CN103230595A - Composition for treating mental diseases - Google Patents
Composition for treating mental diseases Download PDFInfo
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- CN103230595A CN103230595A CN2013101666566A CN201310166656A CN103230595A CN 103230595 A CN103230595 A CN 103230595A CN 2013101666566 A CN2013101666566 A CN 2013101666566A CN 201310166656 A CN201310166656 A CN 201310166656A CN 103230595 A CN103230595 A CN 103230595A
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- 0 C[C@@]1(CC2)C2C1CCC(C)=CN=*1*c(ccc(*)c2)c2C(c2ncccc2)=NC1 Chemical compound C[C@@]1(CC2)C2C1CCC(C)=CN=*1*c(ccc(*)c2)c2C(c2ncccc2)=NC1 0.000 description 2
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Abstract
The invention relates to a composition for treating mental diseases and in particular relates to a solid drug composition. The composition comprises (a) a compound shown in the formula I in the specification or a pharmaceutically acceptable salt of the compound, (b) a fatty acid or a pharmaceutically acceptable salt thereof and (c) optional pharmaceutic adjuvants, wherein in the formula I, R1 is bromine, and R2 and R3 are methyl. The composition has good pharmaceutical properties.
Description
Technical field
The present invention relates to can be used for treating the solid composite medicament of central nervous system disease.
Background technology
With the following formula I chemical compound:
Owing to contain above-mentioned specific structure, this chemical compound of report (60 pages of example I c-8 of description) is fugitive central nervous system (CNS) inhibitor among the WO00/69836, has the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action.They can be used for the intravenously administrable in the following clinical treatment: as calm before the operation in the intra-operative, anxiety with forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis and analgesic and/or simultaneously, as the component of inducing and keeping that is used for general anesthesia; ICU calmness etc., according to CN101501019A (PAION, application number CN200780028964.5) report in, the free alkali of this chemical compound is not very stable, only be suitable for 5 ℃ of preservations of low temperature, under the condition of 40 ℃/75% relative humidity (opening), the sample deliquescence of storage, the color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.So the salt of people's synthesis type (I) chemical compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing CN101501019A and US20100075955A1 (TILBROOK) have reported benzene sulfonate, the esilate of formula I chemical compound respectively.CN102964349A (permanent auspicious, application number 201110456864.0) has reported the tosilate of formula I chemical compound.
There is the worry of stable aspect in existing report formula I compound or its salt, and this is used for the clinical treatment relevant disease for this compounds is disadvantageous.
Summary of the invention
The object of the invention is particularly solid composite medicament of a kind of useful pharmaceutical composition, expects that it has for example stability of good pharmaceutical properties.Unexpectedly finding, when formula I compound or its salt is mixed with solid composite medicament with pharmaceutic adjuvant, wherein comprise fatty acid or its salt is favourable, is favourable for its chemical stability particularly.
Therefore, first aspect present invention provides a kind of solid composite medicament, wherein comprises:
(a) with following formula I chemical compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl;
(b) fatty acid or the acceptable salt of its pharmacy; And optional
(c) pharmaceutic adjuvant.
According to the solid composite medicament of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate, benzene sulfonate or esilate.
According to the solid composite medicament of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate or benzene sulfonate.
According to the solid composite medicament of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is selected from following formula Ia chemical compound or formula Ib chemical compound:
In the present invention, above-mentioned formula Ia chemical compound is the tosilate of formula I chemical compound, and formula Ib chemical compound is the benzene sulfonate of formula I chemical compound.In the present invention, when mentioning formula I chemical compound, as not specializing in its linguistic context, refer to free alkali shown in the formula I and the acceptable salt of its pharmacy for example above-mentioned tosilate and benzene sulfonate.
According to the solid composite medicament of first aspect present invention, wherein said fatty acid is stearic acid.
According to the solid composite medicament of first aspect present invention, the acceptable salt of the pharmacy of wherein said fatty acid is magnesium salt, sodium salt, calcium salt, the zinc salt of fatty acid.
According to the solid composite medicament of first aspect present invention, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate and combination thereof.
According to the solid composite medicament of first aspect present invention, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate and combination thereof.
The inventor unexpectedly finds, beat all good result is being appearred in formula I chemical compound when particularly formula Ia chemical compound or formula Ib chemical compound are prepared with fatty acid or the acceptable salt of its pharmacy, Wen Dingxing effect particularly, and this effect can not disappear for other used pharmaceutic adjuvant of preparations shaping purpose because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I chemical compound of the present invention or the acceptable salt of its pharmacy and fatty acid of the present invention or the acceptable salt of its pharmacy, can also be to comprise other optional pharmaceutics conventional pharmaceutic adjuvant commonly used further.
According to the solid composite medicament of first aspect present invention, wherein said pharmaceutic adjuvant includes but not limited to diluent or filler, disintegrating agent, binding agent, lubricant or fluidizer.
According to the solid composite medicament of first aspect present invention, wherein said diluent or filler include but not limited to: starch is corn starch, dextrin, microcrystalline Cellulose, modified starch, pregelatinized Starch, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose etc. for example.Preferred mannitol and the lactose of comprising.
According to the solid composite medicament of first aspect present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch etc.
According to the solid composite medicament of first aspect present invention, wherein said binding agent is such as but not limited to hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.The preferred hydroxypropyl cellulose that comprises, hydroxypropyl emthylcellulose, polyvinylpyrrolidone or polyvinyl alcohol.Described binding agent can use separately, also can two or more unite use.Described water-soluble copolymer adhesive combined amount for example be the tablet total weight amount 0.5 to 10wt%, preferred l to 5wt%.Adopt the oral formulations of pharmaceutical compositions of the present invention to refer to be mixed with tablet, capsule, granule or fine grain pharmaceutical preparation.Described preparation can the application of the invention prescription etc. be made tablet, capsule, granule or fine grained through traditional method.
In the present invention, lubricant and fluidizer can rise and be referred to as lubricant.Lubricant includes but not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid Paraffin, Polyethylene Glycol, silicon dioxide, silica sol, micropowder silica gel, Pulvis Talci, hydrogenated vegetable wet goods or its combination.Although the above-mentioned fatty acid of the present invention or the acceptable salt of its pharmacy have the effect of lubricant, yet the inventor unexpectedly finds to have occurred beat all good result when formula I chemical compound is prepared with fatty acid or the acceptable salt of its pharmacy.
Solid composite medicament according to first aspect present invention, the weight ratio of wherein said formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.01～100, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.05～50, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.1～20, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.2～20, and for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.5～10.
Solid composite medicament according to first aspect present invention, wherein said pharmaceutic adjuvant accounts for 0～99.5% of said composition weight, for example described pharmaceutic adjuvant accounts for 10～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 25～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 50～98% of said composition weight, and for example described pharmaceutic adjuvant accounts for 75～95% of said composition weight.The consumption of described pharmaceutic adjuvant can rule of thumb be determined easily according to those skilled in the art.For example, as disintegrating agent, its gross weight in compositions usually can be in 3～30% scopes, for example usually can be in 5～20% scopes.Again for example, as binding agent, its gross weight in compositions usually can be in 2～20% scopes, for example usually can be in 5～10% scopes.Again for example, as diluent or filler, it typically is and make the medicament can molding, so its amount can not determine especially that for example its gross weight in compositions usually can be in 1～95% scope, for example usually can be in 10～90% scopes.Again for example, as lubricant, its gross weight in compositions usually can be in 1～20% scope, for example usually can be in 1～10% scope, and for example usually can be in 1～8% scope; Yet, because used fatty acid or the acceptable salt of its pharmacy may produce enough lubrications in the present composition, therefore can not add lubricant in addition in the present invention.
According to the solid composite medicament of first aspect present invention, it is the dosage form that is tablet, capsule, granule, piller etc.In one embodiment, described solid composite medicament is the dosage form that is tablet, capsule, granule.In one embodiment, described solid composite medicament is the dosage form that is tablet or capsule.
According to the solid composite medicament of first aspect present invention, it is the unit dose formulations form that is tablet, capsule, granule, piller etc.Term " unit dose formulations form " for example refers to the dosage form an of tablet, a seed lac wafer etc.In one embodiment, the amount that comprises formula I chemical compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.The amount that for example comprises formula I chemical compound or the acceptable salt of its pharmacy in every tablet is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
According to the solid composite medicament of first aspect present invention, also comprise organic acid for example citric acid or tartaric acid or its combination in the wherein said pharmaceutic adjuvant.Have been found that it is favourable adding an amount of above-mentioned organic acid in solid composite medicament of the present invention.Although those skilled in the art it has been generally acknowledged that this class organic acid has the character relevant with Acidity of Aikalinity and for example cushions character, yet unexpectedly finding having of this type of acid, the inventor helps improve the stability of active component in the product.In an embodiment of the solid composite medicament of first aspect present invention, described formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.01～100, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.05～50, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.1～20, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.2～20, and for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.5～10.
Further, second aspect present invention provides a kind of solid composite medicament, wherein comprises
(a) with following formula I chemical compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl;
(b) organic acid; And optional
(c) pharmaceutic adjuvant.
According to the solid composite medicament of second aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate, benzene sulfonate or esilate.
According to the solid composite medicament of second aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate or benzene sulfonate.
According to the solid composite medicament of second aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is selected from following formula Ia chemical compound or formula Ib chemical compound:
According to the solid composite medicament of second aspect present invention, wherein said organic acid is selected from citric acid or tartaric acid or its combination.Have been found that it is favourable adding an amount of above-mentioned organic acid in solid composite medicament of the present invention.Although those skilled in the art it has been generally acknowledged that this class organic acid has the character relevant with Acidity of Aikalinity and for example cushions character, yet unexpectedly finding having of this type of acid, the inventor helps improve the stability of active component in the product.In an embodiment of the solid composite medicament of second aspect present invention, described formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.01～100, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.05～50, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.1～20, for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.2～20, and for example formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.5～10.
According to the solid composite medicament of second aspect present invention, wherein said pharmaceutic adjuvant includes but not limited to diluent or filler, disintegrating agent, binding agent, lubricant or fluidizer.
According to the solid composite medicament of second aspect present invention, wherein said diluent or filler include but not limited to: starch is corn starch, dextrin, microcrystalline Cellulose, modified starch, pregelatinized Starch, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose etc. for example.Preferred mannitol and the lactose of comprising.
According to the solid composite medicament of second aspect present invention, wherein said disintegrating agent includes but not limited to: low-substituted hydroxypropyl cellulose, crosslinked carboxymethyl fecula sodium, sodium starch glycolate, cross-linked carboxymethyl cellulose sodium, starch etc.
According to the solid composite medicament of second aspect present invention, wherein said binding agent is such as but not limited to hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, etc.The preferred hydroxypropyl cellulose that comprises, hydroxypropyl emthylcellulose, polyvinylpyrrolidone or polyvinyl alcohol.Described binding agent can use separately, also can two or more unite use.Described water-soluble copolymer adhesive combined amount for example be the tablet total weight amount 0.5 to 10wt%, preferred l to 5wt%.Adopt the oral formulations of pharmaceutical compositions of the present invention to refer to be mixed with tablet, capsule, granule or fine grain pharmaceutical preparation.Described preparation can the application of the invention prescription etc. be made tablet, capsule, granule or fine grained through traditional method.
In the present invention, lubricant and fluidizer can rise and be referred to as lubricant.Lubricant includes but not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid Paraffin, Polyethylene Glycol, silicon dioxide, silica sol, micropowder silica gel, Pulvis Talci, hydrogenated vegetable wet goods or its combination.
Solid composite medicament according to second aspect present invention, wherein said pharmaceutic adjuvant accounts for 0～99.5% of said composition weight, for example described pharmaceutic adjuvant accounts for 10～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 25～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 50～98% of said composition weight, and for example described pharmaceutic adjuvant accounts for 75～95% of said composition weight.The consumption of described pharmaceutic adjuvant can rule of thumb be determined easily according to those skilled in the art.For example, as disintegrating agent, its gross weight in compositions usually can be in 3～30% scopes, for example usually can be in 5～20% scopes.Again for example, as binding agent, its gross weight in compositions usually can be in 2～20% scopes, for example usually can be in 5～10% scopes.Again for example, as diluent or filler, it typically is and make the medicament can molding, so its amount can not determine especially that for example its gross weight in compositions usually can be in 1～95% scope, for example usually can be in 10～90% scopes.Again for example, as lubricant, its gross weight in compositions usually can be in 1～20% scope, for example usually can be in 1～10% scope, and for example usually can be in 1～8% scope.
According to the solid composite medicament of second aspect present invention, it is the dosage form that is tablet, capsule, granule, piller etc.In one embodiment, described solid composite medicament is the dosage form that is tablet, capsule, granule.In one embodiment, described solid composite medicament is the dosage form that is tablet or capsule.
According to the solid composite medicament of second aspect present invention, it is the unit dose formulations form that is tablet, capsule, granule, piller etc.Term " unit dose formulations form " for example refers to the dosage form an of tablet, a seed lac wafer etc.In one embodiment, the amount that comprises formula I chemical compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.The amount that for example comprises formula I chemical compound or the acceptable salt of its pharmacy in every tablet is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
According to the solid composite medicament of second aspect present invention, also comprise fatty acid or the acceptable salt of its pharmacy in the wherein said pharmaceutic adjuvant.
According to the solid composite medicament of second aspect present invention, wherein said fatty acid is stearic acid.
According to the solid composite medicament of second aspect present invention, the acceptable salt of the pharmacy of wherein said fatty acid is magnesium salt, sodium salt, calcium salt, the zinc salt of fatty acid.
According to the solid composite medicament of second aspect present invention, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate and combination thereof.
According to the solid composite medicament of second aspect present invention, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate and combination thereof.
Although the above-mentioned fatty acid of the present invention or the acceptable salt of its pharmacy have the effect of lubricant, yet the inventor unexpectedly finds to have occurred beat all good result when formula I chemical compound is prepared with fatty acid or the acceptable salt of its pharmacy.The inventor unexpectedly finds, beat all good result is being appearred in formula I chemical compound when particularly formula Ia chemical compound or formula Ib chemical compound are prepared with fatty acid or the acceptable salt of its pharmacy, Wen Dingxing effect particularly, and this effect can not disappear for other used pharmaceutic adjuvant of preparations shaping purpose because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I chemical compound of the present invention or the acceptable salt of its pharmacy and fatty acid of the present invention or the acceptable salt of its pharmacy, can also be to comprise other optional pharmaceutics conventional pharmaceutic adjuvant commonly used further.
Solid composite medicament according to second aspect present invention, the weight ratio of wherein said formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.01～100, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.05～50, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.1～20, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.2～20, and for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.5～10.
Third aspect present invention provides the method for preparing any solid composite medicament of first aspect present invention, and it comprises following steps:
(i) provide formula I chemical compound or the acceptable salt of its pharmacy, fatty acid or the acceptable salt of its pharmacy and optional pharmaceutic adjuvant;
Formula I chemical compound or the acceptable salt of its pharmacy and fatty acid or the acceptable salt of its pharmacy and optional pharmaceutic adjuvant are mixed with random order, obtain mixture;
(iii) step mixture is (ii) made pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example for the preparation tablet, have been found that the hybrid mode of formula I chemical compound or the acceptable salt of its pharmacy and fatty acid or the acceptable salt of its pharmacy is not seen influential to realizing the object of the invention; For example formula I chemical compound or the acceptable salt of its pharmacy are pre-mixed with fatty acid or the acceptable salt of its pharmacy and then mix with other pharmaceutic adjuvant, last repress is made tablet, with being mixed at last with other pharmaceutic adjuvant earlier, mixes with fatty acid or the acceptable salt of its pharmacy the more acceptable salt of formula I chemical compound or its pharmacy, last repress is made tablet, and dual mode gained tablet all shows good properties.
Fourth aspect present invention provides the method for preparing any solid composite medicament of second aspect present invention, and it comprises following steps:
(i) provide formula I chemical compound or the acceptable salt of its pharmacy, organic acid and optional pharmaceutic adjuvant;
Formula I chemical compound or the acceptable salt of its pharmacy and organic acid and optional pharmaceutic adjuvant are mixed with random order, obtain mixture;
(iii) step mixture is (ii) made pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example for the preparation tablet, have been found that formula I chemical compound or the acceptable salt of its pharmacy and organic acid hybrid mode to the realization the object of the invention do not see influential; For example formula I chemical compound or the acceptable salt of its pharmacy are pre-mixed with organic acid and then mix with other pharmaceutic adjuvant, last repress is made tablet, with being mixed at last with other pharmaceutic adjuvant earlier, mixes with organic acid the more acceptable salt of formula I chemical compound or its pharmacy, last repress is made tablet, and dual mode gained tablet all shows good properties.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with characteristics to various aspects of the present invention below.
The present invention relates to following formula I chemical compound or the acceptable salt of its pharmacy:
R1 is bromine in the formula, and R2 and R3 are methyl;
The chemistry of formula 1 chemical compound is called 3-[(4S)-8-bromo-1-methyl-6-(2-pyridine radicals)-4H-imidazoles [1,2-a] [1,4] benzodiazepine
-4-yl] methyl propionate,
In the present invention, preferred formula I chemical compound is its benzene sulfonate or tosilate.
In the present invention, preferred formula I chemical compound is to be selected from following formula Ia chemical compound or formula Ib chemical compound:
The present invention also is provided among the experimenter calm or the hypnogenic method of producing, and this method comprises uses the formula I chemical compound of the present invention that comprises calmness or hypnosis effective dose or first aspect present invention or the described solid composite medicament of second aspect of the acceptable salt of its pharmacy to this experimenter.
Also be provided at according to the present invention and cause method antianxity among the experimenter, this method comprises uses the formula I chemical compound of the present invention that comprises the anxiety effective dose or first aspect present invention or the described solid composite medicament of second aspect of the acceptable salt of its pharmacy to this experimenter.
Cause method of flaccid muscles according to the present invention further provides in the experimenter, this method comprises uses the formula I chemical compound of the present invention that comprises effective dose of flaccid muscles or first aspect present invention or the described solid composite medicament of second aspect of the acceptable salt of its pharmacy to this experimenter.
According to the method that the present invention further provides in the experimenter treatment convulsions state, this method comprises uses the formula I chemical compound of the present invention that comprises the anticonvulsant effective dose or first aspect present invention or the described solid composite medicament of second aspect of the acceptable salt of its pharmacy to this experimenter.
In the present invention, described experimenter compatibly is mammal, and is preferred human.
The first aspect present invention or the described solid composite medicament of second aspect that are used for above-mentioned disease, its give mammal for example people's dosage can be 0.001-5.0mg/kg body weight/day, preferably 0.001-2.0mg/kg body weight/day usually.
The described solid composite medicament of first aspect present invention or second aspect can be used as fugitive CNS inhibitor, and they can be used for by following clinical settings oral administration: calm before the operation in the peri-operation period event, anxiety and forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis or analgesic and/or simultaneously, as the component of inducing and keeping that is used for general anesthesia; The ICU calmness.In addition, the described solid composite medicament of first aspect present invention or second aspect can be used for mental sickness such as calmness, hypnosis, anxiety, of flaccid muscles, convulsion.
The specific embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Though for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.Following examples further specify the present invention, rather than restriction the present invention.When preparing compositions below in the listed prescription, formula I chemical compound amount of calculation is all calculated with the form of its free alkali, listed prescription is the amount of contained formula I chemical compound free alkali in the per unit dosage particles (for example every tablet, every seed lac wafer), below preparation during compositions every batch of preparation amount be the amount of 10000 unit dose formulations, for example the amount with 10,000 or 10,000 seed lac wafers feeds intake.
In the various chromatography of the present invention, the chromatographic peak that acid group shows is all ignored when calculating.
Analysis test method
Below [HPLC method A] can be used for measuring related substance and situation of change thereof in the present composition.
[HPLC method A]:
Carry out purity analysis at the HP1100Agilent chromatograph:
Chromatographic column: Phenomenex Gemini C185 μ m (2.0 * 50mm) (guard column Phenomenex Gemini C18,2x4mm), U.S. F door company
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 0.8ml/ minute
Detect: ultraviolet detection, wavelength: 254nm;
The NH of mobile phase A: 2mmol
4HCO
3(use NH
3Solution is adjusted to pHl0)
Mobile phase B: acetonitrile
The gradient elution program:
| Elution time/minute | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 25 | 10 | 90 |
| 28.8 | 10 | 90 |
| 29 | 90 | 10 |
| 34 | 90 | 10 |
Sample preparation: it is an amount of to get various samples (crude drug or compositions), and (acetonitrile: water=50:50 wherein contains the NH of 1mmol to add the acetonitrile-water mixed liquor
4HCO
3, and use NH
3Solution is adjusted to pHl0) dissolve and make the solution of the about 1mg/ml of concentration in right amount, filter in case of necessity.
Computational methods: be main peak with formula I chemical compound chromatographic peak, its relative retention time is 1, read the peak area (peak area is ignored less than 0.01% impurity peaks of main peak area) of the whole chromatographic peaks of relative retention time between 0.60～2.00, calculate the content of each impurity peaks and the content of main peak (also being called chromatographic purity) with area normalization method, and calculate maximum single impurity content and total impurities content.
4 of its heptatomic rings of active component in the pharmaceutical composition of the present invention are the S-isomer, and may mix in the medicine has a spot of R-isomer.Below [HPLC method B] can be used for measuring R-isomer (i.e. the chemical compound of representing with following formula Ix) and situation of change thereof in the present composition.
[HPLC method B]:
Carry out purity analysis at HP1100 Agilent chromatograph:
Running time: to more than 2.5 times of main peak retention time
Chromatographic column: Daicel Chrialcel OJ-H (5 μ m) 4.6 * 250mm (guard column Daicel Chrialcel OJ-H analysis guard column 5 μ m4.0 * 10mm), Japanese Daicel (Daicel)
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 1.0ml/ minute
Detect: ultraviolet detection, wavelength: 225nm (single wavelength detecting);
Mobile phase: hexane: ethanol=93:7
The sample preparation: it is an amount of to get various samples (crude drug or compositions), adds the solution that an amount of supersound process of mobile phase makes dissolving and the about 1mg/ml of diluted concentration, filters in case of necessity.
Computational methods: be main peak with formula I chemical compound chromatographic peak, its relative retention time is 1, read the peak area of main peak and the peak area of the impurity peaks (it for R isomer be formula Ix chemical compound) of relative retention time between 1.10～1.25, R content of isomer (%)=[R isomer peak area ÷ (R isomer peak area+S isomer peak area)] * 100%.
In above various HPLC methods, no matter formula I chemical compound is with its free alkali form dosing or with the form dosing of its pharmaceutical salts, because of dissociating of benzenesulfonic acid or p-methyl benzenesulfonic acid or other acid group, they all show to have identical retention time with formula I free alkali in chromatographic system, this is that the chromatography field is known.
The test material sample:
Below in all kinds of tests I crystal formation, II crystal formation, III crystal formation, the IV crystal formation of employed formula Ia chemical compound be respectively the method acquisition of putting down in writing according to [0049] section (being embodiment 2), [0053] section (being embodiment 4) of description, [0057] section (being embodiment 6), [0061] section (being embodiment 8) among the CN102964349A.Also prepared by the following method and determined concrete crystal formation formula Ia chemical compound: the formula Ia compound dissolution that [0047] section method of putting down in writing of description among the photograph CN102964349A obtains is in 50% ethanol water, spray drying gets dry powder, its X-ray diffraction feature with above-mentioned four kinds of crystal formations is all different after measured, shows no typical diffraction maximum (being designated as the V crystal formation of formula Ia chemical compound in the present invention).
Below employed formula Ib chemical compound in all kinds of tests, relate to its 1 crystal formation, 2 crystal formations, 3 crystal formations, 4 crystal formations, they are all with reference to CN101501019A (PAION, application number CN200780028964.5) method of record prepares in, and its XRPD figure and DSC test result all with CN101501019A put down in writing identical, specifically:
1 crystal formation of formula Ib chemical compound: 2 θ places comprise the X-ray powder diffraction figure of characteristic peak at about 7.3,7.8,9.4,12.1,14.1,14.4,14.7 or 15.6 degree, and have differential scanning calorimetry open the beginning melt temperature in about 191-192 ℃ scope;
2 crystal formations of formula Ib chemical compound: comprise the XRPD pattern of characteristic peak at about 8.6,10.5,12.0,13.1,14.4 and 15.9 degree 2 θ places, and have the initial melt temperature of differential scanning calorimetry at about 180 ℃;
3 crystal formations of formula Ib chemical compound: 2 θ places comprise the XRPD pattern of characteristic peak at about 7.6,11.2,12.4,14.6,15.2,16.4 and 17.7 degree, and have the initial melt temperature of differential scanning calorimetry in about 200-201 ℃ scope;
4 crystal formations of formula Ib chemical compound: comprise the XRPD pattern of characteristic peak at about 7.6,10.8,15.2,15.9 and 22.0 degree 2 θ places, and have the initial melt temperature of differential scanning calorimetry at about 182 ℃;
Also prepared by the following method and do not determined concrete crystal formation formula Ib chemical compound: 1 crystal formation of above-mentioned formula Ib chemical compound is dissolved in 30% ethanol water, spray drying gets dry powder, its X-ray diffraction feature with above-mentioned four kinds of crystal formations is all different after measured, shows no typical diffraction maximum (being designated as 5 crystal formations of formula Ib chemical compound in the present invention).
Below in all kinds of tests esilate of employed formula I chemical compound prepare (the following formula I esilate that is called for short) with reference to the method for [0101] section record of US20100075955A1 description.
Below in all kinds of tests employed formula I chemical compound (free alkali) obtain with reference to the preparation method of this chemical compound of reporting among the WO00/69836 (60 pages of example I c-8 of description).
More than each test equal with the chromatographic purity of material sample salt or free alkali 99.0%[HPLC method A], the R content of isomer all＜1.0%[HPLC method B].
The R-isomer that the present invention relates to (being the chemical compound that formula Ix represents) can be carried out with reference to the method for putting down in writing among the WO00/69836, and is specific as follows:
Step 1: with reference to the preparation method of WO00/69836 description 23-24 page or leaf Int-1, use Fmoc-D-Glu (OMe)-OH (available from gill biochemistry) to obtain with following formula Int-1x intermediate (it is the isomer of Int-1) as raw material:
Step 2: follow the preparation method with reference to WO00/69836 description 34-35 page or leaf Example I-1, use the intermediate compound I nt-2 of Int-1x intermediate and 24 records of WO00/69836 description to be raw material, obtain following Ex I-10x chemical compound (it is the isomer of the Example I-10 chemical compound of 38 pages of records of WO00/69836 description):
Step 3: follow the preparation method with reference to WO00/69836 description 60-61 page or leaf Example Ic-8, use Ex I-10x to be raw material, obtain the chemical compound of representing with following formula Ix (it is the R-isomer of the Example Ic-8 chemical compound of 60 pages of records of WO00/69836 description)
R1 is bromine in the formula, and R2 and R3 are methyl, molecular formula C
21H
19BrN
4O
2, ESIMS 461 (M+Na, alkali), 439 (M+H).Chromatographic purity〉99.0%[HPLC method A], S content of isomer＜1.0%[HPLC method B].For the S isomer, the relative retention time of this R isomer is about 1.17 in the test of [HPLC method B] method.This R isomer is treated as the isomer impurities of active component formula I compound or its salt in the present invention.
Test example 1: formula I chemical compound and fatty acid composite test
Get the I crystal formation that can pass through the formula Ia chemical compound of 80 order fine powder states, other gets can be by stearic acid or the magnesium stearate of 80 order fine powder states, formula Ia chemical compound (be mixed at every turn and use the amount of 10g at least) and a certain amount of stearic acid as shown in the table or salt are ground well in mortar (fully to be ground all, test by X-ray diffraction, herein and hereinafter grind the crystal formation that equal process can not change formula I chemical compound), pack in the aluminum-plastic composite membrane sack, then each sample is placed 50 ° of C calorstats to place 4 months (can abbreviate " 50 ° of C4 months " disposal in the present invention as).For each sample, use [HPLC method A] to measure their maximum single impurity content and total impurities content in the time of 0 month, and measure them at maximum single impurity content and the total impurities content of 50 ° of C4 during the month, calculating maximum single impurity respectively by following formula increases percent and total impurities increase percent:
Maximum single impurity increases percent=[(50 ° C4 month maximum single impurity content-0 month maximum single impurity content) 0 month maximum single impurity content of ÷] * 100%
Total impurities increases percent=[(50 ° of C4 month total impurities content-0 month total impurities content) 0 month total impurities content of ÷] * 100%
The results are shown in following table 1.
Table 1:
Stearic acid when first hurdle in the last table " stearic acid: I crystal formation " expression mixes: the two weight ratio of I crystal formation, for example this value is to represent that 0 part of stearic acid mixed with 1 part of I crystal formation at 0 o'clock, this value is to represent that 0.01 part of stearic acid mixed with 1 part of I crystal formation at 0.01 o'clock, this value is to represent that 200 parts of stearic acid mixed with 1 part of I crystal formation at 200 o'clock, etc.; The 4th hurdle also has similar meaning similarly.
According to last table result as seen, withstand high temperatures environment better during the combination of the I crystal formation of formula Ia chemical compound and stearic acid or stearyl ester magnesium, particularly the weight ratio at formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is in 1:0.2～20 scopes, result with obvious excellence, although the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is that the impurity increase is not remarkable in 1:50～200 scopes, but excess fats acid or the acceptable salt of its pharmacy are present in other performance tabletting performance for example that may have influence on medicine in the prescription, because fatty acid or the acceptable salt of its pharmacy have the function of tablet lubricants, usually consumption is 1～10% particularly in 1～5% scope of tablet weight.
Test example 2: formula I chemical compound and fatty acid composite test
With reference to the method for above test example 1, different only is that active medicine is used the II crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).For example, stearic acid: in II crystal formation=5 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 26% and 36%; Again for example, magnesium stearate: in II crystal formation=5 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 25% and 35%.
With reference to the method for above test example 1, different only is that active medicine is used the III crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used the IV crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used the V crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
Test example 3: formula I chemical compound and fatty acid composite test
With reference to the method for above test example 1, different only is that active medicine is used 1 crystal formation into formula Ib chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).For example, stearic acid: in II crystal formation=5 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 23% and 39%; Again for example, magnesium stearate: in II crystal formation=5 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 26% and 42%.
With reference to the method for above test example 1, different only is that active medicine is used 2 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used 3 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used 4 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used 5 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 1, maximum single impurity increase (%) and total impurities and increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is in 1:0.2～20 scopes) or all be no more than 15 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or all be no more than 10 percentage points (weight ratio of the salt of formula I chemical compound and described fatty acid or its salt is that 1:50～200 scopes are interior).
With reference to the method for above test example 1, different only is that active medicine is used the esilate into formula I instead.The result shows lamentedly, is in 1:0～200 scopes in the weight ratio of formula I chemical compound and described fatty acid or its salt, and maximum single impurity increases (%) and total impurities increase (%) all in 200～400% scopes.For example, stearic acid: in esilate=20 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 242% and 343%; Again for example, magnesium stearate: in esilate=20 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 234% and 325%.As seen, even be the acid-addition salts of formula I chemical compound equally, the esilate of formula I chemical compound but shows and is difficult to realize the effect obviously improved as the stability as shown in benzene sulfonate or the tosilate.
With reference to the method for above test example 1, different only is, and active medicine uses instead is formula I chemical compound (being free alkali).The result shows lamentedly, is in 1:0～200 scopes in the weight ratio of formula I chemical compound and described fatty acid or its salt, and maximum single impurity increases (%) and total impurities increase (%) all in 200～400% scopes.For example, stearic acid: in free alkali=20 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 223% and 319%; Again for example, magnesium stearate: in free alkali=20 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 211% and 345%.
Test example 4: the test of formula I chemical compound, fatty acid and pharmaceutic adjuvant combination
Get the I crystal formation that can pass through the formula Ia chemical compound of 80 order fine powder states, other gets stearic acid or the magnesium stearate that can pass through 80 order fine powder states, and can be by the pharmaceutic adjuvant described below of 80 order fine powder states.By weight formula Ia chemical compound: stearic acid or salt: starch: microcrystalline Cellulose: lactose=1:(0,0.2,2,20 or 50): 50:50:50, in mortar, these materials are ground well, pack in the aluminum-plastic composite membrane sack, then each sample is placed 50 ° of C calorstats to place 4 months.Measure each sample with reference to the method for test example 1 and increase percent and total impurities increase percent through the maximum single impurity of 50 ° of C4 after the month.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.For example, stearic acid: in I crystal formation=2 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 22% and 34%; Again for example, magnesium stearate: in I crystal formation=2 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 22% and 37%.
Test example 5: the test of formula I chemical compound, fatty acid and pharmaceutic adjuvant combination
With reference to the method for above test example 4, different only is that active medicine is used the II crystal formation into formula Ia chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used the III crystal formation into formula Ia chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used the IV crystal formation into formula Ia chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used the V crystal formation into formula Ia chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used 1 crystal formation into formula Ib chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used 2 crystal formations into formula Ib chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used 3 crystal formations into formula Ib chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used 4 crystal formations into formula Ib chemical compound instead.Stearic acid or salt=0.2,2 or 20) or all be no more than 20 percentage points of (formula Ia chemical compounds: stearic acid or salt=0) or all be no more than 15 percentage points of (formula Ia chemical compounds: stearic acid or salt=50) basic identical in result and the table 1, maximum single impurity increases (%) and total impurities increases corresponding formula Ia chemical compound in (%) and the table 1: stearic acid or salt proportioning gained result differ and all are no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 4, different only is that active medicine is used the esilate into formula I instead.The result shows lamentedly, is in 1:0～50 scopes in the weight ratio of formula I chemical compound and described fatty acid or its salt, and maximum single impurity increases (%) and total impurities increase (%) all in 200～400% scopes.
With reference to the method for above test example 4, different only is, and active medicine uses instead is formula I chemical compound (being free alkali).The result shows lamentedly, is in 1:0～50 scopes in the weight ratio of formula I chemical compound and described fatty acid or its salt, and maximum single impurity increases (%) and total impurities increase (%) all in 200～400% scopes.
Above result shows that stearic acid or its salt pair active component stablizing effect can not change because adding pharmaceutic adjuvant.
Test example 6: formula I chemical compound and organic acid composite test
Get the I crystal formation that can pass through the formula Ia chemical compound of 80 order fine powder states, other gets can be by citric acid or the tartaric acid of 80 order fine powder states, formula Ia chemical compound and a certain amount of organic acid as shown in the table are ground well in mortar (fully to be ground all, test by X-ray diffraction, herein and hereinafter grind the crystal formation that equal process can not change formula I chemical compound), pack in the aluminum-plastic composite membrane sack, then each sample is placed 50 ° of C calorstats to place 4 months (can abbreviate " 50 ° of C4 months " disposal in the present invention as).For each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure them at the R content of isomer (%) of 50 ° of C4 during the month, being calculated as follows the R isomer increases percent:
The R isomer increases percent=[(50 ° of C4 month R content of isomer-0 month R content of isomer) 0 month R content of isomer of ÷] * 100%
The results are shown in following table 2.
Table 2:
| Citric acid: I crystal formation | The R isomer increases (%) | Tartaric acid: I crystal formation | The R isomer increases (%) |
| 0 | 285 | 0 | 285 |
| 0.01 | 247 | 0.01 | 256 |
| 0.05 | 204 | 0.05 | 211 |
| 0.1 | 143 | 0.1 | 155 |
| 0.15 | 63 | 0.15 | 70 |
| 0.2 | 34 | 0.2 | 37 |
| 0.25 | 37 | 0.25 | 38 |
| 0.5 | 28 | 0.5 | 33 |
| 1 | 27 | 1 | 29 |
| 2 | 31 | 2 | 28 |
| 5 | 34 | 5 | 35 |
| 10 | 28 | 10 | 27 |
| 15 | 35 | 15 | 34 |
| 20 | 33 | 20 | 32 |
| 50 | 37 | 50 | 31 |
| 100 | 38 | 100 | 38 |
| 200 | 43 | 200 | 38 |
Citric acid when first hurdle in the last table " citric acid: I crystal formation " expression mixes: the two weight ratio of I crystal formation, for example this value is to represent that 0 part of citric acid mixed with 1 part of I crystal formation at 0 o'clock, this value is to represent that 0.01 part of citric acid mixed with 1 part of I crystal formation at 0.01 o'clock, this value is to represent that 200 parts of citric acid mixed with 1 part of I crystal formation at 200 o'clock, etc.; Third column also has similar meaning similarly.
According to last table result as seen, withstand high temperatures environment better during the combination of the I crystal formation of formula Ia chemical compound and citric acid or tartaric acid, be in 1:0.2～20 scopes at formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio particularly, result with obvious excellence, namely the R content of isomer increases not obvious.When although the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described citric acid is 1:50,1:100 or 1:200, the increase of R isomer impurities is not remarkable, but find after measured, use [HPLC method A] to measure the maximum single impurity increase percent of 50 ° of C4 during the month and be respectively 81%, 141%, 186%, total impurities increases percent and is respectively 89%, 153%, 217%.I crystal formation and tartaric acid also show that the single impurity of essentially identical maximum increases percent and total impurities increases percent when this three kinds of weight ratios combination, for example compare with the citric acid result who uses corresponding proportioning relevantly to be no more than 10 percentage points.As seen the organic acid amount is after a little while for the no effect of generation that suppresses the R isomer impurities, but when the organic acid amount be increased to I crystal formation weight more than 50 times the time other impurity significantly increase.
Test example 7: formula I chemical compound and organic acid composite test
With reference to the method for above test example 6, different only is that active medicine is used the II crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 7 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).For example, citric acid: in II crystal formation=5 proportionings, it is 33% that the R isomer increases (%); Again for example, tartaric acid: in II crystal formation=5 proportionings, it is 32% that the R isomer increases (%).
With reference to the method for above test example 6, different only is that active medicine is used the III crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used the IV crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 6 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used the V crystal formation into formula Ia chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 14 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
Test example 8: formula I chemical compound and organic acid composite test
With reference to the method for above test example 6, different only is that active medicine is used 1 crystal formation into formula Ib chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 14 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 6 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).For example, citric acid: in II crystal formation=5 proportionings, it is 36% that the R isomer increases (%); Again for example, tartaric acid: in II crystal formation=5 proportionings, it is 36% that the R isomer increases (%).
With reference to the method for above test example 6, different only is that active medicine is used 2 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used 3 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 14 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used 4 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 6 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used 5 crystal formations into formula Ib chemical compound instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 6 percentage points (salt of formula I chemical compound and described organic acid weight ratio are in 1:0.2～20 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or all be no more than 5 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:50～200 scopes are interior).
With reference to the method for above test example 6, different only is that active medicine is used the esilate into formula I instead.The result shows lamentedly, is in 1:0～200 scopes at formula I chemical compound and described organic acid weight ratio, and the R isomer increases (%) all in 150～300% scopes.For example, citric acid: in esilate=20 proportionings, it is 212% that the R isomer increases (%); Again for example, tartaric acid: in esilate=20 proportionings, it is 193% that the R isomer increases (%).As seen, even be the acid-addition salts of formula I chemical compound equally, the esilate of formula I chemical compound but shows and is difficult to realize the effect obviously improved as the stability as shown in benzene sulfonate or the tosilate.
With reference to the method for above test example 6, different only is, and active medicine uses instead is formula I chemical compound (being free alkali).The result shows lamentedly, is in 1:0～200 scopes at formula I chemical compound and described organic acid weight ratio, and maximum single impurity increases (%) and total impurities increases (%) all in 150～300% scopes.For example, citric acid: in free alkali=20 proportionings, it is 219% that the R isomer increases (%); Again for example, tartaric acid: in free alkali=20 proportionings, it is 234% that the R isomer increases (%).
Test example 9: the test of formula I chemical compound, organic acid and pharmaceutic adjuvant combination
Get the I crystal formation that can pass through the formula Ia chemical compound of 80 order fine powder states, other gets citric acid or the tartaric acid that can pass through 80 order fine powder states, and can be by the pharmaceutic adjuvant described below of 80 order fine powder states.By weight formula Ia chemical compound: organic acid: starch: microcrystalline Cellulose: lactose=1:(0,0.2,2,20 or 50): 50:50:50, in mortar, these materials are ground well, pack in the aluminum-plastic composite membrane sack, then each sample is placed 50 ° of C calorstats to place 4 months.Measure each sample with reference to the method for test example 6 and increase (%) through the R isomer of 50 ° of C4 after the month.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 6 percentage points of (formula Ia chemical compounds:.For example, citric acid: in I crystal formation=2 proportionings, it is 34% that the R isomer increases (%); Again for example, tartaric acid: in I crystal formation=2 proportionings, maximum single impurity increases (%) and total impurities increase (%) is respectively 31%.
Test example 10: the test of formula I chemical compound, organic acid and pharmaceutic adjuvant combination
With reference to the method for above test example 9, different only is that active medicine is used the II crystal formation into formula Ia chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used the III crystal formation into formula Ia chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used the IV crystal formation into formula Ia chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used the V crystal formation into formula Ia chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used 1 crystal formation into formula Ib chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used 2 crystal formations into formula Ib chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used 3 crystal formations into formula Ib chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used 4 crystal formations into formula Ib chemical compound instead.Organic acid=0.2,2,20 or 50) or all be no more than 20 percentage points of (formula Ia chemical compounds: organic acid=0) basic identical in result and the table 2, R isomer increase corresponding formula Ia chemical compound in (%) and the table 2: organic acid proportioning gained result differs and all is no more than 8 percentage points of (formula Ia chemical compounds:.
With reference to the method for above test example 9, different only is that active medicine is used the esilate into formula I instead.The result shows lamentedly, is in 1:0～50 scopes at formula I chemical compound and described organic acid weight ratio, and maximum single impurity increases (%) and total impurities increases (%) all in 150～300% scopes.
With reference to the method for above test example 9, different only is, and active medicine uses instead is formula I chemical compound (being free alkali).The result shows lamentedly, is in 1:0～50 scopes at formula I chemical compound and described organic acid weight ratio, and maximum single impurity increases (%) and total impurities increases (%) all in 150～300% scopes.
Above result shows that organic acid can not change because adding pharmaceutic adjuvant the active component stablizing effect.
Preparation of compositions example part
Following preparation example preparation is the solid composite of the present invention of pharmaceutical dosage forms.
Preparation example 1: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I crystal formation | 2 |
| Stearic acid | 5 |
| Starch | 50 |
| Microcrystalline Cellulose | 35 |
| Crosslinked carboxymethyl fecula sodium | 5 |
| HPMC | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that HPMC is made into 5% aqueous solution.Formula I chemical compound, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate drying.With the dried granule of gained and stearic acid and crosslinked carboxymethyl fecula sodium mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 2mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 2mg with free alkali.
Preparation example 2: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I I crystal formation | 0.5 |
| Stearic acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.With formula I chemical compound with partly measure stearic acid and mix, fully mix with starch, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and surplus stearic acid and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 0.5mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 0.5mg with free alkali.
Preparation example 3: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound III crystal formation | 10 |
| Stearic acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 2 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.Formula I chemical compound is mixed with stearic acid, fully mix with dextrin, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and silica sol and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 10mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 10mg with free alkali.
Preparation example 4: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound IV crystal formation | 5 |
| Stearic acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 5 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.Each material is fully mixed, and the block that its compacting is large stretch of is broken into and can passes through 18 purpose granules, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 5mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 5mg with free alkali.
Preparation example 5: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia chemical compound V crystal formation | 1 |
| Stearic acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 5 |
| PVP?K30 | 3 |
Method for making: the method with reference to preparation example 4 prepares tablet or capsule.
Preparation example 6:With reference to prescription and the method for making of preparation example 1, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 7:With reference to prescription and the method for making of preparation example 2, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 8:With reference to prescription and the method for making of preparation example 3, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 9:With reference to prescription and the method for making of preparation example 4, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 10:With reference to prescription and the method for making of preparation example 5, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 11:With reference to prescription and the method for making of preparation example 1, different is only activating agent wherein to be replaced with formula Ib chemical compound 1 crystal formation.
Preparation example 12:With reference to prescription and the method for making of preparation example 2, different is only activating agent wherein to be replaced with formula Ib chemical compound 2 crystal formations.
Preparation example 13:With reference to prescription and the method for making of preparation example 3, different is only activating agent wherein to be replaced with formula Ib chemical compound 3 crystal formations.
Preparation example 14:With reference to prescription and the method for making of preparation example 4, different is only activating agent wherein to be replaced with formula Ib chemical compound 4 crystal formations.
Preparation example 15:With reference to prescription and the method for making of preparation example 5, different is only activating agent wherein to be replaced with formula Ib chemical compound 5 crystal formations.
Preparation example 16:With reference to prescription and the method for making of preparation example 11, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 17:With reference to prescription and the method for making of preparation example 12, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 18:With reference to prescription and the method for making of preparation example 13, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 19:With reference to prescription and the method for making of preparation example 14, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 20:With reference to prescription and the method for making of preparation example 15, different is only stearic acid wherein to be replaced with magnesium stearate.
Preparation example 21: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I crystal formation | 2 |
| Citric acid | 5 |
| Starch | 50 |
| Microcrystalline Cellulose | 35 |
| Crosslinked carboxymethyl fecula sodium | 5 |
| Pulvis Talci | 5 |
| HPMC | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that HPMC is made into 5% aqueous solution.Formula I chemical compound, citric acid, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate drying.With the dried granule of gained and Pulvis Talci and crosslinked carboxymethyl fecula sodium mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 2mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 2mg with free alkali.
Preparation example 22: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I I crystal formation | 0.5 |
| Citric acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 5 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.Formula I chemical compound is mixed with citric acid, fully mix with starch, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and silica sol and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 0.5mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 0.5mg with free alkali.
Preparation example 23: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound III crystal formation | 10 |
| Citric acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PEG6000 | 2 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.Formula I chemical compound is mixed with citric acid, fully mix with dextrin, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and PEG6000 and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 10mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 10mg with free alkali.
Preparation example 24: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound IV crystal formation | 5 |
| Citric acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 5 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.Each material is fully mixed, and the block that its compacting is large stretch of is broken into and can passes through 18 purpose granules, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 5mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 5mg with free alkali.
Preparation example 25: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia chemical compound V crystal formation | 1 |
| Citric acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 5 |
| PVP?K30 | 3 |
Method for making: the method with reference to preparation example 4 prepares tablet or capsule.
Preparation example 26:With reference to prescription and the method for making of preparation example 21, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 27:With reference to prescription and the method for making of preparation example 22, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 28:With reference to prescription and the method for making of preparation example 23, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 29:With reference to prescription and the method for making of preparation example 24, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 30:With reference to prescription and the method for making of preparation example 25, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 31:With reference to prescription and the method for making of preparation example 21, different is only activating agent wherein to be replaced with formula Ib chemical compound 1 crystal formation.
Preparation example 32:With reference to prescription and the method for making of preparation example 22, different is only activating agent wherein to be replaced with formula Ib chemical compound 2 crystal formations.
Preparation example 33:With reference to prescription and the method for making of preparation example 23, different is only activating agent wherein to be replaced with formula Ib chemical compound 3 crystal formations.
Preparation example 34:With reference to prescription and the method for making of preparation example 24, different is only activating agent wherein to be replaced with formula Ib chemical compound 4 crystal formations.
Preparation example 35:With reference to prescription and the method for making of preparation example 25, different is only activating agent wherein to be replaced with formula Ib chemical compound 5 crystal formations.
Preparation example 36:With reference to prescription and the method for making of preparation example 31, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 37:With reference to prescription and the method for making of preparation example 32, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 38:With reference to prescription and the method for making of preparation example 33, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 39:With reference to prescription and the method for making of preparation example 34, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 40:With reference to prescription and the method for making of preparation example 35, different is only citric acid wherein to be replaced with tartaric acid.
Preparation example 41: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I crystal formation | 2 |
| Citric acid | 3 |
| Tartaric acid | 2 |
| Magnesium stearate | 5 |
| Starch | 50 |
| Microcrystalline Cellulose | 35 |
| Crosslinked carboxymethyl fecula sodium | 5 |
| HPMC | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that HPMC is made into 5% aqueous solution.Formula I chemical compound, citric acid, tartaric acid, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate drying.With the dried granule of gained and magnesium stearate and crosslinked carboxymethyl fecula sodium mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 2mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 2mg with free alkali.
Preparation example 42: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound I I crystal formation | 0.5 |
| Citric acid | 10 |
| Stearic acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Silica sol | 3 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.Formula I chemical compound is mixed with citric acid, fully mix with starch, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and stearic acid, silica sol and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 0.5mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 0.5mg with free alkali.
Preparation example 43: prepare tablet of the present invention or capsule
Prescription (every amount, mg):
| Formula Ia compound III crystal formation | 10 |
| Citric acid | 2 |
| Stearic acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PVP?K30 | 3 |
Method for making: 100 mesh sieves are pulverized and crossed to each material respectively.It is standby as binding agent that PVP K30 is made into 5% aqueous solution.Formula I chemical compound is mixed with citric acid, fully mix with dextrin, lactose again, with binding agent soft material processed, granulate drying.With the dried granule of gained and stearic acid and low-substituted hydroxypropyl cellulose mix homogeneously, for mixing granule eventually.Mix granule and be pressed into tablet the end with 2/3, and every contains formula Ia chemical compound and counts 10mg with free alkali.Mix granule and directly be filled in the hard capsule case end with other 1/3, and every capsules contains formula Ia chemical compound and counts 10mg with free alkali.
Preparation example 44,45,46:Respectively with reference to preparation example 41,42,43 prescription and technology, different only is replaces with formula Ib chemical compound 1 crystal formation, formula Ib chemical compound 2 crystal formations, formula Ib chemical compound 3 crystal formations with wherein active component.
Reference examples 1,2,3:Respectively with reference to preparation example 41,42,43 prescription and technology, different only is replaces with formula I chemical compound esilate with wherein active component.
Reference examples 4,5,6:Respectively with reference to preparation example 41,42,43 prescription and technology, different only is replaces with formula I chemical compound free alkali with wherein active component.
Test example 11: the study on the stability of compositions
Get the various tablets of above preparation example or reference examples gained, pack in the aluminum-plastic composite membrane sack, then each sample is placed 45 ° of C calorstats to place 5 months (can abbreviate " 45 ° of C5 months " disposal in the present invention as).For each sample, use [HPLC method A] to measure their maximum single impurity content and total impurities content in the time of 0 month, and measure them at maximum single impurity content and the total impurities content of 45 ° of C5 during the month, calculating maximum single impurity respectively by following formula increases percent and total impurities increase percent:
Maximum single impurity increases percent=[(45 ° C5 month maximum single impurity content-0 month maximum single impurity content) 0 month maximum single impurity content of ÷] * 100%
Total impurities increases percent=[(45 ° of C5 month total impurities content-0 month total impurities content) 0 month total impurities content of ÷] * 100%
In addition, for each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure them at the R content of isomer (%) of 45 ° of C5 during the month, being calculated as follows the R isomer increases percent:
The R isomer increases percent=[(45 ° of C5 month R content of isomer-0 month R content of isomer) 0 month R content of isomer of ÷] * 100%
Measurement result shows, beat allly be, whole each samples of preparation examples 1 to 46, maximum single impurity increases the percentage number average less than 50%, and total impurities increases the percentage number average and increases the percentage number average less than 45% less than 60%, R isomer.Yet reference examples 1 to 6 each sample, maximum single impurity increases the percentage number average in 150～350% scopes, and total impurities increases the percentage number average in 200～400% scopes,, the R isomer increases the percentage number average in 150～300% scopes.
Claims (10)
1. solid composite medicament wherein comprises:
(a) with following formula I chemical compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl;
(b) fatty acid or the acceptable salt of its pharmacy; And optional
(c) pharmaceutic adjuvant.
2. according to the solid composite medicament of claim 1, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate, benzene sulfonate or esilate; Perhaps, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate or benzene sulfonate; Perhaps, the acceptable salt of the pharmacy of wherein said formula I chemical compound is selected from following formula Ia chemical compound or formula Ib chemical compound:
3. according to the solid composite medicament of claim 1, wherein said fatty acid is stearic acid; Perhaps, the acceptable salt of the pharmacy of wherein said fatty acid is magnesium salt, sodium salt, calcium salt, the zinc salt of fatty acid; Perhaps, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate and combination thereof; Perhaps, wherein said fatty acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate and combination thereof.
4. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant includes but not limited to diluent or filler, disintegrating agent, binding agent, lubricant or fluidizer.
5. according to the solid composite medicament of claim 1, the weight ratio of wherein said formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.01～100, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.05～50, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.1～20, for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.2～20, and for example the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.5～10.
6. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant accounts for 0～99.5% of said composition weight, for example described pharmaceutic adjuvant accounts for 10～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 25～99% of said composition weight, for example described pharmaceutic adjuvant accounts for 50～98% of said composition weight, and for example described pharmaceutic adjuvant accounts for 75～95% of said composition weight.
7. according to the solid composite medicament of claim 1, it is the unit dose formulations form that is tablet, capsule, granule, piller etc.; Further, the amount that comprises formula I chemical compound or the acceptable salt of its pharmacy in described each unit dose formulations form is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
8. according to the solid composite medicament of claim 1, also comprise organic acid for example citric acid or tartaric acid or its combination in the wherein said pharmaceutic adjuvant.
9. solid composite medicament according to Claim 8, described formula I chemical compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.1～20.
10. a solid composite medicament wherein comprises
(a) with following formula I chemical compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl;
(b) organic acid; And optional
(c) pharmaceutic adjuvant; It is further as described in the arbitrary embodiment of description second aspect.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105726495A (en) * | 2014-12-12 | 2016-07-06 | 宜昌人福药业有限责任公司 | Short-term effect benzodiazepines salt medicine composition for injection and preparation method thereof |
| CN105130996B (en) * | 2015-08-07 | 2017-05-03 | 成都倍特药业有限公司 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| CN111346065A (en) * | 2018-12-21 | 2020-06-30 | 宜昌人福药业有限责任公司 | Solid pharmaceutical composition for oral cavity of benzodiazepine compound and preparation method thereof |
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| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and polymorphs thereof |
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Cited By (6)
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| CN105726495A (en) * | 2014-12-12 | 2016-07-06 | 宜昌人福药业有限责任公司 | Short-term effect benzodiazepines salt medicine composition for injection and preparation method thereof |
| CN105726495B (en) * | 2014-12-12 | 2019-03-29 | 宜昌人福药业有限责任公司 | A kind of short-acting benzodiazepine salt pharmaceutical composition of injection and preparation method thereof |
| CN105130996B (en) * | 2015-08-07 | 2017-05-03 | 成都倍特药业有限公司 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| CN111346065A (en) * | 2018-12-21 | 2020-06-30 | 宜昌人福药业有限责任公司 | Solid pharmaceutical composition for oral cavity of benzodiazepine compound and preparation method thereof |
| CN111346065B (en) * | 2018-12-21 | 2022-05-20 | 宜昌人福药业有限责任公司 | Solid pharmaceutical composition for oral cavity containing benzodiazepine compound and its preparation method |
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| CN103230595B (en) | 2014-10-08 |
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