CN104352468A - Preparation method of olanzapine tablet highly dissolved out in vitro in pH range of 5.5-7.0 - Google Patents
Preparation method of olanzapine tablet highly dissolved out in vitro in pH range of 5.5-7.0 Download PDFInfo
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- CN104352468A CN104352468A CN201410675111.2A CN201410675111A CN104352468A CN 104352468 A CN104352468 A CN 104352468A CN 201410675111 A CN201410675111 A CN 201410675111A CN 104352468 A CN104352468 A CN 104352468A
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Abstract
The invention discloses a preparation method of olanzapine tablet highly dissolved out in vitro in a pH range of 5.5-7.0. The preparation method of the olanzapine tablet highly dissolved out in vitro in the pH range of 5.5-7.0 has the advantages that the olanzapine tablet can be quickly dissolved out in different pH value environments in a digestive system of a human body without being influenced by the pH value environment, the absorption bioavailability of the human body is improved, and the clinical treatment effect is guaranteed.
Description
Technical field
The present invention relates to the manufacture method of the Olanzapine Tablets of external high stripping in a kind of pH value 5.5 ~ 7.0 scope, belong to field of pharmaceutical preparations.
Background technology
Olanzapine, chemical name is: 2-methyl isophthalic acid 0-(4-methyl isophthalic acid-piperazine)-4H-thieno [2,3-b] [1,5] benzodiazepine.Olanzapine is a kind of psychosis, has pharmacological action to multiple receptor system.Animal experiment shows, olanzapine has affinity to 5-HT, dopamine D, multiple receptor such as α-epinephrine, histamine H etc.Animal behavior research shows, olanzapine has 5-HT, dopamine and cholinergic antagonism, conforms to its receptors bind situation.The in vitro and in vivo 5-HT2 receptor affinity of olanzapine is greater than the affinity of itself and d2 dopamine receptor.Electrophysiologic study shows, olanzapine optionally reduces the electric discharge of a Limbic system of brain (A10) dopaminergic neuron, and very little on the motor function path impact of striatum (A9).Olanzapine can reduce conditioned avoidance response when the dosage level lower than the stiff firmly reaction of generation.Different from other psychosis, olanzapine can increase reaction in anxiety test.Contrast clinical trial result shows, olanzapine can significantly improve feminine gender and the positive symptom.
Olanzapine is a kind of BCS II grade of compound, and the olanzapine under general particle size range is in pH value 5.5 ~ 7.0 scope, and the dissolubility of olanzapine in water and pH6.8 phosphate buffer is almost insoluble.
Summary of the invention
For above-mentioned technical problem, the object of the present invention is to provide the preparation method of the Olanzapine Tablets of external high stripping in a kind of pH value 5.5 ~ 7.0 scope.
Above-mentioned purpose of the present invention is achieved by the following technical solution: the manufacture method of the Olanzapine Tablets of external high stripping in a kind of pH value 5.5 ~ 7.0 scope, comprises the steps:
1) comminution by gas stream micronization, by olanzapine is crossed, Particle size requirements D90 < 110 μm, for subsequent use;
2) diluent, disintegrating agent are sieved respectively, Particle size requirements D90 < 75 μm, for subsequent use;
3) step 1 gained olanzapine and step 2 gained diluent, disintegrating agent are mixed;
4) by step 3 gained material dry method panel;
5) by step 4 gained material granulate;
6) by step 5 gained material and mix lubricant, upper machine tabletting.
In the present invention, the preferred D90 < of the Particle size requirements described in step 1 30 μm, more preferably D90 < 5 μm.
In the present invention, diluent described in step 2 refers to the inert substance in order to dilution, specifically, is selected from one or more in lactose monohydrate, mannitol or microcrystalline Cellulose; Described disintegrating agent refers in pharmaceutical composition, tablet is made to split rapidly the material being broken into fine particle, thus make the rapid solution absorption of functional component, play a role, include but not limited to dried starch (such as corn starch or potato starch), carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose (PH101); Described sieving preferably crosses 100 mesh sieves.Further, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone are preferably crossed 100 mesh sieves by step 2 respectively, and Particle size requirements D90 < 75 μm is for subsequent use.
In the present invention, step 3 preferably adopts times amount to progressively increase method, is first mixed with lactose (1:2) by olanzapine, then after mixing respectively with microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross 100 mesh sieves, to put in V-Mixer premix 30 minutes.
In the present invention; step 4 preferably presses dry granulating machine panel; oil pressure is risen to 1.5MPa, adds the material of mix homogeneously, according to compacting medicine bulk strength and machine operation; regulate extrusion wheel velocity 3.6-5.3rpm; feeding spiro rod rotating speed 1-24rpm, oil cylinder working-pressure (oil cylinder working-pressure with 1.0MPa ~ 2.0MPa for degree), makes its three effectively coordinate; to compacting medicine block hardness moderate (such as 1 ~ 2kg), rewinding.
In the present invention, step 5 is that material is carried out granulate with being provided with 24 order steel-wire screen rocking type granule-finishing machines; Granulate is complete, removes thick head with 24 mesh sieves, removes fine powder with 100 mesh sieves; Collect thick head and fine powder, machine of again going up is granulated, and carries out granulate with 24 order steel-wire screen rocking type granule-finishing machines, and sieves granule; The fine powder amount crossing 100 mesh sieves should cross whole particulate matter doses 40%.If the fine powder amount crossing 100 mesh sieves is undesirable, continue above-mentioned steps, until meet the requirements.
In the present invention, in step 6, described lubricant refers in pharmaceutical composition, increase the mobility of (or powder) grain, reduce the material of (or powder) frictional force between grain and punch die, include but not limited to magnesium stearate, micropowder silica gel, Pulvis Talci, magnesium laurylsulfate etc.Further, satisfactory granule is preferably put in V-Mixer by step 6, adds magnesium stearate, mix 5 minutes, rewinding, by machine tabletting on granule, in tableting processes, monitoring tablet weight variation (± 3%) and hardness (more than 12.0kg).
As preferably, the step of coating after said method step 6, can also be comprised, specifically take Opadry film-coating premixing auxiliary material by coating element sheet weightening finish 4.0%, stir and be dissolved in quantitative purified water the coating solution being mixed with 15.0%, continuous stirring 40 minutes.It is the Film coated tablets (sheet temperature: 40 ~ 50 DEG C) of uniform color, bright and clean exquisiteness by plain sheet bag.
In a preferred version of the present invention, the adjuvant (i.e. diluent, disintegrating agent and lubricant) adopted in said method is lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate.Described olanzapine is 10 weight portions preferably; The preferred 30-60 weight portion of microcrystalline Cellulose, more preferably 50-60 weight portion; Lactose 90-120 weight portion, more preferably 100-120 weight portion; The preferred 4-5 weight portion of polyvinylpolypyrrolidone; The preferred 25-35 weight portion of low-substituted hydroxypropyl cellulose, more preferably 25-30 weight portion; The preferred 7-8 weight portion of magnesium stearate, more preferably 7.60-7.86 weight portion, most preferably 7.76-7.8 weight portion.
Further, in an instantiation of said method, olanzapine and each adjuvant have following weight portion: olanzapine 10 weight portion, microcrystalline Cellulose 50 weight portion, lactose 100 weight portion, low-substituted hydroxypropyl cellulose 30 weight portion, polyvinylpolypyrrolidone 4 weight portion, magnesium stearate 7.76 weight portion.
In another instantiation of said method, olanzapine and each adjuvant have following weight portion: olanzapine 10 weight portion, microcrystalline Cellulose 50 weight portion, lactose 100 weight portion, low-substituted hydroxypropyl cellulose 30 weight portion, polyvinylpolypyrrolidone 5 weight portion, magnesium stearate 7.80 weight portion.
In another instantiation of said method, olanzapine and each adjuvant have following weight portion: olanzapine 10 weight portion, microcrystalline Cellulose 30 weight portion, lactose 120 weight portion, low-substituted hydroxypropyl cellulose 35 weight portion, polyvinylpolypyrrolidone 4 weight portion, magnesium stearate 7.86 weight portion.
In another instantiation of said method, olanzapine and each adjuvant have following weight portion: olanzapine 10 weight portion, microcrystalline Cellulose 60 weight portion, lactose 90 weight portion, low-substituted hydroxypropyl cellulose 25 weight portion, polyvinylpolypyrrolidone 5 weight portion, magnesium stearate 7.60 weight portion.
The invention has the beneficial effects as follows that solve under the pH value environment different in digestion of Olanzapine Tablets all can Fast Stripping, not by the interference of pH value environment, improve absorption of human body bioavailability, ensure clinical therapeutic efficacy.
Accompanying drawing explanation
Fig. 1 is the dissolubility comparison diagram of olanzapine in different pH value environment.
Fig. 2 is the particle size distribution figure of olanzapine D90 < 5 μm in the embodiment of the present invention.
Fig. 3 is the particle size distribution figure of olanzapine D90 < 100 μm in the embodiment of the present invention.
Fig. 4 is the particle size distribution figure of olanzapine D90 < 30 μm in the embodiment of the present invention.
Fig. 5 is embodiment 1-9 Olanzapine Tablets accumulation stripping curve figure in water.
Fig. 6 is embodiment 1-9 Olanzapine Tablets accumulation stripping curve in phosphate buffer (pH6.8).
Fig. 7 is embodiment 11-14 Olanzapine Tablets accumulation stripping curve figure in water.
Fig. 8 is embodiment 11 Olanzapine Tablets accumulation stripping curve figure in four kinds of solvents.
Detailed description of the invention
Prescription 1
Olanzapine crude drug particle size distribution data
Embodiment 1
Olanzapine is crossed comminution by gas stream micronization, particle diameter is by requirement D90 < 110 μm in prescription, for subsequent use.Lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone are crossed 100 mesh sieves respectively, Particle size requirements D90 < 75 μm, for subsequent use.Prescription 1 takes olanzapine, lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, magnesium stearate respectively according to plan, for subsequent use.Adopt times amount to progressively increase method, first olanzapine is mixed with lactose (1:2), then after mixing respectively with microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, mistake 100 mesh sieves, to put in V-Mixer premix 30 minutes.Confirm that equipment is normal by dry granulating machine S.O.P.; open facility for granulating; conditioning equipment; oil pressure is risen to 1.5MPa; add the material of mix homogeneously; according to compacting medicine bulk strength and machine operation; regulate extrusion wheel velocity, feeding spiro rod rotating speed, oil cylinder working-pressure (oil cylinder working-pressure with 1.0MPa ~ 2.0MPa for degree); its three is effectively coordinated; to compacting medicine block hardness (1 ~ 2kg) moderate (can make the moderate granule of hardness for degree), rewinding.Material is carried out granulate with being provided with 24 order steel-wire screen rocking type granule-finishing machines; Granulate is complete, removes thick head with 24 mesh sieves, removes fine powder with 100 mesh sieves; Collect thick head and fine powder, machine of again going up is granulated, and carries out granulate with 24 order steel-wire screen rocking type granule-finishing machines, and sieves granule; The fine powder amount crossing 100 mesh sieves should cross whole particulate matter doses 40%.If the fine powder amount crossing 100 mesh sieves is undesirable, continue above-mentioned steps, until meet the requirements.Satisfactory granule is put in V-Mixer, adds magnesium stearate, mix 5 minutes, rewinding.Tabletting: by machine tabletting on granule, in tableting processes, monitoring tablet weight variation (± 3%) and hardness (more than 12.0kg).Collect plain sheet, remove medicated powder, lucifuge, sealing is preserved, for coating.Take Opadry film-coating premixing auxiliary material by coating element sheet weightening finish 4.0%, stir and be dissolved in quantitative purified water the coating solution being mixed with 15.0%, continuous stirring 40 minutes.It is the Film coated tablets (sheet temperature: 40 ~ 50 DEG C) of uniform color, bright and clean exquisiteness by plain sheet bag.
Embodiment 2-9
With reference to method described in embodiment 1, prepare according to prescription 2-9.
Embodiment 10 dissolution in vitro detects
Get product, according to dissolution method (Chinese Pharmacopoeia 2010 editions two annex Ⅹ C second methods), using each solvent 900ml as dissolution medium, 50 turns per minute of rotating speed, measure in accordance with the law, after 5,10,20,30 clocks, get 10ml respectively, filter, get subsequent filtrate, according to ultraviolet visible spectrophotometry (Chinese Pharmacopoeia 2010 editions two annex IV A), take dissolution medium as blank, in 258 ± 2nm wavelength, place measures absorbance in accordance with the law.It is appropriate that precision takes olanzapine reference substance, and add 0.1mol/L hydrochloric acid solution and be prepared into stock solution, each precision measures in right amount, carries out being diluted to mensuration concentration, shake up, be measured in the same method with the solvent of correspondence.Accumulative stripping quantity is calculated by reference substance relative method.
Testing result is as follows:
Known from the stripping curve water, olanzapine raw material particle size controls D90 < 10 μm, the size controlling D90 < 75 μm of adjuvant, coordinate dry technology for production, product hardness is at more than 12kg, and when 10min, stripping quantity also reaches more than 85%, when 30min, complete stripping.
Known from the stripping curve phosphate buffer (pH6.8), olanzapine raw material particle size controls D90 < 10 μm, the size controlling D90 < 75 μm of adjuvant, coordinate dry technology for production, product hardness is at more than 12kg, and when 10min, stripping quantity also reaches more than 85%, when 30min, complete stripping.
Dry granulation production technology product-degradation impurity monitoring
From degradation impurity, coordinate dry granulation production technology, the impurity of product is more stable.
Embodiment 11-14
In order to adapt to the raw material particle size distribution of maximum possible, simultaneously also in order to avoid stripping failure possibility, have selected olanzapine raw material particle size distribution d
(0.9)the particle of 10 μm compares, and in addition, microcrystalline Cellulose/lactose is ratio (50/100) 50%, and namely prescription 7 can proceed the optimization of prescription adjuvant variable.
Adopt 7a-7d prescription respectively, with embodiment 1 preparation method.
Embodiment 15 dissolution in vitro detects
Optimize from prescription 7, these adjuvant prescriptions may be used to produce, and do not affect dissolution in vitro.Get prescription 7a and carry out stripping curve mensuration at other three kinds of dissolution mediums.
From four kinds of stripping curves, olanzapine is through micronization, and control D90 < 10 μm, after dry technology for production, the dissolved corrosion in product four kinds of dissolution mediums is consistent.
Claims (10)
1. the manufacture method of the Olanzapine Tablets of external high stripping within the scope of pH value 5.5-7.0, comprises the steps:
1) comminution by gas stream micronization, by olanzapine is crossed, Particle size requirements D90 < 110 μm, for subsequent use;
2) diluent, disintegrating agent are sieved respectively, Particle size requirements D90 < 75 μm, for subsequent use;
3) step 1 gained olanzapine and step 2 gained diluent, disintegrating agent are mixed;
4) by step 3 gained material dry method panel;
5) by step 4 gained material granulate;
6) by step 5 gained material and mix lubricant, upper machine tabletting.
2. the method for claim 1, the preferred D90 < of the Particle size requirements wherein described in step 1 30 μm, more preferably D90 < 5 μm.
3. method as claimed in claim 1 or 2, one or more wherein in diluent lactose monohydrate, mannitol or microcrystalline Cellulose described in step 2; Described disintegrating agent is selected from one or more in corn starch, potato starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose, microcrystalline Cellulose (PH101); Described sieving preferably crosses 100 mesh sieves; Preferably lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone are crossed 100 mesh sieves respectively, Particle size requirements D90 < 75 μm.
4. the method as described in any one of claim 1-3, wherein step 3 adopts times amount to progressively increase method, is first mixed by 1:2 with lactose by olanzapine, then after mixing respectively with microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone, cross 100 mesh sieves, premix 30 minutes.
5. the method as described in any one of claim 1-4; wherein step 4 presses dry granulating machine panel; oil pressure is risen to 1.5MPa; add the material of mix homogeneously; regulate extrusion wheel velocity 3.6-5.3rpm; feeding spiro rod rotating speed 1-24rpm, oil cylinder working-pressure 1.0MPa-2.0MPa, to compacting medicine block hardness 1-2kg rewinding.
6. the method as described in any one of claim 1-5, wherein step 5 is that material is carried out granulate with being provided with 24 order steel-wire screen rocking type granule-finishing machines; Granulate is complete, removes thick head with 24 mesh sieves, removes fine powder with 100 mesh sieves; Collect thick head and fine powder, machine of again going up is granulated, and carries out granulate with 24 order steel-wire screen rocking type granule-finishing machines, and sieves granule; Cross the fine powder amount of 100 mesh sieves to being no more than whole particulate matter doses 40%.
7. the method as described in any one of claim 1-6, wherein in step 6, described lubricant is selected from one or more in magnesium stearate, micropowder silica gel, Pulvis Talci, magnesium laurylsulfate; Preferably satisfactory granule is put in mixer, add magnesium stearate, mix 5 minutes, rewinding, by machine tabletting on granule.
8. the method as described in any one of claim 1-7, wherein adopted diluent, disintegrating agent and lubricant are respectively lactose, microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, polyvinylpolypyrrolidone and magnesium stearate.
9. the method as described in any one of claim 1-8, wherein said olanzapine is 10 weight portions preferably; The preferred 30-60 weight portion of microcrystalline Cellulose, more preferably 50-60 weight portion; Lactose 90-120 weight portion, more preferably 100-120 weight portion; The preferred 4-5 weight portion of polyvinylpolypyrrolidone; The preferred 25-35 weight portion of low-substituted hydroxypropyl cellulose, more preferably 25-30 weight portion; The preferred 7-8 weight portion of magnesium stearate, more preferably 7.60-7.86 weight portion, most preferably 7.76-7.8 weight portion.
10. method, wherein olanzapine 10 weight portion, microcrystalline Cellulose 50 weight portion, lactose 100 weight portion, low-substituted hydroxypropyl cellulose 30 weight portion as claimed in claim 9, polyvinylpolypyrrolidone 4 weight portion, magnesium stearate 7.76 weight portion;
Or olanzapine 10 weight portion, microcrystalline Cellulose 50 weight portion, lactose 100 weight portion, low-substituted hydroxypropyl cellulose 30 weight portion, polyvinylpolypyrrolidone 5 weight portion, magnesium stearate 7.80 weight portion;
Or olanzapine 10 weight portion, microcrystalline Cellulose 30 weight portion, lactose 120 weight portion, low-substituted hydroxypropyl cellulose 35 weight portion, polyvinylpolypyrrolidone 4 weight portion, magnesium stearate 7.86 weight portion;
Or olanzapine 10 weight portion, microcrystalline Cellulose 60 weight portion, lactose 90 weight portion, low-substituted hydroxypropyl cellulose 25 weight portion, polyvinylpolypyrrolidone 5 weight portion, magnesium stearate 7.60 weight portion.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410675111.2A CN104352468A (en) | 2014-11-21 | 2014-11-21 | Preparation method of olanzapine tablet highly dissolved out in vitro in pH range of 5.5-7.0 |
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| CN201410675111.2A CN104352468A (en) | 2014-11-21 | 2014-11-21 | Preparation method of olanzapine tablet highly dissolved out in vitro in pH range of 5.5-7.0 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105106141A (en) * | 2015-09-22 | 2015-12-02 | 成都欣捷高新技术开发有限公司 | Freeze-drying oral preparation containing olanzapine and preparation method of freeze-drying oral preparation |
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| CN101904824A (en) * | 2009-06-04 | 2010-12-08 | 齐鲁制药有限公司 | Olanzapine orally-disintegrating tablet preparation and preparation method thereof |
| CN102451162A (en) * | 2010-10-21 | 2012-05-16 | 重庆市力扬医药开发有限公司 | Olanzapine medicine absorbed through oral mucosa |
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2014
- 2014-11-21 CN CN201410675111.2A patent/CN104352468A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101904824A (en) * | 2009-06-04 | 2010-12-08 | 齐鲁制药有限公司 | Olanzapine orally-disintegrating tablet preparation and preparation method thereof |
| CN102451162A (en) * | 2010-10-21 | 2012-05-16 | 重庆市力扬医药开发有限公司 | Olanzapine medicine absorbed through oral mucosa |
Non-Patent Citations (2)
| Title |
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| 刘春平 等: "粉末直接压片法概述及其应用思考", 《北方药学》 * |
| 刘春平: "片剂工艺创新及其产业化应用的思考", 《中国医药导报》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105106141A (en) * | 2015-09-22 | 2015-12-02 | 成都欣捷高新技术开发有限公司 | Freeze-drying oral preparation containing olanzapine and preparation method of freeze-drying oral preparation |
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Application publication date: 20150218 |