CN110917200A - Oral solid pharmaceutical composition containing micronized form and preparation method thereof - Google Patents
Oral solid pharmaceutical composition containing micronized form and preparation method thereof Download PDFInfo
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- CN110917200A CN110917200A CN201911255516.XA CN201911255516A CN110917200A CN 110917200 A CN110917200 A CN 110917200A CN 201911255516 A CN201911255516 A CN 201911255516A CN 110917200 A CN110917200 A CN 110917200A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
Abstract
The invention discloses a solid preparation taking the micronized homoharringtonine derivative as an active ingredient, and discloses an oral solid pharmaceutical composition containing a micronized form, wherein the composition contains a pharmacologically active agent with a therapeutically effective amount; crospovidone or povidone; and oral solid pharmaceutical compositions for pharmacologically active agents. The homoharringtonine derivative has excellent in-vitro dissolution rate and better dissolution rate under various pH conditions, effectively ensures that the medicament can be well absorbed in different crowds, and solves the problem that the bioavailability of the medicament in vivo is reduced to influence the curative effect because the existing homoharringtonine derivative medicament is not easy to dissolve in the gastrointestinal tract environment in vivo.
Description
Technical Field
The invention relates to an oral solid pharmaceutical composition containing a micronized form, belonging to the technical field of medicines.
Background
Chronic myelogenous leukemia is a malignant myeloproliferative disease, accounting for about 20% of adult leukemias. According to the research data of Globocan in 2012, 351965 new leukemia cases and 265461 death cases are shared in 2012 all over the world. The emergence of the Bcr-Abl fusion protein is the major pathogenic mechanism of CML. With the application of Bcr-Abl inhibitors, the problem of acquired drug resistance, particularly the emergence of Bcr-ablT315I mutant, has become a great challenge in treating CML, and the development of novel Bcr-Abl inhibitors or drugs with other action mechanisms is urgently needed.
The appearance of Bcr-Abl fusion proteins is the major pathogenic mechanism of CML, and acquired point mutations in Bcr-Abl kinase are the major cause of drug resistance. In 2001, imatinib, a first generation Bcr-Abl kinase inhibitor, was approved by the FDA in the united states for marketing, and its potent inhibitory activity, good selectivity, low toxic side effects and good in vivo properties brought breakthrough progress for clinical treatment of CML. However, with the large-scale clinical use of imatinib, more and more clinical medical records show different degrees of drug resistance, the target gene Bcr-Abl mutation is the main cause of drug resistance, and more than 100 drug resistance mutations have been found. The second generation Bcr-Abl drugs nilotinib and dasatinib and the like can overcome various mutation drug resistance. The T315I mutant drug resistance has the widest distribution and the stubborn, and the second generation drugs have no effect. The third generation Bcr-Abl drug ponatinib is the only third generation Bcr-Abl inhibitor marketed against T315I, has severe toxic side effects and is warned by the FDA black box. The problem of drug resistance caused by Bcr-Abl inhibitors, particularly the problem of drug resistance of T315I, remains a great challenge in the treatment of chronic granulocytic leukemia, and the development of novel Bcr-Abl third-generation inhibitors and other action mechanism drugs is urgently needed.
The cephalotaxine compounds show high-efficiency inhibitory activity on various Bcr-Abl inhibitor drug-resistant mutations in the treatment of the chronic myelocytic leukemia, including Bcr-ablT315I mutation, and have good development prospect. Cephalotaxine represents a compound, homoharringtonine (HHT), which is approved by the FDA in the united states on day 26/10/2012 for the treatment of chronic myeloid leukemia in the Chronic Phase (CP) or Accelerated Phase (AP) that is resistant to two or more tyrosine kinase inhibitors. HHT was the first approved natural drug for the treatment of CML and was also the first approved inhibitor of protein synthesis. HHT can bind to ribosome 60S large subunit A site, competitively inhibit the binding of transfer RNA and ribosome, and further inhibit the extension of peptide chain and the synthesis of downstream oncogenic protein.
Although HHT shows potent inhibitory activity against a variety of Bcr-Abl mutations including Bcr-AblT315I, it still has many problems to be improved upon: 1) serious toxic and side effects including bone marrow suppression, cardiotoxicity, gastrointestinal reaction and the like; 2) poor bioavailability, slow and incomplete oral absorption of HHT.
Systematic chemical composition studies were performed on cephalotaxine alkaloids in cephalotaxus ricini (c. Aiming at a protein synthesis inhibitor cephalotaxine compound, reasonable structure optimization and anti-CML activity evaluation are carried out by using computer-aided drug design, the anti-CML activity of the compound is researched by a structural-activity relationship, a homoharringtonine derivative CY0076 with high activity, good drug forming property and small side effect is obtained, and the potential treatment effect of the compound on chronic granulocytic leukemia is deeply researched. The project belongs to the research of new targets and new molecules for treating chronic granulocytic leukemia, and lays a foundation for further developing novel anti-chronic granulocytic leukemia innovative drugs. The derivatives were initially evaluated for cellular activity in vitro, and for preferred compounds, their pharmacokinetics and anti-CML activity in vivo were further evaluated.
An oral solid pharmaceutical composition for said homoharringtonine derivative, wherein the oral solid pharmaceutical composition is in micronized form. In another embodiment of the invention, the pharmaceutically acceptable inactive excipient may be one or both of polymeric crospovidone or povidone. In another embodiment of the present invention, the solid oral solid pharmaceutical composition suitable for oral delivery may further comprise a diluent. Furthermore, in another embodiment of the present invention, the solid oral solid pharmaceutical composition suitable for oral delivery may further comprise a lubricant. In another embodiment, the present invention relates to a method of increasing the oral bioavailability of a pharmacologically active agent comprising administering to a subject in need of said pharmacologically active agent an effective amount of an oral solid pharmaceutical composition of the present invention.
The medicine micro powder is prepared into oral preparation, and has fast absorption in body, high bioavailability, low medicine dosage, low resource consumption and environment friendship.
Disclosure of Invention
The present invention has been made to overcome the above-mentioned problems of the prior art.
It is an object of the present invention to provide an oral solid pharmaceutical composition in micronized form.
It is another object of the present invention to provide a process for the preparation of said oral solid pharmaceutical composition in micronized form.
The invention can be realized by the following technical scheme: the micronized homoharringtonine derivative and the water-soluble high molecular carrier material are subjected to high-shear mixing granulation, so that the aggregation of particles can be prevented, and the particle size of the medicine is kept below 20 mu m, and more preferably, the average particle size is smaller than 10 mu m.
The invention aims to solve the problems and provide a micronized homoharringtonine derivative with proper solubility, wherein the micronized homoharringtonine derivative has good dissolution characteristics under various pH conditions, and effectively ensures that the medicine can play corresponding roles in different crowds. Meanwhile, the invention also provides an oral solid pharmaceutical composition containing the micronized homoharringtonine derivative as an active ingredient, and the micronized homoharringtonine derivative and a water-soluble high molecular carrier material are subjected to high-shear mixing granulation, so that the aggregation of particles in the standing process can be prevented.
Another object of the present invention is to provide a process for preparing the above micronized homoharringtonite derivatives oral solid pharmaceutical composition.
Micronized homoharzia serrataEster derivatives characterized by a 95% cumulative volume (D) of homoharringtonine derivatives90) The particle diameter of (2) is 10 μm or less.
The micronized homoharringtonite derivative is preferably characterized by a 95% cumulative particle size (D)90) Is less than 20 mu m; more preferably, it has a 95% cumulative particle diameter (D)90) Below 10 μm.
As a preferred embodiment of the present invention, the present invention also provides a process for preparing micronized homoharringtonin derivative, which comprises pre-pulverizing homoharringtonin derivative to obtain a powder with a particle size D90Micronizing below 10 μm by micronizing technology to obtain superfine particles with particle size of 5-15 μm.
As a preferred embodiment of the present invention, the pre-pulverization is carried out by using conventional pulverization techniques in the art, including, but not limited to, milling, extrusion, collision, cutting, and the pulverization apparatus used includes, but not limited to, a ball mill, a jet mill, and preferably a jet mill using collision technique.
As a preferred embodiment of the present invention, the micronization technique is selected from mechanical pulverization, jet pulverization, ultrasonic pulverization; jet milling techniques are preferred.
Preferably, the jet milling technology adopts the following specific operation steps: injecting the pre-pulverized homoharringtonine derivative into a superfine pulverizer together with freeze-dried inert gas, and pulverizing by using high-speed airflow, preferably, the freeze-dried inert gas, preferably air or nitrogen, is at a temperature of 5-25 ℃, preferably 5-10 ℃, and has a water content of less than or equal to 2%, and the air is injected into the superfine pulverizer at a pressure of 1.5-2.0MPa, preferably 1.5-1.8MPa, and the working pressure of the superfine pulverizer is 1.5-2.0MPa, preferably 1.5-1.8MPa, and the internal working temperature is 2-10 ℃, preferably 2-6 ℃.
The invention also aims to provide an oral solid pharmaceutical composition, which consists of the micronized homoharringtonine derivative, a water-soluble high polymer carrier material and other pharmaceutically acceptable auxiliary materials, wherein the micronized homoharringtonine derivative accounts for 10-40% of the total weight of the oral solid pharmaceutical composition, the water-soluble high polymer carrier material accounts for 10-30% of the total weight of the oral solid pharmaceutical composition, and the other auxiliary materials are selected from more than one of a disintegrating agent, a binding agent, a wetting agent, a lubricating agent and a glidant. The pharmaceutically acceptable carrier is widely used in the technical field of medicament, and can be appropriately selected by a person skilled in the art, or other carriers or auxiliary materials which can be thought of by the person skilled in the art.
It is another object of the present invention to provide an oral solid pharmaceutical composition containing homoharringtonite derivatives, which can be tablets, capsules and granules, preferably tablets. The preparation method of the micronized homoharringtonite derivative oral solid pharmaceutical composition comprises the following steps:
(1) micronised particle size D90High-shear mixing granulation is carried out on homoharringtonine derivative with 10 mu m and carrier material in a wet mixing granulator;
(2) adding other adjuvants into the mixture, mixing, adding binder solution or wetting agent to obtain soft material, sieving with 20-30 mesh sieve to obtain wet granule, and air drying at 50-70 deg.C until the water content is less than 4%;
(3) sieving the dry granules with a 20-mesh sieve, grading, adding a lubricant, and mixing;
(4) tabletting, and making into capsule or bag.
As one of the preferable embodiments, the invention adopts the ultramicro pulverization technology to prepare the homoharringtonine derivative with the grain diameter of 10 μm, and the micronized homoharringtonine derivative and the water-soluble high molecular carrier material are subjected to high-shear mixing granulation, so that the aggregation of particles in the standing process can be prevented, the water solubility of the homoharringtonine derivative is improved, the bioavailability is improved, and the treatment effect of the medicine can be improved.
It is still another object of the present invention to provide a micronized homoharringtonite derivative oral solid pharmaceutical composition, wherein the particle size of the micronized homoharringtonite derivative at 95% cumulative volume is below 60 μm; preferably the particle size of the micronized homoharringtonite derivative at 95% cumulative volume is below 30 μm.
It is a further object of the present invention to provide the use of an oral solid pharmaceutical composition of micronized homoharringtonite derivatives for the preparation of a pharmaceutical formulation with antihistamine action.
The micronized homoharringtonite derivative and the composition thereof have the following treatment effects of treating patients in acute stage and accelerated stage of Chronic Myelogenous Leukemia (CML) or chronic stage after α -interferon treatment failure.
The preparation method of the micronized homoharringtonine derivative comprises the steps of crushing, grinding, spray drying or sieving by a proper sieve and the like of homoharringtonine derivative raw materials. The inventors of the present application have surprisingly found that only homoharringtonite derivative D90The solid preparation taking the micronized homoharringtonine derivative as an active ingredient has excellent in-vitro dissolution rate below 20 microns, and most preferably below 10 microns, the micronized homoharringtonine derivative and a water-soluble high molecular carrier material are subjected to high-shear mixing granulation, so that aggregation of particles in a placing process can be prevented, the water solubility of the homoharringtonine derivative is improved, the bioavailability is improved, the medicine can effectively play corresponding roles in different crowds, and the problem that the existing homoharringtonine derivative medicine is not easy to dissolve when being influenced by other medicines or food in the in-vivo gastrointestinal tract environment, the bioavailability of the medicine in the body is reduced, and the curative effect is influenced is solved.
The in vitro dissolution rate of the micronized homoharringtonine derivative provided by the invention is evaluated by measuring the dissolution rate of the derivative in a medium with various pH values, and the measuring method is implemented according to the first method or the second method of the appendix XC of the Chinese pharmacopoeia 2015 edition.
Drawings
FIG. 1 example 1 particle size determination profile of homoharringtonite derivatives after jet milling.
Detailed Description
The following examples are further illustrative of the present invention and are in no way intended to limit the scope of the invention. The present invention is further illustrated in detail below with reference to examples, but it should be understood by those skilled in the art that the present invention is not limited to these examples and the preparation method used.
Example 1
Micronizing homoharringtonin derivative with MQP01 jet mill to obtain D90Pulverizing fine powder with particle size of less than 10 μm under the following conditions: the low-temperature drying air temperature is 6 deg.C, water content is 0.5%, air inlet pressure is 0.8MPa, the working pressure of the ultra-micro pulverizer is 0.8MPa, the internal working temperature is 6 deg.C, and pulverizing times are 3 times.
Example 2
Micronizing homoharringtonin derivative raw material with jet mill, collecting the pulverized raw material particles, measuring the particle diameter of the fine powder with Beckmann LS 13320 XR laser diffraction particle size analyzer, and collecting micronized homoharringtonin derivative with particle diameter below 10 μm at 95% cumulative volume.
Example 3 solid pharmaceutical composition for oral administration 1-4
| Raw and auxiliary materials (g)/1000 | Prescription | 1 | |
|
|
Comparative example 1 |
| Homoharringtonine derivative | 50 | 15 | 50 | 50 | 50 (not crushed, particle size 80 μm or more) | |
| Hydroxypropyl cellulose | 30 | 30 | 45 | 15 | 30 | |
| |
20 | 30 | 10 | 30 | 20 | |
| Microcrystalline cellulose | 35 | 60 | 30 | 40 | 35 | |
| |
10 | 10 | 10 | 10 | 10 | |
| |
3 | 3 | 3 | 3 | 3 | |
| |
2 | 2 | 2 | 2 | 2 |
Example 4 solid pharmaceutical composition for oral administration 5-7
| Raw and auxiliary materials (g)/1000 | Prescription | 5 | |
Prescription 7 | Comparative example 2 |
| Homoharringtonine derivative | 50 | 50 | 50 | 50 (not crushed, particle size 80 μm or more) | |
| Polyethylene glycol 4000 | 15 | 30 | 0 | 15 | |
| Polyethylene glycol 6000 | 0 | 0 | 30 | 0 | |
| Microcrystalline cellulose | 18 | 20 | 20 | 18 | |
| Starch | 52 | 35 | 35 | 52 | |
| |
10 | 10 | 10 | 10 | |
| |
3 | 3 | 3 | 3 | |
| |
2 | 2 | 2 | 2 |
Example 5
The formulations 1 to 4 of preparation example 3
(1) Firstly, adding micronized homoharringtonine derivative and hydroxypropyl cellulose into a granulating pot, and carrying out high-shear mixing at a stirring speed of 1000rpm and a chopping speed of 1500rpm for 20 min;
(2) adding lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into water in a granulating pan, granulating at stirring speed of 400rpm and chopping speed of 200rpm, adding liquid within 4min, and granulating for 2 min;
(3) drying the sieved wet granules in a drying oven at 60 ℃, controlling the moisture of the granules to be below 3%, and sieving the granules by a 30-mesh sieve for finishing;
(4) adding the dry particles and the micro silica gel powder into a mixing device, setting parameters to be high frequency 30HZ and low frequency 5HZ, and mixing for 20 min;
(5) tabletting, and controlling the hardness to be 70N-80N to obtain the finished product.
Example 6
The formulations 5 to 7 of preparation example 4
(1) Firstly, adding micronized homoharringtonine derivative and polyethylene glycol 4000/polyethylene glycol 6000 into a granulating pot, and carrying out high-shear mixing at a stirring speed of 1200rpm and a chopping speed of 1400rpm for 15 min;
(2) adding starch, microcrystalline cellulose, croscarmellose sodium and sodium lauryl sulfate into water in a granulating pan, granulating at stirring speed of 400rpm and chopping speed of 200rpm, adding liquid within 4min, and granulating for 2 min;
(3) drying the sieved wet granules in a drying oven at 60 ℃, controlling the moisture of the granules to be below 3%, and sieving the granules by a 30-mesh sieve for finishing;
(4) adding the dry particles and the micro silica gel powder into a mixing device, setting parameters to be high frequency 30HZ and low frequency 5HZ, and mixing for 20 min;
(5) and (3) filling the granules into a No. 1 capsule to obtain the capsule.
Comparative example 1
(1) Mixing conventional homoharringtonine derivative (with particle diameter of above 80 μm) with hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium laurylsulfate, adding appropriate amount of water, wet granulating, oven drying, grading, adding silica gel micropowder, mixing, and tabletting.
Comparative example 2
(1) Mixing conventional homoharringtonine derivative (with particle diameter of above 80 μm) with polyethylene glycol 4000, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, and sodium laurylsulfate, adding appropriate amount of water, wet granulating, oven drying, grading, adding superfine silica gel powder, mixing, and making into No. 1 capsule.
Example 7 dissolution
Determination of the laboratory apparatus: AT-7smart dissolution apparatus SOTAXAgilent1100, Switzerland, Agilent instruments, Inc
The dissolution conditions were determined by dissolution and release rate measurement (second method of 0931 in the four ministry of the chinese pharmacopoeia 2015 edition), using 900ml of acetate buffer (containing 0.2 part of sodium dodecyl sulfate) with ph4.5 as dissolution medium, rotating at 50 rpm, and sampling at 45 min.
The 45 minute dissolution rates are shown in tables 1 and 2 below.
| Sample (I) | Water +0.3% tween 80 | Tween 80 pH1.0+0.3% | Tween 80 pH4.5+0.3% | Tween 80 pH6.8+0.3% |
| Example 3 |
84.8±8.8 | 83.0±5.2 | 85.1±3.0 | 83.8±8.8 |
| EXAMPLE 4 |
89.8±9.8 | 88.5±10.8 | 89.1±9.8 | 87.8±9.8 |
| Comparative example 1 | 22.1±9.8 | 20.9±6.3 | 21.9±4.5 | 20.1±9.8 |
| Comparative example 2 | 14.1±6.8 | 19.3±6.0 | 15.8±4.7 | 16.1±6.8 |
As a result: example 3 both formula 1 and formula 5 of example 4 are superior to comparative examples 1 and 2, and it can be seen that the preparation consisting of homoharringtonite derivatives having a specific particle size distribution according to the present invention has better dissolution than the prior art preparation prepared using homoharringtonite derivatives having a conventional particle size distribution.
Test example 2
Determination of the solubility of homoharringtonite derivatives of different particle size:
according to preparation examples 1 to 3, homoharringtonite derivatives having a specific particle size were prepared to prepare supersaturated solutions, and the solubilities of homoharringtonite derivatives in an aqueous solution of 0.3% tween 80 were calculated by measuring the contents, with the results as follows:
| D90 | more than 100 μm | 80~ |
40~20μm | Less than 10 μm |
| Solubility μ g/ml | 29.58 | 25.77 | 69.63 | 193.82 |
And (4) conclusion: from the above test data, it is found that the solubility of homoharringtonite derivatives decreases with increasing particle size, and particularly, the solubility increases greatly at 10 μm or less.
Claims (11)
1. An oral solid pharmaceutical composition comprising a micronized form and a process for its preparation, comprising:
a. a homoharringtonine derivative is used as active ingredient of medicine;
b. micronizing the pharmaceutically active ingredient to an average particle size of less than 20 μm; and
c. a water-soluble polymer material that prevents aggregation of the micronized pharmaceutically active ingredient during placement; and
d. other pharmaceutically acceptable inactive excipients.
2. A composition according to claim 1 wherein said average particle size is less than 10 μm.
3. The composition of claim 1 wherein the homoharringtonine derivative is a homoharringtonine derivative.
4. The composition according to claim 1, wherein the water-soluble polymer material is selected from one of polyethylene glycol 4000-6000 and hydroxypropyl cellulose.
5. The composition according to claim 1, wherein the oral solid pharmaceutical composition is selected from homoharringtonite derivatives.
6. The composition according to claim 1, further comprising a diluent.
7. A composition according to claim 6 wherein the diluent is selected from microcrystalline cellulose, lactose.
8. The composition according to claim 1, further comprising a glidant.
9. The composition of claim 8 wherein the glidant is aerosil.
10. Solid oral solid pharmaceutical composition of homoharringtonine derivatives according to any of claims 1 to 9, having the use of increasing oral bioavailability.
11. Use of a composition according to any one of claims 1 to 9 for the preparation of a medicament for the treatment of chronic myeloid leukemia.
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| CN202010864952.3A CN111743902A (en) | 2019-12-10 | 2020-08-25 | Oral solid pharmaceutical composition containing micronized form and preparation method thereof |
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| CN103610674B (en) * | 2013-12-09 | 2015-01-07 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
| CN104257611B (en) * | 2014-09-28 | 2015-06-17 | 昆山龙灯瑞迪制药有限公司 | Pharmaceutical composition containing micronized fexofenadine hydrochloride |
| CN110917200A (en) * | 2019-12-10 | 2020-03-27 | 广州艾格生物科技有限公司 | Oral solid pharmaceutical composition containing micronized form and preparation method thereof |
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