CN111743902A - 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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- CN111743902A CN111743902A CN202010864952.3A CN202010864952A CN111743902A CN 111743902 A CN111743902 A CN 111743902A CN 202010864952 A CN202010864952 A CN 202010864952A CN 111743902 A CN111743902 A CN 111743902A
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- pharmaceutical composition
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- oral solid
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- homoharringtonine
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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 relates to the technical field of medicines, in particular to an oral solid pharmaceutical composition containing a micronized form and a preparation method thereof. The invention discloses an oral solid pharmaceutical composition containing a micronized form, wherein the micronized homoharringtonine derivative has good dissolution characteristics under various pH conditions, and the corresponding effects of the medicine in different crowds are effectively ensured. Moreover, the interaction of the micronized homoharringtonine derivative and the water-soluble polymer carrier material can prevent the aggregation of particles in the process of placing, improve the solubility of the homoharringtonine derivative, improve the bioavailability and avoid that the homoharringtonine derivative medicine is not easy to dissolve out when being influenced by other medicines or foods in the gastrointestinal tract environment in vivo, so that the bioavailability of the medicine in vivo is reduced to influence the curative effect.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to an oral solid pharmaceutical composition containing a micronized form and a preparation method thereof. The present invention claims the benefit of a chinese patent (application No. 201911255516.X) filed 2019, 12, 10, all of which are incorporated herein in their entirety.
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 showed potent inhibitory activity against a variety of Bcr-Abl mutations including Bcr-ablT315I, HHT was absorbed slowly and incompletely by oral administration and had poor bioavailability.
Disclosure of Invention
The invention provides an oral solid pharmaceutical composition containing a micronized form and a preparation method thereof, which solve the problem of poor bioavailability of homoharringtonine.
The specific technical scheme is as follows:
the present invention provides an oral solid pharmaceutical composition comprising a micronized form comprising:
a. the active ingredients of the medicine are as follows: homoharringtonine derivatives, said pharmaceutically active ingredient being micronized to an average particle size below 20 μm;
b. a water-soluble polymer material that prevents aggregation of the micronized pharmaceutically active ingredient during placement;
d. other pharmaceutically acceptable inactive excipients.
In the invention, the water-soluble polymer material and the homoharringtonine derivative are adsorbed together through the physical and chemical adsorption, so that the particles can be prevented from being aggregated and enlarged, and the reduction of the dissolution of the medicine caused by the increase of the particle size in the storage process after production is avoided.
The micronized homoharringtonine derivative provided by the invention has good dissolution characteristics under various pH conditions, and effectively ensures that the medicine can play corresponding roles in different crowds. Moreover, the interaction of the micronized homoharringtonine derivative and the water-soluble polymer carrier material can prevent the aggregation of particles in the process of placing, improve the solubility of the homoharringtonine derivative, improve the bioavailability and avoid that the homoharringtonine derivative medicine is not easy to dissolve out when being influenced by other medicines or foods in the gastrointestinal tract environment in vivo, so that the bioavailability of the medicine in vivo is reduced to influence the curative effect.
In the present invention, homoharringtonine derivatives are micronized to an average particle size below 20 μm, in particular D90Is 20 μm or less, preferably the homoharringtonine derivative is micronized to an average particle size below 10 μm, in particular D90Is 10 μm or less. The applicants have surprisingly found that D of homoharringtonine derivatives is higher than that of homoharringtonine derivatives having an average particle size of 80 μm or more90The homoharringtonine derivative has excellent dissolution rate under various pH conditions and significance under the condition of less than 10 mu m. The Applicant has also found, surprisingly, that when the particle size D of the homoharringtonine derivative is large90Below 10 μm, the solubility of the homoharringtonine derivative does not increase gradually with decreasing particle size, but rather increases greatly (nearly three-fold), with unexpected technical effects.
In the invention, the homoharringtonine derivative is a compound with a structure shown in a formula (I), a compound with a structure shown in a formula (II) or a compound with a structure shown in a formula (III);
the homoharringtonine derivative serving as a medicinal active ingredient is not particularly limited, and can be any homoharringtonine derivative.
In the invention, the water-soluble polymer material is selected from one of polyethylene glycol 4000-6000 and hydroxypropyl cellulose.
In the invention, the oral solid pharmaceutical composition containing the micronized form contains the homoharringtonine derivative and the water-soluble high polymer material respectively with the mass content of 10% -40% and 10% -30%.
In the present invention, the pharmaceutically acceptable inactive excipient may be one or more than two of polymer crospovidone, povidone, and croscarmellose sodium.
The oral solid pharmaceutical composition of the invention also comprises auxiliary materials;
the auxiliary material is selected from more than one of diluent, lubricant, glidant, adhesive and wetting agent.
The diluent is selected from lactose monohydrate and/or microcrystalline cellulose;
the binder is selected from hydroxypropyl cellulose and/or starch;
the wetting agent is water;
the lubricant is sodium dodecyl sulfate;
the glidant is micro-powder silica gel.
The present invention also provides a process for the preparation of an oral solid pharmaceutical composition comprising a micronized form, comprising the steps of:
step 1: mixing micronized homoharringtonine derivative with average particle size of less than 20 μm with water-soluble polymer material by high shear mixing wet granulation to obtain mixture, adding inactive excipient and adjuvants into the mixture, mixing, preparing soft material, and drying until water content is less than 4%;
step 2: the dry granules are screened through a 30 mesh sieve, and are subjected to total mixing by adding a lubricant or a glidant to obtain the oral solid pharmaceutical composition containing a micronized form.
In the invention, the micronized homoharringtonine derivative and the water-soluble high polymer material are subjected to high-shear mixing and wet granulation, so that fine powder can be fully dispersed, and aggregation of particles in the standing process is prevented.
If the lubricant is added in the step 2, the lubricant may be added to the auxiliary materials in the step 1, or the lubricant may not be added to the auxiliary materials in the step 1, and preferably, the lubricant is added to the auxiliary materials only in the step 2 or the step 1; if the glidant is added in the step 2, the glidant can be added into the auxiliary materials in the step 1, or the glidant can not be added, and preferably, the glidant is only added into the auxiliary materials in the step 2 or the step 1.
In the invention, the preparation of the micronized homoharringtonine derivative specifically comprises the following steps: the homoharringtonine derivative is pre-pulverized to obtain superfine particles with particle diameter D90 below 10 μm, preferably 5-10 μm.
The pre-pulverization is carried out by conventional pulverization techniques in the art, including, but not limited to, milling, extruding, colliding, cutting, and the pulverization apparatus used includes, but not limited to, a ball mill, a jet mill, and a jet mill employing a collision technique.
The superfine pulverizing technology is selected from mechanical pulverizing, airflow pulverizing or ultrasonic pulverizing, preferably airflow pulverizing technology.
The jet milling technology comprises the following specific operation steps: pre-pulverizing into coarse particles, injecting into a micronizer together with freeze-dried air or nitrogen, and pulverizing with high-speed airflow. The temperature of the air or nitrogen after freeze drying is 5-25 ℃, preferably 5-10 ℃, the water content is less than or equal to 2%, the pressure of the air injected into the ultrafine pulverizer is 1.5-2.0MPa, preferably 1.5-1.8MPa, the working pressure of the ultrafine pulverizer is 1.5-2.0MPa, preferably 1.5-1.8MPa, and the internal working temperature is 2-10 ℃, preferably 2-6 ℃.
In the step 1 of the invention, in the high-shear mixing wet granulation, the stirring speed is 1200rpm, the chopping speed is 1400rpm, and the mixing time is 15 min;
after the soft material is prepared and before the drying, the method preferably further comprises the following steps: sieving with 20-30 mesh sieve to obtain wet granule.
The oral solid pharmaceutical composition of the present invention can be in the dosage forms of tablets, capsules and granules, preferably tablets.
The oral solid pharmaceutical composition provided by the invention has the advantages of quick absorption in vivo, improved bioavailability, reduced administration dosage under the same curative effect, reduced resource consumption by saving raw materials, and indirect effect of protecting environment.
The invention also provides the application of the oral solid pharmaceutical composition or the oral solid pharmaceutical composition prepared by the preparation method in preparing a medicine for treating chronic myeloid leukemia, and the oral solid pharmaceutical composition can be used for treating patients in acute stage, accelerated stage or chronic stage after failure of treatment of Chronic Myeloid Leukemia (CML).
The invention also provides the application of the oral solid pharmaceutical composition or the oral solid pharmaceutical composition prepared by the preparation method in preparing antihistamine medicines.
According to the technical scheme, the invention has the following advantages:
the invention provides an oral solid pharmaceutical composition containing a micronized form, wherein the micronized homoharringtonine derivative has good dissolution characteristics under various pH conditions, and the corresponding effects of the medicine in different crowds are effectively ensured. Moreover, the interaction of the micronized homoharringtonine derivative and the water-soluble polymer carrier material can prevent the aggregation of particles in the process of placing, improve the solubility of the homoharringtonine derivative, improve the bioavailability and avoid that the homoharringtonine derivative medicine is not easy to dissolve out when being influenced by other medicines or foods in the gastrointestinal tract environment in vivo, so that the bioavailability of the medicine in vivo is reduced to influence the curative effect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, and it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to these drawings without inventive exercise.
FIG. 1 is a graph showing the particle size measurement of the harringtonite derivative after being pulverized by a jet mill in example 2 of the present invention.
Detailed Description
In order to make the objects, features and advantages of the present invention more obvious and understandable, the technical solutions in the embodiments of the present invention will be clearly and completely described below, and it should be apparent that the embodiments described below are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The homoharringtonine derivative (compound of formula I, CAS181133-84-6) was subjected to micronization using MQP01 jet mill. And (3) crushing 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. The particle size of the micropowder is measured by a Beckmann LS 13320 XR laser diffraction particle size analyzer, and D90 is below 10 μm.
Example 2
The method of example 1 is used to micronize homoharringtonine derivative (compound of formula I) raw material, and the micronized particles of the raw material are collected to obtain micronized homoharringtonine derivative. The micro powder particle size is measured by a Beckmann LS 13320 XR laser diffraction particle size analyzer.
FIG. 1 is a graph showing the particle size measurement of homoharringtonine derivative obtained by jet milling in the jet mill of this example. As can be seen from FIG. 1, in this example D90 is 10 μm or less.
Example 3
The method of example 1 is used to micronize homoharringtonine derivative (compound of formula II) raw material, and the micronized particles of the raw material are collected to obtain micronized homoharringtonine derivative. The particle size of the micropowder is measured by a Beckmann LS 13320 XR laser diffraction particle size analyzer, and D90 is below 10 μm.
Example 4
The method of example 1 is used to micronize homoharringtonine derivative (compound of formula III) raw material, and the micronized particles of the raw material are collected to obtain micronized homoharringtonine derivative. The particle size of the micropowder is measured by a Beckmann LS 13320 XR laser diffraction particle size analyzer, and D90 is below 10 μm.
Example 5
(1) Respectively adopting the dosage of the prescription 1-the prescription 4 in the table 1, adding the micronized homoharringtonine derivative in the example 2 and the hydroxypropyl cellulose into a granulating pot, and carrying out high-shear mixing at the stirring speed of 1000rpm and the 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.
TABLE 1 amounts of the components
Comparative example 1
(1) Adopting the dosage of each component in comparative example 1 in Table 1, the homoharringtonite derivative (compound with the grain diameter of more than 80 μm in formula I) is evenly mixed with hydroxypropyl cellulose, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and sodium dodecyl sulfate;
(2) same as in steps (2) to (5) of example 5: adding appropriate amount of water, granulating by wet method, oven drying, grading, adding silica gel micropowder, mixing, and tabletting.
Example 6
(1) Respectively adopting the dosage of formula 5-formula 7 in Table 2, firstly adding the micronized homoharringtonine derivative and polyethylene glycol 4000/polyethylene glycol 6000 into a granulating pot, carrying out high-shear mixing, wherein the stirring speed is 1200rpm, the chopping speed is 1400rpm, and the mixing time is 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.
TABLE 2 amounts of the components
Comparative example 2
(1) Adopting the dosage of each component in comparative example 2 in Table 2, the homoharringtonite derivative (the grain diameter is more than 80 μm) is evenly mixed with polyethylene glycol 4000, lactose monohydrate, microcrystalline cellulose, croscarmellose sodium and sodium dodecyl sulfate;
(2) same as in steps (2) to (5) of example 4: adding appropriate amount of water, granulating by wet method, oven drying, grading, adding silica gel micropowder, mixing, and making into No. 1 capsule.
Test example 1 dissolution measurement
Determination of the laboratory apparatus: AT-7smart dissolution apparatus SOTAXAgilent1100, Switzerland, Agilent instruments, Inc
The dissolution conditions were determined by dissolution and release assay (second method 0931 of the general rule of the four parts of the 2020 edition of Chinese pharmacopoeia) using 900ml of acetate buffer (containing 0.2 part of sodium dodecyl sulfate) with pH 4.5 as dissolution medium at 50 rpm according to the method, and sampling at 45 min.
45 minute dissolution is shown in table 3.
TABLE 3 dissolution rate measurement results
As can be seen from Table 3, both of formula 1 of example 5 and formula 5 of example 6 are superior to those of comparative examples 1 and 2, and it can be seen that the present invention has a specific particle size distribution (D)90Less than 10 μm) of homoharringtonine derivatives, compared with the prior art, with a conventional particle size distribution (D)9080 μm or more) has better dissolution and is remarkable.
Test example 2 measurement of solubility
The homoharringtonite derivatives prepared in example 1 and example 2 were prepared into supersaturated solutions, and the solubility of the homoharringtonite derivatives in an aqueous solution of 0.3% tween 80 was calculated by measuring the contents, and the results are shown in table 4.
TABLE 4 results of solubility measurement
| D90 | More than 100 μm | 80～ |
40～20μm | Less than 10 μm |
| Solubility μ g/ml | 29.58 | 25.77 | 69.63 | 193.82 |
As is clear from Table 4, the present invention shows that the homoharringtonine derivative has a particle size distribution of 100 μm or more, which is higher in solubility than that of 80 to 30 μm, and that the homoharringtonine derivative has a particle size distribution of 20 μm to 80 μm, which decreases in solubility with increasing particle size, and particularly, increases in solubility significantly with a particle size of 10 μm or less.
The above-mentioned embodiments are only used for illustrating the technical solutions of the present invention, and not for limiting the same; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. An oral solid pharmaceutical composition comprising a micronized form, comprising:
a. the active ingredients of the medicine are as follows: homoharringtonine derivatives, said pharmaceutically active ingredient being micronized to an average particle size below 20 μm;
b. a water-soluble polymer material that prevents aggregation of the micronized pharmaceutically active ingredient during placement;
d. other pharmaceutically acceptable inactive excipients.
2. The oral solid pharmaceutical composition according to claim 1, wherein the pharmaceutically active ingredient is micronized to an average particle size below 10 μm.
3. The oral solid pharmaceutical composition of claim 1, wherein the homoharringtonine derivative is a compound of formula (i), a compound of formula (ii) or a compound of formula (iii);
4. the oral solid pharmaceutical composition as claimed in claim 1, wherein the water-soluble polymer material is selected from one of polyethylene glycol 4000-6000 and hydroxypropyl cellulose.
5. The oral solid pharmaceutical composition of claim 1, wherein the oral solid pharmaceutical composition in micronized form comprises 10% to 40% and 10% to 30% of the homoharringtonine derivative and the water-soluble polymeric material, respectively, by mass.
6. The oral solid pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable inactive excipients comprise one or more of the polymers crospovidone, povidone, and croscarmellose sodium.
7. The oral solid pharmaceutical composition of claim 6, further comprising an excipient;
the auxiliary materials comprise: one or more of diluents, lubricants, glidants, binders and wetting agents.
8. A process for the preparation of an oral solid pharmaceutical composition comprising a micronized form, characterized in that it comprises the following steps:
step 1: mixing micronized homoharringtonine derivative with average particle size of less than 20 μm with water-soluble polymer material by high shear mixing wet granulation to obtain mixture, adding inactive excipient and adjuvants into the mixture, mixing, preparing soft material, and drying until water content is less than 4%;
step 2: the dry granules are screened through a 30 mesh sieve, and are subjected to total mixing by adding a lubricant or a glidant to obtain the oral solid pharmaceutical composition containing a micronized form.
9. The method of claim 8, wherein the high shear mixing wet granulation process comprises a stirring speed of 1200rpm, a chopping speed of 1400rpm, and a mixing time of 15 min.
10. Use of the oral solid pharmaceutical composition of any one of claims 1 to 7 or the oral solid pharmaceutical composition prepared by the preparation method of claim 8 or 9 for preparing a medicament for treating chronic myeloid leukemia.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911255516.XA CN110917200A (en) | 2019-12-10 | 2019-12-10 | Oral solid pharmaceutical composition containing micronized form and preparation method thereof |
| CN201911255516X | 2019-12-10 |
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| CN111743902A true CN111743902A (en) | 2020-10-09 |
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| CN202010864952.3A Pending CN111743902A (en) | 2019-12-10 | 2020-08-25 | Oral solid pharmaceutical composition containing micronized form and preparation method thereof |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103610674A (en) * | 2013-12-09 | 2014-03-05 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
| CN104257611A (en) * | 2014-09-28 | 2015-01-07 | 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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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103610674A (en) * | 2013-12-09 | 2014-03-05 | 海南灵康制药有限公司 | Solid preparation containing micronized prasugrel |
| CN104257611A (en) * | 2014-09-28 | 2015-01-07 | 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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Application publication date: 20201009 |