CN104367551A - Aprepitant compound and its preparation method - Google Patents
Aprepitant compound and its preparation method Download PDFInfo
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Abstract
The invention provides an aprepitant compound. The compound comprises 30-70wt% of aprepitant, 20-60wt% of monosaccharide and 10-50wt% of a suspending agent. The monosaccharide in the compound is helpful for forming aprepitant nanocrystals; and the suspending agent can avoid local non-uniformity caused by wet grinding and settlement of a suspension in the spray drying process. The prepared aprepitant compound greatly improves the solubility of aprepitant, is helpful for improving the bioavailability of aprepitant, and has great clinical application values. The method of the invention is simple, and is suitable for industrial production.
Description
Technical field
The present invention relates to pharmaceutical preparation, Aprepitant complex being specifically related to a kind of highly dissoluble and preparation method thereof.
Background technology
Aprepitant is that U.S. FDA is in first neurokinin nk 1 receptor blocker of approval listing in 2003.Its former exploitation producer of grinding product is Merck company, is mainly used in the prevention of postoperative vomiting, and the prevention and corntrol vomitted after using chemotherapeutic.Its chemistry 5-[[(2R by name, 3S)-2-[(R)-1-[3,5-bis-(trifluoromethyl) phenyl] ethyoxyl]-3-(4-fluorophenyl) morpholinyl] methyl]-1 hydrogen-1,2,4-triazole-3(2 hydrogen)-one, molecular formula is C
23h
21f
7n
4o
3.Its structural formula is as follows:
Aprepitant is almost insoluble in water, and the Log P(P under pH7.0 condition is Determination of oil-water partition coefficient) be 4.8, therefore, according to Biopharmaceutics Classification, it belongs to the 4th class medicine, i.e. low-solubility hypotonicity medicine.Such medicine is often difficult to the product making clinical efficacy, and its reason is that medicine is difficult to be absorbed by body, and eliminate excessive velocities in body, bioavailability is poor.
For the character of the low-solubility hypotonicity of Aprepitant, industry professional has carried out many-sided research, and has achieved certain achievement.Namely the former triturate of Merck & Co., Inc.'s listing have employed the technology preparation of wet grinding, first its patented technology is disclosed in WO2003049718, describe in this patent and adopt wet grinding device that Aprepitant particle diameter is ground to below 1000 nanometers, and add the surface stabilizers such as sodium lauryl sulphate when it grinds to maintain its effective grain size, with this, by reducing the particle diameter of Aprepitant, improve dissolubility, and then improving bioavailability.
The present inventor person also for ease of the problem of the low-solubility hypotonicity solving above-mentioned Aprepitant, has carried out large quantifier elimination, has groped number of ways.In research process, invention personnel be surprised to find, and after Aprepitant and monosaccharide combinations of substances, under certain process conditions, is prepared into the complex of Aprepitant, the solubility property of this complex is improved greatly, can study new preparation further.
Summary of the invention
Technical problem to be solved by this invention is, overcomes above-mentioned weak point, and research design improves Aprepitant dissolubility, improves preparation and the preparation method of its bioavailability.
The invention provides a kind of complex of Aprepitant.
Aprepitant complex of the present invention is made up of Aprepitant, monosaccharide and suspending agent.
Aprepitant complex of the present invention is grouped into by the one-tenth of following weight percent proportioning:
Aprepitant 30%-70%, monosaccharide 20%-60%, suspending agent 10%-50%.
In complex of the present invention, monosaccharide be selected from glucose, sucrose or fructose one or more; Suspending agent is selected from sodium carboxymethyl cellulose, hypromellose, hydroxyethyl-cellulose, poloxamer or polyvidone.
In complex of the present invention, monosaccharide act as the formation helping Aprepitant nanocrystal; The acting as of suspending agent avoids the sedimentation of suspension in wet grinding and spray-drying process and the local caused is uneven.
Another object of the present invention there is provided the preparation method of described Aprepitant complex.
The method comprises the following steps:
(1) respectively wet grinding mill is connected water-cooling system, the Agitation Tank of jacketed and stirring paddle is connected water-cooling system, and cold water temperature is 7 DEG C-10 DEG C;
(2) get the purified water being equivalent to raw material Aprepitant weight 5-20 times and be placed in Agitation Tank, open stirring, Aprepitant and suspending agent are slowly added in Agitation Tank, adds while stirring, form uniform suspension, maintain stirring, for subsequent use;
(3) discharging opening of above-mentioned Agitation Tank is connected the charging aperture of wet grinding mill with pipeline, the discharging opening of wet grinding mill is connected the charging aperture of Agitation Tank with pipeline, open grinder, grinding chamber internal rotor rotates and forms negative pressure, by the suspension of Aprepitant from the sucking-off of Agitation Tank discharging opening, enter in wet grinding mill by the charging aperture of wet grinding mill, of short duration grinding is after 1-2 minute, the suspension of Aprepitant is got back in Agitation Tank by the discharging opening of wet grinding mill, formation circulation like this, grinding injection speed is 1-10L/ minute, grinding bead particle diameter is 0.1-0.5 millimeter,
(4) after formation circulation, slowly added in Agitation Tank by monosaccharide, circulation limit, limit adds, and after having added, maintains circular grinding state;
(5) sample in circular grinding process, the particle diameter of granule in suspension is measured with laser particle analyzer, when the grain diameter of test result display more than 90% is less than 600 nanometer (calculatings of laser particle analyzer programming count), stop grinding, obtain the suspension of Aprepitant complex;
(6) suspension of Aprepitant complex is adopted spraying dry, temperature is 60 DEG C-80 DEG C, and centrifugal atomizing dish frequency is 40, and spraying dry terminates the complex of rear obtained Aprepitant.
In the wet grinding stage of preparation method of the present invention, in Aprepitant suspension, the concentration of monosaccharide maintains critical statisfaction CONCENTRATION STATE.In the low temperature wet method process of lapping of 7 DEG C-10 DEG C, due to the water-insoluble of Aprepitant, monosaccharide is that nucleus forms Aprepitant complex crystallization lentamente with Aprepitant.Due to the effect of wet grinding, slightly large complex crystallization is polished broken, then more easily maintains in the crystallization of Nano grade.In the motor process that whole crystallization is broken with grinding, when the grain diameter of crystallization more than 90% is less than 600 nanometer, just define the suspension of Aprepitant complex of the present invention.
In the wet grinding stage of preparation method of the present invention, temperature maintains 7 DEG C-10 DEG C.Find in research process, during this temperature, preferred monosaccharide, comprising glucose, sucrose or the fructose critical statisfaction concentration under the formula proportion condition of 20%-60% is dissolve 0.04g-0.2g in every 1g purified water.
The spray-drying stage of preparation method of the present invention, the suspension of Aprepitant complex is atomized into by centrifugal pan the form being less than 10 microns of droplets and is sprayed onto in the drying chamber of spray dryer, moisture rapid evaporation thus define the high supersaturated solution of monosaccharide, under the product temperatures of 60 DEG C-80 DEG C control, monosaccharide promptly forms crystallization and nano level Aprepitant is wrapped in crystallization the complex defining Aprepitant.
Preparation method of the present invention obtain Aprepitant complex convenient technical process well known in the art can be adopted to be prepared into as dosage forms such as capsule, tablet, powder, granule, Oral Dry Suspensions.
By comparative test, the 15 minute dissolubility of Aprepitant crude drug in 37 DEG C of 0.1%SLS aqueous solutions that the present invention uses are 0.36 mcg/ml.The present invention obtain the complex of Aprepitant by the second method paddle method of Chinese Pharmacopoeia 2005 editions, with 37 DEG C of 900ml 0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and result shows its 15 minutes burst sizes and namely reaches more than 80%, and the dissolving solubility of 15 minutes reaches 71 mcg/ml, drastically increases dissolubility, improves the bioavailability of Aprepitant.
The Aprepitant complex that the present invention obtains overcomes the lower problem of Aprepitant dissolubility, contributes to the bioavailability improving Aprepitant, has larger clinical value.The inventive method is easy, is suitable for suitability for industrialized production.
Accompanying drawing explanation
D90 in accompanying drawing 1 embodiment 6 measures change of size figure
Vertical coordinate: D90 particle size values (micron), abscissa: time (dividing)
Dissolution release profiles in accompanying drawing 2 embodiment 8
Vertical coordinate: burst size %, abscissa: time (dividing)
The dissolution release profiles of square expression embodiment 7 in figure
Figure intermediate cam shape represents the dissolution release profiles of embodiment 6
Detailed description of the invention
The all material below used is commercially available acquisition.
Embodiment 1 prepares Aprepitant complex
Aprepitant, sucrose and suspending agent hypromellose and poloxamer are carried out wet grinding.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 250 | 44.64 |
| Hypromellose E5 | 54 | 9.64 |
| Poloxamer F127 | 6 | 1.07 |
| Sucrose | 250 | 44.65 |
| Purified water * | 2500 | -- |
| Solid amounts to | 560 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system respectively with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 10 DEG C.Aprepitant, poloxamer F127 and hypromellose E5 are mixed into homogeneous solid mixture.Separately get purified water and be placed in Agitation Tank, open stirring, Aprepitant, poloxamer F127 and hypromellose E5 are slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintain stirring, for subsequent use.The discharging opening of Agitation Tank is connected the charging aperture of wet grinding mill with pipeline, the discharging opening of wet grinding mill is connected the charging aperture of Agitation Tank with pipeline, open grinder, grinding chamber internal rotor rotates and forms negative pressure, by the suspension of Aprepitant from the sucking-off of Agitation Tank discharging opening, enter in wet grinding mill by the charging aperture of wet grinding mill, of short duration grinding is after 2 minutes, the suspension of Aprepitant is got back in Agitation Tank by the discharging opening of wet grinding mill, formation circulation like this, grinding injection speed is 3L/ minute, and grinding bead particle diameter is 0.3 millimeter.
Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
After grinding reaches 110 minutes, grinding terminates, and above-mentioned suspension is adopted spray dryer LPG-10 spraying dry, temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, has all been sprayed by suspension, the complex 540 grams of obtained Aprepitant after spraying dry completes.
Above-mentioned complex is pressed the second method paddle method of Chinese Pharmacopoeia 2005 editions, with 37 degrees Celsius of 900ml0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and stripping result is as follows:
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution (%) | 77 | 87 | 90 |
。
Embodiment 2
Aprepitant, fructose and suspending agent sodium carboxymethyl cellulose are carried out wet grinding.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 300 | 30.00 |
| Sodium carboxymethyl cellulose | 500 | 50.00 |
| Fructose | 200 | 20.00 |
| Purified water * | 5000 | -- |
| Solid amounts to | 1000 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 8 degree.Aprepitant and sodium carboxymethyl cellulose are mixed into homogeneous solid mixture.Taking a certain amount of purified water puts in Agitation Tank, opens stirring, Aprepitant and sodium carboxymethyl cellulose is slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintains stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, grinding injection speed is 3L/ minute, and grinding bead particle diameter is 0.5 millimeter.After grinding starts, in Agitation Tank, slowly add the fructose of recipe quantity, add rear maintenance circular grinding.Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 150 minutes |
| d10 | 85.2 | 0.56 | 0.20 | 0.17 | 0.12 | 0.12 |
| d50 | 214 | 0.89 | 0.37 | 0.28 | 0.25 | 0.22 |
| d90 | 934 | 3.26 | 0.99 | 0.77 | 0.60 | 0.52 |
After grinding reaches 150 minutes, grinding terminates, and above-mentioned suspension is adopted spray dryer LPG-10 spraying dry, temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, the complex 980 grams of obtained Aprepitant after drying completes.
Above-mentioned complex is pressed the second method paddle method of Chinese Pharmacopoeia 2005 editions, with 37 degrees Celsius of 900ml0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and stripping result is as follows:
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution (%) | 64 | 80 | 83 |
。
Embodiment 3
Aprepitant, glucose and suspending agent hydroxyethyl-cellulose are carried out wet grinding.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 300 | 30.00 |
| Hydroxyethyl-cellulose | 100 | 10.00 |
| Glucose | 600 | 60.00 |
| Purified water * | 3000 | -- |
| Solid amounts to | 1000 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 7 degree.Aprepitant and hydroxyethyl-cellulose are mixed into homogeneous solid mixture.Taking a certain amount of purified water puts in Agitation Tank, opens stirring, Aprepitant and hydroxyethyl-cellulose is slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintains stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, grinding injection speed is 4L/ minute, and grinding bead particle diameter is 0.1 millimeter.After grinding starts, in Agitation Tank, slowly add the glucose of recipe quantity, add rear maintenance circular grinding.Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 150 minutes |
| d10 | 77.8 | 1.20 | 0.50 | 0.33 | 0.24 | 0.20 |
| d50 | 198 | 5.87 | 0.86 | 0.56 | 0.43 | 0.32 |
| d90 | 897 | 10.26 | 1.24 | 0.86 | 0.77 | 0.59 |
After grinding reaches 150 minutes, grinding terminates, and above-mentioned suspension is adopted spray dryer LPG-10 spraying dry, temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, the complex 983 grams of obtained Aprepitant after drying completes.
Above-mentioned complex is pressed the second method paddle method of Chinese Pharmacopoeia, with 37 degrees Celsius of 900ml 0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and stripping result is as follows:
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution (%) | 71 | 82 | 84 |
。
Embodiment 4
Aprepitant, glucose, fructose and suspending agent polyvidone, poloxamer are carried out wet grinding.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 700 | 70.00 |
| Polyvidone | 50 | 5.00 |
| Poloxamer | 50 | 5.00 |
| Glucose | 50 | 5.00 |
| Fructose | 150 | 15.00 |
| Purified water * | 4000 | -- |
| Solid amounts to | 1000 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 10 degree.Aprepitant, polyvidone and poloxamer are mixed into homogeneous solid mixture.Taking a certain amount of purified water puts in Agitation Tank, opens stirring, is slowly added in above-mentioned Agitation Tank by the mixture of Aprepitant, polyvidone and poloxamer, adds while stirring, forms uniform suspension, maintains stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, grinding injection speed is 10L/ minute, and grinding bead particle diameter is 0.3 millimeter.After grinding starts, in Agitation Tank, slowly add glucose and the fructose of recipe quantity, add rear maintenance circular grinding.Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 60 minutes | 90 minutes |
| d10 | 79.8 | 0.61 | 0.33 | 0.11 |
| d50 | 201 | 0.83 | 0.56 | 0.31 |
| d90 | 937 | 1.09 | 0.77 | 0.52 |
After grinding reaches 90 minutes, grinding terminates, and above-mentioned suspension is adopted spray dryer LPG-10 spraying dry, product temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, the complex 965 grams of obtained Aprepitant after drying completes.
Above-mentioned complex is pressed the second method paddle method of Chinese Pharmacopoeia, with 37 degrees Celsius of 900ml0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and stripping result is as follows:
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution (%) | 61 | 81 | 82 |
。
Embodiment 5
Aprepitant, sucrose and suspending agent hypromellose and poloxamer are carried out wet grinding.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 250 | 43.86 |
| Hypromellose E5 | 60 | 10.53 |
| Poloxamer F127 | 10 | 1.75 |
| Sucrose | 250 | 43.86 |
| Purified water * | 2500 | -- |
| Solid amounts to | 570 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 9 degree.Aprepitant, poloxamer F127 and hypromellose E5 are mixed into homogeneous solid mixture.Taking a certain amount of purified water puts in Agitation Tank, opens stirring, Aprepitant, poloxamer F127 and hypromellose E5 is slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintains stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, grinding injection speed is 7L/ minute, and grinding bead particle diameter is 0.3 millimeter.After grinding starts, in Agitation Tank, slowly add the sucrose of recipe quantity, add rear maintenance circular grinding.Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 60 minutes | 90 minutes | 120 minutes | 180 minutes |
| d10 | 95.2 | 0.23 | 0.15 | 0.13 | 0.11 | 0.11 |
| d50 | 264 | 0.41 | 0.25 | 0.22 | 0.20 | 0.19 |
| d90 | 997 | 0.98 | 0.62 | 0.53 | 0.42 | 0.29 |
After grinding reaches 180 minutes, grinding terminates, and above-mentioned suspension is adopted spray dryer LPG-10 spraying dry, temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, the complex 546 grams of obtained Aprepitant after drying completes.
Above-mentioned complex is become capsule by the fill of Aprepitant 80 milligrams/unit dose.Capsule filling machine model is IN-CAP, and fill material total amount is 342 grams, and the fill amount of unit dose is 183 milligrams, and fill grain number is 1860.
By the second method paddle method of Chinese Pharmacopoeia, with 37 degrees Celsius of 900ml0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects the dissolution of above-mentioned capsule.Stripping result is as follows:
| 10 minutes | 15 minutes | 30 minutes | |
| Dissolution (%) | 77 | 86 | 94 |
。
Embodiment 6
Aprepitant, sucrose and suspending agent hypromellose are carried out wet grinding, and comparative example compares, investigate the effect that monosaccharide adds.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 125 | 50.00 |
| Hypromellose E5 | 25 | 10.00 |
| Sucrose | 100 | 40.00 |
| Purified water * | 850 | -- |
| Solid amounts to | 250 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP 05 is connected water-cooling system with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 7 degree.Aprepitant and hypromellose E5 are mixed into homogeneous solid mixture.Taking a certain amount of purified water puts in Agitation Tank, opens stirring, Aprepitant and hypromellose E5 is slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintains stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, grinding injection speed is 1L/ minute, and grinding bead particle diameter is 0.3 millimeter.After grinding starts, the sucrose slowly added in Agitation Tank, adds rear maintenance circular grinding.Sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 50 minutes | 70 minutes | 90 minutes | 110 minutes |
| d10 | 87.5 | 0.33 | 0.17 | 0.16 | 0.13 | 0.13 |
| d50 | 242 | 0.64 | 0.33 | 0.27 | 0.25 | 0.24 |
| d90 | 950 | 2.95 | 0.97 | 0.65 | 0.60 | 0.58 |
Under the prescription adding sucrose, when being ground to 70 minutes, particle diameter reaches minima substantially, and along with the prolongation of time, agglomeration does not occur granule, minimum grain size when can maintain 70 minutes.As can be seen here, sucrose has good protective effect to the nano microcrystalline of Aprepitant in process of lapping, avoids the reunion crystallization of Aprepitant.
See accompanying drawing 1
Embodiment 7(comparative example)
Aprepitant and suspending agent hypromellose are carried out wet grinding, does not add monosaccharide, as a comparison embodiment.
Formula:
| Title | Amount (gram) | Percentage by weight |
| Aprepitant | 125 | 83.33 |
| Hypromellose E5 | 25 | 16.67 |
| Purified water * | 850 | -- |
| Solid amounts to | 150 | 100.00 |
*: remove in technical process
Preparation:
Wet grinding mill ECM-AP05 is connected water-cooling system respectively with Agitation Tank (jacketed and stirring paddle), and cold water temperature is 7 DEG C.Aprepitant and hypromellose E5 are mixed into homogeneous solid mixture.Separately get purified water and be placed in Agitation Tank, open stirring, Aprepitant and hypromellose E5 are slowly added in above-mentioned Agitation Tank, adds while stirring, form uniform suspension, maintain stirring, for subsequent use.Be connected with wet grinding mill pipeline by above-mentioned Agitation Tank, open grinder, the suspension of Aprepitant is inhaled in wet grinding mill from Agitation Tank, and after of short duration grinding, grinding injection speed is 1L/ minute, and grinding bead particle diameter is 0.3 millimeter.Get back in Agitation Tank by another root pipeline again, so form circulation, sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer BetterSize2000, measurement result is as follows:
| Particle size distribution (um) | Initially | 30 minutes | 50 minutes | 70 minutes | 90 minutes |
| d10 | 86.5 | 0.30 | 0.18 | 0.16 | 0.15 |
| d50 | 235 | 0.60 | 0.36 | 0.30 | 0.30 |
| d90 | 924 | 2.90 | 0.90 | 0.80 | 1.90 |
Under the prescription not adding monosaccharide, when being ground to 70 minutes, particle diameter reaches minima, and along with the prolongation of time, Aprepitant generation reunion crystallization, particle diameter increases, and cannot return to minimum particle diameter state.
Embodiment 8
Aprepitant suspension above-described embodiment 6 and embodiment 7 obtained respectively adopts spray dryer LPG-10 spraying dry, and product temperature is 60-80 degree, and centrifugal atomizing dish frequency is 40, the complex of obtained Aprepitant after drying completes.The Aprepitant complex above-mentioned two embodiments 6 and embodiment 7 obtained respectively is by the second method paddle method of Chinese Pharmacopoeia 2005 editions, and with 37 degrees Celsius of 900ml0.1%SLS aqueous solutions for dissolution medium, rotating speed is 100 turns per minute, detects.Input amount counts 80 milligrams with Aprepitant, and stripping result is as follows:
| Dissolution (%) | 10 minutes | 15 minutes | 30 minutes |
| Embodiment 7 | 63 | 74 | 70 |
| Embodiment 6 | 79 | 85 | 89 |
Dissolution results shows, is obviously better than embodiment 7 at the Aprepitant solubility property of embodiment 6.The product of embodiment 7, in process in leaching, occurred the state that dissolubility reduces, and embodiment 6 does not have similar phenomenon to produce, sees accompanying drawing 2.
Claims (6)
1. an Aprepitant complex, is characterized in that, described Aprepitant complex is grouped into by the one-tenth of following weight percent proportioning:
Aprepitant 30%-70%, monosaccharide 20%-60%, suspending agent 10%-50%.
2. Aprepitant complex according to claim 1, is characterized in that, described monosaccharide be selected from glucose, sucrose or fructose one or more; Suspending agent is selected from sodium carboxymethyl cellulose, hypromellose, polyoxyethylene, hydroxypropyl cellulose, hydroxyethyl-cellulose, poloxamer or polyvidone.
3. prepare the method for Aprepitant complex as claimed in claim 1, it is characterized in that, the method comprises the following steps:
(1) respectively wet grinding mill is connected water-cooling system, the Agitation Tank of jacketed and stirring paddle is connected water-cooling system, and cold water temperature is 7 DEG C-10 DEG C;
(2) get the purified water being equivalent to raw material Aprepitant weight 5-20 times and be placed in Agitation Tank, open stirring, Aprepitant and suspending agent are slowly added in Agitation Tank, adds while stirring, form uniform suspension, maintain stirring, for subsequent use;
(3) discharging opening of above-mentioned Agitation Tank is connected the charging aperture of wet grinding mill with pipeline, the discharging opening of wet grinding mill is connected the charging aperture of Agitation Tank with pipeline, open grinder, grinding chamber internal rotor rotates and forms negative pressure, by the suspension of Aprepitant from the sucking-off of Agitation Tank discharging opening, enter in wet grinding mill by the charging aperture of wet grinding mill, of short duration grinding is after 1-2 minute, the suspension of Aprepitant is got back in Agitation Tank by the discharging opening of wet grinding mill, so forms circulation;
(4) after formation circulation, slowly added in Agitation Tank by monosaccharide, circulation limit, limit adds, and after having added, maintains circular grinding state;
(5) sample in circular grinding process, measure the particle diameter of granule in suspension with laser particle analyzer, when the grain diameter of test result display more than 90% is less than 600 nanometer, stop grinding, the suspension of obtained Aprepitant complex;
(6) suspension of Aprepitant complex is adopted spraying dry, temperature is 60 DEG C-80 DEG C, and centrifugal atomizing dish frequency is 40, and spraying dry terminates the complex of rear obtained Aprepitant.
4. prepare the method for Aprepitant complex according to claim 3, it is characterized in that, step (3) grinding injection speed is 1-10L/ minute, and grinding bead particle diameter is 0.1-0.5 millimeter.
5. prepare the method for Aprepitant complex according to claim 3, it is characterized in that, temperature during step (6) spraying dry is 60 DEG C-80 DEG C, and centrifugal atomizing dish frequency is 40.
6. according to the Aprepitant complex described in claim 1, it is characterized in that, described Aprepitant complex is prepared into capsule, tablet, powder, granule or Oral Dry Suspensions according to a conventional method.
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| CN107198690A (en) * | 2017-06-14 | 2017-09-26 | 武汉励合生物医药科技有限公司 | A kind of preparation method of Aprepitant compound |
| CN108030924A (en) * | 2017-12-29 | 2018-05-15 | 成都百裕制药股份有限公司 | A kind of preparation method of high stability Aprepitant composition |
| CN109134373A (en) * | 2018-08-28 | 2019-01-04 | 常州市阳光药业有限公司 | The preparation method of tolvaptan nanocrystal and oral solid formulation containing tolvaptan nanocrystal |
| CN110787125A (en) * | 2018-08-02 | 2020-02-14 | 北京化工大学 | Aprepitant nano preparation and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107198690A (en) * | 2017-06-14 | 2017-09-26 | 武汉励合生物医药科技有限公司 | A kind of preparation method of Aprepitant compound |
| CN108030924A (en) * | 2017-12-29 | 2018-05-15 | 成都百裕制药股份有限公司 | A kind of preparation method of high stability Aprepitant composition |
| CN108030924B (en) * | 2017-12-29 | 2021-01-05 | 成都百裕制药股份有限公司 | Preparation method of high-stability aprepitant composition |
| CN110787125A (en) * | 2018-08-02 | 2020-02-14 | 北京化工大学 | Aprepitant nano preparation and preparation method thereof |
| CN110787125B (en) * | 2018-08-02 | 2021-07-13 | 北京化工大学 | Aprepitant nano preparation and preparation method thereof |
| CN109134373A (en) * | 2018-08-28 | 2019-01-04 | 常州市阳光药业有限公司 | The preparation method of tolvaptan nanocrystal and oral solid formulation containing tolvaptan nanocrystal |
| CN109134373B (en) * | 2018-08-28 | 2024-01-12 | 常州市阳光药业有限公司 | Preparation method of tolvaptan nanocrystals and oral solid preparation containing tolvaptan nanocrystals |
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| Publication number | Publication date |
|---|---|
| CN104367551B (en) | 2017-06-13 |
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