CN108289897B - Pharmaceutical composition of remazolam - Google Patents
Pharmaceutical composition of remazolam Download PDFInfo
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- CN108289897B CN108289897B CN201780004159.2A CN201780004159A CN108289897B CN 108289897 B CN108289897 B CN 108289897B CN 201780004159 A CN201780004159 A CN 201780004159A CN 108289897 B CN108289897 B CN 108289897B
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- remazolam
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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
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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
- A61K47/30—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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- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Pharmacology & Pharmacy (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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Abstract
The invention provides a pharmaceutical composition of remazolam. Specifically, the invention provides a pharmaceutical composition comprising remazolam or a pharmaceutically acceptable salt thereof and a hydroxyethyl starch and/or monosaccharide composition. The remazolin composition provided by the invention has short reconstitution time after drying, is convenient for clinical medication, and has good stability.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a composition containing remazolam and pharmaceutically acceptable salts thereof.
Background
Remazolam (Remimazolam) chemical name: the compound is designed by GSK company and developed by PAION company, and has a code number of CNS7056, is an ultra-quick-acting sedative and anesthetic, acts on a GABAA receptor, is metabolized by tissue esterase, and is split into an inactive metabolite CNS7054, and the structural formula is shown as a formula (II).
Remazolin is a sedative superior to the like products currently used, has quick response and failure, stable sedative effect, short recovery time, short half-life, inactive metabolite, predictable pharmacokinetics, wide treatment window, low potential of interaction among medicaments, reversible sedation of flumazenil and no sedation again. The aim of its development is to obtain a new drug which combines the positive activities of midazolam and propofol, without the associated drawbacks. According to research results, remazol is superior to the two commercially available products, is a breakthrough new chemical entity and is very likely to become a new gold standard in the field of sedation/anesthesia.
CN101501019A discloses the besylate salt of remazolam and its polymorphs and discloses a series of possible compositions made thereof, but does not disclose how to obtain a stable composition; CN103221414A discloses the p-toluenesulfonate salt of remazolam and its polymorphs, but does not disclose the composition thereof.
Currently, remazolam is not on the market, and CN103202815A discloses a remazolam freeze-dried preparation containing mannitol or glycine, but in a solution before freeze-drying or a solution after reconstruction, the remazolam concentration of the preparation is low, the relative proportion of auxiliary materials is high, a large amount of solution is needed for clinical use, and the preparation is very inconvenient.
CN104968348A discloses a composition of benzodiazepine compound and at least one hygroscopic excipient, especially lactose and/or dextran, but lactose is an animal-derived excipient, and there is a certain safety risk in large-scale injection due to the possible residual impurity protein in the excipient.
Remazolam hydrolyzes in aqueous solution and during long-term storage to produce inactive impurities as shown in formula (II), and therefore it is necessary to provide a stable remazolam composition.
Disclosure of Invention
The invention aims to provide a composition containing remazolam or pharmaceutically acceptable salt thereof and hydroxyethyl starch.
The hydroxyethyl starch can be selected from any type, such as hydroxyethyl starch 200/0.5, hydroxyethyl starch 130/0.4, preferably hydroxyethyl starch 130/0.4.
The composition of the invention has an impurity increase of not more than 0.15% in the form of a compound of formula (II) or a salt thereof after being left at 50 ℃ for 7 days; or the presence of an impurity in the form of a compound of formula (II) or a salt thereof does not increase by more than 0.3%, preferably by 0.2%, more preferably by more than 0.2%, when left at 50 ℃ for 14 days.
In a preferred embodiment of the invention, the composition does not contain mannitol or glycine.
The ratio of remazolam or a pharmaceutically acceptable salt thereof to hydroxyethyl starch in the composition of the present invention is not particularly limited, and in a preferred embodiment of the present invention, the weight ratio of remazolam or a pharmaceutically acceptable salt thereof to hydroxyethyl starch is 1: 0.1 to 1000, preferably 1:1 to 1:50, more preferably 1:1 to 1:20, and most preferably 1:1 to 1: 10.
In a preferred embodiment of the invention, the composition is a lyophilized formulation.
In a more preferred embodiment, monosaccharides may also be added to the compositions of the invention. The monosaccharide can be selected from glucose, fructose, galactose, mannose, galactosamine, glucosamine, etc.
The freeze-dried preparation is reconstituted by water to the volume before freeze-drying, and the pH of the solution is 2-7, more preferably 2-5, and most preferably 2-4 according to the method in appendix VI H of the second part of the 2010 edition of Chinese pharmacopoeia.
The lyophilized formulation of the present invention can be reconstituted using various aqueous diluents, which are widely known in the art, such as water for injection, physiological saline, 5% dextrose in water, and the like, to obtain a solution for injection.
The ratio of hydroxyethyl starch to monosaccharide is not particularly limited, and in a preferred embodiment of the invention, the weight ratio of hydroxyethyl starch to monosaccharide is 1:9 to 9:1, more preferably 1:5 to 5:1, and most preferably 1:3 to 3: 1.
In the composition of the invention, the concentration of remazolen (calculated as free base) in the solution before freeze-drying or after reconstitution with an aqueous diluent is about 0.5-30 mg/ml, preferably 1-20 mg/ml, and particularly preferably 2-15 mg/ml.
In the invention, the pharmaceutically acceptable salt of remazolam can be benzene sulfonate, p-toluene sulfonate, isethionate and the like.
After the composition preparation provided by the invention is dried, an injection solvent is added, and the mixture is slightly shaken to be reconstructed to obtain a clear solution, wherein the reconstruction time is less than 3min, more preferably less than 2min, and most preferably less than 1.5 min; the medicine crystal can not be separated out after long-time standing after dissolution or dilution.
In another aspect, the present invention also provides a method for inhibiting the degradation of remazolam or a pharmaceutically acceptable salt thereof to a compound of formula (II) or a salt thereof, which comprises adding hydroxyethyl starch as described above or adding hydroxyethyl starch and a monosaccharide.
The invention unexpectedly discovers that hydroxyethyl starch, monosaccharide and a composition thereof can inhibit the degradation of remazolam or pharmaceutically acceptable salt thereof into a compound shown as a formula (II) or salt thereof, thereby further solving the problem of stability; the hydroxyethyl starch, monosaccharide and combination thereof have stronger inhibiting effect on the degradation products than known common auxiliary materials such as glycine, mannitol, lactose and the like.
On the other hand, the invention also provides a method for preparing the composition containing the remazolen and the pharmaceutically acceptable salts thereof, and the method is simple to operate, good in reproducibility and easy to industrialize. The method comprises the following steps:
1) dissolving hydroxyethyl starch and optionally other adjuvants (such as monosaccharide) in aqueous diluent, adjusting pH to 2-4,
2) adding remazolin or salt thereof, adjusting the pH value to 2-4,
3) the aqueous diluent is added to the final volume.
Preferably, the method further comprises the step of lyophilizing the solution obtained in step 3).
In order to achieve low storage cost and good stability of the product, the composition preparation provided by the invention shows excellent stability after being dried, and the redissolution rate is unchanged after the composition preparation is placed.
Detailed Description
The following examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
Examples 1 to 11
The pharmaceutical formulation of the present invention is generally prepared by the following steps:
1. weighing 130/0.4 of hydroxyethyl starch (containing monosaccharide added in the step) in a prescription amount, stirring and dissolving in at least one aqueous diluent, wherein the aqueous diluent accounts for about 80% of the prescription amount, the water temperature is controlled to be 0-30 ℃, the pH value of the solution is measured, and the pH value of the solution is adjusted by using a pH regulator as required and is controlled to be 2-4.
2. Weighing remazolin in a prescription amount, stirring and dissolving the remazolin in the solution, measuring the pH value of the solution after the remazolin is completely dissolved, and adjusting the pH value of the solution by using a pH regulator according to needs, wherein the pH value is controlled to be 2-4.
3. The aqueous diluent was added to the final volume and the solution was stirred until well mixed.
4. The above solution was sterilized by filtration.
5. The solution was freeze dried.
And (3) freeze drying:
2ml of the liquid medicine is filled in a 6ml bottle, and freeze-drying is carried out according to the following procedures after half plugging.
Freeze-drying procedure:
the freeze-dried products obtained by freeze-drying the products of examples 1 to 11 were examined for appearance, reconstitution time, appearance of the solution after reconstitution, moisture, and related substances, and stability was examined at a high temperature of 50 ℃.
The detection method comprises the following steps:
1. reconstructing time
Reconstitution of 2 vials of the product was reconstituted with 2.0ml of water for injection using a 5ml syringe and appropriate needle and the time required for complete dissolution of the solid was recorded.
2. Appearance after redissolving
The appearance of the solution after reconstitution was recorded.
3. Moisture content
The water content was determined by Karl Fischer (Karl Fischer) titration and calculated by the volume of the titration solution consumed, and the results were displayed by the instrument.
4. Related substances
The most major degradation impurity of the product was CNS7054 (i.e. the compound of formula (II)) as measured by the HP L C method.
The results are shown in tables 1 and 2.
The freeze-dried products of the embodiments are quick to reconstitute, the appearance, the reconstitution time and the appearance of the solution after reconstitution are not obviously changed in the storage process at the high temperature of 50 ℃, and related substances of CNS7054 slowly grow and show excellent stability. The formula with further addition of monosaccharide shows better stability.
Example 12
Referring to the lactose formulation of example II (A01P310 formulation) disclosed in CN104968348A patent and the glycine formulation of example 6 of CN103202815A, the lyophilized powder injection of Remazolam was prepared by using lyophilized samples of a process disclosed in the patent, and the stability of the lyophilized powder injection was examined at 50 ℃ and high temperature, and the results are shown in Table 1. In addition, lactose and glycine formula lyophilized products and the lyophilized products of example 4, example 7 and example 10 were respectively reconstituted with water for injection, and then subjected to a solution stability test at room temperature, and the results were compared and shown in table 3.
The results in tables 1, 2 and 3 show that the stability of the lyophilized remazolam composition in the invention at high temperature and the stability of the solution after reconstitution are superior to those of the patent prescription, especially the composition of remazolam, hydroxyethyl starch and monosaccharide.
Table 3 solution stability results after reconstitution
Claims (20)
1. A pharmaceutical composition contains remazolam or pharmaceutically acceptable salts thereof, hydroxyethyl starch and monosaccharide, wherein the monosaccharide is one or more selected from glucose, fructose, galactose, mannose, galactosamine and glucosamine.
2. The composition of claim 1 wherein the hydroxyethyl starch is selected from one or both of hydroxyethyl starch 200/0.5 and hydroxyethyl starch 130/0.4.
3. The composition according to claim 1, wherein the weight ratio of remazolam or a pharmaceutically acceptable salt thereof to hydroxyethyl starch is 1: 0.1 to 1000.
4. The composition according to claim 1, wherein the weight ratio of the remazolam or the pharmaceutically acceptable salt thereof to the hydroxyethyl starch is 1: 1-1: 50.
5. The composition according to claim 1, wherein the weight ratio of the remazolam or the pharmaceutically acceptable salt thereof to the hydroxyethyl starch is 1: 1-1: 20.
6. The composition according to claim 1, wherein the weight ratio of the remazolam or the pharmaceutically acceptable salt thereof to the hydroxyethyl starch is 1: 1-1: 10.
7. The composition of claim 1, wherein the weight ratio of hydroxyethyl starch to monosaccharide is 1:9 to 9: 1.
8. The composition according to claim 1, wherein the weight ratio of hydroxyethyl starch to monosaccharide is 1:5 to 5: 1.
9. The composition according to claim 1, wherein the weight ratio of hydroxyethyl starch to monosaccharide is 1:3 to 3: 1.
10. The composition according to claim 1 in the form of a solution, wherein the concentration of remazolam or its salts is 0.5-30 mg/ml calculated as remazolam base.
11. The composition according to claim 1 in the form of a solution, wherein the concentration of remazolam or its salt is 1-20 mg/ml in remazolam base.
12. The composition according to claim 1 in the form of a solution, wherein the concentration of remazolam or its salts is 2-15 mg/ml in remazolam base.
13. The composition according to any one of claims 1 to 12, wherein the salt of remazolam is selected from one of benzene sulfonate, p-toluene sulfonate, and isethionate.
14. The composition of any one of claims 1 to 9, wherein the composition is a lyophilized formulation.
15. The composition according to claim 14, wherein the concentration of remazolam or its salt in the pre-lyophilization solution or the post-reconstitution solution of the lyophilized formulation is 0.5-30 mg/ml in remazolam base.
16. The composition according to claim 14, wherein the concentration of remazolam or its salt in the pre-lyophilization solution or the post-reconstitution solution of the lyophilized formulation is 1-20 mg/ml in remazolam base.
17. The composition according to claim 14, wherein the concentration of remazolam or its salt in the pre-lyophilization solution or the post-reconstitution solution of the lyophilized formulation is 2-15 mg/ml in remazolam base.
18. A process for the preparation of a composition as claimed in any one of claims 1 to 9, comprising the steps of:
1) dissolving hydroxyethyl starch or hydroxyethyl starch and monosaccharide in aqueous diluent,
2) adding the remazolin or the salt thereof,
3) the aqueous diluent is added to the final volume.
19. The method according to claim 18, further comprising the step of lyophilizing the solution obtained in step 3).
20. The method according to claim 18, further comprising the step of adjusting the pH of the solution obtained in any one or more of the steps 1), 2), 3) to 2 to 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 CN108289897A (en) | 2018-07-17 |
| CN108289897B true 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) |
Families Citing this family (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 |
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2017
- 2017-05-19 WO PCT/CN2017/085141 patent/WO2017198224A1/en active Application Filing
- 2017-05-19 CN CN201780004159.2A patent/CN108289897B/en active Active
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 |
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| Publication number | Publication date |
|---|---|
| WO2017198224A1 (en) | 2017-11-23 |
| CN108289897A (en) | 2018-07-17 |
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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. |
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