CN201260791Y - Equipment for preparing micronizing medicament - Google Patents

Abstract

The utility model relates to a micronized medicine preparing device which belongs to the field of medicine preparation and solves the problem of uneven granularity caused by the condition that medicines are prepared by unevenly stirring in a traditional stirring kettle. The micronized medicine preparing device comprises a microreactor, a material medicine solution storing bottle, a desolvation storing bottle and two flat flowing pumps, wherein the microreactor is a Y-shaped or linear microreactor, the shape of the section of the microreactor is square or circular, one flat flowing pump is respectively connected with the microreactor and the material medicine solution storing bottle, and the other flat flowing pump is respectively connected with the microreactor and the desolvation storing bottle. The utility model can obtain medical granules with controllable and even granule diameters, preparations are easy for split charging, and moreover, the utility model has higher biological availability.

Description

A kind of equipment for preparing micronized medicine

Technical field

This utility model relates to a kind of equipment for preparing micronized medicine, makes that particle diameter is controlled, the nanoscale of narrow particle size distribution or micron-sized medicament powder.

Background technology

Medicine in the market comprises dosage forms such as Foradil Aerolizer formoterol fumarate, aerosol, tablet, capsule and suspensoid.

Carry out administration for inhalant dosage forms such as Foradil Aerolizer formoterol fumarate and aerosol (as beclometasone) by pulmonary.Because the special physiological structure of pulmonary will reach pulmonary deposition preferably, the granule that sucks medicine is all had certain requirement: (1) particle diameter: particle diameter enters bronchus and brings into play drug effect fast in that the medicine of 0.5-5 μ m is the easiest; (2) particle size distribution of medicine is narrow; (3) medicine will have reasonable dispersibility and flowability etc.; (4) because unformed medicine has thermodynamic phase, so medicine should be crystal type.In above-mentioned influence factor, particle grain size is the key factor that can the decision medicine reach site of action, and therefore, the micronization of medicine is to improve the key point that sucks medicine effect.

For oral formulations such as tablet, capsule and suspensoids, the water solublity of some medicine (as azithromycin and danazol) is low, bioavailability is poor, so not only causes very big waste clinically, but also can increase side effect.For oral formulations, the dissolution rate of medicine activity component in body determined the size of bioavailability.Get rid of other factor affecting, the dissolution rate of solid drugs depends primarily on the size of the granule surface area that contacts with solvent liquid.Therefore, particle diameter is more little, and dissolution rate is fast more.By insoluble drug is carried out micronization,, very important meaning is arranged to improving bioavailability to reduce the drug particles particle diameter and then to increase its specific surface area.

Comminution by gas stream (preparation of ultra-fine azithromycin and sign. Long Tao etc. the chemical industry progress, 2005,24 (7): though 763-766) and ball-milling method be the common method that reduces drug particle size, but, exist generally that energy consumption is big, efficient is low, Granularity Distribution is wide, easily make shortcomings such as the structural deterioration of thermally labile medicine and degraded, in addition, also can cause problems such as dust pollution and electrostatic safety.Though spray drying method and supercritical fluid technology can make the micronized medicine of narrow particle size distribution, but the equipment manufacturing cost height.The operating procedure and the operating equipment of anti-solvent recrystallization method are simpler, are easy to large-scale production, have excellent industrial application foreground.(Micronization of anti-Inflammatory drugs for pulmonary delivery bya controlled crystallization process.Norbert Rasenack such as NorbertRasenack, et al.Journal ofPharmaceutical Sciences, 2003,92 (1): 35-44) adopt anti-solvent recrystallization method to prepare the needle-like beclometasone, but use hydroxypropyl emthylcellulose in the recrystallization process as stabilizing agent, and hydroxypropyl emthylcellulose is not used in inhalation so far, does not have relevant toxicology data.At United States Patent (USP) 20020081334, a kind of micron order or nano level danazol preparation method have been described in 20040067251: danazol solution is sprayed in the deionized water solution that is added with surfactant, then organic solvent is vapored away, thus the dispersion liquid of formation danazol fine particle.Particle diameter is controlled, pattern is controlled and the danazol powder of narrow particle size distribution but this method of this patent introduction can not prepare, and also there is inhomogeneous, the local oversaturated problem of mixing at the solvent precipitation that traditional stirred tank carries out, thereby influences the quality of danazol powder.And the adding of surfactant has increased the difficulty of cost and operation, has also increased potential medicine side effect.In addition, the method of utilizing the ultrasonic emulsification solvent diffusion method to prepare the azithromycin superfine powder has been described: among the Chinese patent CN1634113A under ultransonic condition, the azithromycin alcoholic solution is splashed in the aqueous solution that contains stabilizing agent, become muddy until system, again after the solution system ageing a period of time with muddiness, high speed centrifugation separate solid matter, and washing, drying have made the azithromycin superfine powder.The method relates to ultrasound condition, and the introducing of not only energy consumption height, and emulsifying agent is made troubles to subsequent processes, has increased the cost of raw material.

The utility model content

The purpose of this utility model provides nanoscale or micron-sized mean diameter is controlled, the equipment of the medicament powder of narrow particle size distribution, and prepared nanoscale or micron-sized drug particles have characteristics such as particle diameter is controlled, narrow particle size distribution.

This utility model provides a kind of equipment for preparing micronized medicine, it is characterized in that, comprising:

(1) microreactor is used to carry out anti-solvent recrystallization process; Described microreactor is Y type or linear type microreactor, and cross sectional shape is a square or circular, and material is a rustless steel.

(2) raw material medicine solution storage bottles and an anti-solvent storage bottle;

(3) two constant-flux pumps, one of them constant-flux pump links to each other with the raw material medicine solution storage bottle with microreactor respectively, be used for the transferring raw material drug solns to microreactor, another constant-flux pump links to each other with anti-solvent storage bottle with microreactor respectively, is used for carrying anti-solvent to microreactor.

In the equipment of the present utility model, employed microreactor is Y type or linear type, and the inner microchannel size that supplies fluid flow of microreactor is from the submicron to the submillimeter level, and cross sectional shape is a square or circular.Two bursts of chargings of solution and anti-solvent are by separately constant-flux pump control flow, carry out fully after converging, contact equably, can reach good microcosmic rapidly and mix, and collect slurry after the crystallization from the serosity outlet.Because the passage of microreactor is narrow, the equivalent diameter order of magnitude is a micron order, and its mass transfer characteristic makes reactant can mix in the Millisecond scope in microreactor, thereby has greatly strengthened mass transport process.

Use the method that this utility model prepares micronized medicine, comprise the steps:

(1) crude drug is dissolved in the certain density raw material medicine solution of preparation in the organic solvent; The volume ratio of raw material medicine solution and anti-solvent is 1:5 to 1:30; The concentration of raw material medicine solution be under the uniform temp saturated solution concentration 5% to 98%;

(2) make raw material medicine solution and anti-solvent enter microreactor simultaneously through solution inlet and anti-colvent inlet respectively, intersect, and mix the anti-solvent recrystallization process of carrying out fully rapidly in the crossing of microreactor by constant-flux pump; The flow velocity that raw material medicine solution and anti-solvent enter microreactor is 1ml/min to 80ml/min; Recrystallization temperature is-10 ℃ to 50 ℃;

(3) slurry that recrystallization is obtained filter, wash, drying, promptly get micronized medicine.

Employed raw material medicine solution is the solution of crude drug in methanol, ethanol, acetone, isopropyl alcohol, propylene glycol, glycerol, n-butyl alcohol, the tert-butyl alcohol, amylalcohol, capryl alcohol, dichloromethane, chloroform or their mixture, but is not limited to above-mentioned solvent.So-called " dissolving " is meant that medicine forms basic clear solutions in solvent.In the above-mentioned drug solution, medicine can any suitable concentration exist, as long as it can satisfy dissolved requirement.Raw material medicine solution concentration be under the uniform temp saturated solution concentration 5% to 98%.

Employed anti-solvent is water, normal hexane, cyclohexane extraction, petroleum ether, diisopropyl ether, ether, heptane, octane or their mixture.

The volume ratio of raw material medicine solution and anti-solvent is 1:5 to 1:30, and the flow velocity that preferred 1:10 to 1:20, and obtain by the flow velocity of regulating two strands of materials, two strands of materials enter microreactor is 1ml/min to 80ml/min.

Recrystallization temperature is-10 ℃ to 50 ℃, preferred 10 ℃ to 20 ℃.When the amount of anti-solvent during much larger than the amount of raw material medicine solution, the temperature of system can realize by the temperature of controlling anti-solvent.

The medicine that can prepare is: (1) beclometasone, asthma class medicine; (2) azithromycin, antibiotics; (3) danazol, weak androgen is mainly used in the treatment endometriosis, but is not limited to said medicine.

In this utility model, microchannel size, shape and the angle etc. of charging rate by adjusting raw material medicine solution and anti-solvent and ratio, solution concentration, crystallization temperature, microreactor, can access mean diameter controlled, drug particles uniformly.Mean diameter micronized medicine granule controlled, narrow particle size distribution particularly.And this utility model resulting granules is owing to there not being the problem that stirs the inhomogeneous relative granularity inequality that causes in traditional stirred tank, so can be used for tablet or capsule effectively in field of medicaments.With respect to prior art, for example, for tablet and capsule, because uniform particles, granularity is less, thus easy packaged preparation, and high bioavailability is arranged.

Description of drawings

Fig. 1 is the sketch map of Y shape microreactor.

Fig. 2 is the sketch map of linear microreactor.

The specific embodiment

Embodiment 1

The microreactor that adopts is a Y shape microreactor, the cross section of the passage of raw material medicine solution inlet 1 and the 2 two bursts of chargings in anti-colvent inlet is a square, be of a size of 0.5mm * 1mm, the length of two passages is 20mm, angle is 60 °, and serosity exports the cross section of 3 passages for square, is of a size of 1mm * 1mm, the passage length overall is 57.32nm, and channel center's distance of solution and two bursts of chargings of anti-solvent is 20mm.

Take by weighing beclometasone crude drug 1.5g, it is dissolved in is mixed with the beclometasone methanol solution 50ml that concentration is 0.03g/ml in the methanol, place the raw material medicine solution storage bottle, get the 1000ml deionized water in anti-solvent storage bottle, as anti-solvent.Substantially simultaneously enter in the microreactor through solution inlet and anti-colvent inlet beclometasone methanol solution and deionized water respectively by constant-flux pump, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, the products therefrom slurry is collected from discharging opening.The charging rate of beclometasone methanol solution and water is respectively 3ml/min and 60ml/min, and recrystallization temperature is 10 ℃.The slurry of collecting is filtered, washs, in 105 ℃ of vacuum drying ovens, be drying to obtain micronization beclometasone powder body then.As can be seen, the average minor axis of beclometasone is 1.14 μ m from stereoscan photograph, is distributed in 0.4-3.5 μ m.

Embodiment 2

The microreactor that adopts is the linear microreactor, and the cross section of the passage of raw material medicine solution inlet 1 and the 2 two bursts of chargings in anti-colvent inlet is a square, is of a size of 0.4mm * 0.4mm, and the passage length overall is 40mm, and the centre distance of two imports is 20mm.

Take by weighing beclometasone crude drug 1.5g, it is dissolved in is mixed with the beclometasone methanol solution 50ml that concentration is 0.03g/ml in the chloroform, place the raw material medicine solution storage bottle, get the 1000ml cyclohexane extraction in anti-solvent storage bottle, as anti-solvent.By constant-flux pump beclometasone methanol solution and deionized water are entered microreactor substantially simultaneously through solution inlet and anti-colvent inlet respectively, two fluid streams intersect in the crossing of microchannel, and mix fully rapidly, the products therefrom slurry is collected from serosity outlet 3.The charging rate of beclometasone solution and water is respectively 3ml/min and 60ml/min, and recrystallization temperature is 10 ℃.The slurry of collecting is filtered, washs, in 105 ℃ of vacuum drying ovens, be drying to obtain micronization beclometasone powder body then.As can be seen, the average minor axis of beclometasone is 1.07 μ m from stereoscan photograph, is distributed in 0.3-2.7 μ m.

Claims (1)

1. an equipment for preparing micronized medicine is characterized in that, comprising:

A microreactor, described microreactor are Y type or linear type microreactor, and cross sectional shape is a square or circular;

A raw material medicine solution storage bottle and an anti-solvent storage bottle;

Two constant-flux pumps, one of them constant-flux pump link to each other with the raw material medicine solution storage bottle with microreactor respectively, and another constant-flux pump links to each other with anti-solvent storage bottle with microreactor respectively.

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