CN111096947A - Oral amisulpride solution - Google Patents
Oral amisulpride solution Download PDFInfo
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- CN111096947A CN111096947A CN201811251080.2A CN201811251080A CN111096947A CN 111096947 A CN111096947 A CN 111096947A CN 201811251080 A CN201811251080 A CN 201811251080A CN 111096947 A CN111096947 A CN 111096947A
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- Prior art keywords
- amisulpride
- cyclodextrin
- oral
- solution
- derivative
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K47/40—Cyclodextrins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Inorganic Chemistry (AREA)
- Psychiatry (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a pharmaceutical solution suitable for oral administration comprising amisulpride, cyclodextrin or a derivative thereof, a suitable pharmaceutically acceptable solvent system and other excipients. The cyclodextrin or the derivative thereof and the drug cosolvent system can obviously increase the solubility of amisulpride in the solvent system, promote drug absorption and enhance the treatment effect. The oral liquid preparation of amisulpride has the advantages of high absorption speed, quick drug effect exertion, convenient taking and easy dosage division, and can simultaneously meet various requirements of clinical medication, patient compliance, industrialized mass production and the like.
Description
Technical Field
The present invention relates to an amisulpride pharmaceutical solution suitable for oral administration.
Background
Amisulpride is an atypical antipsychotic drug used for the treatment of paranoid progressive schizophrenia, acute empty psychosis, and for the treatment of defective states of schizophrenia, residual psychotic development and depressive states associated with dullness. Early diagnosis and treatment of such diseases can significantly improve their recovery and outcome. Furthermore, early therapeutic intervention can avoid costly hospitalizations.
At present, the dosage form of amisulpride on the market at home and abroad is a tablet. The amisulpride oral solution can meet the specific requirements of patients suffering from paranoid progressive schizophrenia and acute empty psychosis, and the patients have difficulty in swallowing solid oral preparations. Oral solutions also allow physicians greater flexibility in designing dosage regimens for their patients. However, amisulpride is a poorly soluble drug, and the difficulty in preparing amisulpride oral solutions is to increase the solubility of the drug in the solvent system, while masking the unpleasant taste of the drug and maintaining a good taste.
Disclosure of Invention
Accordingly, the present invention provides an oral amisulpride solution comprising amisulpride, cyclodextrin or a derivative thereof, a suitable pharmaceutically acceptable solvent system and other excipients.
The cyclodextrin or the derivative thereof is α -cyclodextrin or the derivative thereof, β -cyclodextrin or the derivative thereof, and gamma-cyclodextrin or the derivative thereof.
The cyclodextrin is hydroxypropyl- β cyclodextrin.
The suitable pharmaceutically acceptable solvent system is comprised of one or more solvents selected from the group consisting of water, surfactants, and water-miscible solvents.
The water-miscible solvent is selected from ethanol, glycerol, propylene glycol, sorbitol solution, polyethylene glycol.
The surfactant is a pharmaceutically acceptable surfactant having a hydrophilic-lipophilic balance (HBL) of not less than 15.
The other auxiliary materials comprise a preservative, a flavoring agent and a pH regulator.
The amisulpride oral solution comprises 2-8% (w/v) of amisulpride, 2-40% (w/v) of hydroxypropyl- β -cyclodextrin, 10-40% (w/v) of propylene glycol, 0.05% (w/v) of tween 80, a preservative, a pH regulator, a flavoring agent and the balance of water.
The oral solution of amisulpride comprises 5% (w/v) of amisulpride, 25% (w/v) of hydroxypropyl- β -cyclodextrin, 20% (w/v) of propylene glycol, 20% (w/v) of sorbitol, 0.05% (w/v) of saccharin sodium, 0.05% (w/v) of tween 80, a proper amount of sodium hydroxide and the balance of water.
Examples
The present invention will be described in detail with reference to examples
The present invention is specifically illustrated by way of examples, but is not limited to the following examples.
Example 1
1000mL of an oral solution of amisulpride with a concentration of 5% (w/v) was prepared, which contained 50g of amisulpride, 150g of hydroxypropyl- β -cyclodextrin, 300mL of propylene glycol, 200mL of 70% sorbitol, 0.5g of Tween 80, 0.1g of ethylparaben, 0.5g of sodium saccharin, a suitable amount of sodium hydroxide, and distilled water was added to 1000 mL.
The preparation method comprises the steps of firstly adding 0.5g of Tween 80 into 200ml of distilled water, adding 150g of hydroxypropyl- β cyclodextrin, stirring, continuously adding 300ml of propylene glycol, stirring uniformly, adding 50g of amisulpride into a hydroxypropyl- β cyclodextrin solution under continuous stirring to obtain an amisulpride inclusion compound solution, then adding 200ml of 70% sorbitol solution, 0.1g of ethylparaben and 0.5g of saccharin sodium, adjusting the pH to 3.5 by using 1mol/L of sodium hydroxide solution, diluting the obtained solution to 1000ml by using distilled water, and filtering to obtain the amisulpride oral solution.
Example 2
1000mL of an oral solution of amisulpride with a concentration of 8% (w/v) was prepared, which contained 80g of amisulpride, 240g of hydroxypropyl- β -cyclodextrin, 200mL of propylene glycol, 200mL of 70% sorbitol, 0.5g of Tween 80, 0.1g of benzoic acid, 0.5g of sodium saccharin, a suitable amount of sodium hydroxide, and distilled water was added to 1000 mL.
The preparation method comprises the steps of firstly adding 0.5g of Tween 80 into 200ml of distilled water, adding 240g of hydroxypropyl- β cyclodextrin, stirring, continuously adding 200ml of propylene glycol, stirring uniformly, adding 80g of amisulpride into a hydroxypropyl- β cyclodextrin solution under continuous stirring to obtain an amisulpride inclusion compound solution, then adding 200ml of 70% sorbitol solution, 0.1g of benzoic acid and 0.5g of saccharin sodium, adjusting the pH value to 3.5 by using 1mol/L of sodium hydroxide solution, diluting the obtained solution to 1000ml by using distilled water, and filtering to obtain the amisulpride oral solution.
Example 3
1000mL of an oral solution of amisulpride with a concentration of 2% (w/v) was prepared, which contained 20g of amisulpride, 100g of hydroxypropyl- β -cyclodextrin, 400mL of propylene glycol, 200mL of 70% sorbitol, 0.5g of Tween 80, 0.1g of benzoic acid, 0.5g of sodium saccharin, a suitable amount of sodium hydroxide, and distilled water was added to 1000 mL.
The preparation method comprises the steps of firstly adding 0.5g of Tween 80 into 200ml of distilled water, adding 100g of hydroxypropyl- β cyclodextrin, stirring, continuously adding 400ml of propylene glycol, stirring uniformly, adding 20g of amisulpride into a hydroxypropyl- β cyclodextrin solution under continuous stirring to obtain an amisulpride inclusion compound solution, then adding 200ml of 70% sorbitol solution, 0.1g of benzoic acid and 0.5g of saccharin sodium, adjusting the pH value to 3.5 by using 1mol/L of sodium hydroxide solution, diluting the obtained solution to 1000ml by using distilled water, and filtering to obtain the amisulpride oral solution.
Example 4
1000mL of an oral solution of amisulpride with a concentration of 5% (w/v) was prepared, which contained 50g of amisulpride, 250g of hydroxypropyl- β -cyclodextrin, 200mL of propylene glycol, 200mL of 70% sorbitol, 0.5g of Tween 80, 0.1g of ethylparaben, 0.5g of sodium saccharin, a suitable amount of sodium hydroxide, and distilled water was added to 1000 mL.
The preparation method comprises the steps of firstly adding 0.5g of Tween 80 into 200ml of distilled water, adding 250g of hydroxypropyl- β cyclodextrin, stirring, continuously adding 200ml of propylene glycol, stirring uniformly, adding 50g of amisulpride into a hydroxypropyl- β cyclodextrin solution under continuous stirring to obtain an amisulpride inclusion compound solution, then adding 200ml of 70% sorbitol solution, 0.1g of ethylparaben and 0.5g of saccharin sodium, adjusting the pH to 3.5 by using 1mol/L of sodium hydroxide solution, diluting the obtained solution to 1000ml by using distilled water, and filtering to obtain the amisulpride oral solution.
Example 5
1000mL of an oral solution of amisulpride at a concentration of 5% (w/v) was prepared, which contained 50g of amisulpride, 250g of hydroxypropyl- β -cyclodextrin, 200mL of propylene glycol, 200mL of 70% sorbitol, 1.0g of sodium lauryl sulfate, 0.1g of ethylparaben, 0.5g of sodium saccharin, an appropriate amount of sodium hydroxide, and distilled water was added to 1000 mL.
The preparation method comprises the steps of firstly adding 1.0g of sodium dodecyl sulfate into 200ml of distilled water, adding 250g of hydroxypropyl- β cyclodextrin, stirring, continuously adding 200ml of propylene glycol, stirring uniformly, adding 50g of amisulpride into a hydroxypropyl- β cyclodextrin solution under continuous stirring to obtain an amisulpride inclusion compound solution, then adding 200ml of 70% sorbitol solution, 0.1g of ethyl hydroxybenzoate and 0.5g of saccharin sodium, adjusting the pH to 3.5 by using 1mol/L of sodium hydroxide solution, diluting the obtained solution to 1000ml by using distilled water, and filtering to obtain the amisulpride oral solution.
The effect factor experiment of amisulpride oral liquid formulations described in examples 1 and 5 was followed.
An influence factor experiment is carried out on the oral liquid preparation of amisulpride described in examples 1 and 5 according to the 2015 version of the guidance principle 9001 of the four parts of Chinese pharmacopoeia and the guidance principle of the stability of the bulk drug and the pharmaceutical preparation. And (3) performing high temperature 60 ℃ (10 days), low temperature-40 ℃ (3 circulation for 12 days), freeze thawing-40 ℃ (3 circulation for 12 days), and lighting experiment (10 days), sampling, lofting influencing factor samples under various conditions, and detecting according to stability focus investigation items. The results are shown in Table 1.
Table 1 examples 1 and 5 influence factor test results
The results show that: examples 1 and 5 stable oral solutions can be prepared using the formulations and processes provided by the present invention.
Accelerated testing of amisulpride oral liquid formulations described in example 1.
An accelerated experiment was performed on the oral liquid preparation described in example 1 according to 2015 edition of the four guidelines 9001 of the chinese pharmacopoeia for stability of bulk drug and pharmaceutical preparation. Three batches of amisulpride oral solution prepared in example 1 are taken and packaged according to a package material which is planned to be sold on the market, placed for 6 months under the conditions that the temperature is 40 +/-2 ℃ and the relative humidity is 60 +/-5 percent, and sampled for 1 month, 2 months, 3 months and 6 months during the test period, and the test is carried out according to key research items. The results of the accelerated test are shown in Table 2.
Table 2 example 1 accelerated test results
The stability test of the oral amisulpride solution prepared in example 1 for 6 months is accelerated, and compared with 0 month, the tests have no obvious change, which shows that the oral amisulpride liquid preparation prepared in example 1 has good stability and stable process.
Claims (9)
1. An oral amisulpride solution, which is characterized by comprising amisulpride, cyclodextrin or derivatives thereof, a suitable medicinal solvent system and other auxiliary materials.
2. Amisulpride oral solution according to claim 1, wherein the cyclodextrin or derivative thereof is α -cyclodextrin or derivative thereof, β -cyclodextrin or derivative thereof, γ -cyclodextrin or derivative thereof.
3. Amisulpride oral solution according to claim 2, wherein the cyclodextrin is hydroxypropyl- β cyclodextrin.
4. Amisulpride oral solution according to claim 1, wherein the suitable pharmaceutically acceptable solvent system consists of one or more selected from water, surfactants, water-miscible solvents.
5. Amisulpride oral solution according to claim 4, characterized in that the water-miscible solvent is selected from ethanol, glycerol, propylene glycol, sorbitol solution, polyethylene glycol.
6. Amisulpride oral solution according to claim 4, characterized in that the surfactant is a pharmaceutically acceptable surfactant having a hydrophilic-lipophilic balance (HBL) of not less than 15.
7. Amisulpride oral solution according to claim 1, wherein the other excipients include preservatives, flavouring agents and pH adjusting agents.
8. The amisulpride oral solution of claim 1, which comprises 2-8% (w/v) amisulpride, 2-40% (w/v) hydroxypropyl- β -cyclodextrin, 10-40% (w/v) propylene glycol, 0.05% (w/v) tween 80, a preservative, a pH regulator, a flavoring agent, and the balance water.
9. The oral solution of amisulpride according to claim 1, which comprises 5% (w/v) amisulpride, 25% (w/v) hydroxypropyl- β -cyclodextrin, 20% (w/v) propylene glycol, 20% (w/v) sorbitol, 0.05% (w/v) sodium saccharin, 0.05% (w/v) Tween 80, a suitable amount of sodium hydroxide, and the balance water.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811251080.2A CN111096947A (en) | 2018-10-25 | 2018-10-25 | Oral amisulpride solution |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811251080.2A CN111096947A (en) | 2018-10-25 | 2018-10-25 | Oral amisulpride solution |
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| Publication Number | Publication Date |
|---|---|
| CN111096947A true CN111096947A (en) | 2020-05-05 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811251080.2A Pending CN111096947A (en) | 2018-10-25 | 2018-10-25 | Oral amisulpride solution |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114088845A (en) * | 2021-12-06 | 2022-02-25 | 广东金城金素制药有限公司 | Analysis method for determining content of saccharin sodium and benzamide degradation impurities in amisulpride oral solution |
-
2018
- 2018-10-25 CN CN201811251080.2A patent/CN111096947A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114088845A (en) * | 2021-12-06 | 2022-02-25 | 广东金城金素制药有限公司 | Analysis method for determining content of saccharin sodium and benzamide degradation impurities in amisulpride oral solution |
| CN114088845B (en) * | 2021-12-06 | 2022-08-16 | 广东金城金素制药有限公司 | Analysis method for determining content of saccharin sodium and benzamide degradation impurities in amisulpride oral solution |
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