CN103230595B - Composition for treating mental diseases - Google Patents
Composition for treating mental diseases Download PDFInfo
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- 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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- Medicinal Preparation (AREA)
Abstract
The invention relates to a composition for treating mental diseases and in particular relates to a solid drug composition. The composition comprises (a) a compound shown in the formula I in the specification or a pharmaceutically acceptable salt of the compound, (b) a fatty acid or a pharmaceutically acceptable salt thereof and (c) optional pharmaceutic adjuvants, wherein in the formula I, R1 is bromine, and R2 and R3 are methyl. The composition has good pharmaceutical properties.
Description
Technical Field
The present invention relates to solid pharmaceutical compositions useful for treating central nervous system disorders.
Background
A compound of the following formula I:
wherein R1 is bromo, R2 and R3 are methyl,
having the above-specified structure, WO00/69836 reports that the compound (example Ic-8 on page 60 of the specification) is a short-acting Central Nervous System (CNS) inhibitor with sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant effects. They can be used for intravenous administration in the following clinical treatment regimens: pre-operative sedation, anxiolytic and amnesic uses such as during surgery; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics and analgesics; ICU quiz et al reported in CN101501019A (PAION, application No. CN200780028964.5) that the free base of this compound is not very stable, is only suitable for storage at low temperatures of 5 ℃, and stored samples deliquesced under 40 ℃/75% relative humidity (open) with a yellow to orange color and showed a significant decrease in content relative to the initial content. It is therefore desirable to synthesize salts of the compounds of formula (I) with increased chemical stability for use in the preparation of pharmaceuticals.
The besylate and ethanesulfonate of the compound of formula I have been reported in CN101501019A and US20100075955a1(TILBROOK), respectively. CN102964349A (henry, application No. 201110456864.0) reports the p-toluenesulfonate salt of the compound of formula I.
There have been reported concerns about the stability of compounds of formula I or their salts, which is disadvantageous for such compounds for use in clinical treatment of related diseases.
Disclosure of Invention
The present invention aims at an advantageous pharmaceutical composition, in particular a solid pharmaceutical composition, which is expected to have good pharmaceutical properties such as stability. It has surprisingly been found that the inclusion of a fatty acid or a salt thereof is advantageous, in particular with respect to its chemical stability, when a compound of formula I or a salt thereof is formulated together with pharmaceutical excipients into a solid pharmaceutical composition.
Accordingly, in a first aspect the present invention provides a solid pharmaceutical composition comprising:
(a) a compound of formula I:
wherein R1 is bromo, R2 and R3 are methyl;
(b) a fatty acid or a pharmaceutically acceptable salt thereof; and optionally
(c) And (3) a medicinal auxiliary material.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the pharmaceutically acceptable salt of the compound of formula I is a p-toluenesulfonate, benzenesulfonate or ethanesulfonate.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the pharmaceutically acceptable salt of the compound of formula I is a p-toluenesulfonate salt or a benzenesulfonate salt.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the pharmaceutically acceptable salt of the compound of formula I is selected from a compound of formula Ia or a compound of formula Ib:
in the present invention, the compound of formula Ia is p-toluenesulfonate of the compound of formula I, and the compound of formula Ib is benzenesulfonate of the compound of formula I. In the present invention, reference to a compound of formula I, as the context requires, is intended to refer to the free base of formula I as well as its pharmaceutically acceptable salts, such as the p-toluenesulphonate and benzenesulphonate salts mentioned above.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the fatty acid is stearic acid.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the pharmaceutically acceptable salt of a fatty acid is a magnesium salt, a sodium salt, a calcium salt, a zinc salt of a fatty acid.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the fatty acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate, and combinations thereof.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the fatty acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: stearic acid, magnesium stearate, calcium stearate, and combinations thereof.
The present inventors have surprisingly found that unexpectedly good effects, in particular stability effects, occur when a compound of formula I, in particular a compound of formula Ia or a compound of formula Ib, is formulated together with a fatty acid or a pharmaceutically acceptable salt thereof, without this effect being lost by the addition of other pharmaceutical excipients used for formulation shaping purposes. Therefore, the solid pharmaceutical composition of the present invention may be a solid pharmaceutical composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and the fatty acid of the present invention or a pharmaceutically acceptable salt thereof, and may further comprise other optional conventional pharmaceutical excipients commonly used in pharmacy.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the pharmaceutical excipients include, but are not limited to, diluents or fillers, disintegrants, binders, lubricants or glidants.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the diluent or filler includes, but is not limited to: starches such as corn starch, dextrin, microcrystalline cellulose, modified starch, pregelatinized starch, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose, and the like. More preferably, mannitol and lactose are included.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the disintegrant includes, but is not limited to: low-substituted hydroxypropyl cellulose, sodium cross-linked carboxymethyl starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, starch, and the like.
The solid pharmaceutical composition according to the first aspect of the invention, wherein the binder is such as, but not limited to: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. More preferred include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or polyvinyl alcohol. The binders may be used alone or in combination of two or more. The water-soluble polymer binder is blended in an amount of, for example, 0.5 to 10 wt%, preferably l to 5 wt%, based on the total weight of the tablet. The oral preparation in the form of the pharmaceutical composition of the present invention means a pharmaceutical preparation formulated into tablets, capsules, granules or fine granules. The preparation can be prepared into tablets, capsules, granules or fine granules by a conventional method using the formulation of the present invention and the like.
In the present invention, the lubricant and glidant may be collectively referred to as a lubricant. Lubricants include, but are not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid paraffin, polyethylene glycol, silicon dioxide, colloidal silicon dioxide, superfine silica powder, talcum powder, hydrogenated vegetable oil and the like or a combination thereof. Although the above-described fatty acids or pharmaceutically acceptable salts thereof of the present invention have the effect of a lubricant, the present inventors have surprisingly found that unexpectedly good results occur when the compound of formula I is formulated with a fatty acid or pharmaceutically acceptable salt thereof.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the fatty acid or a pharmaceutically acceptable salt thereof is 1: 0.01-100, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.05-50, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.1-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.2-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.5 to 10.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the pharmaceutical excipient accounts for 0-99.5% of the weight of the composition, such as 10-99% of the weight of the composition, such as 25-99% of the weight of the composition, such as 50-98% of the weight of the composition, such as 75-95% of the weight of the composition. The amount of the pharmaceutical excipient can be easily determined empirically by those skilled in the art. For example, as a disintegrant, the total weight thereof in the composition may be generally in the range of 3 to 30%, for example, may be generally in the range of 5 to 20%. For another example, the total weight of the binder in the composition may be generally in the range of 2 to 20%, for example, generally in the range of 5 to 10%. For another example, as a diluent or filler, it is usually used in order to enable the molding of a drug, and therefore the amount thereof may not be particularly determined, and for example, it may be usually in the range of 1 to 95% by weight, for example, usually in the range of 10 to 90% by weight, based on the total weight of the composition. As another example, the total weight of the lubricant in the composition may be generally in the range of 1 to 20%, for example, may be generally in the range of 1 to 10%, for example, may be generally in the range of 1 to 8%; however, since the fatty acid or pharmaceutically acceptable salt thereof used in the composition of the present invention may produce sufficient lubrication, a lubricant may not be additionally added in the present invention.
The solid pharmaceutical composition according to the first aspect of the present invention is in the form of a formulation of tablets, capsules, granules, pellets and the like. In one embodiment, the solid pharmaceutical composition is in the form of a formulation of tablets, capsules, granules. In one embodiment, the solid pharmaceutical composition is in the form of a formulation of a tablet or capsule.
The solid pharmaceutical composition according to the first aspect of the present invention is in the form of a unit dose formulation of tablets, capsules, granules, pellets and the like. The term "unit dosage formulation" refers to a formulation such as a tablet, a capsule, and the like. In one embodiment, the amount of a compound of formula I or a pharmaceutically acceptable salt thereof contained in each "unit dosage formulation" is 0.1 to 100mg, such as 0.1 to 50mg, such as 0.1 to 25mg, such as 0.5 to 20mg, such as about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, in terms of its free base represented by formula I. For example, the compound of formula I or a pharmaceutically acceptable salt thereof is contained in an amount of 0.1 to 100mg, such as 0.1 to 50mg, such as 0.1 to 25mg, such as 0.5 to 20mg, such as about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg per tablet, in terms of its free base represented by formula I.
The solid pharmaceutical composition according to the first aspect of the present invention, wherein the pharmaceutical excipient further comprises an organic acid such as citric acid or tartaric acid or a combination thereof. It has been found to be advantageous to add a suitable amount of the above-mentioned organic acids to the solid pharmaceutical compositions of the present invention. Although such organic acids are generally considered by those skilled in the art to have properties related to the acid-base nature, such as buffering properties, the present inventors have surprisingly found that the presence of such acids helps to improve the stability of the active ingredient in the product. In one embodiment of the solid pharmaceutical composition of the first aspect of the invention, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the organic acid is 1: 0.01-100, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the organic acid is 1: 0.05-50, for example, the weight ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to the organic acid is 1: 0.1-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the organic acid is 1: 0.2-20, for example, the weight ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to the organic acid is 1: 0.5 to 10.
Further, the present invention provides in a second aspect a solid pharmaceutical composition comprising
(a) A compound of formula I:
wherein R1 is bromo, R2 and R3 are methyl;
(b) an organic acid; and optionally
(c) And (3) a medicinal auxiliary material.
The solid pharmaceutical composition according to the second aspect of the invention, wherein the pharmaceutically acceptable salt of the compound of formula I is a p-toluenesulfonate, benzenesulfonate or ethanesulfonate.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the pharmaceutically acceptable salt of the compound of formula I is a p-toluenesulfonate salt or a benzenesulfonate salt.
The solid pharmaceutical composition according to the second aspect of the invention, wherein the pharmaceutically acceptable salt of the compound of formula I is selected from a compound of formula Ia or a compound of formula Ib:
the solid pharmaceutical composition according to the second aspect of the present invention, wherein the organic acid is selected from citric acid or tartaric acid or a combination thereof. It has been found to be advantageous to add a suitable amount of the above-mentioned organic acids to the solid pharmaceutical compositions of the present invention. Although such organic acids are generally considered by those skilled in the art to have properties related to the acid-base nature, such as buffering properties, the present inventors have surprisingly found that the presence of such acids helps to improve the stability of the active ingredient in the product. In one embodiment of the solid pharmaceutical composition of the second aspect of the invention, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the organic acid is 1: 0.01-100, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the organic acid is 1: 0.05-50, for example, the weight ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to the organic acid is 1: 0.1-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the organic acid is 1: 0.2-20, for example, the weight ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to the organic acid is 1: 0.5 to 10.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the pharmaceutical excipients include, but are not limited to, diluents or fillers, disintegrants, binders, lubricants or glidants.
The solid pharmaceutical composition according to the second aspect of the invention, wherein the diluents or fillers include, but are not limited to: starches such as corn starch, dextrin, microcrystalline cellulose, modified starch, pregelatinized starch, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose, and the like. More preferably, mannitol and lactose are included.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the disintegrant includes, but is not limited to: low-substituted hydroxypropyl cellulose, sodium cross-linked carboxymethyl starch, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, starch, and the like.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the binder is such as, but not limited to: hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and the like. More preferred include hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or polyvinyl alcohol. The binders may be used alone or in combination of two or more. The water-soluble polymer binder is blended in an amount of, for example, 0.5 to 10 wt%, preferably l to 5 wt%, based on the total weight of the tablet. The oral preparation in the form of the pharmaceutical composition of the present invention means a pharmaceutical preparation formulated into tablets, capsules, granules or fine granules. The preparation can be prepared into tablets, capsules, granules or fine granules by a conventional method using the formulation of the present invention and the like.
In the present invention, the lubricant and glidant may be collectively referred to as a lubricant. Lubricants include, but are not limited to: magnesium stearate, stearic acid, calcium stearate, zinc stearate, liquid paraffin, polyethylene glycol, silicon dioxide, colloidal silicon dioxide, superfine silica powder, talcum powder, hydrogenated vegetable oil and the like or a combination thereof.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the pharmaceutical excipient accounts for 0-99.5% of the composition, for example, the pharmaceutical excipient accounts for 10-99% of the composition, for example, the pharmaceutical excipient accounts for 25-99% of the composition, for example, the pharmaceutical excipient accounts for 50-98% of the composition, for example, the pharmaceutical excipient accounts for 75-95% of the composition. The amount of the pharmaceutical excipient can be easily determined empirically by those skilled in the art. For example, as a disintegrant, the total weight thereof in the composition may be generally in the range of 3 to 30%, for example, may be generally in the range of 5 to 20%. For another example, the total weight of the binder in the composition may be generally in the range of 2 to 20%, for example, generally in the range of 5 to 10%. For another example, as a diluent or filler, it is usually used in order to enable the molding of a drug, and therefore the amount thereof may not be particularly determined, and for example, it may be usually in the range of 1 to 95% by weight, for example, usually in the range of 10 to 90% by weight, based on the total weight of the composition. As another example, the total weight of the lubricant in the composition may be generally in the range of 1 to 20%, for example, may be generally in the range of 1 to 10%, for example, may be generally in the range of 1 to 8%.
The solid pharmaceutical composition according to the second aspect of the present invention is in the form of a formulation of tablets, capsules, granules, pellets and the like. In one embodiment, the solid pharmaceutical composition is in the form of a formulation of tablets, capsules, granules. In one embodiment, the solid pharmaceutical composition is in the form of a formulation of a tablet or capsule.
The solid pharmaceutical composition according to the second aspect of the present invention is in the form of a unit dose formulation of tablets, capsules, granules, pellets and the like. The term "unit dosage formulation" refers to a formulation such as a tablet, a capsule, and the like. In one embodiment, the amount of a compound of formula I or a pharmaceutically acceptable salt thereof contained in each "unit dosage formulation" is 0.1 to 100mg, such as 0.1 to 50mg, such as 0.1 to 25mg, such as 0.5 to 20mg, such as about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg, in terms of its free base represented by formula I. For example, the compound of formula I or a pharmaceutically acceptable salt thereof is contained in an amount of 0.1 to 100mg, such as 0.1 to 50mg, such as 0.1 to 25mg, such as 0.5 to 20mg, such as about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg per tablet, in terms of its free base represented by formula I.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the pharmaceutical excipient further comprises a fatty acid or a pharmaceutically acceptable salt thereof.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the fatty acid is stearic acid.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the pharmaceutically acceptable salt of a fatty acid is a magnesium salt, a sodium salt, a calcium salt, a zinc salt of a fatty acid.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the fatty acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate, and combinations thereof.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the fatty acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: stearic acid, magnesium stearate, calcium stearate, and combinations thereof.
Although the above-described fatty acids or pharmaceutically acceptable salts thereof of the present invention have the effect of a lubricant, the present inventors have surprisingly found that unexpectedly good results occur when the compound of formula I is formulated with a fatty acid or pharmaceutically acceptable salt thereof. The present inventors have surprisingly found that unexpectedly good effects, in particular stability effects, occur when a compound of formula I, in particular a compound of formula Ia or a compound of formula Ib, is formulated together with a fatty acid or a pharmaceutically acceptable salt thereof, without this effect being lost by the addition of other pharmaceutical excipients used for formulation shaping purposes. Therefore, the solid pharmaceutical composition of the present invention may be a solid pharmaceutical composition comprising the compound of formula I of the present invention or a pharmaceutically acceptable salt thereof and the fatty acid of the present invention or a pharmaceutically acceptable salt thereof, and may further comprise other optional conventional pharmaceutical excipients commonly used in pharmacy.
The solid pharmaceutical composition according to the second aspect of the present invention, wherein the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the fatty acid or a pharmaceutically acceptable salt thereof is 1: 0.01-100, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.05-50, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.1-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.2-20, for example, the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the fatty acid or its pharmaceutically acceptable salt is 1: 0.5 to 10.
In a third aspect, the present invention provides a process for the preparation of any solid pharmaceutical composition of the first aspect of the invention, comprising the steps of:
(i) providing a compound of formula I or a pharmaceutically acceptable salt thereof, a fatty acid or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutical adjuvant;
(ii) mixing a compound of formula I or a pharmaceutically acceptable salt thereof with a fatty acid or a pharmaceutically acceptable salt thereof and optionally a pharmaceutical excipient in any order to obtain a mixture;
(iii) (iii) formulating the mixture of step (ii) into a pharmaceutical formulation in the form of a unit dose formulation.
For example, for the preparation of tablets, it has been found that the manner of mixing the compound of formula I or a pharmaceutically acceptable salt thereof with the fatty acid or a pharmaceutically acceptable salt thereof has no effect on achieving the objects of the present invention; for example, the compound of formula I or the pharmaceutically acceptable salt thereof and the fatty acid or the pharmaceutically acceptable salt thereof are premixed and then mixed with other pharmaceutic adjuvants, and finally compressed into tablets, and the compound of formula I or the pharmaceutically acceptable salt thereof is firstly mixed with other pharmaceutic adjuvants, and then mixed with the fatty acid or the pharmaceutically acceptable salt thereof, and finally compressed into tablets, wherein the tablets obtained by the two modes have good properties.
In a fourth aspect, the present invention provides a process for the preparation of any solid pharmaceutical composition of the second aspect of the invention, comprising the steps of:
(i) providing a compound of formula I or a pharmaceutically acceptable salt thereof, an organic acid, and optionally a pharmaceutical adjuvant;
(ii) mixing a compound of formula I or a pharmaceutically acceptable salt thereof with an organic acid and optionally a pharmaceutical excipient in any order to obtain a mixture;
(iii) (iii) formulating the mixture of step (ii) into a pharmaceutical formulation in the form of a unit dose formulation.
For example, for the preparation of tablets, it has been found that the manner in which the compound of formula I or a pharmaceutically acceptable salt thereof is mixed with an organic acid has no effect on achieving the objects of the present invention; for example, the compound of formula I or the pharmaceutically acceptable salt thereof is premixed with the organic acid, then is mixed with other pharmaceutic adjuvants, and finally is compressed into tablets, and the compound of formula I or the pharmaceutically acceptable salt thereof is firstly mixed with other pharmaceutic adjuvants, then is mixed with the organic acid, and finally is compressed into tablets, and the tablets obtained by the two modes have good properties.
Any technical feature possessed by any one aspect of the invention or any embodiment of that aspect is equally applicable to any other embodiment or any embodiment of any other aspect, so long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made as necessary when applicable to each other. Various aspects and features of the disclosure are described further below.
The present invention relates to compounds of formula I below:
wherein R1 is bromine, R2 and R3 are methyl;
the chemical name of the compound of formula 1 is 3- [ (4S) -8-bromo-1-methyl-6- (2-pyridyl) -4H-imidazo [1, 2-a][1，4]Benzodiazepine-4-yl]The methyl propionate is prepared by the reaction of methyl propionate,
in the present invention, the preferred compound of formula I is its benzenesulfonate or p-toluenesulfonate salt.
In the present invention, preferred compounds of formula I are compounds of formula Ia or compounds of formula Ib selected from the group consisting of:
the present invention also provides a method of producing a sedative or hypnotic state in a subject, the method comprising administering to the subject a solid pharmaceutical composition according to the first or second aspect of the invention comprising a sedative or hypnotic effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof.
There is also provided according to the invention a method of inducing anxiolytic activity in a subject, the method comprising administering to the subject a solid pharmaceutical composition according to the first or second aspect of the invention comprising an anxiolytic effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof.
There is further provided according to the present invention a method of inducing muscle relaxation in a subject, the method comprising administering to the subject a solid pharmaceutical composition according to the first or second aspect of the invention comprising a muscle relaxing effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof.
Further provided according to the invention is a method of treating a convulsive state in a subject, the method comprising administering to the subject a solid pharmaceutical composition according to the first or second aspect of the invention comprising an anticonvulsant effective amount of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof.
In the present invention, the subject is suitably a mammal, preferably a human.
The solid pharmaceutical composition according to the first or second aspect of the present invention for the above-mentioned diseases can be administered to a mammal such as a human in a dose of usually 0.001 to 5.0mg/kg body weight/day, preferably 0.001 to 2.0mg/kg body weight/day.
The solid pharmaceutical compositions of the first or second aspect of the invention may be used as short-acting CNS inhibitors, which may be administered orally in the following clinical settings: preoperative sedation, anxiolytic and amnesic use in perioperative events; conscious sedation during short-term diagnostic, surgical, or endoscopic procedures; as a component for induction and maintenance of general anesthesia prior to and/or concurrently with administration of other anesthetics or analgesics; ICU sedation. In addition, the solid pharmaceutical composition according to the first aspect or the second aspect of the present invention may be used for sedation, hypnosis, anxiolysis, muscle relaxation, anticonvulsant and other mental disorders.
Detailed Description
The present invention will be further described by the following examples, however, the scope of the present invention is not limited to the following examples. It will be understood by those skilled in the art that various changes and modifications may be made to the invention without departing from the spirit and scope of the invention. The present invention has been described generally and/or specifically with respect to materials used in testing and testing methods. Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. The following examples further illustrate the invention without limiting it. In the formulations set forth below in the preparation of the compositions, the calculated amount of the compound of formula I is calculated as the free base, and the formulations set forth are the amount of the free base of the compound of formula I contained in each unit dose formulation (e.g., each tablet, each capsule), and the compositions are prepared in the following amounts of 10000 unit dose formulations per batch, e.g., in 1 ten thousand tablets or 1 ten thousand capsules.
In various chromatographic analyses of the invention, chromatographic peaks displayed by acid radicals are ignored in calculation.
Analytical test method
The following [ HPLC method A ] can be used to determine the substances and their changes in the composition of the present invention.
[ HPLC method A ]:
purity analysis was performed on HP1100Agilent chromatograph:
a chromatographic column: phenomenex Gemini C185 μm (2.0X 50mm) (guard bars Phenomenex Gemini C18, 2X4mm), Philomen, USA
Column temperature: 40 deg.C
Sample introduction amount: 10 μ l
Flow rate: 0.8 ml/min
And (3) detection: ultraviolet detection, wavelength: 254 nm;
mobile phase A: 2mmol of NH4HCO3(with NH)3Adjusting the solution to pHl0)
Mobile phase B: acetonitrile
Gradient elution procedure:
| elution time/min | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 25 | 10 | 90 |
| 28.8 | 10 | 90 |
| 29 | 90 | 10 |
| 34 | 90 | 10 |
Sample preparation: taking appropriate amount of each sample (crude drug or composition), adding acetonitrile-water mixture (acetonitrile: water = 50: 50, containing 1mmol of NH)4HCO3And with NH3The solution was adjusted to pHl0) and made into a solution with a concentration of about 1mg/ml by dissolving in an appropriate amount and filtering if necessary.
The calculation method comprises the following steps: taking a chromatographic peak of the compound shown in the formula I as a main peak, wherein the relative retention time of the chromatographic peak is 1, reading the peak areas of all chromatographic peaks with the relative retention time of 0.60-2.00 (the impurity peak with the peak area less than 0.01% of the area of the main peak is ignored), calculating the content of each impurity peak and the content of the main peak (also called chromatographic purity) by an area normalization method, and calculating the maximum single impurity content and the total impurity content.
The 4-bit of the seven-membered ring of the active component in the pharmaceutical composition is S-isomer, and a small amount of R-isomer may be mixed in the medicine. Hereinafter, [ HPLC method B ] is used for determining the R-isomer (i.e., the compound represented by the following formula Ix) and its variation in the composition of the present invention.
Wherein R1 is bromine, R2 and R3 are methyl;
[ HPLC method B ]:
purity analysis was performed on HP1100Agilent chromatograph:
operating time: retention time to main peak is more than 2.5 times
A chromatographic column: daicel Chrialcel OJ-H (5 μm) 4.6X 250mm (guard bar Daicel Chrialcel OJ-H analysis guard bar 5 μm 4.0X 10mm), Japan xylonite (Daicel)
Column temperature: 40 deg.C
Sample introduction amount: 10 μ l
Flow rate: 1.0 ml/min
And (3) detection: ultraviolet detection, wavelength: 225nm (single wavelength detector);
mobile phase: hexane: ethanol = 93: 7
Sample preparation: taking appropriate amount of each sample (crude drug or composition), adding appropriate amount of mobile phase, ultrasonic treating to dissolve and dilute solution with concentration of about 1mg/ml, and filtering if necessary.
The calculation method comprises the following steps: taking a chromatographic peak of the compound shown in the formula I as a main peak, wherein the relative retention time of the chromatographic peak is 1, reading the peak area of the main peak and the peak area of an impurity peak (which is the compound shown in the formula Ix) with the relative retention time of 1.10-1.25, and determining the content of R isomer (%) = [ R isomer peak area ÷ (R isomer peak area + S isomer peak area) ] × 100%.
In the various HPLC methods above, whether the compound of formula I is formulated as its free base or as a pharmaceutically acceptable salt, they exhibit the same retention time in the chromatographic system as the free base of formula I due to the dissociation of benzenesulfonic acid or p-toluenesulfonic acid or other acid groups, as is well known in the art of chromatographic analysis.
Raw material samples for testing:
the crystal form I, crystal form II, crystal form III and crystal form IV of the compound of formula Ia used in each of the following experiments were obtained according to the methods described in paragraphs [0049] (i.e., example 2), [0053] (i.e., example 4), [0057] (i.e., example 6) and [0061] (i.e., example 8) of the specification of CN102964349A, respectively. A compound of unidentified specific crystalline form Ia is also prepared by the following process: the compound of formula Ia obtained by the method described in paragraph [0047] of the specification of CN102964349A was dissolved in 50% ethanol aqueous solution, and spray-dried to obtain dry powder, which shows no typical diffraction peak (in the present invention, the V crystal form of the compound of formula Ia) when measured to be different from the X-ray diffraction characteristics of the above four crystal forms.
The compound of formula Ib, used in the following tests, relates to form 1, form 2, form 3, form 4, and is prepared according to the method described in CN101501019A (PAION, application No. CN200780028964.5), and its XRPD pattern and DSC test results are the same as those described in CN101501019A, specifically:
a crystalline form 1 of a compound of formula Ib: an X-ray powder diffraction pattern comprising a characteristic peak at about 7.3, 7.8, 9.4, 12.1, 14.1, 14.4, 14.7, or 15.6 degrees 2 Θ and having a differential scanning calorimetry onset melting temperature in the range of about 191-192 ℃;
a crystalline form 2 of a compound of formula Ib: an XRPD pattern comprising characteristic peaks at about 8.6, 10.5, 12.0, 13.1, 14.4, and 15.9 degrees 2 Θ, and having a differential scanning calorimetry onset melting temperature at about 180 ℃;
a crystalline form 3 of a compound of formula Ib: an XRPD pattern comprising characteristic peaks at about 7.6, 11.2, 12.4, 14.6, 15.2, 16.4 and 17.7 degrees 2 Θ and having a differential scanning calorimetry onset melting temperature in the range of about 200-;
a crystalline form 4 of a compound of formula Ib: an XRPD pattern comprising characteristic peaks at about 7.6, 10.8, 15.2, 15.9, and 22.0 degrees 2 Θ, and having a differential scanning calorimetry onset melting temperature at about 182 ℃;
compounds of undetermined specific crystal form Ib were also prepared by the following method: the crystal form 1 of the compound shown in the formula Ib is dissolved in 30% ethanol water solution, and is spray-dried to obtain dry powder, and the dry powder is determined to have different X-ray diffraction characteristics from the four crystal forms and shows no typical diffraction peak (marked as the 5 crystal form of the compound shown in the formula Ib in the invention).
The ethanesulfonate salt of the compound of formula I used in the following tests was prepared by the method described in paragraph [0101] of the specification of US20100075955A1 (hereinafter may be referred to simply as ethanesulfonate salt of formula I).
The compounds of formula I (free bases) used in the various tests below were obtained by reference to the preparation of the compounds reported in WO00/69836 (example Ic-8, page 60 of the description).
The chromatographic purity of the raw material salt or free base for the tests is more than 99.0 percent (HPLC method A), and the content of R isomers is less than 1.0 percent (HPLC method B).
The R-isomer (i.e., the compound represented by formula Ix) according to the present invention can be prepared by referring to the method described in WO00/69836, as follows:
step 1: with reference to WO00/69836, description 23-24, for Int-1 preparation, Fmoc-D-Glu (OMe) -OH (available from Gill Biochemical) was used as starting material to obtain Int-1x intermediate (which is an isomer of Int-1) of the following formula:
step 2: the following Ex I-10x compounds (which are isomers of the Exampe I-10 compounds described on page 38 of WO 00/69836) were obtained by following the procedure for preparing the Exampe I-1 described on pages 34-35 of WO00/69836 using the Int-1x intermediate and the intermediate Int-2 described on page 24 of WO00/69836 as starting materials:
and step 3: then, referring to the preparation method of Example Ic-8 on pages 60-61 of WO00/69836, Ex I-10x was used as a starting material to obtain a compound represented by the following formula Ix (which is the R-isomer of the Example Ic-8 compound on page 60 of WO 00/69836)
Wherein R1 is bromine, R2 and R3 are methyl,molecular formula C21H19BrN4O2ESIMS 461(M + Na, base), 439(M + H). Purity of chromatography>99.0% [ HPLC METHOD A ], S isomer content<1.0% [ HPLC METHOD B ]. The relative retention time of the R isomer relative to the S isomer in the HPLC method B test is about 1.17. The R isomer is treated in the present invention as an isomer impurity of the compound of formula I or a salt thereof as an active ingredient.
Test example 1: test for the combination of the Compound of formula I with a fatty acid
Taking the crystal form I of the compound of the formula Ia in a state of 80-mesh fine powder, taking stearic acid or magnesium stearate in a state of 80-mesh fine powder, uniformly mixing the compound of the formula Ia (at least 10g is used in each mixing) with a certain amount of stearic acid or salt shown in the following table in a mortar (fully grinding, and the grinding is performed by an X-ray diffraction test, and the grinding process does not change the crystal form of the compound of the formula I here and below), sealing and packaging the mixture in an aluminum-plastic composite film bag, and then placing each sample in a 50 ℃ incubator for 4 months (the treatment can be simply referred to as '50 ℃ 4 months' in the invention). For each sample, their maximum single impurity content at 0 months and total impurity content at 50 ℃ at 4 months were determined using [ HPLC method a ] and the maximum single impurity content and total impurity content were calculated as follows:
maximum single impurity increase percentage = [ (maximum single impurity content at 50 ℃ 4 months-maximum single impurity content at 0 months) ÷ maximum single impurity content at 0 months ] × 100%
Percent increase in total impurities = [ (total impurity content at 50 ℃ in 4 months-total impurity content at 0 months) ÷ total impurity content at 0 months ]. times 100%
The results are shown in Table 1 below.
Table 1:
the first column in the table above, "stearic acid: form I "represents stearic acid when mixed: a ratio by weight of form I, for example a value of 0 means 0 parts stearic acid mixed with 1 part of form I, a value of 0.01 means 0.01 parts stearic acid mixed with 1 part of form I, a value of 200 means 200 parts stearic acid mixed with 1 part of form I, etc.; similarly, column four also has similar meaning.
As can be seen from the above results, the crystalline form I of the compound of formula Ia, in combination with magnesium stearate or stearate, is better able to withstand high temperature environments, particularly when the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the fatty acid or pharmaceutically acceptable salt thereof is 1: 0.2 to 20, with significantly superior results, although the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the fatty acid or a pharmaceutically acceptable salt thereof is 1: the increase in impurities is not significant in the range of 50 to 200, but the presence of an excess of fatty acid or pharmaceutically acceptable salt thereof in the formulation may affect other properties of the drug such as tabletting properties, since the fatty acid or pharmaceutically acceptable salt thereof functions as a lubricant for the tablet, and is generally used in an amount in the range of 1 to 10% by weight, particularly 1 to 5% by weight of the tablet.
Test example 2: test for the combination of the Compound of formula I with a fatty acid
With reference to the procedure of test example 1 above, except that the active agent was changed to the compound of formula Ia in crystal form II. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1. For example, stearic acid: in the formula II crystal form =5, the maximum single impurity increase (%) and the total impurity increase (%) are 26% and 36% respectively; as another example, magnesium stearate: form II =5 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 25% and 35%, respectively.
With reference to the procedure of test example 1 above, except that the active agent was changed to the form III of the compound of formula Ia. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
With reference to the procedure of test example 1 above, except that the active agent was changed to the compound of formula Ia in crystalline form IV. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
Referring to the procedure of test example 1 above, except that the active agent was changed to the crystalline form V of the compound of formula Ia. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
Test example 3: test for the combination of the Compound of formula I with a fatty acid
With reference to the procedure of test example 1 above, except that the active agent was changed to the compound of formula Ib in crystal form 1. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1. For example, stearic acid: in form II =5 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 23% and 39%, respectively; as another example, magnesium stearate: form II =5 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 26% and 42%, respectively.
With reference to the procedure of test example 1 above, except that the active agent was changed to the 2 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
With reference to the procedure of test example 1 above, except that the active agent was changed to the 3 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
With reference to the procedure of test example 1 above, except that the active agent was changed to the 4 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
With reference to the procedure of test example 1 above, except that the active agent was changed to the 5 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) neither differing by more than 5 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0.2 to 20) nor more than 15 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 0 to 0.15) nor more than 10 percentage points (weight ratio of the salt of the compound of formula I to the fatty acid or salt thereof being in the range of 1: 50 to 200) from the results obtained with the respective ratios in table 1.
Referring to the procedure of test example 1 above, except that the active agent was changed to the ethanesulfonate of formula I. The results unfortunately show that in a weight ratio of compound of formula I to the fatty acid or salt thereof of 1: in the range of 0-200, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 200-400%. For example, stearic acid: in ethanesulfonate =20 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 242% and 343%, respectively; as another example, magnesium stearate: ethanesulfonate =20 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 234% and 325%, respectively. It can be seen that even though the same acid addition salts of the compound of formula I, the ethanesulfonate salt of the compound of formula I shows a difficulty in achieving a significant improvement in stability as shown by the benzenesulfonate or p-toluenesulfonate salt.
With reference to the procedure of test example 1 above, except that the active agent was changed to the compound of formula I (i.e. the free base). The results unfortunately show that in a weight ratio of compound of formula I to the fatty acid or salt thereof of 1: in the range of 0-200, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 200-400%. For example, stearic acid: free base =20 formulation, maximum single impurity increase (%) and total impurity increase (%) were 223% and 319%, respectively; as another example, magnesium stearate: free base =20 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 211% and 345%, respectively.
Test example 4: testing of the combination of Compounds of formula I, fatty acids and pharmaceutical adjuvants
Taking the crystal form I of the compound shown in the formula Ia in a fine powder state which can pass through 80 meshes, further taking stearic acid or magnesium stearate in a fine powder state which can pass through 80 meshes, and taking the following pharmaceutic adjuvants in a fine powder state which can pass through 80 meshes. A compound of formula Ia: stearic acid or salt: starch: microcrystalline cellulose: lactose = 1: (0, 0.2, 2, 20, or 50): 50: 50: 50, grinding the materials evenly in a mortar, sealing and packaging the materials in an aluminum-plastic composite film bag, and then placing each sample in a 50 ℃ thermostat for 4 months. The maximum percent increase in single impurity and the percent increase in total impurity for each sample after 50 ℃ 4 months were determined by reference to the method of test example 1. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50). For example, stearic acid: in the I crystal form =2 ratio, the maximum single impurity increase (%) and the total impurity increase (%) were 22% and 34%, respectively; as another example, magnesium stearate: in form I =2 formulation, the maximum single impurity increase (%) and total impurity increase (%) were 22% and 37%, respectively.
Test example 5: testing of the combination of Compounds of formula I, fatty acids and pharmaceutical adjuvants
With reference to the procedure of test example 4 above, except that the active agent was changed to the compound of formula Ia in crystal form II. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
Referring to the procedure of test example 4 above, except that the active agent was changed to the form III of the compound of formula Ia. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
Referring to the procedure of test example 4 above, except that the active agent was changed to the compound of formula Ia in crystal form IV. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
Referring to the procedure of test example 4 above, except that the active agent was changed to form V of the compound of formula Ia. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
With reference to the procedure of test example 4 above, except that the active agent was changed to the compound of formula Ib in crystal form 1. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
With reference to the procedure of test example 4 above, except that the active agent was changed to the 2 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
With reference to the procedure of test example 4 above, except that the active agent was changed to the 3 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
With reference to the procedure of test example 4 above, except that the active agent was changed to the 4 crystalline form of the compound of formula Ib. The results are essentially the same as in table 1, with the maximum single impurity increase (%) and total impurity increase (%) corresponding to compounds of formula Ia in table 1: the stearic acid or salt ratios do not differ by more than 8 percentage points (compound of formula Ia: stearic acid or salt =0.2, 2 or 20) or by more than 20 percentage points (compound of formula Ia: stearic acid or salt =0) or by more than 15 percentage points (compound of formula Ia: stearic acid or salt = 50).
Referring to the procedure of test example 4 above, except that the active agent was changed to the ethanesulfonate of formula I. The results unfortunately show that in a weight ratio of compound of formula I to the fatty acid or salt thereof of 1: in the range of 0-50, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 200-400%.
With reference to the procedure of test example 4 above, except that the active agent was changed to the compound of formula I (i.e. the free base). The results unfortunately show that in a weight ratio of compound of formula I to the fatty acid or salt thereof of 1: in the range of 0-50, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 200-400%.
The above results show that the stabilizing effect of stearic acid or a salt thereof on the active ingredient is not changed by the addition of the pharmaceutical excipients.
Test example 6: combination of a Compound of formula I with an organic acid
Taking the crystal form I of the compound of the formula Ia in a state of 80-mesh fine powder, taking citric acid or tartaric acid in a state of 80-mesh fine powder, uniformly grinding the compound of the formula Ia and a certain amount of organic acid shown in the following table in a mortar (fully grinding, and passing an X-ray diffraction test, wherein the grinding process does not change the crystal form of the compound of the formula I in the following and the like), hermetically packaging the mixture in an aluminum-plastic composite film bag, and placing each sample in a 50 ℃ thermostat for 4 months (the treatment can be simply referred to as '50 ℃ 4 months' in the invention). For each sample, their R isomer content (%) at 0 months was determined using "HPLC method B" and their R isomer content (%) at 50 ℃ at 4 months was determined, and the percent increase in R isomer was calculated as follows:
percent increase in R isomer = [ (50 ℃ 4 month R isomer content-0 month R isomer content) ÷ 0 month R isomer content ]. times 100%)
The results are shown in Table 2 below.
Table 2:
| citric acid: crystal form I | Increase in R isomer (%) | Tartaric acid: crystal form I | Increase in R isomer (%) |
| 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 |
The first column in the table above, "citric acid: form I "means citric acid: the weight ratio of the two forms I, for example, a value of 0 means 0 parts citric acid mixed with 1 part of the form I, a value of 0.01 means 0.01 parts citric acid mixed with 1 part of the form I, a value of 200 means 200 parts citric acid mixed with 1 part of the form I, and the like; similarly, the third column has a similar meaning.
As can be seen from the above table, the crystalline form I of the compound of formula Ia, when combined with citric acid or tartaric acid, is better able to withstand high temperature environments, particularly when the weight ratio of the compound of formula I, or a pharmaceutically acceptable salt thereof, to the organic acid is 1: within the range of 0.2-20, the method has obvious excellent results, namely the content of the R isomer is not obviously increased. Although the weight ratio of the compound of formula I or the pharmaceutically acceptable salt thereof to the citric acid is 1: 50. 1: 100. or 1: the increase in the R isomer impurity was insignificant at 200, but the maximum individual impurity increase was found to be 81%, 141%, 186%, respectively, and the total impurity increase was 89%, 153%, 217%, respectively, using the "HPLC method a" assay at 50 ℃ for 4 months. The form I and tartaric acid also showed substantially the same maximum percent single impurity increase and percent total impurity increase when combined at these three weight ratios, e.g., no more than 10 percentage points related to the results using citric acid at the corresponding ratios. It can be seen that a small amount of organic acid has no effect on inhibiting the formation of the R isomer impurity, but other impurities increase significantly when the amount of organic acid increases to more than 50 times the weight of form I.
Test example 7: combination of a Compound of formula I with an organic acid
With reference to the procedure of test example 6 above, except that the active agent was changed to the compound of formula Ia in crystal form II. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 7 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200). For example, citric acid: in the formula II crystal form =5, the increase (%) of R isomer is 33%; as another example, tartaric acid: in the II crystal form =5 proportion, the increase (%) of R isomer is 32%.
With reference to the procedure of test example 6 above, except that the active agent was changed to the form III of the compound of formula Ia. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
With reference to the procedure of test example 6 above, except that the active agent was changed to the compound of formula Ia in crystalline form IV. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 6 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
Referring to the procedure of test example 6 above, except that the active agent was changed to the crystalline form V of the compound of formula Ia. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or not more than 14 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or not more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
Test example 8: combination of a Compound of formula I with an organic acid
With reference to the procedure of test example 6 above, except that the active agent was changed to the compound of formula Ib as form 1. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or not more than 14 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or not more than 6 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200). For example, citric acid: in the formula II crystal form =5, the increase (%) of R isomer is 36%; as another example, tartaric acid: in the II crystal form =5 proportion, the increase (%) of R isomer is 36%.
With reference to the procedure of test example 6 above, except that the active agent was changed to the 2 crystalline form of the compound of formula Ib. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
With reference to the procedure of test example 6 above, except that the active agent was changed to the 3 crystalline form of the compound of formula Ib. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or not more than 14 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or not more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
With reference to the procedure of test example 6 above, except that the active agent was changed to the 4 crystalline form of the compound of formula Ib. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 6 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
With reference to the procedure of test example 6 above, except that the active agent was changed to the 5 crystalline form of the compound of formula Ib. The results are substantially the same as in Table 2, and the R isomer increases (%) do not differ from those obtained in the corresponding proportions in Table 2 by more than 6 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0.2 to 20) or by more than 15 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 0 to 0.15) or by more than 5 percentage points (the weight ratio of the salt of the compound of formula I to the organic acid is in the range of 1: 50 to 200).
Referring to the procedure of test example 6 above, except that the active agent was changed to the ethanesulfonate of formula I. The results unfortunately show that when the weight ratio of the compound of formula I to the organic acid is 1: the increase (%) of R isomer is in the range of 150 to 300% in the range of 0 to 200. For example, citric acid: in the mixture ratio of ethanesulfonate =20, the increase (%) of the R isomer is 212%; as another example, tartaric acid: in ethanesulfonate =20 formulation, the increase (%) of R isomer was 193%. It can be seen that even though the same acid addition salts of the compound of formula I, the ethanesulfonate salt of the compound of formula I shows a difficulty in achieving a significant improvement in stability as shown by the benzenesulfonate or p-toluenesulfonate salt.
With reference to the procedure of test example 6 above, except that the active agent was changed to the compound of formula I (i.e. the free base). The results unfortunately show that when the weight ratio of the compound of formula I to the organic acid is 1: in the range of 0-200, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 150-300%. For example, citric acid: free base =20 formulation, the increase (%) of R isomer is 219%; as another example, tartaric acid: free base =20 formulation, the increase (%) in R isomer was 234%.
Test example 9: testing of the combination of Compounds of formula I, organic acids and pharmaceutical adjuvants
Taking the crystal form I of the compound of the formula Ia which can pass through 80 meshes of fine powder, further taking citric acid or tartaric acid which can pass through 80 meshes of fine powder, and the following medicinal auxiliary materials which can pass through 80 meshes of fine powder. A compound of formula Ia: organic acid: starch: microcrystalline cellulose: lactose = 1: (0, 0.2, 2, 20, or 50): 50: 50: 50, grinding the materials evenly in a mortar, sealing and packaging the materials in an aluminum-plastic composite film bag, and then placing each sample in a 50 ℃ thermostat for 4 months. The increase (%) in the R isomer after 50 ℃ 4 months was measured for each sample by referring to the method of test example 6. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 6 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0). For example, citric acid: in the formula I crystal form =2, the increase (%) of R isomer is 34%; as another example, tartaric acid: in the I crystal form =2 ratio, the maximum single impurity increase (%) and the total impurity increase (%) were 31%, respectively.
Test example 10: testing of the combination of Compounds of formula I, organic acids and pharmaceutical adjuvants
With reference to the procedure of test example 9 above, except that the active agent was changed to the compound of formula Ia in crystal form II. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
Referring to the procedure of test example 9 above, except that the active agent was changed to the form III of the compound of formula Ia. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
Referring to the procedure of test example 9 above, except that the active agent was changed to the compound of formula Ia in crystal form IV. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
Referring to the procedure of test example 9 above, except that the active agent was changed to the crystalline form V of the compound of formula Ia. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
With reference to the procedure of test example 9 above, except that the active agent was changed to the compound of formula Ib in crystal form 1. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
With reference to the procedure of test example 9 above, except that the active agent was changed to the 2 crystalline form of the compound of formula Ib. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
With reference to the procedure of test example 9 above, except that the active agent was changed to the 3 crystalline form of the compound of formula Ib. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
With reference to the procedure of test example 9 above, except that the active agent was changed to the 4 crystalline form of the compound of formula Ib. The results are essentially the same as in table 2, with an increase (%) in the R isomer compared to the corresponding compound of formula Ia in table 2: the organic acid ratios did not differ by more than 8 percentage points (compound of formula Ia: organic acid =0.2, 2, 20, or 50) or by more than 20 percentage points (compound of formula Ia: organic acid = 0).
Referring to the procedure of test example 9 above, except that the active agent was changed to the ethanesulfonate of formula I. The results unfortunately show that when the weight ratio of the compound of formula I to the organic acid is 1: in the range of 0-50, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 150-300%.
With reference to the procedure of test example 9 above, except that the active agent was changed to the compound of formula I (i.e. the free base). The results unfortunately show that when the weight ratio of the compound of formula I to the organic acid is 1: in the range of 0-50, the maximum single impurity increase (%) and the total impurity increase (%) are both in the range of 150-300%.
The above results show that the stabilizing effect of organic acids on active ingredients is not changed by the addition of pharmaceutical excipients.
Composition preparation examples section
The following preparation examples prepare the solid composition of the present invention in the form of a pharmaceutical preparation.
Preparation example 1: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound I of formula Ia | 2 |
| Stearic acid | 5 |
| Starch | 50 |
| Microcrystalline cellulose | 35 |
| Cross-linked sodium carboxymethyl starch | 5 |
| HPMC | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. HPMC is prepared into 5 percent aqueous solution to be used as a bonding agent for standby. Mixing the compound of formula I, starch, and microcrystalline cellulose thoroughly, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry particles with stearic acid and cross-linked sodium carboxymethyl starch to obtain final mixed particles. 2/3 the final blend granules were compressed into tablets each containing 2mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 2mg of the compound of formula Ia as the free base.
Preparation example 2: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a compound of formula Ia in crystal form II | 0.5 |
| Stearic acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with half amount of stearic acid, mixing with starch and lactose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry granules with the balance of stearic acid and low-substituted hydroxypropyl cellulose to obtain final mixed granules. 2/3 the final blend granules were compressed into tablets each containing 0.5mg of the compound of formula Ia, calculated as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 0.5mg of the compound of formula Ia as the free base.
Preparation example 3: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound III of formula Ia | 10 |
| Stearic acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 2 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with stearic acid, mixing with dextrin and lactose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry particles with colloidal silicon dioxide and low-substituted hydroxypropyl cellulose to obtain final mixed particles. 2/3 the final blend of granules was compressed into tablets each containing 10mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 10mg of the compound of formula Ia as the free base.
Preparation example 4: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a compound of formula Ia in crystal form | 5 |
| Stearic acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. Mixing the materials, pressing into large blocks, and pulverizing into 18 mesh granules. 2/3 the final blend of granules was compressed into tablets each containing 5mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 5mg of the compound of formula Ia as the free base.
Preparation example 5: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| crystalline form of compound V of formula Ia | 1 |
| Stearic acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: tablets or capsules were prepared by the method of reference preparation example 4.
Preparation example 6:reference is made to the formulation and preparation of preparation 1, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 7:reference is made to the formulation and preparation of preparation example 2, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 8:reference is made to the formulation and preparation of preparation example 3, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 9:reference is made to the formulation and preparation of preparation 4, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 10:reference is made to the formulation and preparation of preparation example 5, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 11:reference is made to the formulation and preparation of preparation 1, except that the active agent is replaced by the compound of formula Ib 1 in crystalline form only.
Preparation example 12:reference is made to the formulation and preparation of preparation example 2, except that the active agent is replaced by the compound of formula Ib 2 in crystalline form only.
Preparation example 13:reference is made to the formulation and preparation of preparation 3, except that the active agent is replaced by the compound of formula Ib 3 in crystalline form only.
Preparation example 14:reference is made to the formulation and preparation of preparation 4, except that the active agent is replaced by the compound of formula Ib 4 in crystalline form only.
Preparation example 15:reference is made to the formulation and preparation of preparation example 5, except that the active agent is replaced by the compound of formula Ib 5 in crystalline form only.
Preparation example 16:reference is made to the formulation and preparation of preparation example 11, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 17:reference is made to the formulation and preparation of preparation example 12, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 18:reference is made to the formulation and preparation of preparation 13, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 19:reference is made to the formulation and preparation of preparation 14, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 20:reference is made to the formulation and preparation of preparation 15, except that only the stearic acid therein is replaced by magnesium stearate.
Preparation example 21: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound I of formula Ia | 2 |
| Citric acid | 5 |
| Starch | 50 |
| Microcrystalline cellulose | 35 |
| Cross-linked sodium carboxymethyl starch | 5 |
| Talcum powder | 5 |
| HPMC | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. HPMC is prepared into 5 percent aqueous solution to be used as a bonding agent for standby. Mixing the compound of formula I, citric acid, starch, and microcrystalline cellulose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry granules with talcum powder and cross-linked sodium carboxymethyl starch to obtain final mixed granules. 2/3 the final blend granules were compressed into tablets each containing 2mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 2mg of the compound of formula Ia as the free base.
Preparation example 22: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a compound of formula Ia in crystal form II | 0.5 |
| Citric acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with citric acid, mixing with starch and lactose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry particles with colloidal silicon dioxide and low-substituted hydroxypropyl cellulose to obtain final mixed particles. 2/3 the final blend granules were compressed into tablets each containing 0.5mg of the compound of formula Ia, calculated as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 0.5mg of the compound of formula Ia as the free base.
Preparation example 23: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound III of formula Ia | 10 |
| Citric acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PEG6000 | 2 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with citric acid, mixing with dextrin and lactose, making soft mass with binder, granulating, and drying. Mixing the obtained dry granules with PEG6000 and low-substituted hydroxypropyl cellulose to obtain final mixed granules. 2/3 the final blend of granules was compressed into tablets each containing 10mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 10mg of the compound of formula Ia as the free base.
Preparation example 24: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a compound of formula Ia in crystal form | 5 |
| Citric acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. Mixing the materials, pressing into large blocks, and pulverizing into 18 mesh granules. 2/3 the final blend of granules was compressed into tablets each containing 5mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 5mg of the compound of formula Ia as the free base.
Preparation example 25: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| crystalline form of compound V of formula Ia | 1 |
| Citric acid | 5 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: tablets or capsules were prepared by the method of reference preparation example 4.
Preparation example 26:reference is made to the formulation and process of preparation 21 except that only the citric acid is replaced by tartaric acid.
Preparation example 27:reference is made to the formulation and preparation of preparation 22, except that only citric acid is replaced by wineAnd (4) a mineral acid.
Preparation example 28:reference is made to the formulation and process of preparation 23, except that only the citric acid is replaced by tartaric acid.
Preparation example 29:reference is made to the formulation and process of preparation 24 except that only the citric acid is replaced by tartaric acid.
Preparation example 30:reference is made to the formulation and process of preparation 25 except that only the citric acid is replaced by tartaric acid.
Preparation example 31:reference is made to the formulation and preparation of preparation 21, except that the active agent is replaced by the crystalline form of compound 1 of formula Ib.
Preparation example 32:reference is made to the formulation and preparation of preparation 22, except that the active agent is replaced by the crystalline form of compound 2 of formula Ib.
Preparation example 33:reference is made to the formulation and preparation of preparation 23, except that the active agent is replaced by the crystalline form of compound 3 of formula Ib.
Preparation example 34:reference is made to the formulation and preparation of preparation 24 except that the active agent is replaced by the crystalline form of compound 4 of formula Ib.
Preparation example 35:reference is made to the formulation and preparation of preparation 25 except that the active agent is replaced by the crystalline form of compound 5 of formula Ib.
Preparation example 36:reference is made to the formulation and process of preparation 31, except that only the citric acid is replaced by tartaric acid.
Preparation example 37:reference is made to the formulation and preparation of preparation 32, except that only the citric acid is replaced by tartaric acid.
Preparation example 38:reference is made to the formulation and preparation of preparation 33, except thatThe citric acid is replaced by tartaric acid.
Preparation example 39:reference is made to the formulation and process of preparation 34 except that only the citric acid is replaced by tartaric acid.
Preparation example 40:reference is made to the formulation and process of preparation 35, except that only the citric acid is replaced by tartaric acid.
Preparation example 41: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound I of formula Ia | 2 |
| Citric acid | 3 |
| Tartaric acid | 2 |
| Magnesium stearate | 5 |
| Starch | 50 |
| Microcrystalline cellulose | 35 |
| Cross-linked sodium carboxymethyl starch | 5 |
| HPMC | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. HPMC is prepared into 5 percent aqueous solution to be used as a bonding agent for standby. Mixing the compound of formula I, citric acid, tartaric acid, starch, and microcrystalline cellulose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry granules with magnesium stearate and cross-linked sodium carboxymethyl starch to obtain final mixed granules. 2/3 the final blend granules were compressed into tablets each containing 2mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 2mg of the compound of formula Ia as the free base.
Preparation example 42: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a compound of formula Ia in crystal form II | 0.5 |
| Citric acid | 10 |
| Stearic acid | 10 |
| Starch | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| Colloidal silicon dioxide | 3 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with citric acid, mixing with starch and lactose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry particles with stearic acid, colloidal silicon dioxide and low-substituted hydroxypropyl cellulose to obtain final mixed particles. 2/3 the final blend granules were compressed into tablets each containing 0.5mg of the compound of formula Ia, calculated as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 0.5mg of the compound of formula Ia as the free base.
Preparation example 43: preparation of the tablets or capsules of the invention
Formulation (amount per tablet, mg):
| a crystalline form of a compound III of formula Ia | 10 |
| Citric acid | 2 |
| Stearic acid | 2 |
| Dextrin | 50 |
| Lactose | 35 |
| Low-substituted hydroxypropyl cellulose | 5 |
| PVP K30 | 3 |
The preparation method comprises the following steps: the materials were separately crushed and sieved through a 100 mesh sieve. PVP K30 was formulated as a 5% aqueous solution for use as a binder. Mixing the compound of formula I with citric acid, mixing with dextrin and lactose, making soft mass with binder, granulating, and drying. And uniformly mixing the obtained dry granules with stearic acid and low-substituted hydroxypropyl cellulose to obtain final mixed granules. 2/3 the final blend of granules was compressed into tablets each containing 10mg of the compound of formula Ia as the free base. An additional 1/3 final blend of granules was filled directly into hard capsule shells, each capsule containing 10mg of the compound of formula Ia as the free base.
Preparation examples 44, 45, 46:reference is made to the formulations and processes of preparations 41, 42 and 43, respectively, except that the active ingredient therein is replaced by formula IbThe crystal form of the compound 1, the crystal form of the compound 2 in the formula Ib and the crystal form of the compound 3 in the formula Ib.
Comparative examples 1, 2, and 3:reference is made to the formulations and processes of preparations 41, 42 and 43, respectively, except that the active ingredient is replaced by the ethanesulfonate of the compound of formula I.
Comparative examples 4, 5, and 6:reference is made to the formulations and processes of preparations 41, 42 and 43, respectively, except that the active ingredient is replaced by the free base of the compound of formula I.
Test example 11: stability testing of compositions
The tablets obtained in the above preparation examples or comparative examples were sealed and packaged in aluminum-plastic composite film bags, and then each sample was placed in a 45 ℃ incubator for 5 months (in the present invention, the treatment may be abbreviated as "45 ℃ 5 months"). For each sample, their maximum single impurity content and total impurity content at 0 months were determined and their maximum single impurity content and total impurity content at 45 ℃ at 5 months were determined using [ HPLC method a ], and the maximum single impurity increase percentage and the total impurity increase percentage were calculated as follows:
maximum single impurity increase percentage = [ (maximum single impurity content at 45 ℃ 5 months-maximum single impurity content at 0 months) ÷ maximum single impurity content at 0 months ] × 100%
Percent increase in total impurities = [ (total impurity content at 45 ℃ in 5 months-total impurity content at 0 months) ÷ total impurity content at 0 months ] × 100%
In addition, for each sample, their R isomer content (%) at 0 month was measured using [ HPLC method B ], and their R isomer content (%) at 45 ℃ at 5 months was measured, and the percentage increase in R isomer was calculated as follows:
percent increase in R isomer = [ (45 ℃ 5 month R isomer content-0 month R isomer content) ÷ 0 month R isomer content ]. times 100%)
The results of the measurements show that, surprisingly, the maximum individual impurity increases of less than 50%, the total impurity increases of less than 60% and the R isomer increases of less than 45% for all the samples of preparations 1 to 46. However, in each of the comparative examples 1 to 6, the maximum single impurity increase percentage was in the range of 150 to 350%, the total impurity increase percentage was in the range of 200 to 400%, and the R isomer increase percentage was in the range of 150 to 300%.
Claims (1)
1. A solid pharmaceutical composition comprising:
(a) a salt of a compound of formula I:
wherein R1 is bromo, R2 and R3 are methyl;
(b) stearic acid or a pharmaceutically acceptable salt thereof; and optionally
(c) A medicinal auxiliary material, a medical auxiliary material,
wherein,
the salt of the compound of formula I is p-toluenesulfonate of the compound of formula I or benzenesulfonate of the compound of formula I,
the weight ratio of the salt of the compound of formula I to the stearic acid or pharmaceutically acceptable salt thereof is 1: 0.2 to 20.
2. The solid pharmaceutical composition according to claim 1, wherein the salt of the compound of formula I is selected from a compound of formula Ia or a compound of formula Ib:
、 。
3. the solid pharmaceutical composition according to claim 1, wherein the stearic acid or a pharmaceutically acceptable salt thereof is selected from the group consisting of: stearic acid, magnesium stearate, calcium stearate, sodium stearate, zinc stearate, and combinations thereof.
4. The solid pharmaceutical composition according to claim 1, wherein the pharmaceutical excipient is selected from the group consisting of diluents, disintegrants, binders, lubricants or glidants.
5. The solid pharmaceutical composition according to claim 1, wherein the weight ratio of the salt of the compound of formula I to the stearic acid or a pharmaceutically acceptable salt thereof is 1: 0.5 to 10.
6. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutical excipient comprises 0 to 99.5% by weight of the composition.
7. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutical excipient comprises 10 to 99% by weight of the composition.
8. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutical excipient comprises 25 to 99% by weight of the composition.
9. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutical excipient comprises 50 to 98% by weight of the composition.
10. A solid pharmaceutical composition according to claim 1 wherein the pharmaceutical excipient comprises 75 to 95% by weight of the composition.
11. A solid pharmaceutical composition according to claim 1, which is in the form of a unit dose formulation of tablets, capsules, granules or pellets.
12. A solid pharmaceutical composition according to claim 11, comprising the salt of the compound of formula I in an amount of 0.1 to 100mg per unit dose formulation in terms of its free base represented by formula I.
13. The solid pharmaceutical composition according to claim 11, wherein the amount of the salt of the compound of formula I contained in each unit dosage formulation is 0.1 to 50mg in terms of the free base represented by formula I.
14. The solid pharmaceutical composition according to claim 11, which comprises the salt of the compound of formula I in an amount of 0.1 to 25mg in terms of the free base represented by formula I per unit dosage form.
15. The solid pharmaceutical composition according to claim 11, which comprises the salt of the compound of formula I in an amount of 0.5 to 20mg in terms of the free base represented by formula I per unit dosage form.
16. The solid pharmaceutical composition according to any one of claims 1 to 15 wherein the pharmaceutical excipient further comprises an organic acid selected from the group consisting of: citric acid, tartaric acid, or a combination thereof.
17. A solid pharmaceutical composition according to claim 16, wherein the weight ratio of the salt of the compound of formula I to the organic acid is 1: 0.1 to 20.
18. A solid pharmaceutical composition according to claim 16, wherein the weight ratio of the salt of the compound of formula I to the organic acid is 1: 0.2 to 20.
19. A solid pharmaceutical composition according to claim 16, wherein the weight ratio of the salt of the compound of formula I to the organic acid is 1: 0.5 to 10.
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| CN105130996B (en) * | 2015-08-07 | 2017-05-03 | 成都倍特药业有限公司 | 1,5-naphthalenedisulfonate and crystal form of benzodiazepine derivative and preparation methods of 1,5-naphthalenedisulfonate and crystal form |
| CN109956947A (en) * | 2017-12-25 | 2019-07-02 | 江苏恒瑞医药股份有限公司 | A kind of novel crystal forms, the Preparation method and use of CNS inhibitor |
| 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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| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and polymorphs thereof |
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| GB9911152D0 (en) * | 1999-05-14 | 1999-07-14 | Glaxo Group Ltd | Short-acting benzodiazepines |
| GB0613693D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts (3) |
| EP2305647A1 (en) * | 2009-09-18 | 2011-04-06 | PAION UK Limited | Process for preparing 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4 H-imidazo[1,2-a][1,4]benzodiazepine-4-yl] propionic acid methyl ester or the benzene sulfonate salt thereof, and compounds useful in that process |
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2013
- 2013-05-05 CN CN201310166656.6A patent/CN103230595B/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101501019A (en) * | 2006-07-10 | 2009-08-05 | Paion英国有限公司 | Short-acting benzodiazepine salts and polymorphs thereof |
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