CN104095811A - Nimodipine nanosuspension and preparation method thereof - Google Patents
Nimodipine nanosuspension and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a nimodipime nanosuspension and a preparation method thereof, and provides the preparation method of the nimodipime nanosuspension. The preparation method comprises the following steps: (1) crushing nimodipine crude drug; (2) dissolving poloxamer and hydroxypropyl methyl cellulose in a solvent, then slowly adding the crushed nimodipine nimodipine crude drug to obtain an initial suspension; and (3) grinding the initial suspension to obtain the nanosuspension.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to Nimodipime nanometer suspension and preparation method thereof.
Background technology
Nimodipine (Nimodipine) is second filial generation calcium ion antagonist, can selectively acting in cerebrovascular smooth muscle, expansion of cerebral vascular, increases cerebral blood flow, reduces the ischemic brain injury that vasospasm causes.The clinical ischemic cerebrovascular that is usually used in, the diseases such as cerebral vasospasm, apoplexy and migraine that subarachnoid hemorrhage causes, also can improve memory etc.
Nimodipine is that one is dissolved in the organic solvent such as ethanol, ether and water-fast insoluble drug.And there is serious liver first-pass effect in it, oral administration biaavailability is low.Widely used clinically is at present its injection, contains a large amount of ethanol (20-25%) in injection, and ethanol is irritant and easily produce phlebitis to blood vessel.Said preparation is in the time of clinical practice simultaneously, there is concentration low (0.2mg/ml), with easy crystallization after glucose or normal saline dilution, affect safety and the effectiveness of medication, in order to prevent the crystallization after dilution, bayer company of Germany adopts transfusion immediately after three-way valve on-line mixing, and this has improved use cost and operation easier undoubtedly, and its drip velocity and dosage wayward.Therefore efficient, the low toxicity of exploitation and stable nimodipine novel form, have great importance.
Nano suspension is a kind of new form of administration, taking surfactant or polymer as stabilizing agent, the drug particle of nanoscale is dispersed in water to the stable colloid dispersion of formation exactly.Nano suspension has increased the specific surface area of medicine, can significantly improve dissolution rate and the bioavailability of medicine; In addition, because nanocrystal particle diameter is minimum, can also increase and the adhesion of mucosa holdup time in vivo of prolong drug and improve the bioavailability of medicine.No matter be the medicine that is insoluble in water, be still not only insoluble in water but also be insoluble in oily medicine, can prepare corresponding nanocrystal by the method.Nanocrystal is a kind of preparation intermediate, can directly be prepared into injection, eye drop or spray, also can be dried by spraying, lyophilization or fluidization form composite Nano crystalline powder, and further preparation is applicable to oral dosage form.
The preparation method of nano suspension mainly contains the sedimentation method, high pressure homogenization method and polishing at present.The sedimentation method have limited its use because screening the problems such as the wayward and organic solvent residual of suitable organic solvent, process; The shortcomings such as high pressure homogenization method has been avoided adding of organic solvent, and the cycle is long but it homogenizes, equipment energy consumption is high, easy to wear, in industrial application is not very extensive; Polishing is applied widely, and the nano particle diameter of preparation is little, narrow distribution range, and preparation process is simple, and is easy to large-scale industrial production, therefore has very large development space.
The object of the present invention is to provide a kind of Nimodipime nanometer suspension and preparation method thereof, it can prepare Nimodipime nanometer suspension effectively, and the nano particle diameter of preparation is little, narrow distribution range, and cost is low, can be suitable for large-scale industrial production.
Summary of the invention
The present inventor conducts in-depth research its preparation technology of the prescription of Nimodipime nanometer suspension, find the stabilizing agent and the preparation method that use suitable Nimodipime nanometer suspension to use, adopt optional spray drying technology can effectively prepare Nimodipime nanometer suspension simultaneously.
One aspect of the present invention provides a kind of preparation method of Nimodipime nanometer suspension, said method comprising the steps of:
(1) nimodipine crude drug is pulverized;
(2) poloxamer and hypromellose are dissolved in solvent, then slowly add the nimodipine crude drug of pulverizing to obtain just suspension;
(3) first suspension is ground, obtain nano suspension.
In a preferred embodiment of the present invention, described breaking method is selected from comminution by gas stream, ball milling, mechanical activation comminution and combination thereof; Preferably, the mean diameter of crushing rear material is below 5 μ m; More preferably, the mean diameter of crushing rear material is in the scope of 0.1-5 μ m, fortunately in the scope of 0.5-4 μ m, better in the scope of 1-3 μ m.
In a preferred embodiment of the present invention, the consumption of described solvent is poloxamer and hypromellose gross weight 10-1000 times, and more preferably 50-800 doubly, is preferably 100-700 doubly.
In a preferred embodiment of the present invention, the weight ratio between poloxamer and hypromellose is 50:1-1:50, is preferably 20:1-1:20, and more preferably 10:1-1:10, most preferably is 5:1-1:5.
In a preferred embodiment of the present invention, taking described poloxamer and hypromellose gross weight as 1 weight portion, the consumption 0.01-5 weight portion of described nimodipine crude drug, is preferably 0.05-2 weight portion, more preferably 0.1-1.5 weight portion, most preferably is 0.15-1 weight portion.
In a preferred embodiment of the present invention, described grinding condition is 2000-5000RPM, and Abrasive Particle Size is 0.01-1mm; Be preferably 2500-5000RPM, Abrasive Particle Size is 0.05-0.5mm; More preferably 3500-5000RPM, Abrasive Particle Size is 0.08-0.2mm; Most preferably be 4500RPM, Abrasive Particle Size is 0.1mm.
In a preferred embodiment of the present invention, described method also comprises the steps: Nimodipime nanometer suspension to spray dry, obtains Nimodipime nanometer crystalline powder.
The present invention also provides a kind of Nimodipime nanometer suspension, and it is prepared by method of the present invention.
The present invention also provides a kind of Nimodipime nanometer crystallizing and drying powder, and it is prepared by Nimodipime nanometer suspension of the present invention.
Nimodipine is almost insoluble in water, and oral administration biaavailability is lower, and nimodipine is made nano suspension by the present invention, has solved the problems such as nimodipine dissolubility in water is little, stripping is slow, bioavailability is low; In addition, the present invention does not adopt any organic solvent, the toxic and side effects of effectively having avoided organic solvent residual to bring.And the adjuvant poloxamer and the hydroxypropyl cellulose that use in the present invention, be all inexpensive and common adjuvant, and cost is relatively low, and at high temperature stable, be convenient to follow-up dry run.
Brief description of the drawings
Fig. 1 is Nimodipime nanometer suspension particle size distribution figure of the present invention
Fig. 2 is Nimodipime nanometer suspension potential diagram of the present invention
The change of size of Nimodipime nanometer suspension when Fig. 3 is F68 and HPMC different proportion
The change of size of Nimodipime nanometer suspension when Fig. 4 is stabilizing agent and nimodipine different proportion
Fig. 5 is the stripping curve of Nimodipime nanometer suspension of the present invention and nimodipine raw material and micronization raw material
Detailed description of the invention
In the present invention, if not special explanation, percent (%) or part all refer to percetage by weight or the weight portion with respect to compositions.
In the present invention, if not special explanation, related each component or its preferred ingredient can be combined to form new technical scheme mutually.
In the present invention, if not special explanation, all embodiments mentioned in this article and preferred implementation can be combined to form new technical scheme mutually.
In the present invention, if not special explanation, all technical characterictics mentioned in this article and preferred feature can be combined to form new technical scheme mutually.
In the present invention, if there is no contrary explanation, in compositions, the content sum of each component is 100%.
In the present invention, if there is no contrary explanation, in compositions, the umber sum of each component can be 100 weight portions.
In the present invention, unless there are other explanations, numerical range " a-b " represents that the breviary that a closes to the arbitrary real array between b represents, wherein a and b are real numbers.For example numerical range " 0-5 " represents all to have listed the whole real numbers between " 0-5 " herein, and " 0-5 " just the breviary of these combinations of values represents.
In the present invention, unless there are other explanations, integer numerical range " a-b " represents that a represents to the breviary of the arbitrary integer combination between b, and wherein a and b are integers.For example integer numerical range " 1-N " represents 1,2 ... N, wherein N is integer.
In the present invention, unless there are other explanations, " its combination " represents the multicomponent mixture of described each element, for example two kinds, three kinds, four kinds and until the multicomponent mixture of maximum possible.
If do not particularly not pointed out, this description term " " used refers to " at least one ".
If do not particularly not pointed out, the benchmark of percent of the present invention (comprising percetage by weight) is all the gross weight of described compositions.
" scope " disclosed herein is with the form of lower limit and the upper limit.Can be respectively one or more lower limits, and one or more upper limit.Given range limits by a selected lower limit and a upper limit.Selected lower limit and the upper limit define the border of special scope.All scopes that can limit by this way comprise with capable of being combined, and any lower limit can be combined to form a scope with any upper limit.For example, list the scope of 60-120 and 80-110 for special parameter, be interpreted as that the scope of 60-110 and 80-120 also expects.In addition, if the minimum zone value of listing 1 and 2, and if listed maximum magnitude value 3,4 and 5, scope below can all expect: 1-3,1-4,1-5,2-3,2-4 and 2-5.
In this article, except as otherwise noted, the ratio of each component or weight all refer to dry weight.
In this article, except as otherwise noted, each operation is all carried out at normal temperatures and pressures.
In this article, except as otherwise noted, each operating procedure is all carried out in order.
In this article, except as otherwise noted, " nanocrystal ", " nano suspension " or " nanosuspension " have identical implication, can phase trans-substitution use.
According to the preparation method of the nano suspension of current report, inventor has selected multiple single and combinative stability agent to prepare Nimodipime nanometer suspension, as: lecithin, Tween 80, PLURONICS F87 (F68), sodium lauryl sulphate (SDS), hypromellose (HPMC), polyvinylpyrrolidone (PVP) etc.Found that, adopt the particle diameter of Nimodipime nanometer suspension prepared by no combination of stabilizers and stable different.While adopting separately SDS to prepare sample, produce a large amount of foams, particle diameter is larger, and stability is also poor, is that observable has precipitation to produce after placement a period of time.Sample grain prepared by employing F68 and PVP-K90, Tween 80 is through about 1mm, and easily precipitation cannot meet the demands; Sample prepared by coupling HPMC, F68, particle diameter and current potential can meet the demands, and stability is also better, adds after SDS lessly on the impact of its particle diameter, but larger on its current potential impact, stability is better.Based on above-mentioned discovery, the present inventor has completed the present invention.
One aspect of the present invention provides a kind of preparation method of Nimodipime nanometer suspension, said method comprising the steps of:
(1) nimodipine crude drug is pulverized;
(2) poloxamer and hypromellose are dissolved in solvent, then slowly add the nimodipine crude drug of pulverizing to obtain just suspension;
(3) first suspension is ground, obtain nano suspension.
In a preferred embodiment of the present invention, all relating to, is used the operating process of nimodipine all under lucifuge condition, to complete.
In the present invention, described nimodipine crude drug is conventional, can be obtained or be obtained by the method after prior art by commercially available mode.In a preferred embodiment of the present invention, described nimodipine crude drug is to obtain by commercially available mode, purchased from Zhengzhou Rui Kang pharmaceutical Co. Ltd, lot number: 20110703.
In the present invention, the method that described nimodipine crude drug is pulverized is conventional, and those of ordinary skill in the art can directly determine in conjunction with prior art the grinding mode that it is concrete again according to description of the invention.In a preferred embodiment of the present invention, described breaking method includes but not limited to comminution by gas stream, ball milling, mechanical activation comminution etc.In another preferred embodiment of the present invention, described breaking method includes but not limited to comminution by gas stream, mechanical activation comminution etc.Preferably, the mean diameter of crushing rear material is below 5 μ m.
In the present invention, the consumption of described solvent is conventional, as long as can dissolve poloxamer and hypromellose.In a preferred embodiment of the present invention, the consumption of described solvent is poloxamer and hypromellose gross weight 10-1000 times, and more preferably 50-800 doubly, is preferably 100-700 doubly.
In the present invention, described poloxamer is conventional, can be obtained or be obtained by the method after prior art by commercially available mode.In a preferred embodiment of the present invention, described poloxamer is to obtain by commercially available mode, for example, purchased from BASF Co., Ltd, and lot number: WP0D644F.
In the present invention, described hypromellose is conventional, can be obtained or be obtained by the method after prior art by commercially available mode.In a preferred embodiment of the present invention, described hypromellose is to obtain by commercially available mode, for example, purchased from Dow Chemical company, and lot number: XE06012402.
In the present invention, the weight ratio between described poloxamer and hypromellose is conventional, and those of ordinary skill in the art can directly determine in conjunction with prior art the ratio that it is concrete again according to description of the invention.But, in order to obtain better technique effect, for example higher stability etc., the weight ratio between poloxamer and hypromellose is 50:1-1:50, is preferably 20:1-1:20, more preferably 10:1-1:10, most preferably is 5:1-1:5.
In the present invention, the consumption of described nimodipine crude drug is conventional, and those of ordinary skill in the art can directly determine its concrete consumption in conjunction with prior art again according to description of the invention.In a preferred embodiment of the present invention, taking described poloxamer and hypromellose gross weight as 1 weight portion, the consumption 0.01-5 weight portion of described nimodipine crude drug, is preferably 0.05-2 weight portion, more preferably 0.1-1.5 weight portion, most preferably is 0.15-1 weight portion.
In the present invention, described Ginding process is conventional, and those of ordinary skill in the art can directly obtain concrete grinding condition according to description of the invention in conjunction with prior art.In a preferred embodiment of the present invention, in order to obtain better grinding effect, described grinding condition is 2000-5000RPM, and Abrasive Particle Size is 0.01-1mm; Be preferably 2500-5000RPM, Abrasive Particle Size is 0.05-0.5mm; More preferably 3500-5000RPM, Abrasive Particle Size is 0.08-0.2mm; Most preferably be 4500RPM, Abrasive Particle Size is 0.15mm.
The Nimodipime nanometer suspension preparing, adds that to carry out spray dried after appropriate protective agent dry, can be made into stay-in-grade faint yellow Nimodipime nanometer crystalline powder.Detect discovery through X powder diffraction and means of differential scanning calorimetry (DSC), dried Nimodipime nanometer crystalline powder, its crystal formation does not change.After the nanocrystalline powders of gained joins in appropriate distilled water, can be dispersed into rapidly the suspension of homogeneous, but particle diameter has increased slightly.Wherein a kind of or its any mixture in protective agent preferably sucrose, lactose, mannitol, sorbitol.Adopt separately lactose, in spray-drying process, product is easily bonded on cyclone separator, causes its yield lower, adopts mannitol and sorbitol effect better, and yield is high.Spray-dried powders is prepared into injection, eye drop or spray after also can adding water into suspensoid, also can be directly and adjuvant mix after fill capsule or make tablet chewable tablet etc.
The present invention provides a kind of Nimodipime nanometer suspension on the other hand, and it is prepared by method of the present invention.
The present invention provides a kind of nimodipine on the other hand, and it is prepared by nimodipine suspensoid of the present invention.
Describe bright the present invention in detail below in conjunction with embodiment, these embodiment are presented for purposes of illustration, do not limit the scope of the invention.
Embodiment
In the present invention, all supplementary materials are all conventional, can be obtained or be obtained by the method after prior art by commercially available mode.Specific as follows:
Nimodipine is purchased from Zhengzhou Rui Kang pharmaceutical Co. Ltd (lot number: 20110703);
Tween 80 is purchased from Nanjing WeiEr chemical engineering Co., Ltd's (lot number: 20120202);
Sodium lauryl sulphate is purchased from Chemical Reagent Co., Ltd., Sinopharm Group (lot number F20111207);
Polyvinylpyrrolidone is purchased from International Specialty Products company of the U.S. (lot number: WL300091511);
Poloxamer is purchased from BASF Co., Ltd (lot number: WP0D644F);
Hypromellose is purchased from Dow Chemical company (lot number: XE06012402);
Lactose is purchased from KERRY company of the U.S. (lot number 1320011614);
Mannitol is purchased from French Roquette Freres (lot number E623G).
The evaluation experimental of the indexs such as the particle diameter to Nimodipime nanometer suspension of the present invention and dried powder thereof is as follows:
1. measure the size of Nimodipime nanometer suspension
Prepared the present invention Nimodipime nanometer suspension is suitably diluted with distilled water, measure its size with Malvern2000 laser particle analyzer.
2. measure the current potential size of Nimodipime nanometer suspension
Prepared the present invention Nimodipime nanometer suspension is suitably diluted with distilled water, measure its current potential size with Malvern nano ZS laser particle analyzer.
3. spraying is dry
The Nimodipime nanometer suspension preparing is added to adopt BUCHI-290 to spray after appropriate protective agent dry, experiment parameter is sample introduction temperature: 150 DEG C; Outlet temperature: 85 DEG C; Sample introduction speed: 3ml/min.
Embodiment 1
Take PLURONICS F87 0.3g, hypromellose 1.5g, sodium lauryl sulphate 0.05g, joins in 100ml distilled water, and ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 0.2g through comminution by gas stream, continue to stir 10min, obtain just suspension; Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 4000rpm.After 30min, sample, recording particle diameter is 260nm, sees Fig. 1; Current potential is-32.7mv, sees Fig. 2.
Embodiment 2
Take Tween 80 0.1g, get PLURONICS F87 0.15g and join in 100ml distilled water, ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 0.2g through comminution by gas stream, continue to stir 10min, obtain just suspension; Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 2500rpm.After 45min, sample, survey particle diameter is 459nm.Place after 7 days and produce without precipitation, be still uniformly dispersed.
Embodiment 3
Take PLURONICS F87 0.1g, hypromellose 0.5g joins in 100ml distilled water, and ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 0.2g through comminution by gas stream, continue to stir 10min, obtain just suspension.Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 4000rpm.After 30min, sample, survey particle diameter is 222nm.
Embodiment 4
Take PLURONICS F87 0.8g, hypromellose 0.4g joins in 100ml distilled water, and ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 0.4g through comminution by gas stream, continue to stir 10min, obtain just suspension; Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 4000rpm.After 30min, sample, survey particle diameter is 199nm.Place and be still uniformly dispersed for 3 days.
Embodiment 5
Take PLURONICS F87 2.0g, hypromellose 1.0g joins in 100ml distilled water, and ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 1.0g through comminution by gas stream, continue to stir 30min, obtain just suspension; Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 4000rpm.After 30min, sample, survey particle diameter is 204nm.After placing 24h, be still uniformly dispersed.
Embodiment 6
Take PLURONICS F87 0.2g, hypromellose 0.3g joins in 100ml distilled water, and ultrasonic making it dissolved completely; Then under magnetic agitation, slowly add the nimodipine 0.2g through comminution by gas stream, continue to stir 10min, obtain just suspension; Finally pouring first suspension into feed hopper grinds.Grinding condition is: zirconium oxide bead particle diameter is 0.1mm, zirconium oxide bead consumption 65ml, rotating speed 4000rpm.After 30min, sample, survey particle diameter is 254nm.The Nimodipime nanometer suspension making is sprayed dry, inlet temperature: 150 DEG C; Outlet temperature: 85 DEG C; Sample introduction speed: 3ml/min.Obtain loose flaxen Nimodipime nanometer crystallizing and drying powder.Can redissolve rapidly with distilled water, particle diameter increases approximately 15%.
The change of size of Nimodipime nanometer suspension when embodiment 7:F68 and HPMC different proportion
Prepare Nimodipime nanometer suspension according to the mode that embodiment 3 is identical, the weight ratio of different is F68 and HPMC is respectively: 5:1,2:1,1:1,1:2 and 1:5.The particle diameter of test gained Nimodipime nanometer suspension, result is referring to Fig. 3.
Embodiment 8:F68/HPMC(stabilizing agent) change of size of Nimodipime nanometer suspension when the nimodipine crude drug different proportion
Prepare Nimodipime nanometer suspension according to the mode that embodiment 3 is identical, different is F68/HPMC(stabilizing agent) be respectively with the weight ratio of nimodipine crude drug: 1:1,3:1,6:1,9:1 and 12:1.The particle diameter of test gained Nimodipime nanometer suspension, result is referring to Fig. 4.
Embodiment 9: dissolution experiment
The Nimodipime nanometer suspension of the embodiment of the present invention 3 and nimodipine crude drug, micronization crude drug are carried out to dissolution contrast experiment, the prepared Nimodipime nanometer suspension dissolution rate of the result demonstration embodiment of the present invention 3, apparently higher than nimodipine crude drug and micronization raw material thereof, is shown in Fig. 5.Dissolution experimental technique is:
Lucifuge operation.Get the adjuvant that nimodipine crude drug 30mg, micronization crude drug 30mg are equipped with corresponding proportion, with aqueous dispersion; Each six parts of Nimodipime nanometer suspension of the present invention appropriate (containing nimodipine 30mg), measure its dissolution according to slurry method, (get sodium acetate 3g with sodium-acetate buffer, sodium lauryl sulphate 3g, adding water and make in right amount to dissolve, add acetic acid and adjust PH to 4.5, add water to 1000ml) 900ml is dissolution medium, rotating speed is per minute 75 to turn, and water temperature is 37 DEG C.Respectively 5,10,20,30,45,60min draws 10ml solution immediately through 0.22 filtering with microporous membrane, supplements equivalent fresh medium simultaneously, sample calculates the accumulation dissolution of different time after assay.
Claims (9)
1. a preparation method for Nimodipime nanometer suspension, said method comprising the steps of:
(1) nimodipine crude drug is pulverized;
(2) poloxamer and hypromellose are dissolved in solvent, then slowly add the nimodipine crude drug of pulverizing to obtain just suspension;
(3) first suspension is ground, obtain nano suspension.
2. the method for claim 1, is characterized in that, described breaking method is selected from comminution by gas stream, ball milling, mechanical activation comminution and combination thereof; Preferably, the mean diameter of crushing rear material is below 5 μ m; More preferably, the mean diameter of crushing rear material is in the scope of 0.1-5 μ m, fortunately in the scope of 0.5-4 μ m, better in the scope of 1-3 μ m.
3. the method for claim 1, is characterized in that, the consumption of described solvent is poloxamer and hypromellose gross weight 10-1000 times, and more preferably 50-800 doubly, is preferably 100-700 doubly.
4. the method for claim 1, is characterized in that, the weight ratio between poloxamer and hypromellose is 50:1-1:50, is preferably 20:1-1:20, and more preferably 10:1-1:10, most preferably is 5:1-1:5.
5. the method for claim 1, it is characterized in that, taking described poloxamer and hypromellose gross weight as 1 weight portion, the consumption 0.01-5 weight portion of described nimodipine crude drug, be preferably 0.05-2 weight portion, more preferably 0.1-1.5 weight portion, most preferably is 0.15-1 weight portion.
6. the method for claim 1, is characterized in that, described grinding condition is 2000-5000RPM, and Abrasive Particle Size is 0.01-1mm; Be preferably 2500-5000RPM, Abrasive Particle Size is 0.05-0.5mm; More preferably 3500-5000RPM, Abrasive Particle Size is 0.08-0.2mm; Most preferably be 4500RPM, Abrasive Particle Size is 0.1mm.
7. the method for claim 1, is characterized in that, described method also comprises the steps: Nimodipime nanometer suspension to spray dry, obtains Nimodipime nanometer crystalline powder.
8. a Nimodipime nanometer suspension, it is prepared by method claimed in claim 1.
9. a nimodipine, it is prepared by nimodipine suspensoid claimed in claim 8.
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| CN112107546A (en) * | 2020-09-23 | 2020-12-22 | 哈药集团技术中心 | Oral dry suspension containing nimodipine and preparation method thereof |
| CN112546000A (en) * | 2020-12-30 | 2021-03-26 | 海南海神同洲制药有限公司 | Clindamycin palmitate hydrochloride dry suspension and preparation method thereof |
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| CN109528632A (en) * | 2017-09-21 | 2019-03-29 | 广州市恒诺康医药科技有限公司 | Nimodipine pharmaceutical composition, nimotop vial and preparation method thereof |
| CN107837231A (en) * | 2017-11-02 | 2018-03-27 | 中国药科大学 | A kind of Nimodipime nanometer method and its dry suspensoid agent |
| CN112107546A (en) * | 2020-09-23 | 2020-12-22 | 哈药集团技术中心 | Oral dry suspension containing nimodipine and preparation method thereof |
| CN112546000A (en) * | 2020-12-30 | 2021-03-26 | 海南海神同洲制药有限公司 | Clindamycin palmitate hydrochloride dry suspension and preparation method thereof |
| CN112546000B (en) * | 2020-12-30 | 2023-06-20 | 海南海神同洲制药有限公司 | Clindamycin palmitate hydrochloride dry suspension and preparation method thereof |
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