CN103230595B - Composition for treating mental diseases - Google Patents

Composition for treating mental diseases Download PDF

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Publication number
CN103230595B
CN103230595B CN201310166656.6A CN201310166656A CN103230595B CN 103230595 B CN103230595 B CN 103230595B CN 201310166656 A CN201310166656 A CN 201310166656A CN 103230595 B CN103230595 B CN 103230595B
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formula
compound
salt
solid composite
composite medicament
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CN103230595A (en
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李友香
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Beijing Kaili economic and Trade Co., Ltd.
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李友香
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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

The compositions for the treatment of mental sickness
Technical field
The present invention relates to can be used for treating the solid composite medicament of central nervous system disease.
Background technology
With following formula I compound:
wherein R1 is bromine, and R2 and R3 are methyl,
Owing to containing above-mentioned specific structure, in WO00/69836, report that this compound (60 pages of example I c-8 of description) is fugitive central nervous system (CNS) inhibitor, there is the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action.They can be used for the intravenously administrable in following clinical treatment: as calm before the operation in 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 induction for general anesthesia and the component that maintains; ICU calmness etc., according to CN101501019A (PAION, application number CN200780028964.5) report in, the free alkali of this 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, color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.So the salt of people's synthesis type (I) compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing CN101501019A and US20100075955A1 (TILBROOK) have reported respectively benzene sulfonate, the esilate of formula I compound.CN102964349A (permanent auspicious, application number 201110456864.0) has reported the tosilate of formula I compound.
Have been reported the worry of formula I compound or its salt existence and stability aspect, this is disadvantageous for this compounds for clinical treatment relevant disease.
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.Having been surprisingly found that, when formula I compound or its salt is mixed with to solid composite medicament together with pharmaceutic adjuvant, wherein comprise fatty acid or its salt is favourable, is particularly favourable for its chemical stability.
Therefore, first aspect present invention provides a kind of solid composite medicament, wherein comprises:
(a) with following formula I 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 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 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 compound is selected from following formula Ia compound or formula Ib compound:
In the present invention, above-mentioned formula Ia compound is the tosilate of formula I compound, and formula Ib compound is the benzene sulfonate of formula I compound.In the present invention, while mentioning formula I compound, as do not specialized in its linguistic context, refer to free alkali shown in 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 has been surprisingly found that, formula I compound there is to beat all good result when particularly formula Ia compound or formula Ib compound are prepared together with fatty acid or the acceptable salt of its pharmacy, the effect of stability particularly, and this effect can not disappear for preparations shaping object other pharmaceutic adjuvant used because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I 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 further the conventional pharmaceutic adjuvant that other optional pharmaceutics is conventional.
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 such as corn starch, dextrin, microcrystalline Cellulose, modified starch, pregelatinized Starch, mannitol, lactose, sucrose, sorbitol, D-glucitol, erythritol, xylitol, fructose etc.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 be used separately, also can two or more combine use.Described water-soluble copolymer adhesive combined amount be for example tablet total weight amount 0.5 to 10wt%, preferred l to 5wt%.The oral formulations of employing pharmaceutical compositions of the present invention refers to and is mixed with tablet, capsule, granule or fine grain pharmaceutical preparation.Described preparation can the application of the invention formula 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 have been surprisingly found that and when formula I compound is prepared together with fatty acid or the acceptable salt of its pharmacy, occurred beat all good result.
According to the solid composite medicament of first aspect present invention, the weight ratio of wherein said formula I 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 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 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 compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.2～20, for example the weight ratio of formula I compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.5～10.
According to the solid composite medicament of 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 easily be determined according to those skilled in the art.For example, as disintegrating agent, its gross weight in compositions conventionally can be in 3～30% scopes, for example conventionally can be in 5～20% scopes.Again for example, as binding agent, its gross weight in compositions conventionally can be in 2～20% scopes, for example conventionally can be in 5～10% scopes.Again for example, as diluent or filler, it typically is and made the medicament can molding, so its amount can not determine especially, for example its gross weight in compositions conventionally can be in 1～95% scope, for example conventionally can be in 10～90% scopes.Again for example, as lubricant, its gross weight in compositions conventionally can be in 1～20% scope, for example conventionally can be in 1～10% scope, and for example conventionally can be in 1～8% scope; Yet, because fatty acid used in the present composition or the acceptable salt of its pharmacy may produce enough lubrications, therefore can not add in addition lubricant 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 " refers to the dosage form such as a tablet, a seed lac wafer etc.In one embodiment, the amount that comprises formula I compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 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 compound or the acceptable salt of its pharmacy in every tablet is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 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, in wherein said pharmaceutic adjuvant, also comprise organic acid for example citric acid or tartaric acid or its combination.Have been found that it is favourable in solid composite medicament of the present invention, adding appropriate above-mentioned organic acid.Although those skilled in the art it has been generally acknowledged that this class organic acid has for example buffering property of the character relevant with Acidity of Aikalinity, yet have been surprisingly found that having of this type of acid, the inventor helps improve the stability of active component in product.In an embodiment of the solid composite medicament of first aspect present invention, described formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.01～100, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.05～50, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.1～20, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.2～20, for example formula I 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 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 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 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 compound is selected from following formula Ia compound or formula Ib 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 in solid composite medicament of the present invention, adding appropriate above-mentioned organic acid.Although those skilled in the art it has been generally acknowledged that this class organic acid has for example buffering property of the character relevant with Acidity of Aikalinity, yet have been surprisingly found that having of this type of acid, the inventor helps improve the stability of active component in product.In an embodiment of the solid composite medicament of second aspect present invention, described formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.01～100, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.05～50, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.1～20, for example formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio are 1:0.2～20, for example formula I 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 such as corn starch, dextrin, microcrystalline Cellulose, modified starch, pregelatinized Starch, mannitol, lactose, sucrose, sorbitol, D-glucitol, erythritol, xylitol, fructose etc.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 be used separately, also can two or more combine use.Described water-soluble copolymer adhesive combined amount be for example tablet total weight amount 0.5 to 10wt%, preferred l to 5wt%.The oral formulations of employing pharmaceutical compositions of the present invention refers to and is mixed with tablet, capsule, granule or fine grain pharmaceutical preparation.Described preparation can the application of the invention formula 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.
According to the solid composite medicament of 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 easily be determined according to those skilled in the art.For example, as disintegrating agent, its gross weight in compositions conventionally can be in 3～30% scopes, for example conventionally can be in 5～20% scopes.Again for example, as binding agent, its gross weight in compositions conventionally can be in 2～20% scopes, for example conventionally can be in 5～10% scopes.Again for example, as diluent or filler, it typically is and made the medicament can molding, so its amount can not determine especially, for example its gross weight in compositions conventionally can be in 1～95% scope, for example conventionally can be in 10～90% scopes.Again for example, as lubricant, its gross weight in compositions conventionally can be in 1～20% scope, for example conventionally can be in 1～10% scope, and for example conventionally 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 " refers to the dosage form such as a tablet, a seed lac wafer etc.In one embodiment, the amount that comprises formula I compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 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 compound or the acceptable salt of its pharmacy in every tablet is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 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, in wherein said pharmaceutic adjuvant, also comprise fatty acid or the acceptable salt of its pharmacy.
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 have been surprisingly found that and when formula I compound is prepared together with fatty acid or the acceptable salt of its pharmacy, occurred beat all good result.The inventor has been surprisingly found that, formula I compound there is to beat all good result when particularly formula Ia compound or formula Ib compound are prepared together with fatty acid or the acceptable salt of its pharmacy, the effect of stability particularly, and this effect can not disappear for preparations shaping object other pharmaceutic adjuvant used because of adding other.Therefore, solid composite medicament of the present invention can be the solid composite medicament that comprises formula I 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 further the conventional pharmaceutic adjuvant that other optional pharmaceutics is conventional.
According to the solid composite medicament of second aspect present invention, the weight ratio of wherein said formula I 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 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 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 compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is 1:0.2～20, for example the weight ratio of formula I 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 compound or the acceptable salt of its pharmacy, fatty acid or the acceptable salt of its pharmacy and optional pharmaceutic adjuvant;
(ii) formula I 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) mixture of step (ii) is made to pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example, for preparing tablet, have been found that the hybrid mode of formula I compound or the acceptable salt of its pharmacy and fatty acid or the acceptable salt of its pharmacy is on realizing the object of the invention there are no impact; For example formula I 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, finally be pressed into again tablet, with formula I compound or the acceptable salt of its pharmacy are first mixed with other pharmaceutic adjuvant finally and are mixed with fatty acid or the acceptable salt of its pharmacy, finally be pressed into tablet, two kinds of mode gained tablets all show good character again.
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 compound or the acceptable salt of its pharmacy, organic acid and optional pharmaceutic adjuvant;
(ii) formula I compound or the acceptable salt of its pharmacy and organic acid and optional pharmaceutic adjuvant are mixed with random order, obtain mixture;
(iii) mixture of step (ii) is made to pharmaceutical preparation according to the mode of preparation unit dose formulations form.
For example, for preparing tablet, have been found that formula I compound or the acceptable salt of its pharmacy and organic acid hybrid mode are on realizing the object of the invention there are no impact; For example formula I compound or the acceptable salt of its pharmacy are pre-mixed with organic acid and then mix with other pharmaceutic adjuvant, finally be pressed into again tablet, with formula I compound or the acceptable salt of its pharmacy are first mixed finally and are mixed with organic acid with other pharmaceutic adjuvant, finally be pressed into tablet, two kinds of mode gained tablets all show good character again.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, 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 feature to various aspects of the present invention below.
The present invention relates to following formula I compound or the acceptable salt of its pharmacy:
In formula, R1 is bromine, and R2 and R3 are methyl;
The chemistry 3-[(4S by name of formula 1 compound) the bromo-1-methyl-6-of-8-(2-pyridine radicals)-4H-imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine -4-yl] methyl propionate,
In the present invention, preferred formula I compound is its benzene sulfonate or tosilate.
In the present invention, preferred formula I compound is to be selected from following formula Ia compound or formula Ib compound:
The present invention also provides in experimenter calm or the hypnogenic method of producing, and the method comprises uses solid composite medicament described in the first aspect present invention of the formula I compound of the present invention that comprises calmness or hypnosis effective dose or the acceptable salt of its pharmacy or second aspect to this experimenter.
According to the present invention, also provide and in experimenter, cause that method antianxity, the method comprise this experimenter is used to solid composite medicament described in the first aspect present invention of the formula I compound of the present invention that comprises anxiety effective dose or the acceptable salt of its pharmacy or second aspect.
According to the present invention further provides, cause method of flaccid muscles in experimenter, the method comprises uses solid composite medicament described in the first aspect present invention of the formula I compound of the present invention that comprises effective dose of flaccid muscles or the acceptable salt of its pharmacy or second aspect to this experimenter.
According to the present invention further provides the method for the treatment of convulsions state in experimenter, the method comprises uses solid composite medicament described in the first aspect present invention of the formula I compound of the present invention that comprises anticonvulsant effective dose or the acceptable salt of its pharmacy or second aspect to this experimenter.
In the present invention, described experimenter is compatibly mammal, preferably the mankind.
For solid composite medicament described in the first aspect present invention of above-mentioned disease or second aspect, 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 conventionally.
Described in first aspect present invention or second aspect, solid composite medicament can be used as fugitive CNS inhibitor, and they can be used for by following clinical settings oral administration: calm before operation in 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 induction for general anesthesia and the component that maintains; ICU is calm.In addition, described in first aspect present invention or second aspect, solid composite medicament can be used for the mental sickness such as calmness, hypnosis, anxiety, of flaccid muscles, convulsion.
The specific embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of 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 test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, rather than restriction the present invention.While preparing compositions below in listed prescription, formula I compound amount of calculation is all calculated with the form of its free alkali, listed formula is the amount of for example, in per unit dosage particles (every tablet, every seed lac wafer) contained formula I compound free alkali, while preparing compositions below, every batch of preparation amount is the amount of 10000 unit dose formulations, and 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]:
On HP1100Agilent chromatograph, carry out purity analysis:
Chromatographic column: Phenomenex Gemini C185 μ m (2.0 * 50mm) (guard column Phenomenex Gemini C18,2x4mm), U.S. Féraud 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
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: get various samples (crude drug or compositions) appropriate, (acetonitrile: water=50:50 wherein contains the NH of 1mmol to add acetonitrile-water mixed liquor 4hCO 3, and use NH 3solution is adjusted to pHl0) dissolve in right amount and make the solution of the about 1mg/ml of concentration, filter if desired.
Computational methods: the formula I compound chromatographic peak of take is main peak, its relative retention time is 1, read the peak area (peak area is less than 0.01% impurity peaks of main peak area and ignores) of the whole chromatographic peaks of relative retention time between 0.60～2.00, with area normalization method, calculate the content of each impurity peaks and the content of main peak (being also called chromatographic purity), and calculate maximum single contaminant content and total impurities content.
4 of its heptatomic rings of active component in pharmaceutical composition of the present invention are S-isomer, may mix and have a small amount of R-isomer in medicine.Below [HPLC method B] can be used for measuring R-isomer (compound representing with following formula Ix) and the situation of change thereof in the present composition.
in formula, R1 is bromine, and R2 and R3 are methyl;
[HPLC method B]:
On HP1100 Agilent chromatograph, carry out purity analysis:
Running time: to the 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 analyzes 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
Sample preparation: get various samples (crude drug or compositions) appropriate, add the appropriate supersound process of mobile phase and make to dissolve the also solution of the about 1mg/ml of diluted concentration, filter if desired.
Computational methods: the formula I compound chromatographic peak of take is main peak, its relative retention time is 1, read the peak area of impurity peaks between 1.10～1.25 of the peak area of main peak and relative retention time (its be formula Ix compound for R isomer), 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 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 and have identical retention time with formula I free alkali in chromatographic system, and this is that chromatography field is known.
test material sample:
The I crystal formation of the formula Ia compound using in all kinds of tests below, II crystal formation, III crystal formation, IV crystal formation are respectively that the method for recording according to [0049] section of (being embodiment 2), [0053] section (being embodiment 4) of description, [0057] section (being embodiment 6), [0061] section (being embodiment 8) in CN102964349A obtains.Also prepared by the following method and do not determined concrete crystal formation formula Ia compound: the formula Ia compound dissolution obtaining according to [0047] section of method of recording of description in CN102964349A is in 50% ethanol water, spraying is dried to obtain dry powder, they are all different from the X-ray diffraction feature of above-mentioned four kinds of crystal formations after measured, show without typical diffraction maximum (being designated as in the present invention the V crystal formation of formula Ia compound).
The formula Ib compound using in all kinds of tests below, 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 recording in prepares, and it is identical that its XRPD figure and DSC test result are all recorded with CN101501019A, specifically:
1 crystal formation of formula Ib compound: 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 2 θ places, and there is differential scanning calorimetry open beginning melt temperature in the scope of about 191-192 ℃;
2 crystal formations of formula Ib 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 there is the initial melt temperature of differential scanning calorimetry at about 180 ℃;
3 crystal formations of formula Ib compound: 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 2 θ places, and there is the initial melt temperature of differential scanning calorimetry in the scope of about 200-201 ℃;
4 crystal formations of formula Ib 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 there is 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 compound: 1 crystal formation of above-mentioned formula Ib compound is dissolved in 30% ethanol water, spraying is dried to obtain dry powder, they are all different from the X-ray diffraction feature of above-mentioned four kinds of crystal formations after measured, show without typical diffraction maximum (being designated as in the present invention 5 crystal formations of formula Ib compound).
The esilate of the formula I compound using in all kinds of tests below prepares (can be called for short below formula I esilate) with reference to [0101] section of method of recording of US20100075955A1 description.
The formula I compound (free alkali) using in all kinds of tests below obtains with reference to the preparation method of this compound of reporting in WO00/69836 (60 pages of example I c-8 of description).
Each tests the equal >99.0%[HPLC method of the chromatographic purity A with material sample salt or free alkali above], the equal <1.0%[HPLC method of R content of isomer B].
The R-isomer the present invention relates to (being the compound that formula Ix represents) can be carried out with reference to the method for recording in WO00/69836, specific as follows:
Step 1: with reference to the preparation method of WO00/69836 description 23-24 page Int-1, use Fmoc-D-Glu (OMe)-OH (biochemical purchased from gill) to obtain take following formula Int-1x intermediate (its isomer that is Int-1) for raw material:
Step 2: follow the preparation method with reference to WO00/69836 description 34-35 page Example I-1, the intermediate compound I nt-2 that uses Int-1x intermediate and WO00/69836 description 24 to record is raw material, obtains following Ex I-10x compound (it is the isomer of the Example I-10 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 Example Ic-8, using Ex I-10x is raw material, obtains take the compound (the R-isomer of its Example Ic-8 compound that is 60 pages of records of WO00/69836 description) that following formula Ix represents
In formula, R1 is bromine, 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].In the test of [HPLC method B] method, for S isomer, the relative retention time of this R isomer is about 1.17.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 compound and fatty acid composite test
Get the I crystal formation that can pass through the formula Ia compound of 80 order fine powder states, separately get and can pass through stearic acid or the magnesium stearate of 80 order fine powder states, formula Ia compound (be mixed at every turn and at least use the amount of 10g) and a certain amount of stearic acid as shown in the table or salt are ground well in mortar (fully to be ground all, by X-ray diffraction, test, grinding equal process and can not change the crystal formation of formula I compound herein and below), pack in aluminum-plastic composite membrane sack, then each sample is placed in to 50 ° of C calorstats and places 4 months (can dispose referred to as " 50 ° of C4 months " in the present invention).For each sample, use [HPLC method A] to measure their maximum single contaminant content and total impurities content in the time of 0 month, and measure they at 50 ° of C4 maximum single contaminant content and the total impurities content during month, by following formula, calculate respectively that maximum single contaminant increases percent and total impurities increases percent:
Maximum single contaminant increases percent=[(50 ° of maximum single contaminant of C4 month content-0 month maximum single contaminant content) 0 month maximum single contaminant 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 the first hurdle in upper table " stearic acid: I crystal formation " represents to mix: the two weight ratio of I crystal formation, for example this value is to represent that 0 part of stearic acid mixes with 1 part of I crystal formation at 0 o'clock, this value is to represent that 0.01 part of stearic acid mixes with 1 part of I crystal formation at 0.01 o'clock, this value is to represent that 200 parts of stearic acid mix with 1 part of I crystal formation at 200 o'clock, etc.; The 4th hurdle also has similar meaning similarly.
Visible according to upper table result, withstand high temperatures environment better during the combination of the I crystal formation of formula Ia compound and stearic acid or stearyl ester magnesium, particularly the weight ratio at formula I compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is in the scope of 1:0.2～20, the result with obvious excellence, although the weight ratio of formula I compound or the acceptable salt of its pharmacy and described fatty acid or the acceptable salt of its pharmacy is that in the scope of 1:50～200, impurity increase is not remarkable, but excessive fatty acid or the acceptable salt of its pharmacy are present in other performance tabletting performance for example that may have influence on medicine in formula, because fatty acid or the acceptable salt of its pharmacy have the function of tablet lubricants, conventionally consumption is tablet weight 1～10% particularly in 1～5% scope.
test example 2: formula I compound and fatty acid composite test
With reference to the method for above test example 1, different is only that active medicine is used the II crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).For example, stearic acid: in the proportioning of II crystal formation=5, maximum single contaminant increases (%) and total impurities increase (%) is respectively 26% and 36%; Again for example, magnesium stearate: in the proportioning of II crystal formation=5, maximum single contaminant increases (%) and total impurities increase (%) is respectively 25% and 35%.
With reference to the method for above test example 1, different is only that active medicine is used the III crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used the IV crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used the V crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
test example 3: formula I compound and fatty acid composite test
With reference to the method for above test example 1, different is only that active medicine is used 1 crystal formation into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).For example, stearic acid: in the proportioning of II crystal formation=5, maximum single contaminant increases (%) and total impurities increase (%) is respectively 23% and 39%; Again for example, magnesium stearate: in the proportioning of II crystal formation=5, maximum single contaminant increases (%) and total impurities increase (%) is respectively 26% and 42%.
With reference to the method for above test example 1, different is only that active medicine is used 2 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used 3 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used 4 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used 5 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities and increases in (%) and table 1 corresponding proportioning acquired results and differ and be all no more than 5 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is in the scope of 1:0.2～20) or be all no more than 15 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:0～0.15 scope is interior) or be all no more than 10 percentage points (weight ratio of the salt of formula I compound and described fatty acid or its salt is that 1:50～200 scope is interior).
With reference to the method for above test example 1, different is only that active medicine is used the esilate into formula I instead.Result shows lamentedly, in the weight ratio of formula I compound and described fatty acid or its salt, is in the scope of 1:0～200, and maximum single contaminant increases (%) and total impurities increase (%) all in 200～400% scopes.For example, stearic acid: in the proportioning of esilate=20, maximum single contaminant increases (%) and total impurities increase (%) is respectively 242% and 343%; Again for example, magnesium stearate: in the proportioning of esilate=20, maximum single contaminant increases (%) and total impurities increase (%) is respectively 234% and 325%.Visible, even if be equally the acid-addition salts of formula I compound, the esilate of formula I compound but shows the obvious effect of improving of the stability that is difficult to realize as shown in benzene sulfonate or tosilate.
With reference to the method for above test example 1, different is only that active medicine is used instead as formula I compound (being free alkali).Result shows lamentedly, in the weight ratio of formula I compound and described fatty acid or its salt, is in the scope of 1:0～200, and maximum single contaminant increases (%) and total impurities increase (%) all in 200～400% scopes.For example, stearic acid: in the proportioning of free alkali=20, maximum single contaminant increases (%) and total impurities increase (%) is respectively 223% and 319%; Again for example, magnesium stearate: in the proportioning of free alkali=20, maximum single contaminant increases (%) and total impurities increase (%) is respectively 211% and 345%.
test example 4: the test of formula I compound, fatty acid and pharmaceutic adjuvant combination
Get the I crystal formation that can pass through the formula Ia compound of 80 order fine powder states, separately get and can pass through stearic acid or the magnesium stearate of 80 order fine powder states, and can pass through the pharmaceutic adjuvant described below of 80 order fine powder states.By weight formula Ia 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 aluminum-plastic composite membrane sack, then each sample is placed in to 50 ° of C calorstats and places 4 months.The maximum single contaminant after the month increases percent and total impurities increase percent through 50 ° of C4 with reference to the method for test example 1, to measure each sample.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).For example, stearic acid: in the proportioning of I crystal formation=2, maximum single contaminant increases (%) and total impurities increase (%) is respectively 22% and 34%; Again for example, magnesium stearate: in the proportioning of I crystal formation=2, maximum single contaminant increases (%) and total impurities increase (%) is respectively 22% and 37%.
test example 5: the test of formula I compound, fatty acid and pharmaceutic adjuvant combination
With reference to the method for above test example 4, different is only that active medicine is used the II crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used the III crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used the IV crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used the V crystal formation into formula Ia compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used 1 crystal formation into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used 2 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used 3 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used 4 crystal formations into formula Ib compound instead.Basic identical in result and table 1, maximum single contaminant increases (%) and total impurities increases corresponding formula Ia compound in (%) and table 1: stearic acid or salt proportioning acquired results differ and be all no more than 8 percentage points (formula Ia compounds: stearic acid or salt=0.2,2 or 20) or be all no more than 20 percentage points (formula Ia compounds: stearic acid or salt=0) or be all no more than 15 percentage points (formula Ia compounds: stearic acid or salt=50).
With reference to the method for above test example 4, different is only that active medicine is used the esilate into formula I instead.Result shows lamentedly, in the weight ratio of formula I compound and described fatty acid or its salt, is in the scope of 1:0～50, and maximum single contaminant increases (%) and total impurities increase (%) all in 200～400% scopes.
With reference to the method for above test example 4, different is only that active medicine is used instead as formula I compound (being free alkali).Result shows lamentedly, in the weight ratio of formula I compound and described fatty acid or its salt, is in the scope of 1:0～50, and maximum single contaminant increases (%) and total impurities increase (%) all in 200～400% scopes.
Above result demonstration, stearic acid or its salt pair active component stablizing effect can be because not adding pharmaceutic adjuvant to change.
test example 6: formula I compound and organic acid composite test
Get the I crystal formation that can pass through the formula Ia compound of 80 order fine powder states, separately get and can pass through citric acid or the tartaric acid of 80 order fine powder states, formula Ia compound and a certain amount of organic acid as shown in the table are ground well in mortar (fully to be ground all, by X-ray diffraction, test, grinding equal process and can not change the crystal formation of formula I compound herein and below), pack in aluminum-plastic composite membrane sack, then each sample is placed in to 50 ° of C calorstats and places 4 months (can dispose referred to as " 50 ° of C4 months " in the present invention).For each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure they at 50 ° of C4 the R content of isomer (%) during the month, being calculated as follows R isomer increases percent:
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 R isomer increases (%) Tartaric acid: I crystal formation 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 the first hurdle in upper table " citric acid: I crystal formation " represents to mix: the two weight ratio of I crystal formation, for example this value is to represent that 0 part of citric acid mixes with 1 part of I crystal formation at 0 o'clock, this value is to represent that 0.01 part of citric acid mixes with 1 part of I crystal formation at 0.01 o'clock, this value is to represent that 200 parts of citric acid mix with 1 part of I crystal formation at 200 o'clock, etc.; Third column also has similar meaning similarly.
Visible according to upper table result, withstand high temperatures environment better during the combination of the I crystal formation of formula Ia compound and citric acid or tartaric acid, at formula I compound or the acceptable salt of its pharmacy and described organic acid weight ratio, be particularly in the scope of 1:0.2～20, the result with obvious excellence, R content of isomer increases not obvious.When although the weight ratio of formula I 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 contaminant 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 essentially identical maximum single contaminant increases percent and total impurities increases percent when this three kinds of weight ratios combination, for example, compare to the citric acid result of using corresponding proportioning to be relevantly no more than 10 percentage points.When visible organic acid amount is few for the generation that suppresses R isomer impurities without effect, but when organic acid amount be increased to I crystal formation weight more than 50 times time other impurity significantly increase.
test example 7: formula I compound and organic acid composite test
With reference to the method for above test example 6, different is only that active medicine is used the II crystal formation into formula Ia compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 7 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).For example, citric acid: in the proportioning of II crystal formation=5, it is 33% that R isomer increases (%); Again for example, tartaric acid: in the proportioning of II crystal formation=5, it is 32% that R isomer increases (%).
With reference to the method for above test example 6, different is only that active medicine is used the III crystal formation into formula Ia compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used the IV crystal formation into formula Ia compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 6 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used the V crystal formation into formula Ia compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 14 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
test example 8: formula I compound and organic acid composite test
With reference to the method for above test example 6, different is only that active medicine is used 1 crystal formation into formula Ib compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 14 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 6 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).For example, citric acid: in the proportioning of II crystal formation=5, it is 36% that R isomer increases (%); Again for example, tartaric acid: in the proportioning of II crystal formation=5, it is 36% that R isomer increases (%).
With reference to the method for above test example 6, different is only that active medicine is used 2 crystal formations into formula Ib compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used 3 crystal formations into formula Ib compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 14 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used 4 crystal formations into formula Ib compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 6 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used 5 crystal formations into formula Ib compound instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 6 percentage points (salt of formula I compound and described organic acid weight ratio are in the scope of 1:0.2～20) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～0.15 scope is interior) or be all no more than 5 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:50～200 scope is interior).
With reference to the method for above test example 6, different is only that active medicine is used the esilate into formula I instead.Result shows lamentedly, at formula I compound and described organic acid weight ratio, is in the scope of 1:0～200, and R isomer increases (%) all in 150～300% scopes.For example, citric acid: in the proportioning of esilate=20, it is 212% that R isomer increases (%); Again for example, tartaric acid: in the proportioning of esilate=20, it is 193% that R isomer increases (%).Visible, even if be equally the acid-addition salts of formula I compound, the esilate of formula I compound but shows the obvious effect of improving of the stability that is difficult to realize as shown in benzene sulfonate or tosilate.
With reference to the method for above test example 6, different is only that active medicine is used instead as formula I compound (being free alkali).Result shows lamentedly, at formula I compound and described organic acid weight ratio, is in the scope of 1:0～200, and maximum single contaminant increases (%) and total impurities increases (%) all in 150～300% scopes.For example, citric acid: in the proportioning of free alkali=20, it is 219% that R isomer increases (%); Again for example, tartaric acid: in the proportioning of free alkali=20, it is 234% that R isomer increases (%).
test example 9: the test of formula I compound, organic acid and pharmaceutic adjuvant combination
Get the I crystal formation that can pass through the formula Ia compound of 80 order fine powder states, separately get and can pass through citric acid or the tartaric acid of 80 order fine powder states, and can pass through the pharmaceutic adjuvant described below of 80 order fine powder states.By weight formula Ia 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 aluminum-plastic composite membrane sack, then each sample is placed in to 50 ° of C calorstats and places 4 months.The R isomer after the month increases (%) through 50 ° of C4 with reference to the method for test example 6, to measure each sample.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 6 percentage points of (formula Ia compounds:.For example, citric acid: in the proportioning of I crystal formation=2, it is 34% that R isomer increases (%); Again for example, tartaric acid: in the proportioning of I crystal formation=2, maximum single contaminant increases (%) and total impurities increase (%) is respectively 31%.
test example 10: the test of formula I compound, organic acid and pharmaceutic adjuvant combination
With reference to the method for above test example 9, different is only that active medicine is used the II crystal formation into formula Ia compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used the III crystal formation into formula Ia compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used the IV crystal formation into formula Ia compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used the V crystal formation into formula Ia compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used 1 crystal formation into formula Ib compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used 2 crystal formations into formula Ib compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used 3 crystal formations into formula Ib compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used 4 crystal formations into formula Ib compound instead.Organic acid=0.2,2,20 or 50) or be all no more than 20 percentage points of (formula Ia compounds: organic acid=0) basic identical in result and table 2, R isomer increases corresponding formula Ia compound in (%) and table 2: organic acid proportioning acquired results differs and is all no more than 8 percentage points of (formula Ia compounds:.
With reference to the method for above test example 9, different is only that active medicine is used the esilate into formula I instead.Result shows lamentedly, at formula I compound and described organic acid weight ratio, is in the scope of 1:0～50, and maximum single contaminant increases (%) and total impurities increases (%) all in 150～300% scopes.
With reference to the method for above test example 9, different is only that active medicine is used instead as formula I compound (being free alkali).Result shows lamentedly, at formula I compound and described organic acid weight ratio, is in the scope of 1:0～50, and maximum single contaminant increases (%) and total impurities increases (%) all in 150～300% scopes.
Above result demonstration, organic acid can be because not adding pharmaceutic adjuvant to change to active component stablizing effect.
compositions preparation 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
Formula (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 respectively and crossed to each material.HPMC is made into 5% aqueous solution standby as binding agent.Formula I compound, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with stearic acid and crosslinked carboxymethyl fecula sodium, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 2mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 2mg containing formula Ia compound with free alkali.
preparation example 2: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.By formula I compound with partly measure stearic acid and mix, more fully mix with starch, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with surplus stearic acid and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 0.5mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 0.5mg containing formula Ia compound with free alkali.
preparation example 3: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.Formula I compound is mixed with stearic acid, more fully mix with dextrin, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with silica sol and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 10mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 10mg containing formula Ia compound with free alkali.
preparation example 4: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.Each material fully being mixed, suppressed large stretch of block, then be broken into and can pass through 18 object granules, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 5mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 5mg containing formula Ia compound with free alkali.
preparation example 5: prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia 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: prepare tablet or capsule with reference to the method for preparation example 4.
preparation example 6:with reference to formula and the method for making of preparation example 1, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 7:with reference to formula and the method for making of preparation example 2, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 8:with reference to formula and the method for making of preparation example 3, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 9:with reference to formula and the method for making of preparation example 4, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 10:with reference to formula and the method for making of preparation example 5, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 11:with reference to formula and the method for making of preparation example 1, different is only activating agent wherein to be replaced with to formula Ib compound 1 crystal formation.
preparation example 12:with reference to formula and the method for making of preparation example 2, different is only activating agent wherein to be replaced with to formula Ib compound 2 crystal formations.
preparation example 13:with reference to formula and the method for making of preparation example 3, different is only activating agent wherein to be replaced with to formula Ib compound 3 crystal formations.
preparation example 14:with reference to formula and the method for making of preparation example 4, different is only activating agent wherein to be replaced with to formula Ib compound 4 crystal formations.
preparation example 15:with reference to formula and the method for making of preparation example 5, different is only activating agent wherein to be replaced with to formula Ib compound 5 crystal formations.
preparation example 16:with reference to formula and the method for making of preparation example 11, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 17:with reference to formula and the method for making of preparation example 12, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 18:with reference to formula and the method for making of preparation example 13, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 19:with reference to formula and the method for making of preparation example 14, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 20:with reference to formula and the method for making of preparation example 15, different is only stearic acid wherein to be replaced with to magnesium stearate.
preparation example 21: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.HPMC is made into 5% aqueous solution standby as binding agent.Formula I compound, citric acid, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with Pulvis Talci and crosslinked carboxymethyl fecula sodium, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 2mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 2mg containing formula Ia compound with free alkali.
preparation example 22: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.Formula I compound is mixed with citric acid, more fully mix with starch, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with silica sol and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 0.5mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 0.5mg containing formula Ia compound with free alkali.
preparation example 23: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.Formula I compound is mixed with citric acid, more fully mix with dextrin, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with PEG6000 and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 10mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 10mg containing formula Ia compound with free alkali.
preparation example 24: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.Each material fully being mixed, suppressed large stretch of block, then be broken into and can pass through 18 object granules, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 5mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 5mg containing formula Ia compound with free alkali.
preparation example 25: prepare tablet of the present invention or capsule
Formula (every amount, mg):
Formula Ia 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: prepare tablet or capsule with reference to the method for preparation example 4.
preparation example 26:with reference to formula and the method for making of preparation example 21, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 27:with reference to formula and the method for making of preparation example 22, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 28:with reference to formula and the method for making of preparation example 23, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 29:with reference to formula and the method for making of preparation example 24, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 30:with reference to formula and the method for making of preparation example 25, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 31:with reference to formula and the method for making of preparation example 21, different is only activating agent wherein to be replaced with to formula Ib compound 1 crystal formation.
preparation example 32:with reference to formula and the method for making of preparation example 22, different is only activating agent wherein to be replaced with to formula Ib compound 2 crystal formations.
preparation example 33:with reference to formula and the method for making of preparation example 23, different is only activating agent wherein to be replaced with to formula Ib compound 3 crystal formations.
preparation example 34:with reference to formula and the method for making of preparation example 24, different is only activating agent wherein to be replaced with to formula Ib compound 4 crystal formations.
preparation example 35:with reference to formula and the method for making of preparation example 25, different is only activating agent wherein to be replaced with to formula Ib compound 5 crystal formations.
preparation example 36:with reference to formula and the method for making of preparation example 31, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 37:with reference to formula and the method for making of preparation example 32, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 38:with reference to formula and the method for making of preparation example 33, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 39:with reference to formula and the method for making of preparation example 34, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 40:with reference to formula and the method for making of preparation example 35, different is only citric acid wherein to be replaced with to tartaric acid.
preparation example 41: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.HPMC is made into 5% aqueous solution standby as binding agent.Formula I compound, citric acid, tartaric acid, starch, microcrystalline Cellulose are fully mixed, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with magnesium stearate and crosslinked carboxymethyl fecula sodium, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 2mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 2mg containing formula Ia compound with free alkali.
preparation example 42: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.Formula I compound is mixed with citric acid, more fully mix with starch, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with stearic acid, silica sol and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 0.5mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 0.5mg containing formula Ia compound with free alkali.
preparation example 43: prepare tablet of the present invention or capsule
Formula (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 respectively and crossed to each material.PVP K30 is made into 5% aqueous solution standby as binding agent.Formula I compound is mixed with citric acid, more fully mix with dextrin, lactose, with binding agent soft material processed, granulate, dry.The dry granule of gained is mixed homogeneously with stearic acid and low-substituted hydroxypropyl cellulose, is eventually mixed granule.By mixing granule 2/3 end, be pressed into tablet, containing formula Ia compound, with free alkali, count 10mg for every.By mixing granule other 1/3 end, be directly filled in hard capsule case, every capsules is counted 10mg containing formula Ia compound with free alkali.
preparation example 44,45,46:with reference to the composition and engineering of preparation example 41,42,43, different is only that active component is wherein replaced with to formula Ib compound 1 crystal formation, formula Ib compound 2 crystal formations, formula Ib compound 3 crystal formations respectively.
reference examples 1,2,3:with reference to the composition and engineering of preparation example 41,42,43, different is only that active component is wherein replaced with to formula I compound esilate respectively.
reference examples 4,5,6:with reference to the composition and engineering of preparation example 41,42,43, different is only that active component is wherein replaced with to formula I compound free alkali respectively.
test example 11: the study on the stability of compositions
Get the various tablets of above preparation example or reference examples gained, pack in aluminum-plastic composite membrane sack, then each sample is placed in to 45 ° of C calorstats and places 5 months (can dispose referred to as " 45 ° of C5 months " in the present invention).For each sample, use [HPLC method A] to measure their maximum single contaminant content and total impurities content in the time of 0 month, and measure they at 45 ° of C5 maximum single contaminant content and the total impurities content during month, by following formula, calculate respectively that maximum single contaminant increases percent and total impurities increases percent:
Maximum single contaminant increases percent=[(45 ° of maximum single contaminant of C5 month content-0 month maximum single contaminant content) 0 month maximum single contaminant 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 they at 45 ° of C5 the R content of isomer (%) during the month, being calculated as follows R isomer increases percent:
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 demonstration, surprisingly, each sample of whole preparation examples 1 to 46, maximum single contaminant increases percent and is all less than 50%, and total impurities increase percent is all less than 60%, R isomer increase percent and is all less than 45%.Yet reference examples 1 to 6 each sample, maximum single contaminant increases percent all in 150～350% scopes, and total impurities increases percent all in 200～400% scopes,, R isomer increases percent all in 150～300% scopes.

Claims (1)

1. a solid composite medicament, wherein comprises:
(a) with the salt of following formula I compound:
Wherein R1 is bromine, and R2 and R3 are methyl;
(b) stearic acid or the acceptable salt of its pharmacy; And optional
(c) pharmaceutic adjuvant,
Wherein,
The salt of described formula I compound is the tosilate of formula I compound or the benzene sulfonate of formula I compound,
The weight ratio of the salt of described formula I compound and described stearic acid or the acceptable salt of its pharmacy is 1:0.2 ~ 20.
2. according to the solid composite medicament of claim 1, the salt of wherein said formula I compound is selected from following formula Ia compound or formula Ib compound:
、 。
3. according to the solid composite medicament of claim 1, wherein said stearic acid or the acceptable salt of its pharmacy are selected from: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate and combination thereof.
4. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant is selected from diluent, disintegrating agent, binding agent, lubricant or fluidizer.
5. according to the solid composite medicament of claim 1, the weight ratio of the salt of its Chinese style I compound and described stearic 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.
7. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant accounts for 10 ~ 99% of said composition weight.
8. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant accounts for 25 ~ 99% of said composition weight.
9. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant accounts for 50 ~ 98% of said composition weight.
10. according to the solid composite medicament of claim 1, wherein said pharmaceutic adjuvant accounts for 75 ~ 95% of said composition weight.
11. according to the solid composite medicament of claim 1, and it is the unit dose formulations form that is tablet, capsule, granule or piller.
12. according to the solid composite medicament of claim 11, and the amount of the salt that comprises formula I compound in described each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 100mg.
13. according to the solid composite medicament of claim 11, and the amount of the salt that comprises formula I compound in described each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 50mg.
14. according to the solid composite medicament of claim 11, and the amount of the salt that comprises formula I compound in described each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 25mg.
15. according to the solid composite medicament of claim 11, and the amount of the salt that comprises formula I compound in described each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.5 ~ 20mg.
16. according to the solid composite medicament of claim 1 to 15 any one, also comprises and be selected from following organic acid in wherein said pharmaceutic adjuvant: citric acid, tartaric acid or its combination.
17. according to the solid composite medicament of claim 16, and the salt of described formula I compound and described organic acid weight ratio are 1:0.1 ~ 20.
18. according to the solid composite medicament of claim 16, and the salt of described formula I compound and described organic acid weight ratio are 1:0.2 ~ 20.
19. according to the solid composite medicament of claim 16, and the salt of described formula I compound and described organic acid weight ratio are 1:0.5 ~ 10.
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CN106632342B (en) * 2015-08-07 2019-01-25 成都倍特药业有限公司 The 2- naphthalene sulfonate of benzodiazepine * derivative and the preparation method of crystal form and they
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
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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