CN103202815A - Injection for treating mental disease - Google Patents
Injection for treating mental disease Download PDFInfo
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- CN103202815A CN103202815A CN201310161241XA CN201310161241A CN103202815A CN 103202815 A CN103202815 A CN 103202815A CN 201310161241X A CN201310161241X A CN 201310161241XA CN 201310161241 A CN201310161241 A CN 201310161241A CN 103202815 A CN103202815 A CN 103202815A
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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 the following formula I chemical compound:
Wherein R1 is bromine, and R2 and R3 are methyl,
Owing to contain above-mentioned specific structure, this chemical compound of report (60 pages of example I c-8 of description) is fugitive central nervous system (CNS) inhibitor among the WO00/69836, has the tranquilizing soporific of comprising, anxiety, of flaccid muscles and anticonvulsant action.They can be used for the intravenously administrable in the following clinical treatment: as calm before the operation in the intra-operative, anxiety with forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis and analgesic and/or simultaneously, as the component of inducing and keeping that is used for general anesthesia; ICU calmness etc., according to CN101501019A (PAION, application number CN200780028964.5) report in, the free alkali of this chemical compound is not very stable, only be suitable for 5 ℃ of preservations of low temperature, under the condition of 40 ℃/75% relative humidity (opening), the sample deliquescence of storage, the color yellowing arrives orange, and shows that with respect to initial content content reduces significantly.So the salt of people's synthesis type (I) chemical compound, hope can increase its chemical stability, for use in the preparation of medicine.
Existing CN101501019A and US20100075955A1 (TILBROOK) have reported benzene sulfonate, the esilate of formula I chemical compound respectively.CN102964349A (permanent auspicious, application number 201110456864.0) has reported the tosilate of formula I chemical compound.
There is the worry of stable aspect in existing report formula I compound or its salt, and this is used for the clinical treatment relevant disease for this compounds is disadvantageous.
Summary of the invention
The object of the invention is particularly 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.Find unexpectedly that when formula I compound or its salt was mixed with the lyophilization injectable powder with pharmaceutic adjuvant, it was favourable wherein comprising mannitol or glycine, was favourable for its chemical stability particularly.
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 chemical 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 regulator 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 the solution before lyophilization is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).Perhaps, the weight sum of this lyophilized injectable powder Chinese style I chemical compound and mannitol accounts for 2～20% (w/v) of the preceding liquor capacity of lyophilization, for example 3～18% (w/v), for example 5～15% (w/v).
Lyophilization injectable powder according to the arbitrary embodiment of first aspect present invention, it redissolves to identical with solution before the lyophilization basically volume with water for injection, solid content in the gained solution is 2～20% (w/v), for example 3～18% (w/v), for example 5～15% (w/v).Perhaps, this lyophilized injectable powder redissolves to identical with solution before the lyophilization basically volume with water for injection, the weight sum of its Chinese style I chemical 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).
Lyophilization injectable powder according to the arbitrary embodiment of first aspect present invention, it redissolves to identical with solution before the lyophilization basically volume with water for injection, gained solution is measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item, and the pH value of this solution is 2.5～4.5.In one embodiment, pH value is 3.0～4.0.
Lyophilization injectable powder according to the arbitrary embodiment of first aspect present invention, wherein this lyophilized injectable powder water is made the solution that contains formula I chemical compound or the acceptable salt 2mg of its pharmacy among every 1ml and is measured according to the method under two appendix VIH of Chinese Pharmacopoeia version in 2010 item, 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 is lower than 4%, preferably is 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 the pH regulator agent.In one embodiment, the kind of this pH regulator agent is not particularly limited, as long as it can be adjusted to the pH value of described lyophilized injectable powder (and/or will prepare intermedium in this lyophilized injectable powder process of preparation) scope of expectation.In one embodiment, described pH regulator 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 regulator agent also is unrestricted, and for example those skilled in the art's value or scope of usually pH value of material to be regulated being adjusted to expection gets final product.In addition, in the lyophilization injectable powder, can also add have pooling feature material for example the acid-base pair formed of above-mentioned bronsted lowry acids and bases bronsted lowry so that the powder of lyophilization injectable powder of the present invention be under the metastable acid-base value environment, for example can use an amount of acetic acid and sodium hydroxide right to form acetic acid-sodium acetate buffering, perhaps can use phosphate to form acid-base pair, can also use sodium hydroxide and citric acid to form the 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 determine easily, for example it is usually 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%.
Lyophilization injectable powder according to the arbitrary embodiment of first aspect present invention, wherein also comprise other pharmaceutic adjuvant, for example be selected from: sodium chloride, glucose, dextran, sorbitol, HP-, sulphur butyl-beta-schardinger dextrin-, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose, polyvinylpyrrolidine etc.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate, benzene sulfonate or esilate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate or benzene sulfonate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, the acceptable salt of the pharmacy of wherein said formula I chemical compound is selected from following formula Ia chemical compound or formula Ib chemical compound:
In the present invention, above-mentioned formula Ia chemical compound is the tosilate of formula I chemical compound, and formula Ib chemical compound is the benzene sulfonate of formula I chemical compound.In the present invention, when mentioning formula I chemical compound, as not specializing in its linguistic context, refer to free alkali shown in the formula I and the acceptable salt of its pharmacy for example above-mentioned tosilate and benzene sulfonate.
According to the lyophilization injectable powder of the arbitrary embodiment of first aspect present invention, it is by comprising following step preparation basically:
(a) determine the dosing volume according to the solid content in the solution before the lyophilization, take by weighing formula I chemical compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except the pH regulator agent, add the water for injection that accounts for prescription full dose 90%, make dissolving, add active carbon again, stir, filtering decarbonization is adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(b) add water for injection to its recipe quantity, stir, measure solution pH value and optional mensuration active component content, be adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(c) with the medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, tamponade, namely.
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 chemical compound or the acceptable salt of its pharmacy in described each " unit dose formulations form " is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.The amount that for example comprises formula I chemical compound or the acceptable salt of its pharmacy in every bottle of injectable powder agent is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
The inventor unexpectedly finds, beat all good result is being appearred in formula I chemical compound when particularly formula Ia chemical compound or formula Ib chemical compound are prepared with excipient of the present invention, Wen Dingxing effect particularly, and this effect can not disappear because of continuing to add other pharmaceutic adjuvant, and this effect is different fully with described excipient " figuration " effect that application can produce in lyophilization injectable powder manufacturing field usually.
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) determine the dosing volume according to the solid content in the solution before the lyophilization, take by weighing formula I chemical compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except the pH regulator agent, add the water for injection that accounts for prescription full dose 90%, make dissolving, add active carbon again, stir, filtering decarbonization is adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(b) add water for injection to its recipe quantity, stir, measure solution pH value and optional mensuration active component content, be adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(c) with the medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, tamponade, namely.
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, preferred 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 the step (b) are to use and are selected from the aqueous solution that following pH regulator 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, remove in the step (d) wherein behind the moisture content that water content is lower than 5% in the gained lyophilization material, preferably be lower than 4%, preferably be lower than 3%, more preferably less than 2%.
Method according to the arbitrary embodiment of second aspect present invention, though the concrete steps of its description on some details or the step described in the preparation example of language description up and down stationery body embodiment part distinguish to some extent, yet, the open in detail method step that can summarize fully according to the arbitrary embodiment of second aspect present invention of those skilled in the art's full text according to the present invention.
Arbitrary technical characterictic that arbitrary embodiment of either side of the present invention or this either side has is suitable for arbitrary embodiment of other arbitrary embodiment or other either side equally, as long as they can be not conflicting, certainly at where applicable each other, necessary words can be done suitably to modify to individual features.Be further described with characteristics to various aspects of the present invention below.
The active component that lyophilization injectable powder of the present invention relates to is with following formula I chemical compound or the acceptable salt of its pharmacy:
R1 is bromine in the formula, and R2 and R3 are methyl;
The chemistry of formula I chemical compound is called 3-[(4S)-8-bromo-1 methyl-6-(2-pyridine radicals)-4H imidazoles [1,2-a] [1,4] benzodiazepine
-4-yl] methyl propionate,
In the present invention, preferred formula I chemical compound is its benzene sulfonate or tosilate.
In the present invention, preferred formula I chemical compound is to be selected from following formula Ia chemical compound or formula Ib chemical compound:
The present invention also is provided at and produces calm or hypnogenic method among the experimenter, and this method comprises the lyophilization injectable powder of this experimenter being used effective dose.
Also be provided at according to the present invention and cause method antianxity among the experimenter, this method comprises the lyophilization injectable powder of this experimenter being used effective dose.
Cause method of flaccid muscles according to the present invention further provides in the experimenter, this method comprises the lyophilization injectable powder of this experimenter being used effective dose.
According to the method that the present invention further provides treatment convulsions state in the experimenter, this method comprises the lyophilization injectable powder of this experimenter being used effective dose.
In the present invention, described experimenter compatibly is mammal, and is preferred human.
The first aspect present invention or the described solid composite medicament of second aspect that are used for above-mentioned disease, its give mammal for example people's dosage can be 0.001-5.0mg/kg body weight/day, preferably 0.001-2.0mg/kg body weight/day usually.
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 does not have harmful effect basically to organism, and normally organism can tolerate.
In the present invention, preferred lyophilized injectable powder of the present invention is that the pH value algoscopy is measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item after water is made the solution that contains formula I chemical compound 2mg among every 1ml again, and the pH value of this solution is 2.5～4.5.In one embodiment, pH value is 3.0～4.0.The inventor finds that unexpectedly the compositions that obtains like this has excellent especially effect.
Though 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 the 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 prescription 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 measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item after water is made the solution that contains formula I compound or its salt 2mg among every 1ml, the pH value of this solution is 2.5～4.5, and preferred pH value is 3.0～4.0.Like this, in the lyophilized injectable powder that lyophilization obtains, comprise: 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, preferred 5～300 weight portions, preferred 10～300 weight portions) excipient and optional pH regulator 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 during 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 used water for injection is 200～2000 times of formula I chemical compound weight, in this ratio ranges, Pei Zhi lyophilization injectable powder has beat all advantage in the case, for example good stability, to dissolve (namely redissolve) again with water for injection 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 the freeze-drying curve B:
Water content in the lyophilization injectable powder is generally to be lower than 5%, preferably is lower than 4%, preferably is lower than 3%, more preferably less than 2%.Moisture content 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 the pH value of medicinal liquid where necessary, can in compositions, add suitable pH regulator agent.For example sodium hydrate aqueous solution and aqueous hydrochloric acid solution are regulated although the inventor is not only with having the strong acid of buffer capacity or a strong base solution, yet, those skilled in the art understand, if handle the pH requirement that to satisfy system with this pH regulator agent of not having buffer capacity, the pH regulator agent that then has buffer capacity will can realize the object of the invention more, therefore these buffer agents not only can be regulated pH value, and can stablize pH value.Therefore the listed arbitrary pH regulator 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 lyophilized injectable powder normally carries out lyophilization and obtains in the tubulose cillin bottle; those skilled in the art understand this product at the acquisition finished product even before using for the doctor; usually all present a round pie; although lecture lacks (have slightly and dwindle) than the volume of original aqueous solution on the volume theory of this cake; yet this dwindling can not narrow down to former aqueous solution volume 50% usually usually; usually can be between the 80-120% of former aqueous solution volume; be more typically between the 90-100% of former aqueous solution volume; (the main body cake remains in liquid level vestige on bottle wall after dwindling because of lyophilizing and can be observed former aqueous solution liquid level vestige in the finished product cillin bottle; even if the dried frozen aquatic products in the cillin bottle is former thereby be Powdered because a variety of causes for example collides etc.; usually still can keep original liquid level vestige), vestige also can estimate the aqueous solution volume of this freeze-dried composition before lyophilization accordingly.Therefore, though 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, at least the medicine liquid volume before lyophilization begins, weight according to this volume that estimates and the dry end-product in the 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 used whole excipient, weight/gram) join in the solvent (for example water for injection), obtain a solution after the dissolving, the weight of described solid matter is divided by the percent (weight/volume percent, for example g/100ml) of whole liquor capacity.For example in the present invention, add an amount of aqueous solution for injection with 1mg formula Ia chemical compound and excipient 100mg mannitol, be mixed with the solution that final volume is 1ml, its solid content namely is about 10%.
In the present invention, symbol % according to its employed linguistic context, can have the implication that those skilled in the art understand easily.For example when mentioning solid content, the percent of this symbolic representation weight/volume (w/v, for example g/100ml); Again for example during " water content " in mentioning the lyophilization injectable powder, for example water content is below 5%, this moment this symbol % represent w/w percent (w/w, g/100g).Generally speaking, when solid dispersed was in liquid, % represented weight/volume percent; Solid dispersed in solid or liquid dispersion in solid when (for example water content of powder pin), % represents w/w percent.In other cases, as do not have other explanation, symbol % represents w/w percent.
When preparation medicinal liquid of the present invention, as well known to those skilled in the art, for example can use the microporous filter membrane of about 0.45um to carry out coarse filtration and filter, with before liquid medicine filling is in the cillin bottle, for example can use the microporous filter membrane of about 0.22um to carry out fine straining and filter with degerming, can filter repeatedly in case of necessity.
According to lyophilized injectable powder of the present invention, it is the 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 chemical compound can be such as but not limited to 0.1～100mg, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
In lyophilization injectable powder of the present invention, the formula I compound or its salt that wherein comprises can use 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, the mannitol that wherein comprises can differentiate that whether it exists by " mannitol " and/or the discrimination method in " formula mannitol injection liquid " that Chinese Pharmacopoeia two ones of versions in 2010 are recorded, for example with the saturated aqueous solution 1ml of lyophilized injectable powder powder of the present invention preparation, add each 0.5ml of ferric chloride test solution and sodium hydroxide test solution, generate pale brown color precipitation, jolting does not disappear, drip the excessive sodium hydrate test solution, namely be dissolved into brown solution, be added with mannitol if show that this phenomenon shows in the powder pin of the present invention.The method of [assay] in " formula mannitol injection liquid " that can also record by Chinese Pharmacopoeia two ones of versions in 2010 is measured the content of the mannitol in the injectable powder, thereby can calculate the weight ratio of active component and mannitol in the injectable powder.
In lyophilization injectable powder of the present invention, discrimination method in " glycine flushing liquor " that the glycine that wherein comprises can record by Chinese Pharmacopoeia two ones of versions in 2010 differentiates that whether it exists, the content of the glycine in the injectable powder can also be measured by the method for [assay], thereby the weight ratio of active component and glycine in the injectable powder can be calculated.
According to lyophilized injectable powder of the present invention, it redissolves with water for injection, and the redissolution time is in 30 seconds, preferably in 20 seconds, more preferably in 15 seconds usually.
According to lyophilized injectable powder of the present invention, its water is made the solution that contains formula I chemical compound 2mg among every 1ml and is measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item, and the pH value of this solution is 2.5～4.5, and preferred pH value is 3.0～4.0.
In the present invention, formula I chemical compound, perhaps formula Ia chemical compound or formula Ib chemical compound, and their standard substance all can adopt the preparation of prior art disclosed method.
Lyophilized injectable powder provided by the invention can satisfy the storage requirement of general lyophilization injectable powder preserving at least 24 months at dry place below 25 ℃.
The described solid composite medicament of first aspect present invention or second aspect can be used as fugitive CNS inhibitor, and they can be used for by following clinical settings oral administration: calm before the operation in the peri-operation period event, anxiety and forget purposes; Associated with conscious sedation during short-term diagnosis, operation or endoscopic procedure; Before using other anesthetis or analgesic and/or simultaneously, as the component of inducing and keeping that is used for general anesthesia; The ICU calmness.In addition, the described solid composite medicament of first aspect present invention or second aspect can be used for mental sickness such as calmness, hypnosis, anxiety, of flaccid muscles, convulsion.
The specific embodiment
Can further describe the present invention by the following examples, yet scope of the present invention is not limited to following embodiment.One of skill in the art can understand, and under the prerequisite that does not deviate from the spirit and scope of the present invention, can carry out various variations and modification to the present invention.The present invention carries out generality and/or concrete description to the material and the test method that use in the test.Though for realizing that the employed many materials of the object of the invention and operational approach are well known in the art, the present invention still does to describe in detail as far as possible at this.Following examples further specify the present invention, rather than restriction the present invention.When preparing injectable powder below in the listed prescription, formula I chemical compound amount of calculation is all calculated with the form of its free alkali, listed prescription is the amount of contained formula I chemical compound free alkali in the per unit dosage particles (for example injectable powder is every bottle), below preparation during compositions every batch of preparation amount be the amount of 1000 unit dose formulations, 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 the powder pin of the present invention and the content of situation of change and powder pin activating agent thereof.
[HPLC method A]:
Carry out purity analysis at the HP1100Agilent chromatograph:
Chromatographic column: Phenomenex Gemini C185 μ m (2.0 * 50mm) (guard column Phenomenex Gemini C18,2x4mm), U.S. F door company
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 0.8ml/ minute
Detect: ultraviolet detection, wavelength: 254nm;
The NH of mobile phase A: 2mmol
4HCO
3(use NH
3Solution is adjusted to pHl0)
Mobile phase B: acetonitrile
The gradient elution program:
| Elution time/minute | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 90 | 10 |
| 25 | 10 | 90 |
| 28.8 | 10 | 90 |
| 29 | 90 | 10 |
| 34 | 90 | 10 |
Sample preparation: it is an amount of to get various samples (crude drug or injectable powder compositions), and (acetonitrile: water=50:50 wherein contains the NH of 1mmol to add the acetonitrile-water mixed liquor
4HCO
3, and use NH
3Solution is adjusted to pHl0) dissolve and make the solution of the about 1mg/ml of concentration in right amount, filter in case of necessity.
Computational methods: be main peak with formula I chemical compound chromatographic peak, its relative retention time is 1, (peak area is ignored less than 0.01% impurity peaks of main peak area to read the peak area of whole chromatographic peaks of relative retention time between 0.60～2.00, the acid group peak is disregarded), with area normalization method calculate each impurity peaks content and, with the content of external standard method with the calculated by peak area active component, and calculate maximum single impurity content and total impurities content.
4 of its heptatomic rings of active component in the pharmaceutical composition of the present invention are the S-isomer, and may mix in the medicine has a spot of R-isomer.Below [HPLC method B] can be used for measuring R-isomer (i.e. the chemical compound of representing with following formula Ix) and situation of change thereof in the present composition.
[HPLC method B]:
Carry out purity analysis at the HP1100Agilent chromatograph:
Running time: to more than 2.5 times of main peak retention time
Chromatographic column: Daicel Chrialcel OJ-H (5 μ m) 4.6 * 250mm (guard column Daicel Chrialcel OJ-H analysis guard column 5 μ m4.0 * 10mm), Japanese Daicel (Daicel)
Column temperature: 40 ℃
Sample size: 10 μ l
Flow velocity: 1.0ml/ minute
Detect: ultraviolet detection, wavelength: 225nm (single wavelength detecting);
Mobile phase: hexane: ethanol=93:7
The sample preparation: it is an amount of to get various samples (crude drug or injectable powder compositions), adds the solution that an amount of supersound process of mobile phase makes dissolving and the about 1mg/ml of diluted concentration, filters in case of necessity.
Computational methods: be main peak with formula I chemical compound chromatographic peak, its relative retention time is 1, read the peak area of main peak and the peak area of the impurity peaks (it for R isomer be formula Ix chemical compound) of relative retention time between 1.10～1.25, R content of isomer (%)=[R isomer peak area ÷ (R isomer peak area+S isomer peak area)] * 100%.
In above various HPLC methods, no matter formula I chemical compound is with its free alkali form dosing or with the form dosing of its pharmaceutical salts, because of dissociating of benzenesulfonic acid or p-methyl benzenesulfonic acid or other acid group, they all show to have identical retention time with formula I free alkali in chromatographic system, this is that the chromatography field is known.
Preparation example 1: preparation formula Ix chemical compound (it can be used for the reference substance of analyzing and testing)
The R-isomer that the present invention relates to (being the chemical compound that formula Ix represents) can be carried out with reference to the method for putting down in writing among the WO00/69836, and is specific as follows:
Step 1: with reference to the preparation method of WO00/69836 description 23-24 page or leaf Int-1, use Fmoc-D-Glu (OMe)-OH (available from gill biochemistry) to obtain with following formula Int-1x intermediate (it is the isomer of Int-1) as raw material:
Step 2: follow the preparation method with reference to WO00/69836 description 34-35 page or leaf Example I-1, use the intermediate compound I nt-2 of Int-1x intermediate and 24 records of WO00/69836 description to be raw material, obtain following Ex I-10x chemical compound (it is the isomer of the Example I-10 chemical compound of 38 pages of records of WO00/69836 description):
Step 3: follow the preparation method with reference to WO00/69836 description 60-61 page or leaf Example Ic-8, use Ex I-10x to be raw material, obtain the chemical compound of representing with following formula Ix (it is the R-isomer of the Example Ic-8 chemical compound of 60 pages of records of WO00/69836 description)
R1 is bromine in the formula, and R2 and R3 are methyl.
Then with reference to the present invention hereinafter the method for preparation example 7 its purification is obtained 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].For the S isomer, the relative retention time of this R isomer is about 1.17 in the test of [HPLC method A] method.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 the raw material of powder pin preparation)
According to the preparation method of WO00/69836 description 60-61 page or leaf Example Ic-8, use the Ex I-10 of 0.5mol to feed intake as raw material, obtain with the following formula I chemical compound:
R1 is bromine in the formula, and R2 and R3 are methyl.
Get gained formula I chemical compound 100g, add to stir in 800ml ethanol-lactic acid-water (three's volume ratio 45:2:53) mixed solution of 50 ° of C and make dissolving; Filter, make filtrate leave standstill 10～12 hours to carry out recrystallization under the temperature of 5 ° of C, leach crystallization, drying gets formula I chemical compound.Repeat this operation 2 times, the product chromatographic purity 99.65%[HPLC method A that obtains]; R isomer impurities content 0.26%[HPLC method B].
Preparation example 3: the preparation I compound tosilate (be formula Ia chemical compound, its reference substance that can be used for analyzing and testing with
And the raw material of powder pin preparation)
Getting preparation example 2 chemical compound alkali (formula I chemical compound) 10g is dissolved in the 60ml ethyl acetate, to be dissolved in the 10ml methanol with the p-methyl benzenesulfonic acid of mol ratios such as above-mentioned alkali then, and be added drop-wise in the ethyl acetate solution of formula I chemical compound alkali, stirring and crystallizing, sucking filtration, drying under reduced pressure gets the tosilate of formula I chemical compound, white solid.HPLC:99.63%[HPLC method A]; R isomer impurities content 0.27%[HPLC method B].
Preparation example 4: the preparation I compound benzene sulfonate (be formula Ib chemical compound, its can be used for analyzing and testing reference substance and
The raw material of powder pin preparation)
(formula I chemical compound 10g) also adds toluene (60ml) in the adding bottle at ambient temperature to get preparation example 2 chemical compound alkali.Add in this solution with the benzenesulfonic acid (being mixed with the alcoholic solution of 1M) of mol ratio such as above-mentioned alkali and stirred this reactant mixture 15 minutes, after this, filter the solid from this solution precipitation, with toluene wash and under vacuum 40 ℃ of oven dry, get white solid.HPLC:99.47%[HPLC method A]; R isomer impurities content 0.25%[HPLC method B].
In addition, below in all kinds of tests esilate of employed formula I chemical compound prepare (the following formula I esilate that is called for short) with reference to the method for [0101] section of US20100075955A1 description record.
Test example 1: formula I chemical compound and excipient composition test
Modus ponens Ia chemical compound is dissolved in an amount of water for injection (amount of water is that solid content is 10% in the solution that makes after the dissolving) with a certain amount of mannitol as shown in the table or glycine, and with 1M hydrochloric acid and/or 1M sodium hydrate regulator solution value to 3.7, the medicinal liquid branch installs in the cillin bottle of 5ml, every bottle of 1ml medicinal liquid, (freeze-drying curve A) is down to below 1% moisture through lyophilization, close plug.
Place 50 ° of C calorstats to place 4 months (can abbreviate " 50 ° of C4 months " disposal in the present invention as) in each injectable powder sample.For each sample, use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure them at the R content of isomer (%) of 50 ° of C4 during the month, being calculated as follows the R isomer increases percent:
The R isomer increases percent=[(50 ° of C4 month R content of isomer-0 month R content of isomer) 0 month R content of isomer of ÷] * 100%
The results are shown in following table 1.
Table 1:
| Mannitol: formula Ia chemical compound | The R isomer increases (%) | Glycine: formula Ia chemical compound | The 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 first hurdle in the last table " mannitol: formula Ia chemical compound " expression mixes: the two weight ratio of formula Ia chemical 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.
According to last table result as seen, withstand high temperatures environment better during the combination of formula Ia chemical compound and mannitol or glycine, particularly the weight ratio at formula I chemical compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:4～400, for example in 10～300 scopes, result with obvious excellence, namely the R content of isomer increases not obvious.
When although the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:500 or 1:1000, same stability is arranged when showing with low excipient, but because injectable powder of the present invention is when being mixed with medicinal liquid for injection, wherein the liquid of Fu Ronging penetrates that solid concentration should be lower in the liquid, 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 into the solution of 25ml at least, just can reach solid concentration should be lower than 20% degree and hold the 5mg active medicine, and clinically for the fast injection administration, the obvious volume of the solution of 25ml is excessive.Therefore in above table 1, the weight ratio of formula I chemical compound or the acceptable salt of its pharmacy and described mannitol or glycine is 1:4～400, for example is to be fit to very much clinical practice in 10～300 scopes.
In addition, get each injectable powder of gained in the table 1 respectively, open the bottle cap plastic top, inject water for injection (consumption is about 3 times of the preceding liquor capacity of respective sample lyophilization) with syringe from the bottle stopper puncture, with the stopwatch record redissolution time, every batch sample test 5 times is averaged.
As a result, the weight ratio of formula Ia chemical compound and described mannitol or glycine is each sample in 1:4～400 scopes, and the redissolution time, mannitol for example: the sample redissolution time of formula Ia chemical compound=100 was 6 seconds all in 5～12 seconds scopes.Yet beat allly be, the weight ratio of formula Ia chemical compound and described mannitol or glycine is each sample in 1:500～1000 scopes, and the redissolution time, glycine for example: the sample redissolution time of formula Ia chemical compound=500 was 38 seconds all in 26～44 seconds scopes.The weight ratio of display type Ia chemical compound and described mannitol or glycine is that each interior sample of 1:4～400 scopes has the fine solubility energy thus, be very beneficial for clinical use, and when the excipient relative quantity further increased, dissolving slowly was unfavorable for clinical use.
Test example 2: formula I chemical compound and excipient composition test
With reference to the method for above test example 1, different only is that active medicine is used the chemical compound into formula Ib instead.Basic identical in result and the table 1, R isomer increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and the weight ratio of described excipient are in 1:4～1000 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～3 scopes are interior).For example, mannitol: in formula Ib chemical compound=50 proportionings, it is 31% that the R isomer increases (%); Glycine for example again: in formula Ib chemical compound=50 proportionings, it is 34% that the R isomer increases (%).
With reference to table 1 first hurdle and second hurdle in the method for above test example 1, different only is that used mannitol is replaced with mannitol and glycine equal amount of mixture.Basic identical in result and the table 1, R isomer increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and the weight ratio of described excipient are in 1:4～1000 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～3 scopes are interior).This shows the stablizing effect that can bring into play equally when using mannitol and glycine combination as excipient activating agent.
With reference to the method for above test example 1, different only is that active medicine is used the esilate into formula I instead.The result is in 1:0～1000 four corners at the salt of formula I chemical compound and the weight ratio of described excipient regrettably, and the R isomer increases (%) all in 150～250% scopes.Show that mannitol or glycine can not bring into play stablizing effect to activating agent to formula I esilate.
With reference to table 1 first hurdle and second hurdle in the method for above test example 1, different only is that used mannitol is replaced with lyophilization injectable powder excipient dextran, sorbitol, lactose, glucose or sodium chloride commonly used, the result regrettably, be in 1:0～1000 four corners in other the weight ratio of excipient of the salt of formula I chemical compound and these, the R isomer increases (%) all in 150～250% scopes.Show that other conventional excipients all can not bring into play stablizing effect to activating agent to the salt of formula I chemical compound.
With reference to table 1 first hurdle and second hurdle in the method for above test example 1, different is that used formula Ia chemical compound is replaced with formula Ib chemical compound, and used mannitol is replaced with lyophilization injectable powder excipient dextran, sorbitol, lactose, glucose or sodium chloride commonly used, the result regrettably, be in 1:0～1000 four corners in other the weight ratio of excipient of the salt of formula I chemical compound and these, the R isomer increases (%) all in 150～250% scopes.Show that other conventional excipients all can not bring into play stablizing effect to activating agent to the salt of formula I chemical compound.
With reference to table 1 first hurdle and second hurdle in the method for above test example 1, other excipient dextran commonly used, sorbitol, lactose, glucose that different only is adds in each prescription with mannitol equivalent (replenish the calcium disodium edetate that accounts for solid content weight 0.5% again, with the performance metal complexation) or sodium chloride (replenish the sodium citrate account for solid content weight 5% again, with the performance buffer effect of fuluic acid), for example in " mannitol: formula Ia chemical compound " is 50 prescription, a kind of in 50 parts of above-mentioned other excipient wherein adding with weight such as mannitol.Basic identical in result and the table 1, R isomer increase in (%) and the table 1 corresponding proportioning gained result and differ and all be no more than 5 percentage points (salt of formula I chemical compound and the weight ratio of described excipient are in 1:4～1000 scopes) or all be no more than 15 percentage points (salt of formula I chemical compound and described organic acid weight ratio are that 1:0～3 scopes are interior).This shows use mannitol and the fashionable stablizing effect that can bring into play equally activating agent of other vehicle group.
Test example 3: formula I chemical compound and excipient composition test
Modus ponens Ia chemical compound is dissolved in an amount of water for injection (amount of water be in the solution that makes after the dissolving solid content in 10～12% scopes) with a certain amount of mannitol as shown in table 2 below, and with 1M hydrochloric acid and/or 1M sodium hydrate regulator solution value to 2.5,3.0,3.5,4.0,4.5, the medicinal liquid branch installs in the cillin bottle of 5ml, every bottle of 1ml medicinal liquid, (freeze-drying curve A) is down to below 1% moisture through lyophilization, close plug.
Place 50 ° of C calorstats to place 4 months (can abbreviate " 50 ° of C4 months " disposal in the present invention as) in each injectable powder sample.For each sample, to use [HPLC method B] to measure their R content of isomer (%) in the time of 0 month, and measure them at the R content of isomer (%) of 50 ° of C4 during the month, the R isomer of calculating each sample increases percent.
Table 2:
More than the result shows in the table, and after solution was adjusted in pH3.0～4.0 scopes before with lyophilization, the stability of performance improve to(for) performance excipient of the present invention was useful.
Test example 4: formula I chemical compound and excipient composition test
With reference to the method for above test example 3, different only is that active medicine is used the chemical compound into formula Ib instead.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 6 percentage points.For example, mannitol: formula Ib chemical compound=100 proportionings and pH are in 3.5 the test, and it is 33% that the R isomer increases (%).
With reference to the method for above test example 3, different only is that mannitol is replaced with glycine.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 6 percentage points.
With reference to the method for above test example 3, different is to use active medicine instead into formula Ib chemical compound, and mannitol is replaced with glycine.Basic identical in result and the table 2, R isomer increase in (%) and the table 2 corresponding proportioning gained result and differ and all be no more than 6 percentage points.
These results show that after lyophilization injectable powder of the present invention solution before with lyophilization was adjusted in pH3.0～4.0 scopes, the stability of performance improve to(for) performance excipient of the present invention was useful.
The embodiment part
Below prepare lyophilization injectable powder of the present invention with the embodiment form.Use therein pH regulator agent, as there is not an other explanation, be 1M sodium hydroxide solution or 1M hydrochloric acid solution, its consumption is to make preparation during injectable powder, make the pH value of the solution of preparing before the lyophilization be adjusted to setting (indicated value ± 0.05 scope in) or scope.Preparation process purpose for example hereinafter, and done some based on the comparability of respectively giving an example and specifically describe, those skilled in the art can therefrom summarize the method that the present invention prepares lyophilized injectable powder that obtains fully according to existing knowledge.The listed prescription of following embodiment is every bottled amount prescription, during actual fabrication every batch to feed intake 1000 bottles amount preparation.
Embodiment 1: prepare injectable powder of the present invention
Prescription:
| Formula Ia chemical compound | 2mg, |
| Mannitol | 100mg, |
| The pH regulator agent | To pH3.5, |
| Water for injection | To 1ml. |
Preparation method:
(1) takes by weighing principal agent and the excipient of recipe quantity, place stainless steel cask, add the water for injection of recipe quantity about 90%, make each components dissolved, press the active carbon that liquor capacity adds 0.2% (w/v) again, stirred 30 minutes, filtering decarbonization is added water for injection to approaching the prescription full dose.
(2) pH value is measured in filtrate sampling, is adjusted to setting with the pH regulator agent in case of necessity, adds water for injection again to the full dose of writing out a prescription.
(3) medicinal liquid is used the 0.45um filtering with microporous membrane earlier, uses the 0.22um filtering with microporous membrane again 2 times.
(4) in the cillin bottle with 3～6 times of capacity of liquid medicine filling, the false add plug.
(5) carry out lyophilization according to freeze-drying curve A described herein, be lower than 2% to moisture; Lyophilizing is carried out hydraulic pressure and is jumped a queue after finishing; Prick aluminium lid, namely.The sample of embodiment 1 can abbreviate Ex1 or E1 as in the present invention; The sample of other preparation example also can similarly represent that for example the sample of embodiment 2 can abbreviate Ex2 or E2 as.
Embodiment 2:Except the mannitol consumption changed 50mg and adjusting pH to 4.0 into, other was identical with embodiment 1, and control moisture is lower than 3%.
Embodiment 3:Except the mannitol consumption changed 150mg and adjusting pH to 3.0 into, other was identical with embodiment 1.
Embodiment 4:Except the active medicine consumption changed 25mg into, other was identical with embodiment 1.
Embodiment 5:Except the active medicine consumption changed 0.25mg into, other was identical with embodiment 1.
Embodiment 6:
Prescription:
| Formula Ia chemical compound | 10mg, |
| Glycine | 100mg, |
| The pH regulator agent | To pH3.5, |
| Water for injection | To 1ml. |
Method for making is with reference to embodiment 1, but is to use freeze-drying curve B to carry out lyophilization.
Embodiment 7:Except the active medicine consumption changed 0.33mg and adding 0.5mg disodiumedetate into, other was identical with embodiment 6.
Embodiment 8:
Prescription:
| Formula Ib chemical compound | 1mg, |
| Mannitol | 100mg, |
| Sodium citrate | 5mg, |
| The pH regulator agent | To pH3.5, |
| Water for injection | To 1ml. |
Method for making is with reference to embodiment 1.
Embodiment 9:Except excipient changed glycine into, other was identical with embodiment 8.
Embodiment 10:Except excipient changed mannitol 50mg and glycine 50mg into, other was identical with embodiment 8.
Embodiment 11:Except adding 9mg sodium chloride, other is identical with embodiment 8.
Embodiment 12:
Prescription:
| Formula Ia chemical compound | 2.5mg, |
| Glycine | 80mg, |
| Sodium chloride | 9mg, |
| Calcium disodium edetate | 0.125mg, |
| The pH regulator agent | To pH3.5, |
| Water for injection | To 1ml. |
Method for making is with reference to embodiment 1, and the injectable powder moisture that obtains is 2.89%.
Test example 5: the outward appearance of injectable powder and dissolubility are measured
Get above each embodiment 1～12 gained injectable powder respectively, open the bottle cap plastic top, inject water for injection (consumption is about 3 times of the preceding liquor capacity of respective sample lyophilization) with syringe from the bottle stopper puncture, with the stopwatch record redissolution time, every batch sample test 5 times is averaged.
As a result, all the redissolution time of embodiment powder pins all in 4～12 seconds scopes, shows that powder needle set of the present invention has fine solubility.The powder pin outward appearance of Ex1 to Ex12 all is solid, complete round pie in addition, and abnormal conditions such as no cleavage block, spray bottle show 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 after placing 6 months under 40 ° of C, content [40 ° of C of its Chinese style I chemical compound, June, can be described as the high temperature average content, the mg/ bottle is measured 10 bottles meansigma methods] under 20 ° of C, handle content [20 ° of C of corresponding time up-to-date style I chemical compound with respect to this sample, June, can be described as the room temperature average content, the mg/ bottle is measured 10 bottles meansigma methods] percent, be remaining percent (%), namely
Wherein, the content (10 bottles averages) of high temperature average content (mg/ bottle) and room temperature average content (mg/ bottle) every bottle of Chinese style I chemical compound that to be sample dissolution measure and calculate by [HPLC method A] mentioned above.
The result shows that all between 97.5%～100.5%, for example the remaining percent (%) of Ex1 is 98.8% to the remaining percent (%) of Ex1 to Ex12.Ex1 to Ex12 under 40 ° of C after handling in 6 months the color no change.
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, namely the R isomer is with respect to the content of R isomer and S isomer summation in the injectable powder powder, 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 the R content of isomer (%) of these samples under 20 ° of C6 month disposal conditions in addition.The R isomer that the method for reference test example 1 is calculated these samples increases percent, and calculating formula is as follows:
The R isomer increases percent=[(40 ° of C6 month R content of isomer-20 ° C6 month R content of isomer) 20 ° of C6 of ÷ month R content of isomer] * 100%
The result shows that the R isomer of Ex1 to Ex12 increases the percentage number average 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 impurity with respect to the content of active component and the total impurities content with respect to active component.The result shows that the maximum single impurity content of each sample of Ex1 to Ex12 all is lower than 0.5%, all in 0.1～0.25% scope; The total impurities content of each sample of Ex1 to Ex12 all is 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 impurity with respect to the content of active component and the total impurities content with respect to active component.The result shows that the maximum single impurity content of each sample of Ex1 to Ex12 all is lower than 0.5%, all in 0.20～0.33% scope; The total impurities content of each sample of Ex1 to Ex12 all is 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 stable accelerated test requirement of general medicine listing.
Test example 7: the mensuration of injectable powder acid-base value
It is an amount of to get each embodiment gained injectable powder powder respectively, and water is made the solution that contains formula I chemical compound 2mg among every 1ml, measures the pH value of this solution according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item.As a result, the pH value the when pH value of each sample of embodiment 1-12 and its preparation differs all in 0.1 pH unit.For example the prescription pH value of embodiment 1 is pH3.5, and its gained injectable powder is measured by above method, and the result is pH3.54, differs 0.04 pH unit.
Get each embodiment gained injectable powder powder respectively, observe the preceding residual metal line of its lyophilization, to wherein slowly adding the dissolving of injection water and being diluted to metal line, measure the pH value of this solution according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item.As a result, the pH value the when pH value of each sample of embodiment 1-12 and its preparation differs all in 0.1 pH unit.For example the prescription pH value of embodiment 1 is pH3.5, and its gained injectable powder is measured by above method, and the result is pH3.53, differs 0.03 pH unit.
Claims (10)
1. lyophilization injectable powder wherein comprises:
As active component with following formula I chemical 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 regulator agent,
The weight ratio of described excipient and described active component is 1～1000:1, for example 4～400:1, for example 10～300:1.
2. according to the lyophilization injectable powder of claim 1, it redissolves to identical with solution before the lyophilization basically volume with water for injection, and the solid content in the gained solution is 2～20% (w/v); Perhaps, this lyophilized injectable powder redissolves to identical with solution before the lyophilization basically volume with water for injection, and the weight sum of its Chinese style I chemical compound and mannitol accounts for 2～20% (w/v) of redissolution liquor capacity.
3. according to the lyophilization injectable powder of claim 1, its solid content in the solution before lyophilization is 2～20% (w/v); Perhaps, the weight sum of this lyophilized injectable powder Chinese style I chemical compound and mannitol accounts for 2～20% (w/v) of the preceding liquor capacity of lyophilization.
4. according to each lyophilization injectable powder of claim 1 to 3, it redissolves to identical with solution before the lyophilization basically volume with water for injection, gained solution is measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item, and the pH value of this solution is 2.5～4.5; In one embodiment, pH value is 3.0～4.0.
5. according to each lyophilization injectable powder of claim 1 to 4, wherein this lyophilized injectable powder water is made the solution that contains formula I chemical compound or the acceptable salt 2mg of its pharmacy among every 1ml and is measured according to the method under two appendix VI of Chinese Pharmacopoeia version in 2010 H item, and the pH value of this solution is 2.5～4.5; In one embodiment, pH value is 3.0～4.0.
6. according to each lyophilization injectable powder of claim 1 to 5, wherein water content is lower than 5%, preferably is lower than 4%, preferably is lower than 3%, more preferably less than 2%.
7. according to each lyophilization injectable powder of claim 1 to 6, wherein also comprise pH regulator agent, chelating agent and/or other pharmaceutic adjuvant; Further,
Described pH regulator 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;
Described chelating agent is selected from ethylenediaminetetraacetic acid, disodiumedetate, calcio-disodium edetate or its combination;
Described other pharmaceutic adjuvant is selected from: sodium chloride, glucose, dextran, sorbitol, HP-, sulphur butyl-beta-schardinger dextrin-, mannitol, lactose, sucrose, sorbitol, D-sorbitol, erythritol, xylitol, fructose, polyvinylpyrrolidine etc.
8. according to each lyophilization injectable powder of claim 1 to 7, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate, benzene sulfonate or esilate; Perhaps, the acceptable salt of the pharmacy of wherein said formula I chemical compound is tosilate or benzene sulfonate; Perhaps, the acceptable salt of the pharmacy of wherein said formula I chemical compound is selected from following formula Ia chemical compound or formula Ib chemical compound:
9. according to each lyophilization injectable powder of claim 1 to 8, it is to be the seal-packed unit dose formulations form of vial; In one embodiment, the amount that comprises formula I chemical compound or the acceptable salt of its pharmacy in described each unit dose formulations form is amounted to into it and is counted 0.1～100mg with the free alkali that formula I represents, for example be 0.1～50mg, for example be 0.1～25mg, for example be 0.5～20mg, for example about 0.1mg, about 0.5mg, about 1mg, about 2mg, about 5mg, about 10mg, about 20mg, about 50mg, about 100mg.
10. each lyophilization injectable powder method of preparation claim 1 to 9, it consists essentially of following steps:
(a) determine the dosing volume according to the solid content in the solution before the lyophilization, take by weighing formula I chemical compound or the acceptable salt of its pharmacy and the excipient of recipe quantity, and other optional adjuvant except the pH regulator agent, add the water for injection that accounts for prescription full dose 90%, make dissolving, add active carbon again, stir, filtering decarbonization is adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(b) add water for injection to its recipe quantity, stir, measure solution pH value and optional mensuration active component content, be adjusted to pH2.5～4.5 with acid solution or aqueous slkali in case of necessity, for example pH3.0～4.0;
(c) with the medicinal liquid aseptic filtration, fill is in cillin bottle;
(d) moisture is removed in lyophilization, tamponade, namely.Further, this method is as described in the arbitrary embodiment of second aspect present invention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310161241.XA CN103202815B (en) | 2013-05-05 | 2013-05-05 | Injection for treating mental disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310161241.XA CN103202815B (en) | 2013-05-05 | 2013-05-05 | Injection for treating mental disease |
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| CN201410421972.8A Division CN104146970A (en) | 2013-05-05 | 2013-05-05 | Freeze-dried powder injection for treating mental disease |
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| CN103202815A true CN103202815A (en) | 2013-07-17 |
| CN103202815B CN103202815B (en) | 2014-09-24 |
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Cited By (8)
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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 |
| WO2016011943A1 (en) * | 2014-07-23 | 2016-01-28 | 李勤耕 | New benzodiazepine derivative and use thereof |
| CN105726495A (en) * | 2014-12-12 | 2016-07-06 | 宜昌人福药业有限责任公司 | Short-term effect benzodiazepines salt medicine composition for injection and preparation method thereof |
| 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 |
| CN108143733A (en) * | 2017-12-15 | 2018-06-12 | 宜昌人福药业有限责任公司 | A kind of narcotic analgesics compositions 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 |
| WO2025052259A1 (en) * | 2023-09-05 | 2025-03-13 | Reena Patel | Ready to use compositions of remimazolam |
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| WO2008007081A1 (en) * | 2006-07-10 | 2008-01-17 | Cenes Limited | Short-acting benzodiazepine salts and their polymorphic forms |
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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 |
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| CN106804107A (en) * | 2014-07-23 | 2017-06-06 | 李勤耕 | New benzodiazepine * analog derivatives and application thereof |
| WO2016011943A1 (en) * | 2014-07-23 | 2016-01-28 | 李勤耕 | New benzodiazepine derivative and use thereof |
| CN106804107B (en) * | 2014-07-23 | 2019-03-12 | 江苏恩华络康药物研发有限公司 | New benzodiazepine * analog derivative and application thereof |
| CN105726495A (en) * | 2014-12-12 | 2016-07-06 | 宜昌人福药业有限责任公司 | Short-term effect benzodiazepines salt medicine composition for injection and preparation method thereof |
| CN105726495B (en) * | 2014-12-12 | 2019-03-29 | 宜昌人福药业有限责任公司 | A kind of short-acting benzodiazepine salt pharmaceutical composition of injection and preparation method thereof |
| 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 |
| CN108143733A (en) * | 2017-12-15 | 2018-06-12 | 宜昌人福药业有限责任公司 | A kind of narcotic analgesics compositions and preparation method thereof |
| 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 |
| WO2025052259A1 (en) * | 2023-09-05 | 2025-03-13 | Reena Patel | Ready to use compositions of remimazolam |
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| CN103202815B (en) | 2014-09-24 |
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