Stable butylphthalide oral solution as well as preparation method and application thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a stable-quality butylphthalide oral solution which comprises butylphthalide, a cosolvent and water, and a surfactant is selected from sodium sulfobutyl-beta-cyclodextrin or 15-hydroxystearic acid polyethylene glycol ester.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and specifically relates to a butylphthalide oral solution and a preparation method and application thereof. Background Art

[0002] 3-n-butylphthalide (NBP) has been reported to have indications including mild, moderate and severe stroke, cerebral ischemia, cerebral infarction, dementia, anti-thrombotic, Parkinson's syndrome, etc. The above varieties are only soft capsules and sodium chloride injection. Butylphthalide is an oily liquid that is insoluble in water, sensitive to light, and has a strong celery smell. It contains a chiral carbon atom in the molecule, so it has two optical isomers, namely L-butylphthalide and D-butylphthalide. Its drug form is usually L-butylphthalide or racemic butylphthalide.

[0003] The chemical structure of butylphthalide is as follows: .

[0004] For the above-mentioned cerebral ischemic diseases, especially moderate to severe cerebral stroke, cerebral ischemia, cerebral infarction, etc., it is very easy to cause patients to experience coma, impaired consciousness, paralysis, limb numbness and other symptoms, causing patients to have difficulty swallowing or be unable to eat orally. The existing technology uses nasogastric feeding of oral solutions, but the stability of the oral solutions in the existing technology is not good enough and is not suitable for long-term storage.

[0005] In view of this, how to provide a long-term, stable and controllable oral solution of butylphthalide is a difficult problem that needs to be solved urgently in clinical practice. Summary of the invention

[0006] In view of the problems existing in the prior art, the object of the present invention is to provide a butylphthalide oral solution with high concentration, small volume and simple preparation process. The butylphthalide oral solution of the present invention uses sodium sulfobutyl beta-cyclodextrin or 15-hydroxystearate polyethylene glycol as a cosolvent to provide long-term stability of the preparation.

[0007] The invention provides a butylphthalide oral solution, comprising butylphthalide, a cosolvent and water, wherein the cosolvent is sodium sulfobutyl beta-cyclodextrin or 15-hydroxystearate polyethylene glycol, and the solution is characterized in that the mass ratio of the butylphthalide to the cosolvent is 1:12-32.

[0008] Furthermore, the above-mentioned cosolvent may also include cyclodextrin, cyclodextrin derivatives or polyethylene glycols; the cyclodextrin derivatives include but are not limited to one or more of α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, glucose cyclodextrin, maltose cyclodextrin, maltotriose cyclodextrin, carboxymethyl cyclodextrin, sulfoalkyl cyclodextrin, and sulfobutyl-β-cyclodextrin; the polyethylene glycols include but are not limited to one or more of polyethylene glycol-12-hydroxystearate, polyethylene glycol-VE-carbonate, polyethylene glycol-VE succinate, polyethylene glycol-distearoylphosphatidylethanolamine, polyethylene glycol-cholesterol succinate, polyethylene glycol-cholesterol methyl ester, polyethylene glycol-cholesterol sulfate, polyoxyethylene sorbitan fatty acid esters, and poloxamers.

[0009] Furthermore, the mass ratio of the above-mentioned butylphthalide and the cosolvent is 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, and 1:31.

[0010] Furthermore, the content of butylphthalide in the single-dose form of the above-mentioned oral solution is 100-150 mg, preferably 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, and 150 mg.

[0011] Furthermore, the pH value of the above oral solution is 3.0-5.5; preferably the pH value is 3.5-5.0; more preferably the pH value is 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9.

[0012] Furthermore, the pH adjuster of the above-mentioned oral solution is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, sodium hydroxide, tartaric acid or sodium tartrate.

[0013] Furthermore, the pH adjuster of the above oral solution is selected from hydrochloric acid, sodium hydroxide, acetic acid or sodium dihydrogen phosphate.

[0014] Furthermore, the above-mentioned oral solution also includes a flavoring agent.

[0015] Furthermore, the flavoring agent is selected from one or more of salty agents, sweeteners, aromatics, and sour agents.

[0016] Furthermore, the above-mentioned flavoring agent is selected from salty agents, sweeteners and aromatics.

[0017] Furthermore, the above-mentioned salting agents, sweeteners, aromatics, and sour agents refer to excipients that have been included in the scope of pharmaceutical excipients in the field or pharmaceutical excipients that are widely used in the field.

[0018] Furthermore, the flavoring agent is selected from one or more of sodium chloride, potassium chloride, ammonium chloride, sodium malate, sucralose, stevioside, white sugar, sweet orange flavor, apple flavor, orange flavor, banana flavor or lemon flavor.

[0019] Furthermore, the flavoring agent is selected from one or more of sodium chloride, sucralose, and sweet orange flavor.

[0020] Furthermore, the above-mentioned oral solution also contains a preservative, and the preservative includes but is not limited to one or more of benzoic acid and sodium salt, sorbic acid, potassium sorbate, methylparaben, ethylparaben, propylparaben, sodium methylparaben, sodium ethylparaben, sodium propylparaben, and benzyl alcohol.

[0021] Furthermore, the specification of the above oral solution is 2 to 15 ml; preferably, the specification of the oral solution is 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 6.5 ml, 7 ml, 7.5 ml, 8 ml, 8.5 ml, 9 ml, 9.5 ml, 10 ml, 10.5 ml, 11 ml, 11.5 ml, 12 ml, 12.5 ml, 13 ml, 13.5 ml, 14 ml, 14.5 ml, 15 ml.

[0022] Furthermore, the present invention provides a method for preparing the above-mentioned oral solution, comprising the following steps: (1) Weigh the prescribed amount of co-solvent and pH regulator, add 50-70% of water at a temperature of 60-90°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 60-90°C for 80-120 minutes until completely dissolved, then cool to 20-35°C; (2) Add water to make up the volume and use a pH adjuster to adjust the pH value of the solution to the target value; (3) Filtration, filling and sterilization.

[0023] Furthermore, the preparation method of the above oral solution comprises the following steps: (1) Weigh the prescribed amount of cosolvent and pH adjuster, add 50-70% water at a temperature of 60-90°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 60-90°C for 80-120 minutes until completely dissolved, then cool to 20-35°C; (2) Add water to make up the volume and use a pH adjuster to adjust the pH value of the solution to the target value; (3) Filtration, filling and sterilization.

[0024] Furthermore, in the above step (3), the filtration is performed by 0.22-0.85 μm filter membrane filtration, and the sterilization condition is sterilization at 121° C. for 5-20 min.

[0025] Furthermore, the above-mentioned oral solution is used for oral administration or nasogastric feeding.

[0026] The above-mentioned "butylphthalide" includes but is not limited to racemic butylphthalide, levorotatory butylphthalide, and dextrorotatory butylphthalide. The mass of butylphthalide in the specific prescription is C 12 H 14 O2 calculation.

[0027] The above-mentioned water includes but is not limited to purified water, ultrapure water, and distilled water.

[0028] The container of the butylphthalide oral solution includes, but is not limited to, a soda-lime glass controlled oral liquid bottle, a low borosilicate glass controlled oral liquid bottle, a medium borosilicate glass controlled oral liquid bottle, an oral liquid medicinal polyester bottle, an oral liquid medicinal polypropylene bottle, an oral liquid medicinal high-density polyethylene bottle, etc. The container of the butylphthalide oral solution is colorless or brown.

[0029] In the present invention, "above" or "below" includes the number itself.

[0030] Beneficial Effects The butylphthalide oral solution of the present invention has stable, safe and controllable quality and meets the pharmaceutical grade quality standards. DETAILED DESCRIPTION

[0031] The scheme of the present invention will be explained below in conjunction with examples. It will be appreciated by those skilled in the art that the following examples are only used to illustrate the present invention and should not be considered as limiting the scope of the present invention. The specific techniques or conditions not indicated in the examples are carried out according to the techniques or conditions described in the literature in this area or according to the product specifications. The reagents or instruments used that do not indicate the manufacturer are all conventional products obtained through commercial purchase.

[0032] The first group of implementation: Butylphthalide oral solution and its preparation , Preparation process: Weigh the prescribed amount of co-solvent 15-hydroxystearate polyethylene glycol ester and pH adjuster citric acid, add 70-80% purified water at a temperature of 50-60°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 50-60°C for 80-90 minutes until completely dissolved, then cool to 20-30°C; weigh the prescribed amount of flavoring agent sucralose and essence, add 4% purified water of the total volume, stir to dissolve, then add to the above-mentioned drug solution, stir and mix, make up to volume with purified water, and adjust the pH value of the solution to the target value; filter with 0.8μm filter membrane, divide into 10 equal parts, fill with nitrogen, and sterilize at 121°C for 15 minutes.

[0033] Prescription 4: The dosage of butylphthalide is 130 mg, the proportions of other materials are the same as those in Prescription 2, and the preparation method is the same as above.

[0034] Prescription 5: The dosage of butylphthalide is 140 mg, the proportions of other materials are the same as those in Prescription 2, and the preparation method is the same as above.

[0035] Second Group of Examples: Butylphthalide Oral Solution , Preparation process: Weigh the prescribed amount of co-solvent sodium sulfobutyl beta-cyclodextrin and pH adjuster citric acid, add 80-90% purified water at a temperature of 60-80°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 60-80°C for 80-90 minutes until completely dissolved, then cool to 20-30°C; weigh the prescribed amount of flavoring agent sucralose and essence, add 4% purified water of the total volume, stir to dissolve, then add to the above-mentioned drug solution, stir and mix, make up to volume with purified water, and adjust the pH value of the solution to the target value; filter with 0.8μm filter membrane, divide into 10 bottles, fill, and sterilize at 121°C for 20 minutes.

[0036] Prescription 9: The dosage of butylphthalide is 130 mg, the proportions of other materials are the same as those in Prescription 7, and the preparation method is the same as above.

[0037] Prescription 10: The dosage of butylphthalide is 140 mg, the proportions of other materials are the same as those in Prescription 7, and the preparation method is the same as above.

[0038] Test example: long-term stability study

[0039] Samples 1 to 10 of prescription were taken for long-term stability (25℃±2℃, RH65%±5%) inspection for 24 months, and samples were taken for testing at 0 day, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months respectively.

[0040] Related substance detection method: adopt the method of Example 2 of patent CN201910466351.4.

[0041] Content detection method: (1) Chromatographic conditions: octadecylsilane bonded silica gel as filler; 10mmol / L potassium dihydrogen phosphate solution (adjusted to pH 3.0 with phosphoric acid)-acetonitrile (40:60) as mobile phase; detection wavelength 230nm; injection volume 5μl. (2) Determination method: Calculate the content of butylphthalide (C 12 H 14 O2) of the labeled amount.

[0042] Visible foreign matter: Determined according to the first method (light inspection method) of General Chapter 0904 of the Chinese Pharmacopoeia 2020 Edition. If there are 0 foreign matters visible to the naked eye, it is A; if there are 1 to 5 foreign matters, it is B, both of which meet the standard; if there are more than 6 foreign matters, it is C.

[0043] The stability results of each sample at 0 days and 24 months are as follows: .

[0044] The above table shows that the butylphthalide oral solution of the present invention is still stable in quality and safe and controllable after a long-term stability test of 24 months.

Claims

1. A butylphthalide oral solution, comprising butylphthalide, a cosolvent and water, wherein the cosolvent is sodium sulfobutyl beta-cyclodextrin or 15-hydroxystearate polyethylene glycol, characterized in that: The mass ratio of the butylphthalide to the co-solvent is 1:12-32.

2. The oral solution according to claim 1, characterized in that The mass ratio of the butylphthalide to the cosolvent is 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, 1:20, 1:21, 1:22, 1:23, 1:24, 1:25, 1:26, 1:27, 1:28, 1:29, 1:30, and 1:

31.

3. The oral solution according to claim 1, characterized in that The content of butylphthalide in the single dosage form of the oral solution is 100-150 mg, preferably 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 131 mg, 132 mg, 133 mg, 134 mg, 135 mg, 136 mg, 137 mg, 138 mg, 139 mg, 140 mg, 145 mg, 150 mg.

4. The oral solution according to claim 1, characterized in that The pH value of the oral solution is 3.0 to 5.5; preferably the pH value is 3.5 to 5.0; more preferably the pH value is 3.6, 3.7, 3.8, 3.9, 4.0, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.

9.

5. The oral solution according to claim 1, characterized in that The pH adjuster of the oral solution is selected from sodium acetate, acetic acid, glacial acetic acid, aspartic acid, benzenesulfonic acid, benzoic acid, sodium benzoate, sodium carbonate, citric acid, sodium citrate, glycine, glycine hydrochloride, hydrochloric acid, hydrobromic acid, lactic acid, sodium lactate, maleic acid, methanesulfonic acid, sodium dihydrogen phosphate, disodium hydrogen phosphate, sulfuric acid, sodium hydroxide, tartaric acid or sodium tartrate; preferably hydrochloric acid, sodium hydroxide, acetic acid or sodium dihydrogen phosphate.

6. The oral solution according to claim 1, characterized in that The oral solutions may also include flavoring agents and / or preservatives.

7. The oral solution according to claim 6, characterized in that The flavoring agent is selected from one or more of sodium chloride, potassium chloride, ammonium chloride, sodium malate, sucralose, stevioside, white sugar, sweet orange flavor, apple flavor, orange flavor, banana flavor or lemon flavor.

8. The oral solution according to claim 1, characterized in that: The specification of the oral solution is 2 to 15 ml; preferably, the specification of the oral solution is 3 ml, 3.5 ml, 4 ml, 4.5 ml, 5 ml, 5.5 ml, 6 ml, 6.5 ml, 7 ml, 7.5 ml, 8 ml, 8.5 ml, 9 ml, 9.5 ml, 10 ml, 10.5 ml, 11 ml, 11.5 ml, 12 ml, 12.5 ml, 13 ml, 13.5 ml, 14 ml, 14.5 ml, 15 ml.

9. The method for preparing the oral solution according to any one of claims 1 to 8, comprising the following steps: Weigh the prescribed amount of cosolvent and pH adjuster, add 50-70% water at a temperature of 60-90°C, stir until completely dissolved, then add the prescribed amount of butylphthalide, stir at 60-90°C for 70-120 minutes until completely dissolved, then cool to 20-35°C; Water is used to make up the volume, and the pH value of the solution is adjusted to the target value by a pH adjuster; Filtration, filling and sterilization.

10. Use of the oral solution according to any one of claims 1 to 8, characterized in that: The oral solution is used for oral administration or nasogastric administration.