CN108289897A - A kind of pharmaceutical composition of auspicious horse azoles logical sequence - Google Patents
A kind of pharmaceutical composition of auspicious horse azoles logical sequence Download PDFInfo
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- CN108289897A CN108289897A CN201780004159.2A CN201780004159A CN108289897A CN 108289897 A CN108289897 A CN 108289897A CN 201780004159 A CN201780004159 A CN 201780004159A CN 108289897 A CN108289897 A CN 108289897A
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- logical sequence
- azoles logical
- horse azoles
- hydroxyethyl starch
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
- A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
- A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
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- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of pharmaceutical compositions of auspicious horse azoles logical sequence.Specifically, the present invention provides a kind of pharmaceutical composition, it includes auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch and/or monosaccharide compositions.Reconstitution time after composition China and Sweden horse azoles logical sequence drying provided by the invention is short, facilitates clinical application, and with good stability.
Description
The invention belongs to field of pharmaceutical preparations, and in particular to the composition comprising auspicious horse azoles logical sequence and its pharmaceutically acceptable salt.
Auspicious horse azoles logical sequence (Remimazolam) chemical name: (4S) -8- bromo- 1- methyl -6- (2- pyridyl group) -4H- imidazoles [1,2-a] [1,4] Benzodiazepine -4- methyl propionate, shown in structural formula such as formula (I), the compound is designed by GSK company, the exploitation of PAION company, code name CNS7056, calmness, arcotic for a kind of hypervelocity effect, act on GABAA receptor, it is metabolized through tissue esterases, inactive metabolite CNS7054 is split into, shown in structural formula such as formula (II).
Auspicious horse azoles logical sequence is a kind of sedative better than similar product currently in use, it works and failure is rapid, sedation is stablized, and recovery time is short, half-life short, metabolite is inactive, pharmacokinetics is predictable, and therapeutic window is wide, and the potentiality of drug drug interaction is lower, sedation can be reversed in Flumazenil, will not be calm again.It is the positive activity to obtain a kind of set midazolam and propofol that it, which develops purpose, and abandons the newtype drug of related defects.According to result of study, auspicious horse azoles logical sequence is better than the product of both list marketings, is a kind of breakthrough new chemical entities, it is most likely that the novel goldstandard as sedation/anesthesia field.
CN101501019A discloses the benzene sulfonate and its polymorphic of auspicious horse azoles logical sequence, and discloses composition made of a series of its possibility, but fails to disclose how to obtain a kind of stable composition；CN103221414A discloses the tosilate and its polymorphic of auspicious horse azoles logical sequence, but without open its composition.
Current auspicious horse azoles logical sequence is not gone public also, CN103202815A discloses a kind of auspicious horse azoles logical sequence lyophilized preparation containing mannitol or glycine, but such preparation before freeze-drying solution or rebuild after solution in, the concentration of auspicious horse azoles logical sequence is lower, auxiliary material relative scale is higher, clinical use needs tank solution, is inconvenient.
Benzodiazepines compound and at least one hygroscopic excipient are disclosed in CN104968348A, the especially composition of lactose and/or glucan, but excipient lactose is animal origin auxiliary material, due to wherein may remaining foreign protein, there are certain security risks when a large amount of injections.
Auspicious horse azoles logical sequence can hydrolyze in aqueous solution and in long term storage generates impurity inactive as shown in formula (II), therefore the composition for providing a kind of stable auspicious horse azoles logical sequence is highly desirable.
Summary of the invention
The object of the present invention is to provide a kind of composition containing auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch.
The hydroxyethyl starch can be selected from disposable type, such as Hetastarch 200/0.5, hydroxyethyl starch 130/0.4, preferably hydroxyethyl starch 130/0.4.
Composition of the invention placed under the conditions of 50 DEG C 7 days in the form of formula (II) compound or its salt existing for impurity increase be no more than 0.15%；Or placed under the conditions of 50 DEG C 14 days in the form of formula (II) compound or its salt existing for impurity increase be no more than 0.3%, select 0.2%, more preferably no more than 0.2%.
In a preferred embodiment of the present invention, mannitol or sweet is not contained in the composition
Propylhomoserin.
In composition of the invention, the ratio of auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch is not particularly limited, in a preferred embodiment of the present invention, the weight ratio of auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch is 1: 0.1~1000, preferred 1: 1~1: 50, more preferably 1: 1~1: 20, most preferably 1: 1~1: 10.
In a preferred embodiment of the present invention, the composition is lyophilized preparation.
In highly preferred embodiment, monosaccharide can also be added in composition of the invention.The monosaccharide can be selected from glucose, fructose, galactolipin, mannose, amine-galactose, Glucosamine etc..
Lyophilized preparation of the invention reconstructs the volume to freeze-drying with water, and is measured according to the method under Chinese Pharmacopoeia annex VI H of version two in 2010, and the pH of the solution is 2~7, more preferably 2~5, most preferably 2~4.
Lyophilized preparation of the invention, which can be used, obtains the solution for injection after the reconstruct of various aqueous diluents, and the aqueous diluent is widely known in the art, such as water for injection, physiological saline, 5% glucose solution etc..
Hydroxyethyl starch and the ratio of monosaccharide are not particularly limited, and in a preferred embodiment of the present invention, the weight ratio of hydroxyethyl starch and monosaccharide is 1: 9~9: 1, more preferably 1: 5~5: 1, most preferably 1: 3~3: 1.
In the present compositions, solution China and Sweden horse azoles logical sequence (with free base) concentration that preceding solution is lyophilized or obtains after being redissolved using aqueous diluent is about 0.5~30mg/ml, preferably 1~20mg/ml, particularly preferred 2~15mg/ml.
In the present invention, the pharmaceutically acceptable salt of auspicious horse azoles logical sequence can be benzene sulfonate, tosilate, isethionate etc..
Composite preparation provided by the invention after drying, is added after solvent for injection that slightly shaking is i.e. restructural to obtain clear solution, and reconstitution time is less than 3min, more preferably less than 2min, more preferably less than 1.5min；Medicine crystal will not be precipitated by standing for a long time after dissolution or dilution.
On the other hand, the present invention also provides a kind of methods for inhibiting auspicious horse azoles logical sequence or its salt that can pharmaceutically connect to be degraded to compound or its salt shown in formula (II), and the method includes foregoing hydroxyethyl starch is added or hydroxyethyl starch and monosaccharide is added.
It is an unexpected discovery of the invention that hydroxyethyl starch, monosaccharide and combinations thereof are able to suppress auspicious horse azoles logical sequence or its salt that can pharmaceutically connect is degraded to compound or its salt shown in formula (II), to further solve the problems, such as stability；Hydroxyethyl starch, monosaccharide and combinations thereof are greatly to be better than the common auxiliary material such as known glycine, mannitol, lactose to the inhibiting effect of this kind of catabolite.
Another further aspect is the present invention also provides a kind of method for preparing the composition containing auspicious horse azoles logical sequence and its pharmaceutically acceptable salt, and this method is easy to operate, reproducibility is good, is easy to industrialization.Described method includes following steps:
1) hydroxyethyl starch and optional other auxiliary materials (such as monosaccharide) are dissolved in aqueous diluent, adjusting pH value to 2-4,
2) the auspicious horse azoles logical sequence of addition or its salt, adjusting pH value to 2-4,
3) aqueous diluent is added to final volume.
It is preferred that the method also includes step 3) acquired solution is lyophilized.
To reach lower storage cost, product need to be with good stability, and excellent stability is shown after composite preparation provided by the invention is dry, and redissolves rate after placing and do not change.
Following embodiment is not limited the scope of the invention in any way to illustrate invention.
Embodiment 1 to 11
Pharmaceutical preparation of the invention is usually made by following step:
1. weighing the hydroxyethyl starch 130/0.4 (adding containing monosaccharide in the step) of recipe quantity, for stirring and dissolving at least one aqueous diluent, aqueous diluent is 80% or so of recipe quantity, water temperature is controlled at 0-30 DEG C, the pH value of measurement solution makes as needed
Solution ph is adjusted with pH adjusting agent, pH is controlled in 2-4.
2. weighing the auspicious horse azoles logical sequence of recipe quantity, in the above solution, the pH value that solution is measured after being completely dissolved as needed is adjusted solution ph using pH adjusting agent stirring and dissolving, and pH is controlled in 2-4.
3. aqueous diluent is added to final volume, solution is continued to stir to uniformly mixed.
4. by above-mentioned solution filtration sterilization.
5. solution is freeze-dried.
Freeze-drying:
6ml bottles of filling 2ml medical fluids, are lyophilized after partly jumping a queue by following procedure.
Program is lyophilized:
Solution appearance, moisture, related substance after dried frozen aquatic products appearance, reconstitution time, reconstruct after investigating the freeze-drying of embodiment 1-11 product, and study on the stability is carried out under the conditions of 50 DEG C of high temperature respectively.
The method of inspection:
1, reconstitution time
With 2.0ml water for injection, 2 bottle products of reconstruct are redissolved using 5ml syringe and suitable syringe needle, the time required to record solid is completely dissolved.
2, appearance after redissolving
The appearance of solution after restructuring of record.
3, moisture
By karr Fischer (Karl Fischer) titration determination moisture, the volume by consuming titrating solution calculates moisture content, is as a result shown by instrument.
4, related substance
It is detected using HPLC method, the most important degradation impurity of product is CNS7054 (i.e. formula (II) compound).
It the results are shown in Table 1 and table 2.
Rapidly, significant change does not occur for solution appearance after appearance, reconstitution time, reconstruct during 50 DEG C of storages of high temperature, and the related substance of CNS7054 increasess slowly, and shows excellent stability for the freeze-dried products reconstruct of each embodiment.The prescription for further adding monosaccharide shows more preferably stability.
Embodiment 12
Referring to the 6 glycine prescription of embodiment for the embodiment II lactose prescription (A01P310 prescription) and CN103202815A announced in CN104968348A patent, and the freeze-drying auspicious horse azoles logical sequence freeze-dried powder of sample preparation is carried out to a technique with what is announced in patent, study on the stability is carried out under the conditions of 50 DEG C of high temperature, the results are shown in Table 1.In addition, carrying out solution at room temperature study on the stability after lactose and glycine prescription dried frozen aquatic products and embodiment 4, embodiment 7 and 10 dried frozen aquatic products of embodiment are reconstructed with water for injection respectively, as a result comparing, the results are shown in Table 3.
Table 1, table 2 and table 3 the result shows that, the present invention in auspicious horse azoles logical sequence composition freeze-drying product at high temperature stability and reconstruct after stability of solution be superior to patent prescription, the composition of especially auspicious horse azoles logical sequence and hydroxyethyl starch and monosaccharide.
Stability of solution result after table 3 reconstructs
Claims (12)
- A kind of pharmaceutical composition contains auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch.
- Composition according to claim 1, wherein the hydroxyethyl starch is selected from one or both of Hetastarch 200/0.5 and hydroxyethyl starch 130/0.4.
- Composition according to claim 1, wherein the weight ratio of the auspicious horse azoles logical sequence or its pharmaceutically acceptable salt and hydroxyethyl starch is 1:0.1~1000, preferably 1:1~1:50, more preferably 1:1~1:20, most preferably 1:1~1:10.
- Composition according to claim 1 also contains monosaccharide, and the preferably described monosaccharide is selected from one or more of glucose, fructose, galactolipin, mannose, amine-galactose, Glucosamine.
- Composition according to claim 4, wherein the weight ratio of the hydroxyethyl starch and monosaccharide is 1:9~9:1, more preferably 1:5~5:1, most preferably 1:3~3:1.
- Composition according to claim 1, the composition are solution form, and the concentration of China and Sweden's horse azoles logical sequence or its salt is calculated as 0.5~30mg/ml, preferably 1~20mg/ml, more preferable 2~15mg/ml with auspicious horse azoles logical sequence alkali.
- Composition according to any one of claims 1 to 6, wherein the salt of the auspicious horse azoles logical sequence is selected from one of benzene sulfonate, tosilate and isethionate.
- Composition according to any one of claims 1 to 5, wherein the composition is lyophilized preparation.
- Composition according to claim 8, wherein solution or solution China and Sweden horse azoles logical sequence or the concentration of its salt with auspicious horse azoles logical sequence alkali are calculated as 0.5~30mg/ml, preferably 1~20mg/ml, more preferable 2~15mg/ml after redissolving before the freeze-drying of the lyophilized preparation.
- The preparation method of composition described in any one of claim 1 to 5, includes the following steps:1) hydroxyethyl starch or hydroxyethyl starch and monosaccharide are dissolved in aqueous diluent,2) auspicious horse azoles logical sequence or its salt is added,3) aqueous diluent is added to final volume.
- Preparation method according to claim 10 further includes the steps that for step 3) acquired solution being lyophilized.
- Preparation method according to claim 10, wherein further include the steps that step 1), 2), 3) in any one or more steps the pH of acquired solution be adjusted to 2-4.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016103408030 | 2016-05-20 | ||
| CN201610340803 | 2016-05-20 | ||
| PCT/CN2017/085141 WO2017198224A1 (en) | 2016-05-20 | 2017-05-19 | Pharmaceutical composition of remimazolam |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108289897A true CN108289897A (en) | 2018-07-17 |
| CN108289897B CN108289897B (en) | 2020-07-28 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201780004159.2A Active CN108289897B (en) | 2016-05-20 | 2017-05-19 | Pharmaceutical composition of remazolam |
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| Country | Link |
|---|---|
| CN (1) | CN108289897B (en) |
| WO (1) | WO2017198224A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546675A (en) * | 2014-12-25 | 2015-04-29 | 海南卫康制药(潜山)有限公司 | Estazolam composition freeze-dried tablet and preparation method thereof |
| CN104968348A (en) * | 2012-05-22 | 2015-10-07 | Paion英国有限公司 | Compositions comprising short-acting benzodiazepines |
-
2017
- 2017-05-19 CN CN201780004159.2A patent/CN108289897B/en active Active
- 2017-05-19 WO PCT/CN2017/085141 patent/WO2017198224A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104968348A (en) * | 2012-05-22 | 2015-10-07 | Paion英国有限公司 | Compositions comprising short-acting benzodiazepines |
| CN104546675A (en) * | 2014-12-25 | 2015-04-29 | 海南卫康制药(潜山)有限公司 | Estazolam composition freeze-dried tablet and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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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| Publication number | Publication date |
|---|---|
| WO2017198224A1 (en) | 2017-11-23 |
| CN108289897B (en) | 2020-07-28 |
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Effective date of registration: 20220507 Address after: 361026 room 53, floor 1, building A19, Xiamen biomedical industrial park, 2036 wengjiao West Road, Haicang District, Xiamen City, Fujian Province Patentee after: Fujian Shengdi Pharmaceutical Co.,Ltd. Patentee after: Jiangsu Hengrui Pharmaceutical Co., Ltd Address before: 222047 No. 7 Kunlun Shan Road, Lianyungang economic and Technological Development Zone, Jiangsu Patentee before: JIANGSU HENGRUI MEDICINE Co.,Ltd. |