CN104510721A - 2-(alpha-hydroxypentyl) benzoate dropping pill and preparation method thereof - Google Patents
2-(alpha-hydroxypentyl) benzoate dropping pill and preparation method thereof Download PDFInfo
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- CN104510721A CN104510721A CN201410819269.2A CN201410819269A CN104510721A CN 104510721 A CN104510721 A CN 104510721A CN 201410819269 A CN201410819269 A CN 201410819269A CN 104510721 A CN104510721 A CN 104510721A
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Abstract
The invention discloses a 2-(alpha-hydroxypentyl) benzoate dropping pill and a preparation method thereof. The 2-(alpha-hydroxypentyl) benzoate dropping pill comprises a 2-(alpha-hydroxypentyl) benzoate, a stabilizer, and a carrier as a substrate, wherein the 2-(alpha-hydroxypentyl) benzoate, as a solute, is dissolved into a mixture solution of the stabilizer and the carrier. The preparation method comprises the following steps: preparing melted liquid and preparing the dropping pill. The 2-(alpha-hydroxypentyl) benzoate dropping pill can make up defects of the existing 2-(alpha-hydroxypentyl) benzoate preparation, improves the solubility and the dissolution rate of a drug and is quick-acting and high in bioavailability; more importantly, after adoption of the dropping pill preparation, the defect that the 2-(alpha-hydroxypentyl) benzoate is prone to change in the preparation process is overcome, the drug quality is ensured and the stability is improved.
Description
Technical field
The invention belongs to medical art, be specifically related to a kind of 2-(Alpha-hydroxy amyl group) benzoate drop pill and preparation method thereof.
Background technology
2-(Alpha-hydroxy amyl group) benzoate; chemical name: racemization 2-(Alpha-hydroxy amyl group) benzoate; for the neuroprotective of acute ischemic cerebrovascular disease; its dominant mechanism is: expansion of cerebral vascular; increase cerebral blood flow; anticoagulant and thrombosis, the Neuron Apoptosis etc. that protective wire mitochondria function and anti-many factors cause.
Take a broad view of the research of domestic and international associated therapy ischemic cerebrovascular new drug, though explore through long-term endeavour, effect is not remarkable.Be used for the treatment of the medicine of ischemic cerebrovascular, especially determined curative effect, medicine that toxic and side effects is little are very few.Most patient can not get effective treatment.Thus great demand is had to the medicine developing novel anti-cerebral ischemia damnification clinically.In recent years, scholars has carried out further investigated to the Pathophysiology of ischemic brain injury, turns to the new drug found and can block multiple pathology links (Mutiple Targets) of ischemic brain injury from the medicine seeking single target spot gradually.A series of researchs in recent years confirm that namely racemization 2-(Alpha-hydroxy amyl group) benzoates belong to this kind of and have several functions and act on noval chemical compound in the multiple pathology link of cerebral ischemia, are the medicines of the treatment acute ischemic cerebrovascular disease that has a extensive future.
At preparation 2-(Alpha-hydroxy amyl group) in benzoate production process, all may cause 2-(Alpha-hydroxy amyl group) benzoate transforms, thus the therapeutic effect affecting medicine even increases toxic and side effects.There are some 2-(Alpha-hydroxy amyl groups in the market) the part conventional tablet of benzoate and capsule, but the actual demand in market can not be met far away, be particularly badly in need of playing drug effect and improving bioavailability aspect being short of very much.Therefore, develop a kind of preparation that can solve the problems of the technologies described above to be very important.
Summary of the invention
The first object of the present invention is to provide a kind of 2-(Alpha-hydroxy amyl group) benzoate drop pill; Second object is to provide described 2-(Alpha-hydroxy amyl group) preparation method of benzoate drop pill.
The first object of the present invention is achieved in that and comprises 2-(Alpha-hydroxy amyl group) benzoate, stabilizing agent and the carrier as substrate, 2-(Alpha-hydroxy amyl group) benzoate with solute dissolves in the mixture solution of stabilizing agent and carrier.
The second object of the present invention is achieved in that and comprises fused solution preparation, drop pill preparation process, specifically comprises:
Method one:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the water-solubility carrier of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in fat-soluble liquid coolant with the speed of dripping of 35 ~ 45/min under temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, water dropper distance cooling liquid level 6 ~ 7cm, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C;
Method two:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the lipid-soluble carriers of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in Water Soluble Cooling Liquid in temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, the speed of dripping of water dropper with 40 ~ 50/min under cooling liquid level 6 ~ 7cm, Water Soluble Cooling Liquid temperature controls at 16 ~ 20 DEG C, the degree of depth is not less than 100cm, completely to be cooled, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C.
The present invention can supplement existing 2-(Alpha-hydroxy amyl group) deficiency of benzoate preparation, improve dissolubility and the dissolution rate of medicine, act on quick-acting and bioavailability is high, the more important thing is, drop pill is adopted to overcome 2-(Alpha-hydroxy amyl group) benzoate labile deficiency in preparation process, ensure that drug quality, improve stability.
Accompanying drawing explanation
Fig. 1 is traditional oral product metabolic chart schematic diagram in animal body;
Fig. 2 is drop pill of the present invention metabolic chart schematic diagram in animal body;
Fig. 3 is conventional tablet Dissolution profiles schematic diagram;
Fig. 4 is drop pill Dissolution profiles schematic diagram prepared by the embodiment of the present invention 1.
Detailed description of the invention
Below in conjunction with drawings and Examples, the present invention is further illustrated, but limited the present invention never in any form, and any conversion done based on training centre of the present invention or replacement, all belong to protection scope of the present invention.
2-(Alpha-hydroxy amyl group of the present invention) benzoate drop pill, comprise 2-(Alpha-hydroxy amyl group) benzoate, stabilizing agent and the carrier as substrate, 2-(Alpha-hydroxy amyl group) benzoate with solute dissolves in the mixture solution of stabilizing agent and carrier.
Described stabilizing agent and 2-(Alpha-hydroxy amyl group) weight ratio of benzoate is 0.3 ~ 10%:1, described carrier and 2-(Alpha-hydroxy amyl group) weight ratio of benzoate is 0.5 ~ 5:1.
Described 2-(Alpha-hydroxy amyl group) benzoate is compound containing general formula I,
Wherein in general formula I: n=1 or 2, M is the one in potassium, sodium, lithium, calcium, magnesium or zinc.
Described stabilizing agent is stabilizing agent is alkali and/or buffer agent composition; Described alkali be sodium hydroxide, potassium hydroxide, one or more in sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydrogen phosphate; Described buffer agent is one or more in sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, sodium lactate, sodium acetate, ammonium carbonate, sodium propionate, natrium malicum.
Described carrier is water-solubility carrier or lipid-soluble carriers, and described water-solubility carrier is one or more in Polyethylene Glycol PEG, sodium stearate, glycerin gelatine, water, polyoxyethylene monostearate; Described lipid-soluble carriers is one or more in stearic acid, glyceryl monostearate, insect wax, Cera Flava, vegetable oil.
2-(Alpha-hydroxy amyl group of the present invention) preparation method of benzoate drop pill, comprise fused solution preparation, drop pill preparation process, specifically comprise:
Method one:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the water-solubility carrier of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in fat-soluble liquid coolant with the speed of dripping of 35 ~ 45/min under temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, water dropper distance cooling liquid level 6 ~ 7cm, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C;
Method two:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the lipid-soluble carriers of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in Water Soluble Cooling Liquid in temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, the speed of dripping of water dropper with 40 ~ 50/min under cooling liquid level 6 ~ 7cm, Water Soluble Cooling Liquid temperature controls at 16 ~ 20 DEG C, the degree of depth is not less than 100cm, completely to be cooled, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C.
Described fat-soluble liquid coolant is one or more in dimethicone, liquid paraffin, vegetable oil, kerosene.
Described Water Soluble Cooling Liquid is water, ethanol or water-ethanol mixed solution.
The concrete preparation method of drop pill of the present invention is as follows:
(1) method 1: use fat-soluble coolant
1. 2-(Alpha-hydroxy amyl group) benzoate, the preparation of stabilizing agent and carrier fused solution: take 2-(Alpha-hydroxy amyl group by recipe quantity) benzoate powder adds dehydrated alcohol by 1:1, after dissolving below 40 DEG C, obtain lysate, sodium hydrogen phosphate-the sodium hydroxide simultaneously getting recipe quantity adds in the Polyethylene Glycol in 60-65 DEG C of water bath heat preservation of recipe quantity (PEG) liquid, stirring and dissolving is even, then 2-(Alpha-hydroxy amyl group is got) benzoate lysate at the uniform velocity to add in Polyethylene Glycol (PEG) and sodium hydrogen phosphate-caustic lye of soda and to stir 30min mix homogeneously, continue to be statically placed in 60-65 DEG C of water-bath and be incubated 30min, till ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
2. the preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, stabilizing agent and Polyethylene Glycol (PEG) mix fused solution and proceed in the surge drum of pill dripping machine, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 6-7cm, fast by 40 droplets/minute drip, instill dropwise in dimethicone liquid coolant, coolant temperature controls between 10-15 DEG C, the height of liquid coolant is not less than 100cm, completely to be cooled, to incline dimethicone liquid coolant, collect drop pill, drop is clean and remove the liquid coolant on ball with filter paper, being positioned over temperature to be no more than in the drying baker of 40 DEG C after dry 24h, obtain.
(2) method 2: use water solublity coolant
1. 2-(Alpha-hydroxy amyl group) benzoate, the preparation of stabilizing agent and carrier fused solution: take 2-(Alpha-hydroxy amyl group by recipe quantity) benzoate powder adds dehydrated alcohol by 1:1, dissolve below 40 DEG C, sodium hydrogen phosphate-the sodium hydroxide simultaneously getting recipe quantity adds anhydrous alcohol solution by 1:1, what first sodium hydrogen phosphate-sodium hydroxide lysate uniform velocity to be added recipe quantity stirs 30min mix homogeneously in the glyceryl monostearate liquid of 60-65 DEG C of water bath heat preservation, then 2-(Alpha-hydroxy amyl group is got) benzoate lysate to be at the uniform velocity incorporated in the glyceryl monostearate liquid of 60-65 DEG C of water bath heat preservation and to stir 30min mix homogeneously, continue to be statically placed in 60-65 DEG C of water-bath and be incubated 30min, and to ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
2. the preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, stabilizing agent and glyceryl monostearate mix fused solution and proceed in the surge drum of pill dripping machine, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 4-6cm, fast by 45 droplets/minute drip, instill dropwise in water coolant, coolant-temperature gage controls between 16-20 DEG C, the height of water liquid is not less than 100cm, completely to be cooled, incline the solution that anhydrates, collect drop pill, drop is clean and remove the aqueous solution on ball with filter paper, laying temperature to be no more than in the exsiccator of 40 DEG C after dry 24h, obtain.
Embodiment 1
1, prescription:
2-(Alpha-hydroxy amyl group) Potassium Benzoate (PHPB) raw material: 100g
PEG6000 ：300g
Sodium hydrogen phosphate-sodium hydroxide: 1g
Dehydrated alcohol: 100ml
Dimethicone: appropriate
2, preparation process:
(1) 2-(Alpha-hydroxy amyl group) benzoate, the preparation of sodium hydrogen phosphate-sodium hydroxide and PEG6000 fused solution: take 2-(Alpha-hydroxy amyl group) benzoate powder and dehydrated alcohol, after dissolving under less than 40 DEG C water bath heat preservations, obtain lysate, get sodium hydrogen phosphate-sodium hydroxide to be incorporated in Polyethylene Glycol (PEG) 6000 fused solution of 60 DEG C of water bath heat preservations and to be uniformly mixed 30min simultaneously, then 2-(Alpha-hydroxy amyl group is got) benzoate powder and anhydrous alcohol solution liquid at the uniform velocity to add in Polyethylene Glycol (PEG) liquid and to be uniformly mixed 30min, till ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
(2) preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, sodium hydrogen phosphate-sodium hydroxide and Polyethylene Glycol (PEG) 6000 mix fused solution and proceed to fast in the surge drum of pill dripping machine, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 6-7cm, fast by 40 droplets/minute drip, instill dropwise in dimethicone liquid coolant, coolant temperature controls between 10 ~ 15 DEG C, height must not lower than 100cm, completely to be condensed, to incline dimethicone liquid coolant, collect drop pill, drop is clean and remove the liquid coolant on ball with filter paper, be positioned over temperature for being no more than in 30 DEG C of exsiccators after dry 24h, obtain.
(3) points for attention
1. the bubble in fused solution must eliminate, and drop pill just can be made to be high degree of dispersion state and smooth-shaped;
2. pill dripping machine surge drum heat-insulation bathing is used for controlling the viscosity of fused solution in surge drum, and Ying Yineng oozes smoothly as degree, drips a fast using valves and controls;
3. the height of condensed fluid, drip all can affect the profile of drop pill from the distance of condensed fluid and the temperature of ice bath, adhesion degree and hangover etc., should with rounding degree of being.
Embodiment 2
1, prescription:
2-(Alpha-hydroxy amyl group) Potassium Benzoate (PHPB) raw material: 100g
Glyceryl monostearate: 300g
Sodium hydrogen phosphate-sodium hydroxide: 1g
Dehydrated alcohol: 100ml
Water: appropriate
2, preparation process:
(1) 2-(Alpha-hydroxy amyl group) benzoate, the preparation of sodium hydrogen phosphate-sodium hydroxide and glyceryl monostearate fused solution: take 2-(Alpha-hydroxy amyl group) benzoate powder adds dehydrated alcohol, less than 40 DEG C dissolvings, sodium hydrogen phosphate-the sodium hydroxide simultaneously getting recipe quantity adds anhydrous alcohol solution by 1:1, first sodium hydrogen phosphate-sodium hydroxide lysate uniform velocity to be incorporated in the glyceryl monostearate liquid of 65 DEG C of water bath heat preservations and to stir 30min mix homogeneously, then 2-(Alpha-hydroxy amyl group is got) benzoate lysate to be at the uniform velocity incorporated in the glyceryl monostearate caustic lye of soda of 65 DEG C of water bath heat preservations and to stir 30min mix homogeneously, and to ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
(2) preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, the fused solution that sodium hydrogen phosphate-sodium hydroxide and glyceryl monostearate mix proceeds in the surge drum of pill dripping machine fast, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 4-6cm, fast by 45 droplets/minute drip, instill dropwise in water coolant, coolant-temperature gage controls between 16-20 DEG C, water liquid height must not lower than 100cm, completely to be condensed, incline the solution that anhydrates, collect drop pill, drop is clean and remove the aqueous solution on ball with filter paper, being positioned over temperature to be no more than in 30 DEG C of drying baker after dry 24h, obtain.
(3) points for attention
1. the bubble in fused solution must eliminate, and drop pill just can be made to be high degree of dispersion state and smooth-shaped;
2. pill dripping machine surge drum heat-insulation bathing is used for controlling the viscosity of fused solution in surge drum, and Ying Yineng oozes smoothly as degree, drips a fast using valves and controls;
3. the height of condensed fluid, drip all can affect the profile of drop pill from the distance of condensed fluid and the temperature of ice bath, adhesion degree and hangover etc., should with rounding degree of being.
Embodiment 3
1, prescription:
2-(Alpha-hydroxy amyl group) Potassium Benzoate (PHPB) raw material: 100g
PEG6000 ：300g
Sodium hydrogen phosphate-sodium hydroxide: 1g
Dehydrated alcohol: 100ml
Liquid paraffin: appropriate
2, preparation process:
(1) 2-(Alpha-hydroxy amyl group) benzoate, the preparation of sodium hydrogen phosphate-sodium hydroxide and PEG6000 fused solution: take 2-(Alpha-hydroxy amyl group) benzoate powder and dehydrated alcohol, after dissolving under less than 40 DEG C water bath heat preservations, obtain lysate, get sodium hydrogen phosphate-sodium hydroxide to be incorporated in Polyethylene Glycol (PEG) 6000 fused solution of 60 DEG C of water bath heat preservations and to be uniformly mixed 30min simultaneously, then 2-(Alpha-hydroxy amyl group is got) benzoate powder and anhydrous alcohol solution liquid at the uniform velocity to add in Polyethylene Glycol (PEG) liquid and to be uniformly mixed 30min, till ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
(2) preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, sodium hydrogen phosphate-sodium hydroxide and Polyethylene Glycol (PEG) 6000 mix fused solution and proceed to fast in the surge drum of pill dripping machine, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 6-7cm, fast by 40 droplets/minute drip, instill dropwise in liquid paraffin liquid coolant, coolant temperature controls between 10 ~ 15 DEG C, height must not lower than 100cm, completely to be condensed, to incline liquid paraffin liquid coolant, collect drop pill, drop is clean and remove the liquid coolant on ball with filter paper, be positioned over temperature for being no more than in 30 DEG C of exsiccators after dry 24h, obtain.
(3) points for attention
1. the bubble in fused solution must eliminate, and drop pill just can be made to be high degree of dispersion state and smooth-shaped;
2. pill dripping machine surge drum heat-insulation bathing is used for controlling the viscosity of fused solution in surge drum, and Ying Yineng oozes smoothly as degree, drips a fast using valves and controls;
3. the height of condensed fluid, drip all can affect the profile of drop pill from the distance of condensed fluid and the temperature of water-bath, adhesion degree and hangover etc., should with rounding degree of being.
Embodiment 4
1, prescription:
2-(Alpha-hydroxy amyl group) Potassium Benzoate (PHPB) raw material: 100g
PEG4000 ：300g
Sodium hydrogen phosphate-sodium hydroxide: 1g
Dehydrated alcohol: 100ml
Dimethicone: appropriate
2, preparation process:
(1) 2-(Alpha-hydroxy amyl group) benzoate, the preparation of sodium hydrogen phosphate-sodium hydroxide and PEG4000 fused solution: take 2-(Alpha-hydroxy amyl group) benzoate powder and dehydrated alcohol, after dissolving under less than 40 DEG C water bath heat preservations, obtain lysate, get sodium hydrogen phosphate-sodium hydroxide to be incorporated in Polyethylene Glycol (PEG) 4000 fused solution of 60 DEG C of water bath heat preservations and to be uniformly mixed 30min simultaneously, then 2-(Alpha-hydroxy amyl group is got) benzoate powder and anhydrous alcohol solution liquid at the uniform velocity to add in Polyethylene Glycol (PEG) liquid and to be uniformly mixed 30min, till ethanol is waved to the greatest extent, treat that bubble eliminates, for subsequent use.
(2) preparation of drop pill: by the above-mentioned 2-(Alpha-hydroxy amyl group eliminating bubble) benzoate, sodium hydrogen phosphate-sodium hydroxide and Polyethylene Glycol (PEG) 6000 mix fused solution and proceed to fast in the surge drum of pill dripping machine, under the condition of insulation 80 ~ 85 DEG C, water dropper internal diameter controls at 1-2mm, the Altitude control of water dropper distance liquid coolant is at 6-7cm, fast by 40 droplets/minute drip, instill dropwise in dimethicone liquid coolant, coolant temperature controls between 10 ~ 15 DEG C, height must not lower than 100cm, completely to be condensed, to incline dimethicone liquid coolant, collect drop pill, drop is clean and remove the liquid coolant on ball with filter paper, be positioned over temperature for being no more than in 30 DEG C of exsiccators after dry 24h, obtain.
(3) points for attention
1. the bubble in fused solution must eliminate, and drop pill just can be made to be high degree of dispersion state and smooth-shaped;
2. pill dripping machine surge drum heat-insulation bathing is used for controlling the viscosity of fused solution in surge drum, and Ying Yineng oozes smoothly as degree, drips a fast using valves and controls;
3. the height of condensed fluid, drip all can affect the profile of drop pill from the distance of condensed fluid and the temperature of ice bath, adhesion degree and hangover etc., should with rounding degree of being.
Embodiment 5
The Contrast on effect (see Fig. 3, Fig. 4) of conventional tablet and the made drop pill of embodiment 1;
As can be seen from both Dissolution profiles, the dissolution of drop pill is obviously better than conventional tablet, proves that its onset time and action intensity are all better than conventional tablet.
Embodiment 6
Conventional tablet respectively with the Contrast on effect of the made drop pill of embodiment 2,3,4, all show, the dissolution of drop pill is obviously better than conventional tablet, proves that its onset time and action intensity are all better than conventional tablet.
Can find out that drop pill no significant difference on dissolution that different preparation method and adjuvant are made illustrates its onset time and action intensity no significant difference simultaneously.
Claims (8)
1. a 2-(Alpha-hydroxy amyl group) benzoate drop pill, it is characterized in that comprising 2-(Alpha-hydroxy amyl group) benzoate, stabilizing agent and the carrier as substrate, 2-(Alpha-hydroxy amyl group) benzoate with solute dissolves in the mixture solution of stabilizing agent and carrier.
2. 2-(Alpha-hydroxy amyl group according to claim 1) benzoate drop pill, it is characterized in that described stabilizing agent and 2-(Alpha-hydroxy amyl group) weight ratio of benzoate is 0.3 ~ 10%:1, described carrier and 2-(Alpha-hydroxy amyl group) weight ratio of benzoate is 0.5 ~ 5:1.
3. 2-(Alpha-hydroxy amyl group according to claim 1 and 2) benzoate drop pill, it is characterized in that described 2-(Alpha-hydroxy amyl group) benzoate is compound containing general formula I,
Wherein in general formula I: n=1 or 2, M is the one in potassium, sodium, lithium, calcium, magnesium or zinc.
4. 2-(Alpha-hydroxy amyl group according to claim 1 and 2) benzoate drop pill, it is characterized in that described stabilizing agent is alkali and/or buffer agent composition; Described alkali be sodium hydroxide, potassium hydroxide, one or more in sodium carbonate, sodium bicarbonate, potassium carbonate, sodium hydrogen phosphate; Described buffer agent is one or more in sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium citrate, sodium lactate, sodium acetate, ammonium carbonate, sodium propionate, natrium malicum.
5. 2-(Alpha-hydroxy amyl group according to claim 1 and 2) benzoate drop pill, it is characterized in that described carrier is water-solubility carrier or lipid-soluble carriers, described water-solubility carrier is one or more in Polyethylene Glycol PEG, sodium stearate, glycerin gelatine, water, polyoxyethylene monostearate; Described lipid-soluble carriers is one or more in stearic acid, glyceryl monostearate, insect wax, Cera Flava, vegetable oil.
6. the arbitrary described 2-(Alpha-hydroxy amyl group of claim 1 ~ 5) preparation method of benzoate drop pill, it is characterized in that comprising fused solution preparation, drop pill preparation process, specifically comprise:
Method one:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the water-solubility carrier of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in fat-soluble liquid coolant with the speed of dripping of 35 ~ 45/min under temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, water dropper distance cooling liquid level 6 ~ 7cm, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C;
Method two:
Prepared by A, fused solution:
1) 2-(Alpha-hydroxy amyl group is taken by formulation ratio) benzoate powder, add the dehydrated alcohol of solid-liquid volume ratio 1:1 ~ 2, obtain 2-(Alpha-hydroxy amyl group in less than 40 DEG C dissolvings) benzoate lysate;
2) joined by the stabilizing agent of formulation ratio in the lipid-soluble carriers of 60 ~ 65 DEG C of water bath heat preservations, stirring and dissolving evenly obtains the mixture solution of stabilizing agent and carrier;
3) by 1) in the 2-(Alpha-hydroxy amyl group that obtains) benzoate lysate at the uniform velocity joins 2) and in the stabilizing agent that obtains and carrier mixture solution in, stir 20 ~ 40min mix homogeneously, continue to be statically placed in 60 ~ 65 DEG C of water-baths and be incubated 20 ~ 40min and wave to the greatest extent to ethanol, bubble eliminates that to obtain fused solution for subsequent use;
Prepared by B, drop pill: fused solution step A prepared proceeds to pill dripping machine, instill in Water Soluble Cooling Liquid in temperature 80 ~ 85 DEG C, water dropper internal diameter 1 ~ 2mm, the speed of dripping of water dropper with 40 ~ 50/min under cooling liquid level 6 ~ 7cm, Water Soluble Cooling Liquid temperature controls at 16 ~ 20 DEG C, the degree of depth is not less than 100cm, completely to be cooled, collection drop pill is positioned over temperature and obtains object lower than 22 ~ 26h dry in the drying baker of 40 DEG C.
7. preparation method according to claim 6, is characterized in that described fat-soluble liquid coolant is one or more in dimethicone, liquid paraffin, vegetable oil, kerosene.
8. preparation method according to claim 6, is characterized in that described Water Soluble Cooling Liquid is water, ethanol or water-ethanol mixed solution.
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| CN201410819269.2A Pending CN104510721A (en) | 2014-12-25 | 2014-12-25 | 2-(alpha-hydroxypentyl) benzoate dropping pill and preparation method thereof |
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| CN (1) | CN104510721A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN1943571A (en) * | 2005-12-24 | 2007-04-11 | 石药集团中奇制药技术（石家庄）有限公司 | Butylphthalide dripping pill and preparing method |
| CN103127025A (en) * | 2013-03-06 | 2013-06-05 | 石家庄鸯星科技有限公司 | Racemic 2-(alpha-hydroxyl amyl) benzoate tablets and preparation method thereof |
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2014
- 2014-12-25 CN CN201410819269.2A patent/CN104510721A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1382682A (en) * | 2002-05-09 | 2002-12-04 | 中国医学科学院药物研究所 | 2-(alpha-hydroxypentyl) benzoate and its preparing process and usage |
| CN1943571A (en) * | 2005-12-24 | 2007-04-11 | 石药集团中奇制药技术（石家庄）有限公司 | Butylphthalide dripping pill and preparing method |
| CN103127025A (en) * | 2013-03-06 | 2013-06-05 | 石家庄鸯星科技有限公司 | Racemic 2-(alpha-hydroxyl amyl) benzoate tablets and preparation method thereof |
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Application publication date: 20150415 |