CN103202815B - Injection for treating mental disease - Google Patents
Injection for treating mental disease Download PDFInfo
- Publication number
- CN103202815B CN103202815B CN201310161241.XA CN201310161241A CN103202815B CN 103202815 B CN103202815 B CN 103202815B CN 201310161241 A CN201310161241 A CN 201310161241A CN 103202815 B CN103202815 B CN 103202815B
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- injectable powder
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to an injection for treating mental disease, and particularly relates to a freeze drying power-injection. The freeze drying power-injection contains a compound serving as an active ingredient and shown in the formula I shown in the description or pharmaceutically acceptable salts of the compound, mannitol and/or glycine serving as excipient and an optional pH conditioning agent, wherein the weight ratio of the excipient to the active ingredient is (1-1000): 1. The freeze drying power-injection has good stability.
Description
Technical field
The present invention relates to can be used for treat the injection of the lyophilized injectable powder form of central nervous system disease.
Background technology
With following formula I compound:
wherein R1 is bromine, and R2 and R3 are methyl,
Owing to containing above-mentioned specific structure, in WO00/69836, report that this compound (60 pages of example I c-8 of description) is fugitive central nervous system (CNS) inhibitor, there is the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action.They can be used for the intravenously administrable in following clinical treatment: as calm before the operation in intra-operative, anxiety with forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis and analgesic and/or simultaneously, as the induction for general anesthesia and the component that maintains; ICU calmness etc., according to CN101501019A (PAION, application number CN200780028964.5) report in, the free alkali of this compound is not very stable, only be suitable for 5 ℃ of preservations of low temperature, under the condition of 40 ℃/75% relative humidity (opening), the sample deliquescence of storage, color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.So the salt of people's synthesis type (I) compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing CN101501019A and US20100075955A1 (TILBROOK) have reported respectively benzene sulfonate, the esilate of formula I compound.CN102964349A (permanent auspicious, application number 201110456864.0) has reported the tosilate of formula I compound.
Have been reported the worry of formula I compound or its salt existence and stability aspect, this is disadvantageous for this compounds for clinical treatment relevant disease.
Summary of the invention
The object of the invention is particularly cryodesiccated pharmaceutical composition lyophilization injectable powder for example of a kind of useful pharmaceutical composition, expects that it has for example stability of good pharmaceutical properties.Have been surprisingly found that, when formula I compound or its salt is mixed with to lyophilization injectable powder together with pharmaceutic adjuvant, it is favourable wherein comprising mannitol or glycine, for its chemical stability, is particularly favourable.
Therefore, first aspect present invention provides a kind of pharmaceutical composition, and it is the lyophilization injectable powder as ejection preparation, wherein comprises:
As active component with following formula I compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl,
As mannitol and/or the glycine of excipient,
And optional pH adjusting agent,
The weight ratio of described excipient and described active component is 1～1000:1, for example 2～500:1, for example 4～400:1, for example 5～300:1, for example 10～300:1.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, its solid content in solution before lyophilization is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).For example, for example, or the weight sum of this lyophilized injectable powder Chinese style I compound and mannitol accounts for 2～20% (w/v) of the front liquor capacity of lyophilization, 3～18% (w/v), 5～15% (w/v).
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, its with water for injection redissolve to substantially with lyophilization before solution phase with volume, solid content in gained solution is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).Or, this lyophilized injectable powder with water for injection redissolve to substantially with lyophilization before solution phase with volume, the weight sum of its Chinese style I compound and mannitol accounts for 2～20% (w/v) of redissolution liquor capacity, for example 3～18% (w/v), for example 5～15% (w/v).
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, its with water for injection redissolve to substantially with lyophilization before solution phase with volume, gained solution is measured according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 2.5～4.5.In one embodiment, pH value is 3.0～4.0.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, wherein this lyophilized injectable powder water is made and in every 1ml, is contained the solution of formula I compound or the acceptable salt 2mg of its pharmacy and measure according to the method under two appendix VIH items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 2.5～4.5.In one embodiment, pH value is 3.0～4.0.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, wherein water content is lower than 5%, preferably lower than 4%, preferably lower than 3%, more preferably less than 2%.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, wherein also comprise pH adjusting agent.In one embodiment, the kind of this pH adjusting agent is not particularly limited, as long as it can be adjusted to the pH value of described lyophilized injectable powder (and/or will preparing intermedium in this lyophilized injectable powder process of preparation) scope of expectation.In one embodiment, described pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, tartaric acid, maleic acid or its combination.In addition, the amount of pH adjusting agent is also unrestricted, and for example those skilled in the art are adjusted to the pH value of material to be regulated value or the scope of expection conventionally.In addition, in lyophilization injectable powder, can also add there is acid-base pair that the material example bronsted lowry acids and bases bronsted lowry described above of pooling feature forms so that the powder of lyophilization injectable powder of the present invention under metastable acid-base value environment, for example can use appropriate acetic acid and sodium hydroxide right to form acetic acid-sodium acetate buffering, or can use phosphate to form acid-base pair, can also use sodium hydroxide and citric acid to form sodium citrate acid-base pair.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, wherein also comprise chelating agent.In one embodiment, described chelating agent is selected from ethylenediaminetetraacetic acid, disodiumedetate, calcio-disodium edetate or its combination.The selection of chelating agent is that those skilled in the art rule of thumb can easily determine, for example it is conventionally in 0.1～5% of lyophilization injectable powder mid point injectable powder powder gross weight, and particularly 0.1～5%, particularly 0.2～2%, particularly 0.25～1%, particularly 0.5～1%.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, wherein also comprise other pharmaceutic adjuvant, such as being selected from: sodium chloride, glucose, dextran, sorbitol, HP-β-CD, sulphur fourth group-beta-cyclodextrin, mannitol, lactose, sucrose, sorbitol, D-glucitol, erythritol, xylitol, fructose, polyvinylpyrrolidine etc.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of pharmacy of wherein said formula I compound is tosilate, benzene sulfonate or esilate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of pharmacy of wherein said formula I compound is tosilate or benzene sulfonate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of pharmacy of wherein said formula I compound is selected from following formula Ia compound or formula Ib compound:
In the present invention, above-mentioned formula Ia compound is the tosilate of formula I compound, and formula Ib compound is the benzene sulfonate of formula I compound.In the present invention, while mentioning formula I compound, as do not specialized in its linguistic context, refer to free alkali shown in formula I and the acceptable salt of its pharmacy for example above-mentioned tosilate and benzene sulfonate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, it is by comprising prepared by following step substantially:
(a) according to the solid content in solution before lyophilization, determine dosing volume, take formula I compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except pH adjusting agent, add the water for injection that accounts for prescription full dose 90%, make to dissolve, then add active carbon, stir, filtering decarbonization, is adjusted to pH2.5～4.5 with acid solution or aqueous slkali, for example pH3.0～4.0 if desired;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, with acid solution or aqueous slkali, be adjusted to pH2.5～4.5 if desired, for example pH3.0～4.0;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade obtains.
The above-mentioned lyophilization injectable powder according to the present invention, the filtered filtrate of step (c) gained wherein, wherein solid content is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, it is to be the seal-packed unit dose formulations form of vial.In one embodiment, the amount that comprises formula I compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.The amount that for example comprises formula I compound or the acceptable salt of its pharmacy in every bottle of injectable powder agent is amounted to into its free alkali representing with formula I and is counted 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
The inventor has been surprisingly found that, formula I compound there is to beat all good result when particularly formula Ia compound or formula Ib compound are prepared together with excipient of the present invention, the effect of stability particularly, and this effect can not disappear because of continuing to add other pharmaceutic adjuvant, and this effect is completely different from described excipient " figuration " effect that application can produce in lyophilization injectable powder manufacture field conventionally.
Second aspect present invention provides the lyophilization injectable powder method of the arbitrary embodiment of preparation first aspect present invention, and it consists essentially of following steps:
(a) according to the solid content in solution before lyophilization, determine dosing volume, take formula I compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except pH adjusting agent, add the water for injection that accounts for prescription full dose 90%, make to dissolve, then add active carbon, stir, filtering decarbonization, is adjusted to pH2.5～4.5 with acid solution or aqueous slkali, for example pH3.0～4.0 if desired;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, with acid solution or aqueous slkali, be adjusted to pH2.5～4.5 if desired, for example pH3.0～4.0;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade obtains.
According to the method for the arbitrary embodiment of second aspect present invention, the filtered filtrate of step (c) gained wherein, wherein solid content is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).
According to the method for the arbitrary embodiment of second aspect present invention, wherein the described activated carbon dosage of step (a) is 0.05%～1% of solution weight, preferably 0.05%～0.5%.
According to the method for the arbitrary embodiment of second aspect present invention, wherein acid solution and aqueous slkali described in step (b) are to use to be selected from the aqueous solution that following pH adjusting agent is mixed with: sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, tartaric acid, maleic acid or its combination.The concentration of these aqueous solutions is well known to a person skilled in the art, for example 1～10%, for example 2%～5%.
According to the method for the arbitrary embodiment of second aspect present invention, wherein in step (d), remove after moisture content in gained lyophilization material water content lower than 5%, preferably lower than 4%, preferably lower than 3%, more preferably less than 2%.
According to the method for the arbitrary embodiment of second aspect present invention, although the step of the concrete steps of its description in some details or described in the preparation example of language description up and down literary composition specific embodiment part distinguished to some extent, yet the open in detail of those skilled in the art's full text according to the present invention can summarize according to the method step of the arbitrary embodiment of second aspect present invention completely.
Arbitrary embodiment of applicable equally other the arbitrary embodiment of arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has or other either side, as long as they can be not conflicting, certainly, at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with feature to various aspects of the present invention below.
The active component that lyophilization injectable powder of the present invention relates to is with following formula I compound or the acceptable salt of its pharmacy:
In formula, R1 is bromine, and R2 and R3 are methyl;
The chemistry 3-[(4S by name of formula I compound) the bromo-1 methyl-6-of-8-(2-pyridine radicals)-4H imidazoles [1,2-a] [Isosorbide-5-Nitrae] benzodiazepine
-4-yl] methyl propionate,
In the present invention, preferred formula I compound is its benzene sulfonate or tosilate.
In the present invention, preferred formula I compound is to be selected from following formula Ia compound or formula Ib compound:
The present invention also provides and in experimenter, produces calm or hypnogenic method, and the method comprises the lyophilization injectable powder of this experimenter being used to effective dose.
According to the present invention, also provide and in experimenter, cause that method antianxity, the method comprise the lyophilization injectable powder of this experimenter being used to effective dose.
According to the present invention further provides, cause method of flaccid muscles in experimenter, the method comprises the lyophilization injectable powder of this experimenter being used to effective dose.
According to the present invention further provides the method for the treatment of convulsions state in experimenter, the method comprises the lyophilization injectable powder of this experimenter being used to effective dose.
In the present invention, described experimenter is compatibly mammal, preferably the mankind.
For solid composite medicament described in the first aspect present invention of above-mentioned disease or second aspect, its give mammal for example people's dosage can be 0.001-5.0mg/kg body weight/day, preferably 0.001-2.0mg/kg body weight/day conventionally.
According to the present invention, term " excipient " also can be described as adjuvant, filler etc.
" the acceptable excipient of pharmacy " used herein refers to the excipient that can be used for compounding pharmaceutical, it there is no harmful effect to organism, and normally organism can tolerate.
In the present invention, preferred lyophilized injectable powder of the present invention is made in every 1ml and is contained after the solution of formula I compound 2mg at water, then is that pH value algoscopy is measured according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 2.5～4.5.In one embodiment, pH value is 3.0～4.0.The inventor have been surprisingly found that, the compositions obtaining like this has excellent especially effect.
Although those skilled in the art understand, excipient of the present invention can be that any can be used for cryodesiccated excipient, particularly mannitol, lactose, sucrose, glucose, sorbitol, glycine, dextran, sodium chloride and combination thereof, yet in the present invention, particularly preferred excipient is mannitol and/or glycine.
In one embodiment, the present invention is to provide cryodesiccated pharmaceutical preparation, the weight ratio of wherein said excipient and formula I compound or its salt is 1～1000:1,2～500:1 for example, for example 4～400:1, for example 5～300:1, for example 10～300:1.In addition, this lyophilized injectable powder solid content in solution before lyophilization is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).Like this, the medicinal liquid of preparing before lyophilization is the formula that comprises following composition:
In one embodiment, the present composition is cryodesiccated pharmaceutical preparation, and the weight ratio of wherein said excipient and formula I compound or its salt is 1～1000:1,2～500:1 for example, for example 4～400:1, for example 5～300:1, for example 10～300:1.In addition, the lyophilized injectable powder that this lyophilization obtains, it is made in every 1ml containing after the solution of formula I compound or its salt 2mg, according to the method mensuration under two appendix VI H items of Chinese Pharmacopoeia version in 2010 at water, the pH value of this solution is 2.5～4.5, and preferably pH value is 3.0～4.0.Like this, the lyophilized injectable powder obtaining in lyophilization comprises: the formula I compound or its salt of 1 weight portion, 1～1000 weight portion (preferred 2～500 weight portions, preferred 4～400 weight portions, preferably 5～300 weight portions, preferably 10～300 weight portions) excipient and optional pH adjusting agent.In one embodiment, discovery is in the particularly preferred present composition, the weight ratio of described excipient and formula I compound or its salt is 10～300:1, and solid content is 2～20% (w/v) before lyophilization, 3～18% (w/v) for example, for example, have beat all excellent properties when 5～15% (w/v).In one embodiment, discovery is in the particularly preferred present composition, the weight ratio of described excipient and formula I compound or its salt is 10～300:1, and water for injection used is 200～2000 times of formula I compound weight, in this ratio ranges, the lyophilization injectable powder of preparation has beat all advantage in the case, for example good stability, with water for injection, again to dissolve (redissolve) fast.
The preparation process of lyophilization injectable powder is to well known to a person skilled in the art pharmaceutical technology, for example two kinds of schematic freeze-drying curves shown in following freeze-drying curve A and freeze-drying curve B:
Water content in lyophilization injectable powder is generally lower than 5%, preferably lower than 4%, preferably lower than 3%, more preferably less than 2%.Moisture control can be controlled by suitable adjustment lyophilization program.Water content in this lyophilization injectable powder can be measured according to many known methods, for example dry weight-loss method.
In the present invention, in order to regulate where necessary the pH value of medicinal liquid, can in compositions, add suitable pH adjusting agent.Although the inventor is not only with having the strong acid of buffer capacity or a strong base solution, for example sodium hydrate aqueous solution and aqueous hydrochloric acid solution regulate, yet, those skilled in the art understand, if process the pH requirement that can meet system by this pH adjusting agent of not having buffer capacity, the pH adjusting agent with buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can regulate pH value, and can stablize pH value.Therefore the listed arbitrary pH adjusting agent of the present invention or its combination include in spirit and scope of the invention.
When preparation lyophilized injectable powder of the present invention, in the medicinal liquid of preparing, the content of solid content is 2～20% (w/v) preferably, for example 3～18% (w/v), for example 5～15% (w/v).Because normally carrying out lyophilization in tubulose cillin bottle, lyophilized injectable powder obtains, those skilled in the art understand this product and are obtaining finished product even before for doctor, conventionally all present a round pie, although lecture is than the volume of original aqueous solution few (slightly dwindling) in the volume theory of this cake, yet this dwindling can not narrow down to former aqueous solution volume 50% conventionally conventionally, conventionally can be between the 80-120% of former aqueous solution volume, be more typically between the 90-100% of former aqueous solution volume, and can be observed former aqueous solution liquid level vestige in finished product cillin bottle, (main body cake remains in the liquid level vestige on bottle wall dwindling because of lyophilizing, even if the dried frozen aquatic products in cillin bottle because of a variety of causes such as collision etc. former thereby be Powdered, conventionally still can retain original liquid level vestige), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, although the present invention is to provide a kind of substantially anhydrous lyophilization injectable powder, yet still can roughly estimate it when preparing according to this injectable powder, the medicine liquid volume before lyophilization starts at least, the volume estimating according to this and the weight of the dry end-product in cillin bottle, also can calculate when preparation lyophilized injectable powder of the present invention the content of the solid content in the medicinal liquid of preparing.Therefore,, according to the lyophilized injectable powder of first aspect present invention, the solid content of its medicinal liquid when preparation is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).
Term " solid content " refers to solid matter (for example formula I compound or its salt of the present invention and whole excipient used, weight/gram) for example join, in solvent (water for injection), after dissolving, obtain a solution, the weight of described solid matter for example, divided by the percent (weight/volume percent, g/100ml) of whole liquor capacity.For example in the present invention, with 1mg formula Ia compound and excipient 100mg mannitol, add appropriate aqueous solution for injection, be mixed with the solution that final volume is 1ml, its solid content is about 10%.
In the present invention, symbol %, the linguistic context of using according to it, can have those skilled in the art and hold intelligible implication.For example, when mentioning solid content, this symbol represents the percent (w/v, for example g/100ml) of weight/volume; For example during " water content " in mentioning lyophilization injectable powder, for example water content is below 5% again, and now this symbol % represents the percent (w/w, g/100g) of w/w.Generally speaking, when solid is dispersed in liquid, % represents weight/volume percent; Solid be dispersed in solid or liquid dispersion in solid for example, when (water content of powder pin), % represents w/w percent.In other cases, unless otherwise noted, symbol % represents w/w percent.
When preparation medicinal liquid of the present invention, as well known to those skilled in the art, can example according to appointment the microporous filter membrane of 0.45um carry out coarse filtration filtration, by liquid medicine filling to before in cillin bottle, can example according to appointment the microporous filter membrane of 0.22um carry out fine straining filtration with degerming, can filter repeatedly if desired.
According to lyophilized injectable powder of the present invention, it is lyophilization injectable powder.In one embodiment, this lyophilization injectable powder is single-dose preparations (for example bottled injectable powder in XiLin), the amount of per unit dosage Chinese style I compound can be such as but not limited to 0.1～100mg, be for example 0.1～50mg, be for example 0.1～25mg, be for example 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
In lyophilization injectable powder of the present invention, the formula I compound or its salt wherein comprising can be used the present invention [assay method A] method to adopt external standard method to measure with respect to the percentage composition of injectable powder powder gross weight.
In lyophilization injectable powder of the present invention, " mannitol " and/or the discrimination method in " formula mannitol injection liquid " that the mannitol wherein comprising can record by Chinese Pharmacopoeia two of versions in 2010 differentiate that whether it exists, for example, by the saturated aqueous solution 1ml of lyophilized injectable powder powder preparation of the present invention, add each 0.5ml of ferric chloride test solution and sodium hydroxide test solution, generation brown color precipitation, jolting does not disappear, drip excessive sodium hydrate test solution, be dissolved into brown solution, if show that this phenomenon shows to be added with mannitol in powder pin of the present invention.The method of [assay] in " formula mannitol injection liquid " that can also record by Chinese Pharmacopoeia two of versions in 2010 is measured the content of the mannitol in injectable powder, thereby can calculate the weight ratio of active component and mannitol in injectable powder.
In lyophilization injectable powder of the present invention, discrimination method in " glycine flushing liquor " that the glycine wherein comprising can record by Chinese Pharmacopoeia two of versions in 2010 differentiates that whether it exists, the content of the glycine in injectable powder can also be measured by the method for [assay], thereby the weight ratio of active component and glycine in injectable powder can be calculated.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and the time of typically redissolving is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds.
According to lyophilized injectable powder of the present invention, its water is made and in every 1ml, is contained the solution of formula I compound 2mg and measure according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 2.5～4.5, and preferably pH value is 3.0～4.0.
In the present invention, formula I compound, or formula Ia compound or formula Ib compound, and their standard substance, all can adopt the disclosed method preparation of prior art.
Lyophilized injectable powder provided by the invention can, preserving at least 24 months at 25 ℃ of following dry places, can meet the Storage Requirement of general lyophilization injectable powder.
Described in first aspect present invention or second aspect, solid composite medicament can be used as fugitive CNS inhibitor, and they can be used for by following clinical settings oral administration: calm before operation in peri-operation period event, anxiety and forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis or analgesic and/or simultaneously, as the induction for general anesthesia and the component that maintains; ICU is calm.In addition, described in first aspect present invention or second aspect, solid composite medicament can be used for the mental sickness such as calmness, hypnosis, anxiety, of flaccid muscles, convulsion.
The specific embodiment
By the following examples, can conduct further description the present invention, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and is not deviating under the prerequisite of the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although be well known in the art for realizing many materials and the operational approach that the object of the invention used, the present invention still does to describe in detail as far as possible at this.Following examples further illustrate the present invention, rather than restriction the present invention.While preparing injectable powder below in listed prescription, formula I compound amount of calculation is all calculated with the form of its free alkali, listed formula is the amount of for example, in per unit dosage particles (injectable powder is every bottle) contained formula I compound free alkali, while preparing compositions below, every batch of preparation amount is the amount of 1000 unit dose formulations, and for example the amount with 1000 bottles of injectable powder feeds intake.
In the various chromatography of the present invention, the chromatographic peak that acid group shows is all ignored when calculating.
analysis test method
Below [HPLC method A] can be used for measuring related substance in powder pin of the present invention and the content of situation of change and powder pin activating agent thereof.
[HPLC method A]:
On HP1100Agilent chromatograph, carry out purity analysis:
Chromatographic column: Phenomenex Gemini C185 μ m (2.0 * 50mm) (guard column Phenomenex Gemini C18,2x4mm), U.S. Féraud door company
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 0.8ml/ minute
Detect: ultraviolet detection, wavelength: 254nm;
The NH of mobile phase A: 2mmol
4hCO
3(use NH
3solution is adjusted to pHl0)
Mobile phase B: acetonitrile
Gradient elution program:
| Elution time/minute | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 25 | 10 | 90 |
| 28.8 | 10 | 90 |
| 29 | 90 | 10 |
| 34 | 90 | 10 |
Sample preparation: get various samples (crude drug or injectable powder compositions) appropriate, (acetonitrile: water=50:50 wherein contains the NH of 1mmol to add acetonitrile-water mixed liquor
4hCO
3, and use NH
3solution is adjusted to pHl0) dissolve in right amount and make the solution of the about 1mg/ml of concentration, filter if desired.
Computational methods: the formula I compound chromatographic peak of take is main peak, its relative retention time is 1, (peak area is less than 0.01% impurity peaks of main peak area and ignores to read the peak area of whole chromatographic peaks of relative retention time between 0.60～2.00, acid group peak is disregarded), with area normalization method calculate each impurity peaks content and, content by external standard method with calculated by peak area active component, and calculate maximum single contaminant content and total impurities content.
4 of its heptatomic rings of active component in pharmaceutical composition of the present invention are S-isomer, may mix and have a small amount of R-isomer in medicine.Below [HPLC method B] can be used for measuring R-isomer (compound representing with following formula Ix) and the situation of change thereof in the present composition.
in formula, R1 is bromine, and R2 and R3 are methyl;
[HPLC method B]:
On HP1100Agilent chromatograph, carry out purity analysis:
Running time: to the more than 2.5 times of main peak retention time
Chromatographic column: Daicel Chrialcel OJ-H (5 μ m) 4.6 * 250mm (guard column Daicel Chrialcel OJ-H analyzes guard column 5 μ m4.0 * 10mm), Japanese Daicel (Daicel)
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 1.0ml/ minute
Detect: ultraviolet detection, wavelength: 225nm (single wavelength detecting);
Mobile phase: hexane: ethanol=93:7
Sample preparation: get various samples (crude drug or injectable powder compositions) appropriate, add the appropriate supersound process of mobile phase and make to dissolve the also solution of the about 1mg/ml of diluted concentration, filter if desired.
Computational methods: the formula I compound chromatographic peak of take is main peak, its relative retention time is 1, read the peak area of impurity peaks between 1.10～1.25 of the peak area of main peak and relative retention time (its be formula Ix compound for R isomer), R content of isomer (%)=[R isomer peak area ÷ (R isomer peak area+S isomer peak area)] * 100%.
In above various HPLC methods, no matter formula I compound is with its free alkali form dosing or with the form dosing of its pharmaceutical salts, because of dissociating of benzenesulfonic acid or p-methyl benzenesulfonic acid or other acid group, they all show and have identical retention time with formula I free alkali in chromatographic system, and this is that chromatography field is known.
preparation example 1: preparation formula Ix compound (it can be used for the reference substance of analyzing and testing)
The R-isomer the present invention relates to (being the compound that formula Ix represents) can be carried out with reference to the method for recording in WO00/69836, specific as follows:
Step 1: with reference to the preparation method of WO00/69836 description 23-24 page Int-1, use Fmoc-D-Glu (OMe)-OH (biochemical purchased from gill) to obtain take following formula Int-1x intermediate (its isomer that is Int-1) for raw material:
Step 2: follow the preparation method with reference to WO00/69836 description 34-35 page Example I-1, the intermediate compound I nt-2 that uses Int-1x intermediate and WO00/69836 description 24 to record is raw material, obtains following Ex I-10x compound (it is the isomer of the Example I-10 compound of 38 pages of records of WO00/69836 description):
Step 3: follow the preparation method with reference to WO00/69836 description 60-61 page Example Ic-8, using Ex I-10x is raw material, obtains take the compound (the R-isomer of its Example Ic-8 compound that is 60 pages of records of WO00/69836 description) that following formula Ix represents
In formula, R1 is bromine, and R2 and R3 are methyl.
Then with reference to the present invention below the method for preparation example 7 to its purification, obtain white solid.After measured, its molecular formula C
21h
19brN
4o
2, ESIMS461 (M+Na, alkali), 439 (M+H).Chromatographic purity 99.53%[HPLC method B], S content of isomer 0.46%[HPLC method A].In the test of [HPLC method A] method, for S isomer, the relative retention time of this R isomer is about 1.17.This R isomer is treated as the isomer impurities of active component formula I compound or its salt in the present invention.
preparation example 2: preparation I compound (it can be used for the reference substance of analyzing and testing and raw material prepared by powder pin)
According to the preparation method of WO00/69836 description 60-61 page Example Ic-8, use the Ex I-10 of 0.5mol for raw material feeds intake, obtain with following formula I compound:
In formula, R1 is bromine, and R2 and R3 are methyl.
Get gained formula I compound 100g, add in 800ml ethanol-lactic acid-water (three's volume ratio 45:2:53) mixed solution of 50 ° of C and be stirred to dissolve; Filter, make filtrate at the temperature of 5 ° of C standing 10～12 hours to carry out recrystallization, leach crystallization, dry, obtain formula I compound.Repeat this operation 2 times, the product chromatographic purity 99.65%[HPLC method A obtaining]; R isomer impurities content 0.26%[HPLC method B].
preparation example 3: preparation I compound tosilate (be formula Ia compound, its reference substance that can be used for analyzing and testing with
and the raw material prepared of powder pin)
Getting preparation example 2 compound alkali (formula I compound) 10g is dissolved in 60ml ethyl acetate, then the p-methyl benzenesulfonic acid with above-mentioned alkali equimolar ratio is dissolved in 10ml methanol, and be added drop-wise in the ethyl acetate solution of formula I compound alkali, stirring and crystallizing, sucking filtration, drying under reduced pressure obtains the tosilate of formula I compound, white solid.HPLC:99.63%[HPLC method A]; R isomer impurities content 0.27%[HPLC method B].
preparation example 4: preparation I compound benzene sulfonate (be formula Ib compound, its can be used for analyzing and testing reference substance and
raw material prepared by powder pin)
(formula I compound 10g) adds in bottle and adds at ambient temperature toluene (60ml) to get preparation example 2 compound alkali.To adding in this solution with the benzenesulfonic acid (being mixed with the alcoholic solution of 1M) of above-mentioned alkali equimolar ratio and stirring this reactant mixture 15 minutes, after this, filter the solid from this solution precipitation, with toluene wash and under vacuum 40 ℃ of oven dry, obtain white solid.HPLC:99.47%[HPLC method A]; R isomer impurities content 0.25%[HPLC method B].
The esilate of the formula I compound using in all kinds of tests in addition, prepares (can be called for short below formula I esilate) with reference to [0101] section of method of recording of US20100075955A1 description.
test example 1: formula I compound and excipient composition test
Modus ponens Ia compound is dissolved in appropriate water for injection (amount of water is that in the solution making after dissolving, solid content is 10%) together with a certain amount of mannitol as shown in the table or glycine, and by 1M hydrochloric acid and/or 1M sodium hydrate regulator solution value to 3.7, medicinal liquid divides in the cillin bottle that installs to 5ml, every bottle of 1ml medicinal liquid, through lyophilization (freeze-drying curve A), moisture is down to below 1%, close plug.
Each injectable powder sample is placed in to 50 ° of C calorstats and places 4 months (can dispose referred to as " 50 ° of C4 months " in the present invention).For each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure they at 50 ° of C4 the R content of isomer (%) during the month, being calculated as follows R isomer increases percent:
R isomer increases percent=[(50 ° of C4 month R content of isomer-0 month R content of isomer) 0 month R content of isomer of ÷] * 100%
The results are shown in following table 1.
Table 1:
| Mannitol: formula Ia compound | R isomer increases (%) | Glycine: formula Ia compound | R isomer increases (%) |
| 0 | 274 | 0 | 274 |
| 1 | 241 | 1 | 250 |
| 2 | 206 | 2 | 211 |
| 3 | 148 | 3 | 159 |
| 4 | 60 | 4 | 67 |
| 5 | 32 | 5 | 33 |
| 7.5 | 34 | 7.5 | 33 |
| 10 | 28 | 10 | 28 |
| 15 | 26 | 15 | 26 |
| 25 | 30 | 25 | 28 |
| 50 | 33 | 50 | 30 |
| 100 | 29 | 100 | 24 |
| 150 | 32 | 150 | 34 |
| 200 | 28 | 200 | 35 |
| 250 | 27 | 250 | 33 |
| 300 | 31 | 300 | 32 |
| 350 | 33 | 350 | 36 |
| 400 | 34 | 400 | 28 |
| 500 | 32 | 500 | 27 |
| 1000 | 33 | 1000 | 32 |
Mannitol when the first hurdle in upper table " mannitol: formula Ia compound " represents to mix: the two weight ratio of formula Ia compound, for example this value is to represent 0 portion of mannitol and 1 part of formula Ia compound at 0 o'clock, this value is to represent 100 portions of mannitol and 1 part of formula Ia compound at 100 o'clock, etc.; Third column also has similar meaning similarly.
Visible according to upper table result, withstand high temperatures environment better during the combination of formula Ia compound and mannitol or glycine, particularly the weight ratio at formula I compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:4～400, for example, in 10～300 scopes, the result with obvious excellence, R content of isomer increases not obvious.
When although the weight ratio of formula I compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:500 or 1:1000, while showing with lower excipient, there is same stability, but because injectable powder of the present invention is when being mixed with medicinal liquid for injection, the liquid wherein redissolving is penetrated solid concentration in liquid should be lower, for example solid concentration should be lower than 20%, and active component should have certain absolute magnitude so that dose therapeutically effective to be provided, for example, during per injection activating agent 5mg, for 1:1000 powder pin, should be dissolved at least solution of 25ml, just can reach solid concentration and should and hold 5mg active medicine lower than 20% degree, and clinically for fast injection administration, the obvious volume of solution of 25ml is excessive.Therefore in above table 1, the weight ratio of formula I compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:4～400, for example, in 10～300 scopes, be to be applicable to very much clinical practice.
In addition, get respectively each injectable powder of gained in table 1, open bottle cap plastic top, with syringe, from bottle stopper puncture, inject water for injection (consumption is about 3 times of liquor capacity respective sample lyophilization), with stopwatch, record the redissolution time, every batch sample test 5 times, averages.
As a result, the weight ratio of formula Ia compound and described mannitol or glycine is each sample in the scope of 1:4～400, the redissolution time all within the scope of 5～12 seconds, mannitol for example: the sample redissolution time of formula Ia compound=100 is 6 seconds.Yet surprisingly, the weight ratio of formula Ia compound and described mannitol or glycine is each sample in the scope of 1:500～1000, the redissolution time all within the scope of 26～44 seconds, glycine for example: the sample redissolution time of formula Ia compound=500 is 38 seconds.The weight ratio of display type Ia compound and described mannitol or glycine is that each sample in the scope of 1:4～400 has good solubility property thus, be very beneficial for clinical use, and when excipient relative quantity further increases, dissolve and be slowly unfavorable for clinical use.
test example 2: formula I compound and excipient composition test
With reference to the method for above test example 1, different is only that active medicine is used the compound into formula Ib instead.Basic identical in result and table 1, R isomer increases in (%) and table 1 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and the weight ratio of described excipient are in the scope of 1:4～1000) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～3 scope is interior).For example, mannitol: in the proportioning of formula Ib compound=50, it is 31% that R isomer increases (%); Glycine for example again: in the proportioning of formula Ib compound=50, it is 34% that R isomer increases (%).
With reference to table 1 the first hurdle and the second hurdle in the method for above test example 1, different is only that mannitol used is replaced with to mannitol and glycine equal amount of mixture.Basic identical in result and table 1, R isomer increases in (%) and table 1 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and the weight ratio of described excipient are in the scope of 1:4～1000) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～3 scope is interior).This shows while using mannitol and glycine combination as excipient can bring into play the stablizing effect to activating agent equally.
With reference to the method for above test example 1, different is only that active medicine is used the esilate into formula I instead.Result regrettably, is in the four corner of 1:0～1000 at the salt of formula I compound and the weight ratio of described excipient, and R isomer increases (%) all in 150～250% scopes.Demonstration mannitol or glycine can not be brought into play the stablizing effect to activating agent to formula I esilate.
With reference to table 1 the first hurdle and the second hurdle in the method for above test example 1, different is only that mannitol used is replaced with to excipient dextran, sorbitol, lactose, glucose or the sodium chloride that lyophilization injectable powder is conventional, result regrettably, in other the weight ratio of excipient of the salt of formula I compound and these, be in the four corner of 1:0～1000, R isomer increases (%) all in 150～250% scopes.Show that other usual excipients all can not bring into play the stablizing effect to activating agent to the salt of formula I compound.
With reference to table 1 the first hurdle and the second hurdle in the method for above test example 1, different is that formula Ia compound used is replaced with to formula Ib compound, and mannitol used is replaced with to excipient dextran, sorbitol, lactose, glucose or the sodium chloride that lyophilization injectable powder is conventional, result regrettably, in other the weight ratio of excipient of the salt of formula I compound and these, be in the four corner of 1:0～1000, R isomer increases (%) all in 150～250% scopes.Show that other usual excipients all can not bring into play the stablizing effect to activating agent to the salt of formula I compound.
With reference to table 1 the first hurdle and the second hurdle in the method for above test example 1, different is only in each formula, to add with other conventional excipient dextran, sorbitol, lactose, the glucose of mannitol equivalent (to supplement the calcium disodium edetate that accounts for solid content weight 0.5% again, with performance metal complexation) or sodium chloride (supplement again the sodium citrate account for solid content weight 5%, with performance buffer effect of fuluic acid), for example, in " mannitol: formula Ia compound " is 50 formula, add wherein a kind of in 50 parts of above-mentioned other excipient with weight such as mannitol.Basic identical in result and table 1, R isomer increases in (%) and table 1 corresponding proportioning acquired results and differs and be all no more than 5 percentage points (salt of formula I compound and the weight ratio of described excipient are in the scope of 1:4～1000) or be all no more than 15 percentage points (salt of formula I compound and described organic acid weight ratio are that 1:0～3 scope is interior).This shows while using mannitol and other excipient composition can bring into play the stablizing effect to activating agent equally.
test example 3: formula I compound and excipient composition test
Modus ponens Ia compound is dissolved in appropriate water for injection (amount of water be in the solution after making to dissolve solid content in 10～12% scopes) together with a certain amount of mannitol as shown in table 2 below, and by 1M hydrochloric acid and/or 1M sodium hydrate regulator solution value to 2.5,3.0,3.5,4.0,4.5, medicinal liquid divides in the cillin bottle that installs to 5ml, every bottle of 1ml medicinal liquid, through lyophilization (freeze-drying curve A), moisture is down to below 1%, close plug.
Each injectable powder sample is placed in to 50 ° of C calorstats and places 4 months (can dispose referred to as " 50 ° of C4 months " in the present invention).For each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure they at 50 ° of C4 the R content of isomer (%) during the month, the R isomer of calculating each sample increases percent.
Table 2:
More than in table, result shows, after solution before lyophilization is adjusted in the scope of pH3.0～4.0, the stability of performance improve to(for) performance excipient of the present invention is useful.
test example 4: formula I compound and excipient composition test
With reference to the method for above test example 3, different is only that active medicine is used the compound into formula Ib instead.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 6 percentage points.For example, mannitol: in the test that formula Ib compound=100 proportioning and pH are 3.5, it is 33% that R isomer increases (%).
With reference to the method for above test example 3, different is only that mannitol is replaced with to glycine.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 6 percentage points.
With reference to the method for above test example 3, different is to use active medicine instead into formula Ib compound, and mannitol is replaced with to glycine.Basic identical in result and table 2, R isomer increases in (%) and table 2 corresponding proportioning acquired results and differs and be all no more than 6 percentage points.
These results demonstrations, lyophilization injectable powder of the present invention is after being adjusted in the scope of pH3.0～4.0 by solution before lyophilization, and the stability of performance improve to(for) performance excipient of the present invention is useful.
embodiment part
With embodiment form, prepare lyophilization injectable powder of the present invention below.Use therein pH adjusting agent, unless otherwise noted, be 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is while making to prepare injectable powder, make the pH value of the solution prepared before lyophilization be adjusted to setting (indicated value ± 0.05 scope in) or scope.The below object of preparation process in order to give an example, and the comparability based on respectively giving an example and making some specific description, those skilled in the art can therefrom summarize the method that the present invention prepares lyophilized injectable powder that obtains completely according to existing knowledge.The listed formula of embodiment is every bottled amount formula below, during actual preparation every batch to feed intake the amount preparation of 1000 bottles.
embodiment 1: prepare injectable powder of the present invention
Formula:
| formula Ia compound | 2mg, |
| mannitol | 100mg, |
| pH adjusting agent | to pH3.5, |
| water for injection | to 1ml. |
Preparation method:
(1) take principal agent and the excipient of recipe quantity, be placed in stainless steel cask, add the water for injection of recipe quantity approximately 90%, make each components dissolved, then by liquor capacity, add the active carbon of 0.2% (w/v), stir 30 minutes, filtering decarbonization, mends and injects water to approaching prescription full dose.
(2) filtrate sampling, measures pH value, is adjusted to setting if desired by pH adjusting agent, then benefit injects water to prescription full dose.
(3) medicinal liquid is first used 0.45um filtering with microporous membrane, then uses 0.22um filtering with microporous membrane 2 times.
(4) by the cillin bottle of 3～6 times of capacity of liquid medicine filling, false add plug.
(5) according to freeze-drying curve A described herein, carry out lyophilization, to moisture lower than 2%; After lyophilizing finishes, carry out hydraulic pressure and jump a queue; Prick aluminium lid, obtain.The sample of embodiment 1 can be referred to as Ex1 or E1 in the present invention; The sample of other preparation example also can similarly represent, for example the sample of embodiment 2 can be referred to as Ex2 or E2.
embodiment 2:except mannitol consumption changes 50mg and adjusting pH to 4.0 into, other is identical with embodiment 1, controls moisture lower than 3%.
embodiment 3:except mannitol consumption changes 150mg and adjusting pH to 3.0 into, other is identical with embodiment 1.
embodiment 4:except active medicine consumption changes 25mg into, other is identical with embodiment 1.
embodiment 5:except active medicine consumption changes 0.25mg into, other is identical with embodiment 1.
embodiment 6:
Formula:
| formula Ia compound | 10mg, |
| glycine | 100mg, |
| pH adjusting agent | to pH3.5, |
| water for injection | to 1ml. |
Method for making, with reference to embodiment 1, is still used freeze-drying curve B to carry out lyophilization.
embodiment 7:except active medicine consumption changes 0.33mg into and adds 0.5mg disodiumedetate, other is identical with embodiment 6.
embodiment 8:
Formula:
| formula Ib compound | 1mg, |
| mannitol | 100mg, |
| sodium citrate | 5mg, |
| pH adjusting agent | to pH3.5, |
| water for injection | to 1ml. |
Method for making is with reference to embodiment 1.
embodiment 9:except excipient changes glycine into, other is identical with embodiment 8.
embodiment 10:except excipient changes mannitol 50mg and glycine 50mg into, other is identical with embodiment 8.
embodiment 11:except adding 9mg sodium chloride, other is identical with embodiment 8.
embodiment 12:
Formula:
| formula Ia compound | 2.5mg, |
| glycine | 80mg, |
| sodium chloride | 9mg, |
| calcium disodium edetate | 0.125mg, |
| pH adjusting agent | to pH3.5, |
| water for injection | to 1ml. |
Method for making is with reference to embodiment 1, and the injectable powder moisture obtaining is 2.89%.
test example 5: the outward appearance of injectable powder and dissolubility are measured
Get respectively above each embodiment 1～12 gained injectable powder, open bottle cap plastic top, with syringe, from bottle stopper puncture, inject water for injection (consumption is about 3 times of liquor capacity respective sample lyophilization), with stopwatch, record the redissolution time, every batch sample test 5 times, averages.
As a result, all the redissolution time of embodiment powder pin, all within the scope of 4～12 seconds, shows that powder needle set of the present invention has good dissolubility.The powder pin outward appearance of Ex1 to Ex12 is all solid, complete round pie in addition, without abnormal conditions such as cleavage block, spray bottles, shows that the lyophilizing form of product is good.
test example 6: measure the remaining rate after each embodiment powder sample needle high temperature is placed
In this test example, measure the lyophilization injectable powder of each embodiment gained and place after 6 months under 40 ° of C, content [40 ° of C of its Chinese style I compound, June, can be described as high temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] with respect to this sample, under 20 ° of C, process content [20 ° of C of corresponding time up-to-date style I compound, June, can be described as room temperature average content, mg/ bottle, measures the meansigma methods of 10 bottles] percent, be remaining percent (%),
Wherein, high temperature average content (mg/ bottle) and room temperature average content (mg/ bottle) are the content (averages of 10 bottles) of sample dissolution every bottle of Chinese style I compound measuring and calculate by [HPLC method A] mentioned above.
Result demonstration, the remaining percent (%) of Ex1 to Ex12 is all between 97.5%～100.5%, and for example the remaining percent (%) of Ex1 is 98.8%.Ex1 to Ex12 under 40 ° of C after 6 months process color unchanged.
In addition, to the sample of disposing above-mentioned 40 ° of C6 months, test their R content of isomer (%) with [HPLC method B] mentioned above, in injectable powder powder, R isomer is with respect to the content of R isomer and S isomer summation, and calculating formula is as follows:
R content of isomer (%)=[R isomer peak area ÷ (R isomer peak area+S isomer peak area)] * 100%
Also tested in addition the R content of isomer (%) of these samples under 20 ° of C6 month Disposal Conditions.The R isomer that the method for reference test example 1 is calculated these samples increases percent, and calculating formula is as follows:
R isomer increases percent=[(40 ° of C6 month R content of isomer-20 ° C6 month R content of isomer) 20 ° of C6 month R content of isomer of ÷] * 100%
Result demonstration, the R isomer increase percent of Ex1 to Ex12 is all between 22%～38%, and for example the remaining percent (%) of Ex1 is 28%.
In addition, also use [HPLC method A] measured each embodiment sample in the time of 0 month maximum single contaminant with respect to the content of active component and total impurities the content with respect to active component.Result demonstration, the maximum single contaminant content of each sample of Ex1 to Ex12 is all lower than 0.5%, all in 0.1～0.25% scope; The total impurities content of each sample of Ex1 to Ex12 is all lower than 1.0%, all in 0.35～0.45% scope.
In addition, also use [HPLC method A] measured each embodiment sample 40 ° of C6 during the month maximum single contaminant with respect to the content of active component and total impurities the content with respect to active component.Result demonstration, the maximum single contaminant content of each sample of Ex1 to Ex12 is all lower than 0.5%, all in 0.20～0.33% scope; The total impurities content of each sample of Ex1 to Ex12 is all lower than 1.0%, all in 0.40～0.55% scope.
These results show that powder needle set of the present invention has good chemical stability, and meet the Accelerated stability test requirement of general marketing drugs.
test example 7: the mensuration of injectable powder acid-base value
Get respectively each embodiment gained injectable powder powder appropriate, water is made the solution that contains formula I compound 2mg in every 1ml, measures the pH value of this solution according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010.As a result, the pH value when pH value of each sample of embodiment 1-12 and its preparation differs in Jun0.1Ge pH unit.For example the formula pH value of embodiment 1 is pH3.5, and its gained injectable powder is measured by above method, and result is pH3.54, differs 0.04 GepH unit.
Get respectively each embodiment gained injectable powder powder, observe the front residual metal line of its lyophilization, be slowly dissolved in water for injection and be diluted to wherein metal line, according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, measure the pH value of this solution.As a result, the pH value when pH value of each sample of embodiment 1-12 and its preparation differs in Jun0.1Ge pH unit.For example the formula pH value of embodiment 1 is pH3.5, and its gained injectable powder is measured by above method, and result is pH3.53, differs 0.03 GepH unit.
Claims (23)
1. a lyophilization injectable powder, wherein comprises:
As active component with following formula I compound or the acceptable salt of its pharmacy:
Wherein R1 is bromine, and R2 and R3 are methyl,
As mannitol and/or the glycine of excipient,
And optional pH adjusting agent; Wherein:
The weight ratio of described excipient and described active component is 4 ~ 400:1,
The acceptable salt of pharmacy of described formula I compound is the tosilate of formula I compound or the benzene sulfonate of formula I compound,
This lyophilized injectable powder water is made and in every 1ml, is contained the solution of formula I compound or the acceptable salt 2mg of its pharmacy and measure according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 3.0～4.0.
2. according to the lyophilization injectable powder of claim 1, the weight ratio of wherein said excipient and described active component is 5 ~ 300:1.
3. according to the lyophilization injectable powder of claim 1, the weight ratio of wherein said excipient and described active component is 10 ~ 300:1.
4. according to the lyophilization injectable powder of claim 1, its with water for injection redissolve to lyophilization before solution phase with volume, the solid content in gained solution is 2 ~ 20% (w/v).
5. according to the lyophilization injectable powder of claim 1, its with water for injection redissolve to lyophilization before solution phase with volume, the weight sum of its Chinese style I compound and mannitol accounts for redissolves 2 ~ 20% (w/v) of liquor capacity.
6. according to the lyophilization injectable powder of claim 1, its solid content in solution before lyophilization is 2 ~ 20% (w/v).
7. according to the lyophilization injectable powder of claim 1, the weight sum of its Chinese style I compound and mannitol accounts for 2 ~ 20% (w/v) of the front liquor capacity of lyophilization.
8. according to the lyophilization injectable powder of claim 1 to 7 any one, its with water for injection redissolve to lyophilization before solution phase with volume, gained solution is measured according to the method under two appendix VI H items of Chinese Pharmacopoeia version in 2010, and the pH value of this solution is 3.0～4.0.
9. according to the lyophilization injectable powder of claim 1 to 7 any one, wherein water content is lower than 5%.
10. according to the lyophilization injectable powder of claim 1 to 7 any one, wherein water content is lower than 4%.
11. according to the lyophilization injectable powder of claim 1 to 7 any one, and wherein water content is lower than 3%.
12. according to the lyophilization injectable powder of claim 1 to 7 any one, and wherein water content is lower than 2%.
13. according to the lyophilization injectable powder of claim 1 to 7 any one, wherein also comprises pH adjusting agent, chelating agent and/or other pharmaceutic adjuvant.
14. according to the lyophilization injectable powder of claim 13, and wherein said pH adjusting agent is selected from sodium hydroxide, potassium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, acetic acid, hydrochloric acid, phosphoric acid, nitric acid, sulphuric acid, citric acid, sodium citrate, tartaric acid, maleic acid or its combination.
15. according to the lyophilization injectable powder of claim 13, and wherein said chelating agent is selected from ethylenediaminetetraacetic acid, disodiumedetate, calcio-disodium edetate or its combination.
16. according to the lyophilization injectable powder of claim 13, and wherein said other pharmaceutic adjuvant is selected from: sodium chloride, glucose, dextran, sorbitol, HP-β-CD, sulphur fourth group-beta-cyclodextrin, lactose, sucrose, erythritol, xylitol, fructose.
17. according to the lyophilization injectable powder of claim 1 to 7 any one, and the acceptable salt of pharmacy of wherein said formula I compound is selected from following formula Ia compound or formula Ib compound:
、
。
18. according to the lyophilization injectable powder of claim 1 to 7 any one, and it is to be the seal-packed unit dose formulations form of vial.
19. according to the lyophilization injectable powder of claim 18, and the amount that comprises formula I compound or the acceptable salt of its pharmacy in wherein said each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 100mg.
20. according to the lyophilization injectable powder of claim 18, and the amount that comprises formula I compound or the acceptable salt of its pharmacy in wherein said each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 50mg.
21. according to the lyophilization injectable powder of claim 18, and the amount that comprises formula I compound or the acceptable salt of its pharmacy in wherein said each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.1 ~ 25mg.
22. according to the lyophilization injectable powder of claim 18, and the amount that comprises formula I compound or the acceptable salt of its pharmacy in wherein said each unit dose formulations form is amounted to into its free alkali representing with formula I and counted 0.5 ~ 20mg.
The lyophilization injectable powder method of 23. preparation claim 1 to 22 any one, it comprises the following steps:
(a) according to the solid content in solution before lyophilization, determine dosing volume, take formula I compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except pH adjusting agent, add the water for injection that accounts for prescription full dose 90%, make to dissolve, then add active carbon, stir, filtering decarbonization, is adjusted to pH3.0～4.0 with acid solution or aqueous slkali if desired;
(b) mend and inject water to its recipe quantity, stir, measure pH and optional mensuration active component content, with acid solution or aqueous slkali, be adjusted to pH3.0～4.0 if desired;
(c) by medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, and tamponade obtains.
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| WO2015076340A1 (en) * | 2013-11-21 | 2015-05-28 | 小野薬品工業株式会社 | Injectable composition for general anesthesia and/or sedation |
| EP3162804B1 (en) | 2014-07-23 | 2019-10-09 | Jiangsu Nhwaluokang Pharmaceutical Research and Development Co., Ltd. | New benzodiazepine derivative and use thereof |
| CN105726495B (en) * | 2014-12-12 | 2019-03-29 | 宜昌人福药业有限责任公司 | A kind of short-acting benzodiazepine salt pharmaceutical composition of injection and preparation method thereof |
| CN107198691A (en) * | 2016-03-17 | 2017-09-26 | 江苏恒瑞医药股份有限公司 | A kind of pharmaceutical composition of auspicious horse azoles logical sequence |
| CN108143733B (en) * | 2017-12-15 | 2020-12-25 | 宜昌人福药业有限责任公司 | Anesthetic analgesic pharmaceutical composition and preparation method thereof |
| 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 |
| CN111514103A (en) * | 2020-05-18 | 2020-08-11 | 安徽省逸欣铭医药科技有限公司 | Stable remazolam injection composition and preparation method thereof |
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| GB9911152D0 (en) * | 1999-05-14 | 1999-07-14 | Glaxo Group Ltd | Short-acting benzodiazepines |
| GB0613692D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts |
| GB0613693D0 (en) * | 2006-07-10 | 2006-08-16 | Cenes Ltd | Benzodiazepine salts (3) |
| EP3050885B1 (en) * | 2009-11-05 | 2017-10-18 | GlaxoSmithKline LLC | Benzodiazepine bromodomain inhibitor |
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