合物精确称量后,先加入所需体积的5%solutol(5%聚乙二醇(15)-羟基硬脂酸酯,北京凤礼精求医药股份有限公司,批号1760094G0),涡旋混匀2min后,超声30min,搅拌2h后至肉眼无明显可见颗粒,边搅拌边给药,取中层药液用于给药。
给药前,药液需留样分析,混悬液准确取样上、中、下各100μL 2份,当天送分析检测,备份样
品保存在-75℃冰箱备用。
2.2.2化合物1-1的实验准备
大鼠:SD大鼠,SPF级,3只雄性,体重范围220-300g(来源:北京斯贝福生物技术有限公司,合格证号:110324200103216838);
饲养条件:普通级动物房饲养,自由饮食饮水,3只/笼饲养,12/12小时明/暗周期调节(7:00am/7:00pm),温度23±1℃。
配药:PO组化合物1-1精确称量后,先加入所需体积的5%solutol,涡旋混匀2min后,超声30min,搅拌3h后至肉眼无明显可见颗粒后灌胃给药;
现配现用,药液需留样分析,混悬液取上、中、下各100μL 2份,当天送分析检测。
2.3给药方案
大鼠根据体重随机分成3组,具体分组和给药情况如下表:
1.PO组动物给药前通宵禁食不禁水,给药后4h返还食物;
2.取血时间点:PO组取血时间点为0.167、0.5、1、2、3、4、6、9、12和24h。
分组给药信息见下表:
1.PO组动物给药前通宵禁食不禁水,给药后4h返还食物;
2.取血时间点:PO组取血时间点为0.167、0.5、1、2、3、4、6、9、12和24h。
2.4样品的采集和制备
大鼠给药后,根据采样时间点,从眼眶静脉丛收集血液,每个时间点采集约0.2-0.3mL血液于抗凝EP管中(内含4μL EDTA-K2,375mg/mL),缓慢上下倒置3次,置于冰盒内保存(不超过30分钟),在4℃下使用3500×g离心10分钟,移取上清液至标记的EP管中,观察血浆溶血情况并记录,送生物分析检测;如果无法当天检测,样本需储存在-80℃直到检测(注意勿进行多次冷冻/溶解的过程)。
2.5样品分析
2.5.1本发明式I所示化合物的样品分析
2.5.1.1实验仪器:
高效液相色谱泵(Pump):Exion LC AD Pump,Sciex公司
自动进样器(Auto sampler:Exion LC AD Autosampler,Sciex公司
柱温箱(column Oven):Exion LC AD Column Oven,Sciex公司
质谱仪(Mass spectrometer):AB Sciex Qtrap 3500
高速冷冻离心机(centrifuge):Thermo Fisher,ST16R,GG1206085-093
分析天平(Electronic balance):Mettler Toledo,MS-105DU,GG1206363
微型涡旋仪(Vortex):上海沪西分析仪器厂,WH-2,GG1206487
实验材料:大鼠血浆(EDTA-K2)
分析物:化合物1-1
内标:甲苯磺丁脲
分析方法:液质联用法
2.5.1.2质谱条件:
质谱参数
离子源:Ion Electrospray(ESI)
离子化模式(Ionization mode):正离子模式(Positive)
检测模式(Mode):多反应监测(MRM)
电喷雾电压(Ion Spray Voltage):5500
离子喷雾温度(Turbo Ion Spray Temp):550℃
气帘气(Curtain Gas):35
碰撞池气体(CAD Gas):Medium
雾化气(Nebulizing Gas,Gas 1):55.00
辅助气(Auxiliary Gas,Gas 2):55.00
检测离子对,见下表:
2.5.1.3液相方法:
色谱柱:poroshell 120EC-C18(2.1×50mm,2.7μm)
流动相A(Mobile Phase A):0.1%甲酸的水溶液
流动相B(Mobile Phase B):0.1%甲酸的甲醇溶液
自动进样器清洗溶液(Rinse Port Wash Solution):甲醇:水:乙腈:异丙醇=1:1:1:1
柱温箱温度(Column Temperature):40℃
流速(Flow Rate):0.65mL/min
自动进样器温度(Sample Tray Temp):15℃
进样体积(Injection Volume):8μL
压脚提升量(Needle Stroke):49mm
自动进样器清洗设置(Rinse Pump Setting):仅清洗进样口
自动进样器清洗模式(Rinse Mode):吸入前清洗
自动进样器洗针体积(Rinse Volume):500μL
进样针清洗时浸泡时间(Rinse Dip Time):2秒
洗脱梯度,见下表:
2.5.1.4前处理方法
样品前处理过程:取3μL工作液,加入57μL空白基质(大鼠空白血浆)于1.5mL离心管中,加入240μL含200ng/mL甲苯磺丁脲和0.1%FA(甲酸)的乙腈沉淀蛋白,涡旋混合1分钟,样品于4℃的离心机中13000rpm离心15分钟。取上清液100μL于另一96深孔板中,加入100μL的含0.1%FA的甲醇:水(1:3,v:v)溶液,振荡混合1分钟,于96孔板离心机中3500rpm离心5分钟后直接进样。
2.5.2化合物1-1的样品分析
2.5.2.1实验仪器:
高效液相色谱泵(Pump):LC-30AD,Shimadzu公司
自动进样器(Auto sampler):SIL-30AC,Prominence,Shimadzu公司
柱温箱(Column Oven):CTO-30A,Shimadzu公司
质谱仪(Mass spectrometer):AB Sciex Qtrap 3500
高速冷冻离心机(Centrifuge):Thermo Fisher,ST16R,GG1206085-093
分析天平(Electronic balance):Mettler Toledo,MS-105D,GG1206363
微型涡旋仪(Vortex):上海沪西分析仪器厂,WH-2,GG1206487
实验材料:大鼠血浆(EDTA-K2)
分析物:化合物1-1
内标:甲苯磺丁脲
分析方法:液质联用法
2.5.2.2质谱条件:
质谱参数
离子源:Ion Electrospray(ESI)
离子化模式(Ionization mode):正离子模式(Positive)
检测模式(Mode):多反应监测(MRM)
电喷雾电压(Ion Spray Voltage):5500
离子喷雾温度(Turbo Ion Spray Temp):550℃
气帘气(Curtain Gas):35
碰撞池气体(CAD Gas):Medium
雾化气(Nebulizing Gas,Gas 1):55.00
辅助气(Auxiliary Gas,Gas 2):55.00
检测离子对,见下表:
2.5.2.3液相方法:
色谱柱:poroshell 120EC-C18(4.6×50mm,2.7μm)
流动相A(Mobile Phase A):0.1%甲酸的水溶液
流动相B(Mobile Phase B):0.1%甲酸的甲醇溶液
自动进样器清洗溶液(Rinse Port Wash Solution):甲醇:乙腈:水:异丙醇=1:1:1:1
流速(Flow Rate):0.8mL/min
自动进样器温度(Sample Tray Temp):15℃
进样体积(Injection Volume):15μL
压脚提升量(Needle Stroke):49mm
自动进样器清洗设置(Rinse Pump Setting):仅清洗进样口
自动进样器清洗模式(Rinse Mode):吸入前清洗
自动进样器洗针体积(Rinse Volume):500μL
进样针清洗时浸泡时间(Rinse Dip Time):2秒
洗脱梯度,见下表:
2.5.2.4前处理方法
样品前处理过程:取30μL样品,加入120μL含0.1%FA和200ng/mL混标溶液的乙腈沉淀蛋白,涡旋混合均匀,样品于4℃的离心机中13000rpm离心10分钟。取上清液100μL于另一96深孔板中,加入100μL的甲醇:水(1:3,v:v)溶液,振荡混合10分钟。
2.6数据分析
数据将使用WinNonlin(version 5.2.1Pharsight,Mountain View,CA)通过非房室模型进行分析,得到PK参数(根据不同给药途径选择Cmax,Tmax,AUClast,AUCinf,T1/2,MRT等参数)。具体结果见下表,表中所列数据的分析物为化合物1-1。
分析结果见下表:
注:1. 100*在此表示式I所示化合物的125mg/kg相当于化合物1-1的100mg/kg。
2.T1/2中带#的数据为该实验中的异常数据,在计算均值时已剔除。
注:1. 100*在此表示式I所示化合物的125mg/kg相当于化合物1-1的100mg/kg。
2.T1/2中带#的数据为该实验中的异常数据,在计算均值时已剔除。
实验结论:本发明式I所示化合物与化合物1-1相比,具有更好的暴露量。
Claims (12)
- 一种药物组合物Q,其特征在于,其包含物质X和药用辅料;
其中,所述的物质X为式I所示化合物、其药学上可接受的盐、式I所示化合物的溶剂合物或其药学上可接受的盐的溶剂合物;所述的药用辅料选自稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂和助流剂中的一种或多种。 - 如权利要求1所述的药物组合物Q,其特征在于,所述药物组合物满足如下一个或多个条件:(1)所述药用辅料选自崩解剂、填充剂、助流剂和润滑剂中的一种或多种;(2)所述的物质X为唯一活性成分;(3)所述的物质X的用量为治疗有效量;(4)所述式I所示化合物为式I所示化合物的晶型B,其中,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图在8.95±0.20°、12.92±0.20°、16.39±0.20°、17.00±0.20°、17.44±0.20°、17.76±0.20°、18.08±0.20°、19.02±0.20°、21.95±0.20°、22.20±0.20°、23.49±0.20°、24.15±0.20°、24.92±0.20°、25.94±0.20°、27.14±0.20°和29.68±0.20°处有衍射峰;优选地,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图还在以下一处或多处有衍射峰:10.63±0.20°、11.69±0.20°、13.52±0.20°、14.49±0.20°、14.74±0.20°、15.83±0.20°、18.81±0.20°、19.72±0.20°、21.27±0.20°、22.62±0.20°、22.99±0.20°、25.41±0.20°、25.74±0.20°、26.18±0.20°、26.58±0.20°、27.85±0.20°、28.23±0.20°、28.70±0.20°、29.16±0.20°、30.17±0.20°、30.51±0.20°、31.20±0.20°、32.16±0.20°、32.52±0.20°、32.74±0.20°、32.89±0.20°、34.36±0.20°、35.45±0.20°、35.98±0.20°、36.65±0.20°、37.00±0.20°、37.45±0.20°、37.73±0.20°、38.04±0.20°、38.36±0.20°和39.11±0.20°;进一步地,所述式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图在8.95±0.20°、10.63±0.20°、11.69±0.20°、12.92±0.20°、13.52±0.20°、14.49±0.20°、14.74±0.20°、15.83±0.20°、16.39±0.20°、17.00±0.20°、17.44±0.20°、17.76±0.20°、18.08±0.20°、18.81±0.20°、19.02±0.20°、19.72±0.20°、21.27±0.20°、21.95±0.20°、22.20±0.20°、22.62±0.20°、22.99±0.20°、23.49±0.20°、24.15±0.20°、24.92±0.20°、25.41±0.20°、25.74±0.20°、25.94±0.20°、26.18±0.20°、26.58±0.20°、27.14±0.20°、27.85±0.20°、28.23±0.20°、28.70±0.20°、29.16±0.20°、29.68±0.20°、30.17±0.20°、30.51±0.20°、31.20±0.20°、32.16±0.20°、32.52±0.20°、32.74±0.20°、32.89±0.20°、34.36±0.20°、35.45±0.20°、35.98±0.20°、36.65±0.20°、37.00±0.20°、37.45±0.20°、37.73±0.20°、38.04±0.20°、38.36±0.20°和39.11±0.20°处有衍射峰;(5)所述式I所示化合物为式I所示化合物的晶型B,所述式I所示化合物的晶型B为无溶剂合物;(6)所述填充剂为乳糖、一水乳糖、甘露醇和微晶纤维素中的一种或多种,所述微晶纤维素例如为微晶纤维素PH102,所述一水乳糖例如为一水乳糖GRANULAC200,所述甘露醇例如为甘露醇200SD,所述乳糖例如为乳糖Flowlac100;(7)所述崩解剂为交联羧甲基纤维素钠,例如为交联羧甲基纤维素钠SD711;(8)所述助流剂为二氧化硅;(9)所述药物组合物Q由所述物质X和所述药用辅料组成;(10)所述药物组合物Q通过口服使用;(11)所述药物组合物Q为固体制剂,例如为固体口服制剂;(12)所述药物组合物Q为片剂或者胶囊剂,例如为胶囊剂;(13)所述药物组合物Q为10mg/份或40mg/份规格;(14)所述药物组合物Q为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物组合物;(15)所述润滑剂为硬脂酸镁。
- 如权利要求2所述的药物组合物Q,其特征在于,所述药物组合物满足如下一个或多个条件:(1)所述的式I所示化合物的晶型B,其使用Cu-Kα辐射、以2θ角表示的X射线粉末衍射图具有如表1所示的衍射峰;(2)所述的式I所示化合物的晶型B,其使用Cu-Kα辐射,其X射线粉末衍射图谱如图8所示;(3)所述的式I所示化合物的晶型B,其差示扫描量热曲线在247.7℃±3℃处具有吸热峰;(4)所述的式I所示化合物的晶型B,其差示扫描量热曲线如图9所示;(5)所述的式I所示化合物的晶型B,其热重分析曲线在35℃±3℃至220℃±3℃温度范围内失重1.0%;(6)所述的式I所示化合物的晶型B,其热重分析曲线如图10所示;(7)所述药物组合物Q中,所述填充剂为如下任一组:(a)所述填充剂为微晶纤维素和一水乳糖混合物,例如为微晶纤维素PH102和一水乳糖GRANULAC200混合物;(b)所述填充剂为微晶纤维素和乳糖混合物,例如为微晶纤维素PH102和乳糖Flowlac100混合物;(c)所述填充剂为微晶纤维素和甘露醇混合物,例如为微晶纤维素PH102和甘露醇200SD混合物;(d)所述填充剂为甘露醇,例如为甘露醇200SD;(8)所述药物组合物Q由所述物质X、所述崩解剂、所述填充剂、所述助流剂和所述润滑剂组成;(9)所述的精神病症、神经病症或神经退行性病症选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学 习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症;(10)所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选为原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选为IgA肾病)。
- 如权利要求3所述的药物组合物Q,其特征在于,所述药物组合物满足如下一个或多个条件:(1)所述药物组合物Q中,所述物质X含量以重量计为所述的药物组合物总重量的5%~15%,例如为10%;(2)所述药物组合物Q中,所述填充剂含量以重量计为所述的药物组合物总重量的70%~90%,优选为80%~90%,例如为85%或88%;(3)所述药物组合物Q中,所述填充剂为“微晶纤维素和一水乳糖混合物”、“微晶纤维素和乳糖混合物”或“微晶纤维素和甘露醇混合物”,所述填充剂含量以重量计为所述的药物组合物总重量的70%~90%,优选为80%~90%,例如为85%或88%;(4)所述药物组合物Q中,所述填充剂为甘露醇,所述填充剂含量以重量计为所述的药物组合物总重量的80%~90%,例如为85%或88%;(5)所述药物组合物Q中,所述崩解剂含量以重量计为所述的药物组合物总重量的2%~5%,例如3%;(6)所述药物组合物Q中,所述助流剂含量以重量计为所述的药物组合物总重量的1%~5%,例如1%;(7)所述药物组合物Q中,所述润滑剂含量以重量计为所述的药物组合物总重量的1%~5%,例如1%。
- 如权利要求4所述的药物组合物Q,其特征在于,所述药物组合物满足如下一个或多个条件:(1)所述药物组合物Q中,所述填充剂为微晶纤维素和一水乳糖混合物,所述一水乳糖和所述微晶纤维素质量比为50:35至70:15,优选为56:29至64:21,例如56:29或64:21;(2)所述药物组合物Q中,所述填充剂为微晶纤维素和乳糖混合物,所述乳糖和所述微晶纤维素质量比为60:25至68:17,例如64:21;(3)所述药物组合物Q中,所述填充剂为微晶纤维素和甘露醇混合物,所述甘露醇和所述微晶纤维素质量比为60:25至68:17,例如64:21;(4)所述药物组合物Q中,所述崩解剂为交联羧甲纤维素钠,所述交联羧甲纤维素钠含量以重量计为所述的药物组合物总重量的2%~5%,例如3%;(5)所述药物组合物Q中,所述助流剂与所述润滑剂的质量比为0.5:1.5至1.5:0.5,例如1:1;(6)所述药物组合物Q由5%~15%的所述物质X、80%~90%的所述填充剂、2%~5%的所述崩解 剂、1%~5%的所述润滑剂与1%~5%的所述助流剂组成,较佳地,所述药物组合物由10%的所述物质X、85%的所述填充剂、3%的所述崩解剂、1%的所述润滑剂与1%的所述助流剂组成,进一步地,所述药物组合物由10%的所述式I所示化合物的晶型B、85%的所述填充剂、3%的所述交联羧甲纤维素钠、1%的所述硬脂酸镁与1%的所述二氧化硅组成,所述百分比为占所述药物组合物的质量比。
- 如权利要求1至5任一项所述的药物组合物Q,其特征在于,所述药物组合物Q选自如下任一组:药物组合物1:10%物质X、56%一水乳糖、29%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;药物组合物2:10%物质X、64%一水乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;药物组合物3:10%物质X、64%甘露醇、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;药物组合物4:10%物质X、64%乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;药物组合物5:10%物质X、85%甘露醇、3%交联羧甲纤维素钠、1%二氧化硅和1%硬脂酸镁;药物组合物6:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC 200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;药物组合物7:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC 200、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;药物组合物8:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;药物组合物9:10%式I所示化合物的晶型B、64%乳糖Flowlac 100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;药物组合物10:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅和1%硬脂酸镁;所述百分比为占所述药物组合物的质量比。
- 一种权利要求1至6任一项所述药物组合物Q的制备方法,其特征在于,所述药物组合物的制备方法包含如下步骤:(a)将所述物质X和部分所述填充剂混合得混合物M;(b)将剩余所述填充剂、所述崩解剂、所述二氧化硅与混合物M混合,加入硬脂酸镁,得所述药物组合物Q;其中,所述二氧化硅为助流剂,所述硬脂酸镁为润滑剂;较佳地,所述制备方法满足如下一个或多个条件:(1)所述步骤(a)中,所述填充剂和所述物质X的质量比为3:1;(2)所述步骤(a)中,所述填充剂为所述乳糖、所述一水乳糖和所述甘露醇中的一种或多种;(3)所述步骤(b)中,所述崩解剂为交联羧甲纤维素钠;(4)所述步骤(a)中,所述混合前所述物质X或所述填充剂为30目的所述物质X或30目的所述填充剂;(5)所述步骤(b)中,所述填充剂、所述崩解剂或所述二氧化硅为30目的所述填充剂、30目的所述崩解剂或30目的所述二氧化硅;(6)所述步骤(b)中,所述混合条件为20rpm搅拌10~60min,例如为20rpm搅拌20min;(7)所述步骤(b)中,所述硬脂酸镁为60目的硬脂酸镁;(8)所述步骤(b)中,所述加入条件为20rpm搅拌2~10min,例如为3min;(9)所述药物组合物的制备方法优选包含如下步骤:将3倍于所述物质X质量的30目的所述乳糖、30目的所述一水乳糖或30目的所述甘露醇与30目的所述物质X混合得混合物M;将30目的所述填充剂、30目的所述崩解剂与30目的所述二氧化硅与混合物M混合;加入60目的所述硬脂酸镁混合,得所述药物组合物Q。
- 一种药物组合物R,其特征在于,其包含权利要求1至6任一项所述的药物组合物Q和胶囊外壳,所述的药物组合物Q装填于所述的胶囊外壳中;较佳地,所述药物组合物R满足如下一个或多个条件:(1)所述胶囊外壳为HPMC胶囊外壳或明胶胶囊外壳,优选为HPMC胶囊外壳;(2)所述药物组合物R由所述药物组合物Q和胶囊外壳组成;(3)所述药物组合物R通过口服使用;(4)所述药物组合物R为10mg/粒或40mg/粒规格;(5)所述药物组合物R为固体制剂,例如固体口服制剂;(6)所述药物组合物R为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物组合物;较佳地,所述的精神病症、神经病症或神经退行性病症选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症;或者,所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选为原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选IgA肾病)。
- 如权利要求8所述的药物组合物R,其特征在于,所述药物组合物R选自如下任一组:药物组合物1:10%物质X、56%一水乳糖、29%的微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;药物组合物2:10%物质X、64%一水乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;药物组合物3:10%物质X、64%甘露醇、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;药物组合物4:10%物质X、64%乳糖、21%微晶纤维素、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;药物组合物5:10%物质X、85%甘露醇、3%交联羧甲纤维素钠、1%二氧化硅、1%硬脂酸镁和所述胶囊外壳;药物组合物6:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;药物组合物7:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC200、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;药物组合物8:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;药物组合物9:10%式I所示化合物的晶型B、64%乳糖Flowlac100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;药物组合物10:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述HPMC胶囊外壳;药物组合物11:10%式I所示化合物的晶型B、56%一水乳糖GRANULAC200、29%的微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;药物组合物12:10%式I所示化合物的晶型B、64%一水乳糖GRANULAC200、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;药物组合物13:10%式I所示化合物的晶型B、64%甘露醇200SD、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;药物组合物14:10%式I所示化合物的晶型B、64%乳糖Flowlac100、21%微晶纤维素PH102、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;药物组合物15:10%式I所示化合物的晶型B、85%甘露醇200SD、3%交联羧甲基纤维素钠SD711、1%二氧化硅、1%硬脂酸镁和所述明胶胶囊外壳;所述百分比为占所述药物组合物的质量比。
- 一种如权利要求8或9所述药物组合物R的制备方法,其特征在于,其为将权利要求1至6任一项所述药物组合物Q进行胶囊灌装,即可;较佳地,所述制备方法满足如下一个或多个条件:(1)所述药物组合物R的制备方法中,所述胶囊为HPMC胶囊外壳或明胶胶囊外壳,例如为HPMC胶囊外壳;(2)所述药物组合物R的制备方法中,所述灌装利用全自动胶囊灌装机进行胶囊灌装,例如所述全自动胶囊灌装机型号为In-Cap XL。
- 一种物质Y在制备药物中的应用,所述物质Y为权利要求1至7任一项所述的药物组合物Q或权利要求8至10中任一项所述的药物组合物R;所述的药物为用于治疗和/或预防TRPC5介导的疾病的药物;较佳地,在所述的应用中,所述的TRPC5介导的疾病为精神病症、神经病症、神经退行性病症 或肾病;进一步地,所述的精神病症、神经病症或神经退行性病症选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症;或者,所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选为原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化或原发性肾小球疾病(优选为IgA肾病)。
- 一种物质Y在制备药物中的应用,所述物质Y为权利要求1至7任一项所述的药物组合物Q或权利要求8至10中任一项所述的药物组合物R,所述的药物为用于治疗和/或预防精神病症、神经病症、神经退行性病症或肾病的药物;较佳地,在所述的应用中,所述的精神病症、神经病症或神经退行性病症选自:与失调的情绪处理相关的疾病(例如,边缘型人格障碍或抑郁症,诸如重性抑郁症、严重抑郁障碍、精神抑郁症、心境恶劣和产后抑郁症以及双相障碍)、与焦虑及恐惧相关的病症(例如,创伤后应激障碍、惊恐病、广场恐怖症、社交恐惧症、广泛性焦虑症、惊恐病、社交焦虑症、强迫症及分离焦虑)、记忆障碍(例如,阿尔茨海默病、遗忘症、失语症、脑损伤、脑肿瘤、慢性疲劳综合征、克雅氏病、解离性遗忘症、神游遗忘症、亨廷顿病、学习障碍、睡眠障碍、多重人格障碍、疼痛、创伤后应激障碍、精神分裂症、运动损伤、中风及韦-科二氏综合征)、与受损的冲动控制及成瘾相关的病症、帕金森病、肌萎缩侧索硬化、癫痫、以及、由创伤或包括衰老的其他损伤引起的其他脑部病症;或者,所述的肾病为局灶节段性肾小球硬化、微小病变肾病、糖尿病肾病、奥尔波特综合征、高血压肾病、肾病综合征、类固醇耐药性肾病综合征、膜性肾病、特发性膜性肾病、膜增生性肾小球肾炎、免疫复合物介导的MPGN、补体介导的MPGN、狼疮性肾炎、感染后肾小球肾炎、薄基底膜病、肾小球膜增生性肾小球肾炎、淀粉样变性肾病(优选为原发性淀粉样变性肾病)、C1q肾病、快速进行性肾小球肾炎、抗肾小球基底膜病、C3肾小球肾炎、高血压性肾硬化、原发性肾小球疾病(优选为IgA肾病)。
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WO2020210639A1 (en) * | 2019-04-10 | 2020-10-15 | Goldfinch Bio, Inc. | Crystal forms of a pyridazinone trpc inhibitor |
WO2022001767A1 (zh) * | 2020-07-03 | 2022-01-06 | 武汉朗来科技发展有限公司 | 一种杂环化合物及其应用 |
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WO2020210639A1 (en) * | 2019-04-10 | 2020-10-15 | Goldfinch Bio, Inc. | Crystal forms of a pyridazinone trpc inhibitor |
WO2022001767A1 (zh) * | 2020-07-03 | 2022-01-06 | 武汉朗来科技发展有限公司 | 一种杂环化合物及其应用 |
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