CN103893130A - Domperidone particles, domperidone preparation and preparation method thereof - Google Patents
Domperidone particles, domperidone preparation and preparation method thereof Download PDFInfo
- Publication number
- CN103893130A CN103893130A CN201210589736.8A CN201210589736A CN103893130A CN 103893130 A CN103893130 A CN 103893130A CN 201210589736 A CN201210589736 A CN 201210589736A CN 103893130 A CN103893130 A CN 103893130A
- Authority
- CN
- China
- Prior art keywords
- domperidone
- preparation
- acid
- microgranule
- grams
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Abstract
The invention discloses a preparation method of domperidone particles. The method comprises the following steps: dispersing domperidone and dispersion aids into a solvent; adding an acid to dissolve to obtain a solution I; adding an alkali liquor to the solution I under an agitation condition, so as to obtain a mixture containing the domperidone particles; separating the domperidone particles, wherein the mean grain size of the obtained particles is smaller than 20mum, the particles have the specific surface area equivalent to over twice of those of common domperidone particles and are high in dissolution rate. The invention also discloses a preparation method of the preparation containing the domperidone particles. The method for preparing the domperidone particles is simple and convenient to operate, free of harsh process condition and equipment, low in cost and easy for realization of industrial production.
Description
Technical field
The present invention relates to a kind of preparation method of domperidone microgranule, a kind of preparation method of domperidone preparation, and a kind of domperidone microgranule and containing its domperidone preparation.
Background technology
Domperidone, is a kind of anti-Dopaminergics medicine, optionally blocks periphery dopamine, directly acts on gastrointestinal wall, can increase lower esophagus sphincter tone, strengthens gastric peristalsis, promotes gastric emptying, coordinates stomach and uodenal movement.Clinically generally in order to alleviate the indigestion symptom by gastric emptying, gastrointestinal tract instead flow, esophagitis causes, as: the anti-stomach burn feeling of flowing gastric content of with or without in the sense of epigastrium feeling of distension and oppression, abdominal distention, Upper abdominal pain, belch, flatulence, mouth, treat that functional, organic, infectious, Diet, radiation treatment or chemotherapy are causedly felt sick, vomiting, sometimes also for promoting galactopoiesis.
Domperidone chemical name is the chloro-1[1-[3-of 5-(2-oxygen-1-benzimidazoline base) propyl group]-4-piperidyl]-2-Benzimidazolinone, it is a kind of insoluble medicine, while being made oral formulations as tablet, its dissolution has larger impact to bioavailability.
According to Noyes-Whitney equation, improving drug dissolution comparison effective method is to improve its specific surface area.Generally, the method for increase specific surface area is to reduce its particle diameter.The conventional method that reduces drug particles particle diameter mainly contains low-temperature airflow comminuting method, ball-milling method, solid dispersion method etc.Comminution by gas stream is medicine to be placed in to low-temperature airflow super micron mill pulverize, and ball-milling method is that medicine is mixed with some hydrophilicity condiments respectively, then at grinding in ball grinder certain hour, can obtain the powder body of suitable particle size.Solid dispersion method is that as PVP K30 is dissolved in appropriate organic solvent, solvent removed by evaporation at reduced pressure, obtains coprecipitate, obtains solid dispersion after sieving by medicine and certain carrier material.First two method generally exists that energy consumption is large, efficiency is low, Granularity Distribution is wide, easily make the structural deterioration of thermally labile medicine and degraded, in crushing process due to dust from flying the shortcoming such as contaminated environment.Though and solid dispersion method improves the result of extraction of medicine to a certain extent, operating process is more complicated, cost is higher.
There is patent to disclose the method that improves domperidone dissolution.Wherein Chinese patent CN03119042.1 (" a kind of domperidone oral disintegrating tablet formulation and method for making thereof ") adopts and in prescription, directly adds disintegrating agent to reach the effect of rapid disintegrate.The method can improve dissolution and the bioavailability of domperidone, but is not fundamentally solving the difficult problem that domperidone bioavailability is low.The mode of colloid mill that adopted Chinese patent CN102113997A (" a kind of Domperidone suspension and preparation method thereof ") reduces the particle diameter of medicine, to reach the effect that improves dissolubility.The main defect of the method is owing to turning stator and storeroom high-speed friction in operating process, therefore easily produce larger heat and noise, another one defect is that pulverizing initial stage medical surfaces is more easy to wear, and after wearing and tearing, crushing effect can significantly decline and make the dissolution of medicine improve limited.Therefore, need a kind of operation easier, safe, and can guarantee the domperidone microgranule of the various function admirables of product and the preparation method of preparation.
Summary of the invention
Technical problem to be solved by this invention is the various defects that reduce at present diameter of aspirin particle method in order to overcome, and provide a kind of mean diameter to be less than 20 microns, pollute and the preparation method of loss domperidone microgranule little, safe, easy and simple to handle, and the preparation method that contains domperidone microgranule, pharmaceutical preparation that dissolution is good.
In order to improve the dissolution of domperidone.According to Noyes-Whitney equation, improving drug dissolution comparison effective method is to improve its specific surface area.Generally, the method for increase specific surface area is to reduce its particle diameter.For overcoming the shortcoming of the method that reduces at present drug particles particle diameter, the domperidone microgranule that a kind of mean diameter is little is provided, and the preparation method safe, easy and simple to handle, cost is low, the inventor looks for another way, and adopts the method for directly controlling diameter of aspirin particle and dispersion in recrystallization process.Recrystallization method is the very important method of one that reduces diameter of aspirin particle, its basic ideas are: first medicine is dissolved in the good solvent that a kind of dissolubility is good, form certain density drug solution, then under the condition stirring, to the poor solvent that adds another kind of medicine in this drug solution, so medicine will be from the mixed solution of good solvent and poor solvent crystallization, by the condition of crystallization control process, can obtain the drug microparticles of required size and degree of scatter.This method is simple, and energy consumption is low, reduced production cost low.Both avoided comminution by gas stream and ball-milling method efficiency low, the shortcoming of contaminated environment, has improved again solid dispersion method operating process complexity, the shortcoming that cost is high.
The inventor is being prepared in the correlational study of domperidone microgranule, be surprised to find and first domperidone be dissolved in containing in sour solvent, form certain density drug solution, then under the condition stirring, add alkali liquor, can separate and obtain domperidone microgranule.Further research has again new surprised discovery: before adding alkali liquor, first add dispersion aids can more be conducive to the dispersion of microgranule, prepared microgranule not only particle diameter is little, and simultaneously because crystal habit changes, specific surface area significantly increases.The specific surface area of gained microgranule is the more than 2 times of the suitable microgranule of Ordinary pulverization method gained particle diameter, and solubility property also significantly improves.Further research is found again: contain domperidone microgranule that the present invention makes or the preparation of particle mixture, have good dissolving out capability; By designing various technique and formula, can make all kinds of domperidone pharmaceutical preparatioies that have good quality.
Concrete, the present invention relates to following technical proposals:
The present invention relates to a kind of domperidone microgranule, it is characterized in that: average volume particle diameter is less than 20 μ m, and BET specific surface area is at least 4.0m
2/ g, has 2 times of above specific surface areas of the common domperidone microgranule of suitable particle diameter.Its preparation method comprises the steps: that (1) is scattered in domperidone and dispersion aids in solvent, and acid adding, to dissolving, obtains solution I; (2) under stirring condition, in solution I, add alkali liquor, obtain the mixture that contains domperidone microgranule; (3) separate domperidone microgranule.
According to this area general knowledge, the acid described in the present invention should be pharmaceutically acceptable, and with the compatible reagent of domperidone.In the present invention, described compatibility refers to and can coexist, has no adverse effects.Described acid can be single acid, also can be the Compound-acid that two or more one-tenth is grouped into, described acid is one or more in hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, nitric acid, hydrobromic acid, maleic acid, citric acid, methanesulfonic acid, tartaric acid, lactic acid, formic acid, malic acid, fumaric acid, succinic acid, salicylic acid, benzoic acid, ethanedioic acid.Preferably acid is one or more in hydrochloric acid, phosphoric acid, acetic acid, maleic acid, tartaric acid, citric acid.The consumption of described acidulant is to make 1～1.2 times of the consoluet minimum of domperidone, is preferably 1～1.05 times.In the time being hydrochloric acid, the molar ratio of hydrochloric acid and domperidone is 0.9～1.3, is preferably 1.0～1.1.
Solvent described in the present invention is the mixed liquor of organic solvent or water and organic solvent, the described organic solvent principle that the dissolubility to domperidone is better than water according to it is selected in the acceptable solvent in medicament field, be preferably can be miscible with water organic solvent, water-soluble alcohol kind solvent as conventional in medicament field, as one or more in ethanol, propylene glycol, glycerol, ethylene glycol, isopropyl alcohol and benzyl alcohol, preferred alcohol.In the mixed liquor of water and organic solvent, the consumption of organic solvent can be selected arbitrarily, more than 40% concentration of preferred mass percentage ratio, more preferably more than 70% concentration.Use when ethanol water, the concentration of ethanol is preferably mass percent more than 40%, is more preferred from more than 70%.The amount of described solvent, at least can make domperidone dissolve completely, is generally the more than 2 times of domperidone quality, is preferably 4～6 times.
In order to be more conducive to the dispersion of microgranule, can before adding alkali, first add dispersion aids, as one or more in surfactant, solubilizing agent and water-solubility carrier etc.Dispersion aids also can add before adding acid.The dispersion aids that the present invention adopts is selected from one or more in polyvidone, poloxamer, watermiscible vitamin E, Polyethylene Glycol, tween, polyoxyethylene castor oil, sucrose ester and s6.Described dispersion aids is 0.01～5 times of domperidone quality, is preferably 0.5～3 times.Add dispersion aids by aforesaid operations, can increase the dissolubility of domperidone in solution, reduce solvent load, be beneficial to the operation of subsequent step.It will be further appreciated that, add one or more in dispersion aids by aforesaid operations, it is better that especially water-solubility carrier can make the dissolution characteristic of gained domperidone preparation.
Preferably, in the time preparing pastille acid solution, can also be by heating (as adopted the mode of hot bath), the temperature that suitably raises, is beneficial to the dissolving of domperidone, generally can be warming up to 30 ℃～85 ℃.In the time using ethanol water, be preferably warming up to 30 ℃～70 ℃, be more preferably 40～60 ℃.
In the present invention, described alkali refers to the reagent that can make containing the acidity reduction of drug solns, for example inorganic strong alkali (as sodium hydroxide or potassium hydroxide), weak acid strong alkali salt is (as inorganic weak acid highly basic salt, as sodium carbonate, potassium carbonate and sodium hydrogen phosphate), organic base (as meglumine, ethylenediamine, arginine, lysine).Described alkali can be single alkali, also can be the compound alkali that two or more one-tenth is grouped into, most preferably sodium hydroxide or sodium carbonate.According to this area general knowledge, it is pharmaceutically acceptable that described basifier all should be, and with the compatible reagent of domperidone.The amount of described alkali is the amount that at least can make containing the acidity reduction of drug solns.In order to prevent that described alkali from adding local violent raising of pH value that causes system after system, described alkali preferably adds with the form of solution as sodium hydroxide, and described alkali adds with the form of solution or after being uniformly distributed in other adjuvants as sodium carbonate.The described concentration containing alkali in the solution of alkali is preferably 1～20wt%.Described solution is preferably aqueous solution.
In the present invention, the pH separating out by control drug precipitation can make medicine fully separate out.PH value when described medicine is separated out is 6.0～12, and preferred pH value is 6.5～8.0.In the present invention, wait microgranule to form after precipitation, can also under agitation add again water or 10～60wt% ethanol water.In the present invention, described in add the consumption of water or 10～60wt% ethanol water without specific (special) requirements.After this step, before point isolated domperidone microgranule, can carry out dispersion treatment to the mixed liquor of this step with colloid mill or homogenizer as required, further to reduce the particle diameter of microgranule, increase the specific surface area of microgranule.
In the present invention, the strick precaution of described point isolated domperidone microgranule can separate by this area conventional method, is generally sucking filtration, washing sucking filtration, dry.Described washing can water or 10～70wt% ethanol water carry out, the amount of each water or 10～70wt% ethanol water is preferably 1～5 times of domperidone quality.The number of times of washing sucking filtration is generally 1～3 time.Described being dried can adopt the drying means of this area routine to carry out, as dry in static state or dynamically dry.Wherein, described static state is dry as (preferably 50～70 ℃) drying under reduced pressure 2～8 hours (preferably 5～6 hours) at 40～100 ℃, and vacuum condition when decompression is preferably 450mmHg～76mmHg, is more preferably 150mmHg.Described is dynamically dry as at 50～80 ℃ (preferably 60～70 ℃), is dried 2～6 hours (preferably 3～5 hours) in bipyramid vacuum drying mixer.
In the present invention, the speed of described stirring, so that system mix homogeneously is as the criterion, is preferably 150～500 ms/min of agitator linear velocities.
The invention still further relates to a kind of domperidone preparation compositions and preparation method, it comprises the steps: that (1) adopts said method preparation to separate out domperidone microgranule; (2), by domperidone separation of particles or directly particle mixture is mixed with adjuvant, prepare domperidone suspensoid, dry suspension, powder, granule, tablet or capsule.
Prepare domperidone microgranule or particle mixture by the method described in the present invention; and acceptable adjuvant pharmaceutically; described domperidone microgranule or the consumption of particle mixture (take domperidone dry) are 0.01～10% of the quality of the pharmaceutical preparations, and described pharmaceutically acceptable accessory package contains one or more in suspending agent, flocculating agent, wetting agent, filler, disintegrating agent, binding agent, lubricant.
While preparing suspensoid, dry suspension, comprise that described pharmaceutically acceptable accessory package is containing suspending agent, flocculating agent, wetting agent.Described suspending agent is preferably one or more in glycerol, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, xanthan gum; Described wetting agent is preferably one or more in glycerol, Tween 80, poloxamer, sucrose ester; Described flocculating agent is preferably one or more in sodium citrate, sodium tartrate.The preparation method of described preparation is for being undertaken by the conventional dispersion method in this area, by domperidone microgranule with adjuvant dry mixed is evenly prepared dry suspension or further adopt aqueous dispersion to prepare suspensoid again.
Prepare solid preparation, during as granule, tablet or capsule, comprise that described pharmaceutically acceptable accessory package contains one or more in filler, disintegrating agent, binding agent, lubricant.
When preparation method is wet granulation, described adjuvant comprises filler, disintegrating agent, binding agent and lubricant; Described filler is preferably one or more in lactose, Lactis Anhydrous, mannitol, particle cellulose, starch, xylitol, pregelatinized Starch and maltose alcohol; Described disintegrating agent is preferably one or more in carboxymethyl starch sodium, hyprolose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose; Described binding agent is preferably one or more in water or the alcoholic solution of aqueous solution, polyvinylpyrrolidone of starch slurry, hydroxypropyl methylcellulose; Described lubricant is preferably one or more in colloidal silica, sodium stearyl fumarate, Pulvis Talci and magnesium stearate; The consumption sum of described filler and described water-solubility carrier is 70～95% of described preparation content quality, is preferably 80～90%; The consumption of described disintegrating agent is preferably 2～8% of described Capsule content quality; The consumption of described lubricant is preferably 0.5～4% of described Capsule content quality.
While adopting vertical compression technique to carry out the preparation of domperidone tablet, described adjuvant comprises vertical compression adjuvant, disintegrating agent and lubricant; Described vertical compression adjuvant is preferably one or more in vertical compression lactose, vertical compression mannitol, vertical compression particle cellulose and vertical compression complex; Described disintegrating agent is preferably one or more in carboxymethyl starch sodium, hyprolose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose; Described lubricant is preferably one or more in colloidal silica, sodium stearyl fumarate, Pulvis Talci and magnesium stearate; Described vertical compression adjuvant and the consumption sum of described water-solubility carrier are tablet quality 80～98%, are preferably 90～95%; The consumption of described disintegrating agent is 2～5% of tablet quality, and the consumption of described lubricant is tablet quality 0.5～3%.
The present invention relates to a kind of domperidone microgranule, particle diameter is less than 20 μ m, and specific surface area is at least 4.0m
2/ g, has 2 times of above specific surface areas of the common domperidone microgranule of suitable particle diameter, and prepares the preparation method of this domperidone microgranule.
Also further relate to the Aripiprazole solid preparation and the liquid preparation that contain domperidone microgranule of the present invention, solid preparation comprises powder, granule, Tablet and Capsula agent, and liquid preparation comprises suspensoid, dry suspension.
In the present invention, above-mentioned each optimum condition, can be on the basis that meets this area general knowledge combination in any, get final product to obtain the preferred embodiments of the invention.
In the present invention, agents useful for same and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is:
1, it is easy and simple to handle that the present invention prepares the method for domperidone microgranule, do not need harsh process conditions and equipment, cost is low, be easy to suitability for industrialized production, can make mean diameter (D[4,3]) reach 20 microns of following domperidone microgranules, specific surface area is the more than 2 times of the suitable microgranule of Ordinary pulverization gained particle diameter simultaneously.
2, the domperidone preparation dissolving out capability that the preparation method of solid preparation of the present invention makes is good.
3, preferably in embodiment, provide a kind of mean diameter to be less than 20 microns, specific surface area 5.07m one of the present invention
2the domperidone microgranule of/g, and the microgranule specific surface area 1.44m buying
2/ g.Because the microgranule specific surface area that adopts the art of this patent to make significantly improves, relatively existing domperidone microgranule has better dissolving out capability and bioavailability.
Accompanying drawing explanation
The commercially available microgranule of Fig. 1 and embodiment 1 microgranule dissolution comparison diagram
The domperidone tablet of Fig. 2 different manufacturers and embodiment 11 dissolution comparisons
The X diffraction comparison diagram of Fig. 3 embodiment 1 and commercially available microgranule
The DSC comparison diagram of Fig. 4 embodiment 1 and commercially available microgranule
The SEM comparison diagram of Fig. 5 embodiment and commercially available microgranule.(a) be commercially available microgranule; (b) be embodiment 1 gained microgranule
The specific embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to conventional method and condition, or selects according to catalogue.
In following embodiment, dosage form specification is with domperidone content meter, as 10mg/ sheet, refer to every in containing domperidone 10mg.Consumption unit is gram that percentage ratio is mass percent.
Embodiment 1 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain and 2 grams of PLURONICS F87s add in 60 grams of 70% ethanol waters, and dispersed with stirring, adds 4.7 grams of 20% hydrochloric acid to be stirred to completely and dissolve, and obtains solution I.
(2) under stirring at room temperature (stirring 100 ms/min of linear velocities) condition, adding approximately 11 grams of 10% sodium hydrate aqueous solution to pH value is 7.3, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, the microgranule that sucking filtration is separated out, again respectively with 10 grams of water washings 2 times and difference sucking filtration, 60 ℃ of drying under reduced pressure obtain 9.31 grams of domperidone microgranules, yield 93.1%, content 99.1% after 4 hours.
Embodiment 2 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain and 3 grams of Tween 80s add in 50 grams of 80% ethanol waters, and dispersed with stirring, adds 4.7 grams of 20% hydrochloric acid to be stirred to completely and dissolve, and obtains solution I.
(2) under stirring at room temperature (stirring 100 ms/min of linear velocities) condition, adding approximately 10.5 grams of 10% sodium hydrate aqueous solution to pH value is 6.8, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, the microgranule that sucking filtration is separated out, again respectively with 10 grams of water washings 2 times and difference sucking filtration, 60 ℃ of constant pressure and dries obtain 9.06 grams of domperidone microgranules, yield 90.6%, content 98.9% after 6 hours.
Embodiment 3 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain adds in 60 grams of 50% ethanol waters, and dispersed with stirring, adds 4.7 grams of stirrings of 20% hydrochloric acid, and 50 ℃ are warmed to completely and dissolve, and add 2 grams of PLURONICS F87s to dissolve, and obtain solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 11 grams of 10% sodium hydrate aqueous solution to pH value is 7.0, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, setting high fast dispersing emulsification machine 10000 turns and makes a call to after 10 minutes, the microgranule that sucking filtration is separated out, more respectively with 10 grams of water washings 2 times and difference sucking filtration, 50 ℃ of constant pressure and dries obtain 9.12 grams of domperidone microgranules after 7 hours, yield 91.2%, content 99.3%.
(1) 1 gram of watermiscible vitamin E and 1 gram of citric acid one water thing are dissolved in 50 gram of 60% ethanol water, add 10 grams of domperidone coarse-grain dispersed with stirring, add 3.5 grams of 20% hydrochloric acid to stir 45 ℃ and are warmed to dissolving completely, obtain solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 21 grams of 5% sodium hydrate aqueous solution to pH value is 6.7, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, the microgranule that sucking filtration is separated out, again respectively with 10 grams of water washings 2 times and difference sucking filtration, 60 ℃ of drying under reduced pressure obtain 9.24 grams of domperidone microgranules, yield 92.4%, content 98.8% after 4 hours.
Embodiment 5 prepares domperidone microgranule
(1) 10 gram of PVP K30,3.5 grams of DL-malic acids and 10 grams of domperidone coarse-grain stirring and dissolving, in 50 gram of 70% ethanol water, obtain solution I.
(2) under stirring (stirring 80 ms/min of linear velocities) condition, add approximately 18 grams of 20% wet chemicals, to pH value be 7.2, continue to stir 5 minutes, add 40 grams of water to stir again 5 minutes, the crystallization that sucking filtration is separated out, more respectively with 10 grams of water washings 2 times and difference sucking filtration, 60 ℃ of drying under reduced pressure obtain 9.12 grams of domperidone microgranules after 4 hours, yield 91.2%, content 99.4%.
Embodiment 6 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain adds in 60 grams of 70% ethanol waters, and dispersed with stirring, adds gram stirring of 10% phosphatase 79, and 50 ℃ are warmed to completely and dissolve, and add 2 grams of polyethylene glycol 6000s to dissolve, and obtain solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 11 grams of 10% sodium hydrate aqueous solution to pH value is 7.0, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, setting high fast dispersing emulsification machine 10000 turns and makes a call to after 10 minutes, the microgranule that sucking filtration is separated out, more respectively with 10 grams of water washings 2 times and difference sucking filtration, 65 ℃ of constant pressure and dries obtain 9.3 grams of domperidone microgranules after 6 hours, yield 93.0%, content 99.7%.
Embodiment 7 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain adds in 60 grams of 65% ethanol waters, and dispersed with stirring, adds 10.8 grams of stirrings of 15% acetic acid, and 50 ℃ are warmed to completely and dissolve, and add 30 grams of PVP K30s to dissolve, and obtain solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 11 grams of 10% potassium hydroxide aqueous solution to pH value is 7.0, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, the microgranule that sucking filtration is separated out, again respectively with 10 gram of 70% washing with alcohol 2 times difference sucking filtration, after lyophilization, obtain 9.14 grams of domperidone microgranules, yield 91.4%, content 99.2%.
Embodiment 8 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain adds in 70 grams of 50% ethanol waters, and dispersed with stirring, adds 25.3 grams of stirring at room temperature of 5% sulphuric acid, adds 6 grams of PVP K30s to dissolve, and obtains solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 11 grams of 10% potassium hydroxide aqueous solution to pH value is 7.0, continue to stir 5 minutes, add 50 grams of water to stir again 5 minutes, the microgranule that sucking filtration is separated out, again respectively with 10 gram of 60% washing with alcohol 2 times difference sucking filtration, after room temperature drying under reduced pressure, obtain 9.08 grams of domperidone microgranules, yield 90.8%, content 99.6%.
Embodiment 9 prepares domperidone microgranule
(1) 10 gram of domperidone coarse-grain adds in 70 grams of 60% ethanol waters, and dispersed with stirring, adds 22.2 grams of stirring at room temperature of 7% nitric acid, adds 20 grams of PVP K30s to dissolve, and obtains solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 15.7 grams of 7% potassium hydroxide aqueous solution to pH value is 6.8, continue to stir 15 minutes, the microgranule that sucking filtration is separated out, again respectively with 15 grams of water washings 2 times difference sucking filtration, after room temperature drying under reduced pressure, obtain domperidone microgranule 9.13, yield 91.3 content 98.7%.
(1) 10 gram of domperidone coarse-grain adds in 70 grams of 60% ethanol waters, and dispersed with stirring, adds 14.9 grams of stirring at room temperature of 10% maleic acid, adds 5 grams of PLURONICS F87s to dissolve, and obtains solution I.
(2) under stirring (stirring 100 ms/min of linear velocities) condition, adding approximately 103 grams of 1% potassium hydroxide aqueous solution to pH value is 6.8, continue to stir 30 minutes, the microgranule that sucking filtration is separated out, again respectively with 30 grams of water washings 2 times difference sucking filtration, after room temperature drying under reduced pressure, obtain domperidone microgranule 9.09, yield 90.9%, content 99.0%.
Embodiment 11 prepares domperidone tablet (10mg/ sheet)
(1) 1 gram of PLURONICS F87 and 1 gram of citric acid one water thing are dissolved in 60 gram of 70% ethanol water, add 10 grams of domperidone coarse-grain dispersed with stirring, add 3.5 grams of 20% hydrochloric acid to be stirred to completely and dissolve.Limit is stirred (stir linear velocity 100 ms/min) limit and is added approximately 10.5 grams of 10% sodium hydrate aqueous solutions, to pH value be 6.8, add 3 grams of PVP K30s to stir and make granulation liquid.
(2) 60 grams of lactose, 60 grams of microcrystalline Cellulose, 4 grams of carboxymethylstach sodium are put mix homogeneously in fluidized-bed spray granulation machine; spray into above-mentioned granulation liquid and granulate, after granule granulate, add tabletting after 1 gram of magnesium stearate, 2.5 grams of carboxymethylstach sodium and 0.3 gram of micropowder silica gel mix homogeneously.The content of tablet is 99.7%.
Embodiment 12 prepares domperidone tablet (10mg/ sheet)
Mix homogeneously in Quick-stirring granulator is put in 10 grams of domperidone microgranules (microgranule prepared by embodiment 1 method), 40 grams of mannitol, 30 grams of starch, 10 grams of pregelatinized Starch; add approximately 15 gram of 5% polyvidone aqueous solution to stir granulation; 60 ℃ are dried to moisture and are less than 3%, add tabletting after 0.6 gram of magnesium stearate and 1.5 grams of polyvinylpolypyrrolidone mix homogeneously after granule granulate.。The content of tablet is that the dissolution of 99.2%, 45 minute is 91.7%.
Embodiment 13 prepares domperidone tablet (5mg/ sheet)
5 grams of domperidone microgranules (microgranule prepared by embodiment 1 method), 30 grams of lactose, 30 grams of microcrystalline Cellulose, 3 grams of carboxymethylstach sodium mix homogeneously, add approximately 10 gram of 3% hypromellose aqueous solution to stir and make soft material, extruding is granulated, 60 ℃ are dried to moisture and are less than 3%, add tabletting after 0.5 gram of magnesium stearate, 0.1 gram of micropowder silica gel and 1.5 grams of carboxymethylstach sodium mix homogeneously after granule granulate.The content of tablet is that the dissolution of 98.9%, 45 minute is 90.2%.
Embodiment 14 prepares domperidone suspensoid (1mg/ml)
(1) 5 gram of domperidone coarse-grain and 1 gram of PLURONICS F87 add in 50 grams of 50% aqueous solution of propylene glycol, and 50 ℃ of warm dispersed with stirring, add 2.3 grams of 20% hydrochloric acid to be stirred to completely and dissolve, and obtain solution I.
(2) under stirring at room temperature (stirring 100 ms/min of linear velocities) condition, adding approximately 5.5 grams of 10% sodium hydrate aqueous solution to pH value is 6.8, continue to stir 5 minutes, add 25 grams of sodium carboxymethyl cellulose to be dissolved in the rubber cement that 2500 grams of water make, be uniformly dispersed, add pure water and be uniformly dispersed to 5000ml.
1 gram of domperidone microgranule (microgranule that embodiment 3 methods make), adds 10g glycerol and disperses, and adds 5 grams of sodium carboxymethyl cellulose to be dissolved in the rubber cement that 500 grams of water make, and is uniformly dispersed, and adds pure water and is uniformly dispersed to 1000ml.
Embodiment 16 prepares domperidone dry suspension
1 gram of domperidone microgranule (microgranule that embodiment 3 methods make), add 10 grams of sodium carboxymethyl cellulose, 10 grams of steviosin, 2 grams of sunset yellows, 1 gram of flavoring orange essence, 5 grams of micropowder silica gels, 400 grams of sucrose and fully mix, be sub-packed in aluminum-plastic composite membrane bag by specification.
After 10 grams of domperidone microgranules (microgranule prepared by embodiment 2 methods), 10 grams of carboxymethyl starch sodium, 25 grams of microcrystalline Cellulose mix homogeneously, cross 60 mesh sieves, add 50 grams of lactose, 25 grams of microcrystalline Cellulose, 50 grams of pregelatinized Starch, 0.5 gram of colloidal silica, 1 gram of magnesium stearate mix homogeneously, pack hard capsule into.The content of capsule is that the dissolution of 99.5%, 45 minute is 92.4%.
Embodiment 18 prepares domperidone powder
1 gram of domperidone microgranule (microgranule that embodiment 3 methods make), adds 10 grams of carboxymethyl starch sodium, 10 grams of steviosin, 5 grams of micropowder silica gels, 200 grams of dextrin, 200 grams of cane sugar powders and fully mixes, and is sub-packed in aluminum-plastic composite membrane bag by specification.
Embodiment 19 prepares domperidone granule
1 gram of domperidone microgranule (microgranule that embodiment 4 methods make), 30 grams of dextrin, 200 grams of cane sugar powders, 5 grams of carboxymethyl starch sodium are put mix homogeneously in Quick-stirring granulator; add approximately 30 gram of 10% polyvidone aqueous solution to stir granulation; 60 ℃ are dried to moisture and are less than 3%; the screening of granule granulate, is sub-packed in aluminum-plastic composite membrane bag by specification.
Sample determination
Dissolution determination: with reference to Chinese Pharmacopoeia version relevant regulations in 2010, using phosphate buffer (being prepared by citric acid and the sodium hydroxide solution) 1000ml of pH=6.0 as dissolution medium, oar method rotating speed is that 50r/min operates in accordance with the law, extract sample dissolution fluid in the scheduled time and filter, get subsequent filtrate by determined by ultraviolet spectrophotometry and calculate dissolution.
Assay: the assay method with reference to domperidone tablet content in pharmacopoeia of India version in 2007 is measured.
Particle size determination: adopt Ma Erwen Mastersizer 3000, sample dispersion is measured to particle size distribution in 0.05% lauryl sodium sulfate aqueous solution.
Powder X-ray diffraction: adopt D/MAX2550VB/PC (the dynamo-electric Co., Ltd. of Rigaku), measure.Working condition is: copper target K
α 1, voltage 40kV; Voltage 25mA; 2 θ scopes: 3 °～50 °.
Differential scanning calorimetric analysis: adopt DIAMOND DSC (platinum Ai Ermo instrument (Shanghai) Co., Ltd.), working condition is: atmosphere is N
2, 20mL/min; Scanning imaging system, is warming up to 300 ℃ from room temperature with 10 ℃/min, records heating curve.
Specific area measuring: adopt Micromeritics Tristar II 3020 (Micromeritics Instrument Corporation) to measure.
Scanning electron microscope is measured: adopt JSM-6360LV (JEOL, Japan) to observe and take scintigram.
Claims (18)
1. a domperidone microgranule, is characterized in that: average volume particle diameter is less than 20 μ m, and specific surface area is at least 4.0m
2/ g, has 2 times of above specific surface areas of the common domperidone microgranule of suitable particle diameter; Its preparation method comprises the steps: that (1) is scattered in domperidone and dispersion aids in solvent, and acid adding, to dissolving, obtains solution I; (2) under stirring condition, in solution I, add alkali liquor, obtain the mixture that contains domperidone microgranule; (3) separate domperidone microgranule.
2. the preparation method of domperidone microgranule as claimed in claim 1, is characterized in that: described acid is one or more in hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, nitric acid, hydrobromic acid, maleic acid, citric acid, methanesulfonic acid, tartaric acid, lactic acid, formic acid, malic acid, fumaric acid, succinic acid, salicylic acid, benzoic acid, ethanedioic acid; Described sour consumption is to make 1～1.2 times of the consoluet minimum of domperidone, is preferably 1～1.05 times.
3. the preparation method of domperidone microgranule as claimed in claim 1, is characterized in that: in the time that acid is hydrochloric acid, the molar ratio of hydrochloric acid and domperidone is 0.9～1.3, is preferably 1.0～1.1.
4. the preparation method of domperidone microgranule as claimed in claim 1, it is characterized in that: described solvent is the mixed liquor of organic solvent or water and organic solvent, described organic solvent is that the dissolubility of domperidone is better than to water and at the acceptable organic solvent in medicament field; In the mixed liquor of described water and organic solvent, the concentration of organic solvent is preferably mass percent more than 40%, is more preferably more than 70%; The amount of described solvent is the more than 2 times of domperidone quality, is preferably 4～6 times.
5. the preparation method of domperidone microgranule as claimed in claim 4, is characterized in that: described organic solvent is water-soluble alcohol solvent, is preferably one or more in ethanol, propylene glycol, glycerol, ethylene glycol, isopropyl alcohol and benzyl alcohol; In the time that described solvent is ethanol water, in ethanol water, the concentration of ethanol is preferably mass percent more than 40%, is more preferred from more than 70%.
6. the preparation method of domperidone microgranule as claimed in claim 1, is characterized in that: described dispersion aids is selected from one or more in polyvidone, poloxamer, watermiscible vitamin E, Polyethylene Glycol, tween, polyoxyethylene castor oil, sucrose ester and s6.
7. the preparation method of domperidone microgranule as claimed in claim 6, is characterized in that: described dispersion aids is 0.01～5 times of domperidone quality, is preferably 0.5～3 times.
8. the preparation method of domperidone microgranule as claimed in claim 1, is characterized in that: in preparation when the drug solns, rising temperature to 30 ℃～85 ℃; In the time using ethanol water for solvent, be preferably warming up to 30 ℃～70 ℃, be more preferably 40～60 ℃.
9. the preparation method of domperidone microgranule as claimed in claim 1, it is characterized in that: described alkali is inorganic strong alkali and/or weak acid strong alkali salt and/or organic base (as meglumine, ethylenediamine, arginine, lysine), described inorganic strong alkali is preferably sodium hydroxide and/or potassium hydroxide, described weak acid strong alkali salt is preferably one or more in sodium carbonate, potassium carbonate and sodium hydrogen phosphate, and described organic base is preferably one or more of ethylenediamine, arginine, lysine.
10. the preparation method of domperidone microgranule as claimed in claim 9, is characterized in that: described alkali adds with the form of solution, and the described concentration containing alkali is 1～20wt%, and described solution is preferably aqueous solution.
The preparation method of 11. domperidone microgranules as described in claim 9 or 10, is characterized in that: pH value when described medicine is separated out is 6.0～12, and preferred pH value is 6.5～8.0.
The preparation method of 12. domperidone microgranules as described in claim 1 or 10, is characterized in that: before separating, available colloid mill or homogenizer carry out dispersion treatment.
The preparation method of 13. domperidone microgranules as claimed in claim 1, is characterized in that:
Described sucking filtration, washing the sucking filtration, dry of being separated into; Described washing is that water or 10～70wt% ethanol water carry out, and the amount of each water or 10～70wt% ethanol water is 1～5 times of the domperidone quality that drops into; The number of times of washing sucking filtration is 1～3 time; Described being dried as static state is dry or dynamically dry; Described static state is dried at 40～100 ℃, is preferably 50～70 ℃, and drying under reduced pressure 2～8 hours is preferably 5～6 hours, and vacuum condition when decompression is 450mmHg～76mmHg, is preferably 150mmHg; Described is dynamically dried at 50～80 ℃, is preferably 60～70 ℃, in bipyramid vacuum drying mixer, is dried 2～6 hours, is preferably 3～5 hours.
The preparation method of 14. domperidone microgranules as claimed in claim 1, is characterized in that: described stirring is 150～500 ms/min of agitator linear velocities.
15. 1 kinds of domperidone preparation compositions and preparation method thereof; it is characterized in that: adopt the method described in any one in claim 1～14 to prepare domperidone microgranule or particle mixture; and acceptable adjuvant pharmaceutically; described domperidone microgranule or the consumption of particle mixture (take domperidone dry) are 0.01～10% of the quality of the pharmaceutical preparations, and described pharmaceutically acceptable accessory package contains one or more in suspending agent, flocculating agent, wetting agent, filler, disintegrating agent, binding agent, lubricant.
16. preparation compositions as claimed in claim 15, is characterized in that: described preparation is suspensoid or dry suspension, and described pharmaceutically acceptable accessory package is containing suspending agent, flocculating agent, wetting agent; Described suspending agent is preferably one or more in glycerol, hydroxypropyl methylcellulose, methylcellulose, sodium carboxymethyl cellulose, xanthan gum; Described wetting agent is preferably one or more in glycerol, Tween 80, poloxamer, sucrose ester; Described flocculating agent is preferably one or more in sodium citrate, sodium tartrate; The preparation method of described preparation is dispersion method, by domperidone microgranule with adjuvant dry mixed is evenly prepared dry suspension or further adopt aqueous dispersion to prepare suspensoid again.
17. preparation compositions as claimed in claim 15, is characterized in that: described preparation is powder, granule, tablet or capsule; When preparation method is wet granulation, described adjuvant comprises filler, disintegrating agent, binding agent and lubricant; Described filler is preferably one or more in lactose, Lactis Anhydrous, mannitol, particle cellulose, starch, xylitol, pregelatinized Starch and maltose alcohol; Described disintegrating agent is preferably one or more in carboxymethyl starch sodium, hyprolose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose; Described binding agent is preferably one or more in water or the alcoholic solution of aqueous solution, polyvinylpyrrolidone of starch slurry, hydroxypropyl methylcellulose; Described lubricant is preferably one or more in colloidal silica, sodium stearyl fumarate, Pulvis Talci and magnesium stearate; The consumption sum of described filler and described water-solubility carrier is 70～95% of described preparation content quality, is preferably 80～90%; The consumption of described disintegrating agent is preferably 2～8% of described preparation content quality; The consumption of described lubricant is preferably 0.5～4% of described preparation content quality; While adopting vertical compression technique to carry out the preparation of domperidone tablet, described adjuvant comprises vertical compression adjuvant, disintegrating agent and lubricant; Described vertical compression adjuvant is preferably one or more in vertical compression lactose, vertical compression mannitol, vertical compression particle cellulose and vertical compression complex; Described disintegrating agent is preferably one or more in carboxymethyl starch sodium, hyprolose, crospolyvinylpyrrolidone and cross-linking sodium carboxymethyl cellulose; Described lubricant is preferably one or more in colloidal silica, sodium stearyl fumarate, Pulvis Talci and magnesium stearate; Described vertical compression adjuvant and the consumption sum of described water-solubility carrier are tablet quality 80～98%, are preferably 90～95%; The consumption of described disintegrating agent is 2～5% of tablet quality, and the consumption of described lubricant is tablet quality 0.5～3%.
Solid preparation and the liquid preparation of the domperidone that 18. methods as described in claim 1～17 any one make, described solid preparation comprises powder, granule, Tablet and Capsula agent, described liquid preparation comprises suspensoid, dry suspension.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210589736.8A CN103893130A (en) | 2012-12-28 | 2012-12-28 | Domperidone particles, domperidone preparation and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210589736.8A CN103893130A (en) | 2012-12-28 | 2012-12-28 | Domperidone particles, domperidone preparation and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN103893130A true CN103893130A (en) | 2014-07-02 |
Family
ID=50984926
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210589736.8A Pending CN103893130A (en) | 2012-12-28 | 2012-12-28 | Domperidone particles, domperidone preparation and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103893130A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105640890A (en) * | 2014-11-27 | 2016-06-08 | 华东理工大学 | Sparingly soluble active component particle, particle preparation and preparation method thereof |
| CN105663055A (en) * | 2016-03-01 | 2016-06-15 | 山东司邦得制药有限公司 | Children domperidone dry suspension and preparation method of children domperidone dry suspension |
| CN105726477A (en) * | 2016-03-01 | 2016-07-06 | 山东司邦得制药有限公司 | Pediatric domperidone suspension and preparation method thereof |
| EP3380079A4 (en) * | 2015-11-25 | 2019-08-21 | Patheon Development Services Inc. | Amorphous dispersion granules and oral dosage forms |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106807A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Method for preparing solid preparation and solid preparation |
-
2012
- 2012-12-28 CN CN201210589736.8A patent/CN103893130A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106807A (en) * | 2009-12-29 | 2011-06-29 | 上海中西制药有限公司 | Method for preparing solid preparation and solid preparation |
Non-Patent Citations (2)
| Title |
|---|
| 任娟清: "《实用药物手册》", 31 January 1999 * |
| 郑斯骥等: "酸-碱溶析分散技术及在格列吡嗪制剂中的应用", 《上海医药》 * |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105640890A (en) * | 2014-11-27 | 2016-06-08 | 华东理工大学 | Sparingly soluble active component particle, particle preparation and preparation method thereof |
| CN105640890B (en) * | 2014-11-27 | 2020-09-18 | 华东理工大学 | Insoluble active ingredient particle, particle preparation and preparation method thereof |
| EP3380079A4 (en) * | 2015-11-25 | 2019-08-21 | Patheon Development Services Inc. | Amorphous dispersion granules and oral dosage forms |
| CN105663055A (en) * | 2016-03-01 | 2016-06-15 | 山东司邦得制药有限公司 | Children domperidone dry suspension and preparation method of children domperidone dry suspension |
| CN105726477A (en) * | 2016-03-01 | 2016-07-06 | 山东司邦得制药有限公司 | Pediatric domperidone suspension and preparation method thereof |
| CN105663055B (en) * | 2016-03-01 | 2018-07-06 | 山东司邦得制药有限公司 | A kind of children's domperidone dry suspensoid agent and preparation method thereof |
| CN105726477B (en) * | 2016-03-01 | 2018-10-12 | 山东司邦得制药有限公司 | A kind of children's Domperidone suspension and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109078006B (en) | Medicinal preparation of palbociclib and preparation method thereof | |
| TWI263507B (en) | Cilostazol preparation | |
| CN100562317C (en) | The granule that contains a large amount of acid labile drugs | |
| WO2016082705A1 (en) | Insoluble active ingredient particulate, particulate preparation and preparation method therefor | |
| CN106102716A (en) | The solid composite medicament of androgen receptor antagonists | |
| JP4748839B2 (en) | Cilostazol preparation | |
| JP7124107B2 (en) | Porous silica particle composition | |
| WO2013000391A1 (en) | Aripiprazole medicament formulation and preparation method therefor | |
| CN104650091B (en) | The micronization of ticagrelor and crystal formation thereof, and preparation method and medicinal application | |
| CN1102046C (en) | Antibacterial composition for oral administration | |
| WO2005073286A1 (en) | Porous cellulose aggregate and formed product composition comprising the same | |
| CN103893130A (en) | Domperidone particles, domperidone preparation and preparation method thereof | |
| CN103284962B (en) | Moxifloxacin dispersible tablet and preparation method | |
| CN104398477A (en) | Usnic acid nanometer suspension, and preparation method and use thereof | |
| TW200840565A (en) | Pulverized crystal of olmesartan medoxomil | |
| JP5367735B2 (en) | Tablet manufacturing method | |
| CN103156860A (en) | Olanzapine composition and preparation method thereof | |
| CN101938995A (en) | Suspension comprising non-micronized ezetimibe micro-particles | |
| CN105193731A (en) | Ibuprofen particle, ibuprofen preparation and preparation method of ibuprofen particle | |
| CN105801568B (en) | One maleate crystal form of Afatinib and preparation method thereof and pharmaceutical composition | |
| CN107522717A (en) | A kind of lavo-ofloxacin hydrochloride crystal and combinations thereof | |
| CN101066267B (en) | Solid oral medicine composition containing aripiprazole microcrystal | |
| CN104473901B (en) | Cefdinir capsule and preparation method thereof | |
| CN104606139B (en) | A kind of preparation and application of drug powder | |
| CN102349889B (en) | Composition containing dronedarone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20140702 |