CN108186586B - Allylestrenol tablet and preparation method thereof - Google Patents
Allylestrenol tablet and preparation method thereof Download PDFInfo
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- CN108186586B CN108186586B CN201810172722.3A CN201810172722A CN108186586B CN 108186586 B CN108186586 B CN 108186586B CN 201810172722 A CN201810172722 A CN 201810172722A CN 108186586 B CN108186586 B CN 108186586B
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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
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
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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
- A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
Abstract
The invention provides an allylestrenol tablet which is prepared by uniformly mixing and tabletting allylestrenol and auxiliary materials and is characterized in that the auxiliary materials comprise internal auxiliary materials and external auxiliary materials, the allylestrenol and the internal auxiliary materials are uniformly mixed to prepare medicine-containing granules or powder, and the medicine-containing granules or powder and the external auxiliary materials are uniformly mixed and tabletted to prepare the allylestrenol tablet, wherein the internal auxiliary materials are polyethylene glycol carrier materials, and the external auxiliary materials are fillers, disintegrants, adhesives, glidants or lubricants. The allylestrenol tablet disclosed by the invention is very stable, good in quality, less in impurity, higher in dissolution property compared with the originally ground tablet, high in dissolution rate and high in dissolution speed, and the prepared granules have good flowability and compressibility.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to an allylestrenol tablet and a preparation method thereof.
Background
Allylestrenol (Allylestrenol)
Chemical name: (17 beta) -17- (2-propenyl) estr-4-en-17-ol
(17)-17-(2-Propenyl)estr-4-en-17-ol
CAS:432-60-0
Structural formula (xvi):
allylestrenol is an artificially synthesized progestogen, a synthetic orally effective progestone drug. The progestational activity of the allylestrenol is obviously stronger than that of progesterone, the allylestrenol has no androgenic activity, and the activity of trophoblast cells can be increased to stimulate the function of a placenta, so that the allylestrenol can be used for threatened abortion, particularly hormone-deficient abortion. The allylestrenol is close to a natural chemical structure, so that the allylestrenol has the advantages of effective oral absorption, stable metabolism, high selectivity on progesterone receptors, no estrogen and androgen effect, capability of enhancing the concentration and activity of oxytocin, reducing the level of oxytocin, relieving the stimulation of oxytocin on the uterus and antagonizing the stimulation of prostaglandin on the uterus. Progesterone-induced blocking factor (PIBF) is critical for embryo survival. The progesterone receptor is activated early in pregnancy to form PIBF, triggering embryonic protective immunoregulatory mechanisms: inducing the generation of protective asymmetric antibody, forming protective cellular immune response mainly including Th2, and inhibiting the activity of natural killer cells. And the allylestrenol can trigger the formation of PIBF and embryonic protective immunoregulation, so that the immune reaction between the mother body and the embryo is converted from rejection to protection.
Allylestrenol as a synthetic progestogen, which was applied as early as 1973 for the treatment of spontaneous and premature abortion, has been marketed in several tens of countries. The originally developed tablets of allylestrenol were produced by the great pharmaceutical factory of regel, hungari (Gedeon Richter Ltd.), registered in china in 2000 and imported for sale, with the trade names: multi-force mare (Turinal). Each tablet contains 5mg of allylestrenol. The product is favorable for clinical use in China, is popular and has been received in the basic medical insurance medicine catalogue in China.
CN103550179 discloses an allylestrenol tablet and a preparation method thereof, wherein the allylestrenol tablet prepared by controlling the content ratio of allylestrenol and poloxamer within a specific range and carrying out a wet granulation process has rapid and complete dissolution characteristics. However, the invention has not been studied on the aspects of compressibility, content uniformity, stability and the like of the product.
CN1271286A discloses the coating of coated dosage units of a composition comprising a steroid having two hydrogen atoms at position 3 of the steroid skeleton, wherein the steroid comprises allylestrenol, which coating prevents the steroid from migrating from the composition. But does not really relate to the development of an allylestrenol formulation.
CN107073127A discloses a solid oral dosage form of lipophilic compound, which is also allylestrenol, and this invention can realize lymphatic absorption of specific lipophilic compound by adding some fat components containing monoglyceride of long chain fatty acid and/or triglyceride of long chain fatty acid in the prescription, further improving oral bioavailability. In the invention, silicon dioxide is used as an excipient to adsorb the required liquid amount, however, the silicon dioxide cannot be well compressed, the prepared tablet has poor compressibility, various auxiliary materials and complicated process.
Allylestrenol tablets play an important role in the treatment of spontaneous and premature births. However, in the various prior art solutions disclosed, there are 2 major difficulties in developing tablets of allylestrenol, with respect to the lesser number of tablets of allylestrenol: 1. poor water solubility; 2. the specification is small, only 5mg, and the content uniformity is easily unqualified. In addition, the dissolution rate of the traditional process is mainly increased by micronization, and the generated dust can affect the health of workers.
Disclosure of Invention
The invention aims to provide an allylestrenol tablet, which overcomes the technical defects that dust is generated when the dissolution rate is increased by micronization in the prior art to influence the health of workers, the specification is small, the mixing is difficult and the like in the production process, has stable quality, high dissolution speed and high dissolution rate, improves the bioavailability of the medicine, reduces the administration dosage, reduces the adverse reaction of the medicine, has simple and efficient production process, and is suitable for industrial application.
The specific technical scheme of the invention is as follows:
the allylestrenol tablet is prepared by uniformly mixing and tabletting allylestrenol and auxiliary materials, and is characterized in that the auxiliary materials comprise internal auxiliary materials and external auxiliary materials, the allylestrenol and the internal auxiliary materials are uniformly mixed to prepare medicine-containing granules or powder, and the medicine-containing granules or powder and the external auxiliary materials are uniformly mixed and tableted to prepare the allylestrenol tablet, wherein the internal auxiliary materials are selected from one or more than two of polyethylene glycol carrier materials, and the external auxiliary materials are selected from one or more than two of filling agents, disintegrating agents, bonding agents, glidants and lubricating agents.
The allylestrenol tablet, wherein the internal auxiliary materials are selected from one or more than two of solid polyethylene glycol carrier materials; preferably, the internal auxiliary materials are selected from one or more than two of PEG1000, PEG1500, PEG2000, PEG3000, PEG4000, PEG6000, PEG8000 and PEG 20000; more preferably, the internal auxiliary materials are selected from one or more of PEG4000, PEG6000 and PEG 8000.
The allylestrenol tablet comprises 1:2-200 parts by weight of allylestrenol and auxiliary materials added in the allylestrenol tablet; preferably, the weight ratio of the allylestrenol to the auxiliary materials added in the allylestrenol is 1: 5-100; more preferably, the weight ratio of the allylestrenol to the auxiliary materials added internally is 1: 5-50.
The allylestrenol tablet described above, wherein: the filler is selected from one or more of microcrystalline cellulose, lactose, anhydrous lactose, sucrose, starch, pregelatinized starch, mannitol, sorbitol and xylitol, preferably one or more of microcrystalline cellulose, mannitol, lactose and starch, and more preferably one or more of microcrystalline cellulose and lactose; the disintegrating agent is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose, preferably one or more of crospovidone, sodium carboxymethyl starch and croscarmellose sodium, and more preferably is crospovidone; the adhesive is selected from one or more of povidone, starch slurry, hydroxypropyl methyl cellulose and hydroxypropyl cellulose, preferably one or more of povidone, starch slurry and hydroxypropyl methyl cellulose, and more preferably povidone; the lubricant is selected from one or more of magnesium stearate and stearic acid, and is more preferably magnesium stearate; the glidant is selected from one or more of silicon dioxide and talcum powder, and more preferably silicon dioxide.
Preferably, the allylestrenol tablet comprises, by weight, 0.1-10% of allylestrenol, 1-80% of polyethylene glycol carrier material, 15-98% of filler, 0.1-30% of disintegrant, 0.1-30% of binder, 0-5% of lubricant and 0-5% of glidant.
As a specific embodiment, the allylestrenol tablet is characterized in that the internal auxiliary material is polyethylene glycol 4000, polyethylene glycol 6000 or polyethylene glycol 8000; the additional auxiliary materials are microcrystalline cellulose, crospovidone, povidone, magnesium stearate and silicon dioxide.
Preferably, the allylestrenol tablet comprises, by weight, 0.5-5% of allylestrenol, 10-50% of polyethylene glycol carrier material, 1-5% of crospovidone, 1-5% of povidone, 20-80% of microcrystalline cellulose, 0.1-2% of magnesium stearate and 0.1-2% of silicon dioxide.
The allylestrenol tablet is prepared by uniformly mixing allylestrenol and an internal addition auxiliary material, heating to melt, cooling and crushing to obtain medicine-containing granules or powder. Preferably, the heating temperature is controlled to be 90-130 ℃, and more preferably 100-120 ℃.
Preferably, the allylestrenol and the auxiliary materials added in the allylestrenol are heated and melted, and the discharging speed is adjusted to ensure that the residence time of the materials in the heating part of the equipment is 20 seconds to 1 minute, more preferably 30 seconds to 50 seconds, so that the materials have good dispersing effect and the risk of drug impurities caused by temperature is avoided.
In the research of the allylestrenol tablet, through a large number of comparative tests, the inventor surprisingly finds that the polyethylene glycol carrier material is used as an internal addition auxiliary material, the polyethylene glycol internal addition auxiliary material and the allylestrenol are firstly mixed uniformly and prepared into medicine-containing granules or powder, and then the medicine-containing granules or powder and the pharmaceutically acceptable auxiliary material are mixed and then pressed into the tablet, so that the obtained tablet greatly improves the solubility and dissolution rate of the medicine in water, thereby increasing the absorption of the allylestrenol in a human body, improving the bioavailability and increasing the curative effect. And the unexpected effect is also surprisingly obtained, namely, the melted allylestrenol contains hydroxyl, is a high-quality hydrogen bond donor, can form hydrogen bonds with a polyethylene glycol carrier, can be better melted and mixed, so that the uniformity is greatly improved, the melting points of the solid polyethylene glycol and the allylestrenol are close, and the proper heating temperature is controlled, so that the complete melting of the two can be ensured, and the drug decomposition caused by overhigh temperature can be avoided.
The tablet of the invention not only greatly improves the solubility and dissolution speed of the medicine in water, improves the bioavailability of the medicine, increases the curative effect, reduces the administration dosage of the medicine and reduces the adverse reaction of the medicine, but also effectively solves the problem that the content uniformity of the allylestrenol tablet is easy to be unqualified due to small dosage. Moreover, the production process and production equipment are simple, the energy consumption is low, the cost is low, the yield is high, the continuous and closed production is realized, no dust pollution is caused in the production process, no organic solvent is required to be added, and the method is very suitable for industrial production.
Drawings
FIG. 1 is a graph showing the dissolution profiles of example 1 and the original tablets.
Detailed Description
The following examples are presented to illustrate and understand the nature of the invention, but are not intended to limit the scope of the invention in any way.
Example 1:
allylestrenol tablets (5 mg/tablet), 1000 tablets, were prepared using the ingredients listed in table 1.
Table 1:
the preparation process comprises the following steps:
the allylestrenol raw material and polyethylene glycol 6000 are mixed uniformly, the mixture is placed into a hot-melt extruder, the heating temperature is controlled to be 100-120 ℃, and the discharging speed is adjusted to enable the retention time of the material in a heating part of equipment to be 30-50 seconds. The extrudate was cut into small pieces and cooled. Pulverizing with pulverizer, adding polyvinylpolypyrrolidone and polyvinylpolypyrrolidone K30Mixing with microcrystalline cellulose, and adding dioxygenMixing silicon and magnesium stearate for 5 min, and tabletting.
Example 2:
allylestrenol tablets (5 mg/tablet), 1000 tablets, were prepared using the ingredients listed in table 2.
Table 2:
the preparation process comprises the following steps:
the method comprises the steps of uniformly mixing an allylestrenol raw material and polyethylene glycol 4000, putting the mixture into a hot-melt extruder, controlling the heating temperature to be 90-130 ℃, and adjusting the discharging speed to enable the residence time of the material in a heating part of equipment to be 20-60 seconds. The extrudate was cut into small pieces and cooled. Pulverizing with pulverizer, adding sodium carboxymethyl starch and polyvidone K30Mixing with microcrystalline cellulose, adding silicon dioxide and magnesium stearate, mixing for 5 min, and tabletting.
Example 3:
allylestrenol tablets (5 mg/tablet), 1000 tablets, were prepared using the ingredients listed in table 3.
Table 3:
the preparation process comprises the following steps:
the method comprises the steps of uniformly mixing an allylestrenol raw material and polyethylene glycol 6000, putting the mixture into a hot-melt extruder, controlling the heating temperature to be 90-130 ℃, and adjusting the discharging speed to enable the residence time of the material in a heating part of equipment to be 20-60 seconds. The extrudate was cut into small pieces and cooled. Pulverizing with a pulverizer, adding crospovidone, hydroxypropyl methylcellulose and lactose, mixing, adding silicon dioxide and magnesium stearate, mixing for 5 min, and tabletting.
Example 4:
tablets (5 mg/tablet) of allylestrenol were prepared 1000 tablets using the ingredients listed in table 4.
Table 4:
the preparation process comprises the following steps:
the allylestrenol raw material and polyethylene glycol 8000 are uniformly mixed, put into a hot-melt extruder, the heating temperature is controlled to be 100-130 ℃, and the discharging speed is adjusted to ensure that the residence time of the material in the heating part of the equipment is 30-60 seconds. The extrudate was cut into small pieces and cooled. Pulverizing with pulverizer, adding polyvinylpolypyrrolidone and polyvinylpolypyrrolidone K30Mixing with microcrystalline cellulose, adding silicon dioxide and magnesium stearate, mixing for 5 min, and tabletting.
Example 5:
allylestrenol tablets (5 mg/tablet), 1000 tablets, were prepared using the ingredients listed in table 5.
Table 5:
the preparation process comprises the following steps:
the allylestrenol raw material and polyethylene glycol 6000 are mixed uniformly, the mixture is placed into a hot-melt extruder, the heating temperature is controlled to be 100-120 ℃, and the discharging speed is adjusted to enable the retention time of the material in a heating part of equipment to be 30-50 seconds. The extrudate was cut into small pieces and cooled. Pulverizing with pulverizer, adding polyvinylpolypyrrolidone and polyvinylpolypyrrolidone K30Mixing with microcrystalline cellulose, adding silicon dioxide and magnesium stearate, mixing for 5 min, and tabletting.
Accelerated stability study of the examples and original grinding sheet
1. Sample acceleration conditions: the sample is placed in a high-density polyethylene bottle for packaging, placed under the conditions of the temperature of 40 +/-2 ℃ and the relative humidity of 75 +/-5 percent, and sampled for checking the characters, dissolution rate, content and related substances after 6 months of accelerated test.
2. The determination method comprises the following steps:
1) the dissolution method comprises taking sodium dodecyl sulfate solution (1 g sodium dodecyl sulfate dissolved in water to 1000ml)1000ml as dissolution medium, operating at 37 deg.C and 75 rpm, sampling at 60 min, and taking the filtrate as sample solution; the reference substance was prepared into a solution containing about 5. mu.g of allylestrenol per ml as a reference solution, which was injected into a liquid chromatograph, respectively, and the amount of elution was calculated by the peak area according to the external standard method.
2) The content and related substances are measured by high performance liquid chromatography (appendix VD of the second part of the Chinese pharmacopoeia 2010), octadecylsilane chemically bonded silica is used as a filler, a protective column is added, methanol is used as a mobile phase, and the detection wavelength is 215 nm. The theoretical plate number is not less than 2000 calculated according to rasagiline peak. And respectively injecting the sample and the reference substance into a liquid chromatograph, recording a chromatogram, and calculating according to the peak area by an external standard method.
3. And (3) comparing stability data: see table 6.
Table 6 stability data comparison table:
the particle properties of each example were compared to compressibility: see table 7.
Table 7 comparative table of particle properties to compressibility:
| examples | Angle of repose (°) | Fluidity of the resin | One-sided finish | Weight difference (%) | Friability (%) |
| 1 | 33 | Is excellent in | Light brightness | 1.73 | 0.0523 |
| 2 | 37 | Is excellent in | Light brightness | 1.97 | 0.0826 |
| 3 | 38 | Good effect | Light brightness | 2.21 | 0.0741 |
| 4 | 39 | Good effect | Light brightness | 2.36 | 0.1037 |
| 5 | 35 | Is excellent in | Light brightness | 1.88 | 0.0614 |
The dissolution characteristics of each example compared to the original ground tablets: see table 8.
Table 8 comparative dissolution profile table:
the dissolution characteristics of example 1 compared to the original ground tablets are shown in FIG. 1.
The results of tables 6-8 and fig. 1 show that the allylestrenol tablet of the invention is very stable, has good quality and less impurities, and has greatly improved dissolution characteristics compared with the original tablet, high dissolution rate and high dissolution speed, and the prepared granules have good fluidity and compressibility.
While the invention has been described with respect to a preferred embodiment, it will be understood by those skilled in the art that the foregoing and other changes, omissions and deviations in the form and detail thereof may be made without departing from the scope of this invention. Those skilled in the art can make various changes, modifications and equivalent arrangements, which are equivalent to the embodiments of the present invention, without departing from the spirit and scope of the present invention, and which may be made by utilizing the techniques disclosed above; meanwhile, any changes, modifications and variations of the above-described embodiments, which are equivalent to those of the technical spirit of the present invention, are within the scope of the technical solution of the present invention.
Claims (9)
1. An allylestrenol tablet is prepared by uniformly mixing and tabletting allylestrenol and auxiliary materials, and is characterized in that the auxiliary materials consist of internal auxiliary materials and external auxiliary materials, the allylestrenol and the internal auxiliary materials are uniformly mixed, heated and melted, the heating temperature is controlled to be 90-130 ℃, the discharging speed is adjusted to enable the retention time of materials in a heating part of equipment to be 20 seconds to 1 minute, the materials are cooled and crushed into medicine-containing granules or powder, the medicine-containing granules or powder and the external auxiliary materials are uniformly mixed and tabletted, wherein the internal auxiliary materials are polyethylene glycol carrier materials and are selected from one or more than two of polyethylene glycol 4000, polyethylene glycol 6000 or polyethylene glycol 8000, the external auxiliary materials are selected from one or more than two of filling agents, disintegrating agents, adhesives, glidants and lubricating agents, the weight ratio of the allylestrenol to the internal auxiliary materials is 1:2-200, according to weight percentage, 0.1-10 percent of allylestrenol, 1-80 percent of polyethylene glycol carrier material, 15-98 percent of filling agent, 0.1-30 percent of disintegrating agent, 0.1-30 percent of adhesive, 0-5 percent of lubricant and 0-5 percent of glidant.
2. The allylestrenol tablet of claim 1, wherein the weight ratio of allylestrenol to internal excipients is 1: 5-100.
3. The allylestrenol tablet of claim 2, wherein the weight ratio of allylestrenol to internal excipients is 1: 10-50.
4. The allylestrenol tablet of claim 1, wherein:
the filler is selected from one or more of microcrystalline cellulose, lactose, sucrose, starch, mannitol, sorbitol and xylitol;
the disintegrating agent is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose;
the adhesive is selected from one or more of povidone, starch slurry, hydroxypropyl methyl cellulose and hydroxypropyl cellulose;
the lubricant is selected from one or more of magnesium stearate and stearic acid;
the glidant is selected from one or more of silicon dioxide and talcum powder.
5. The allylestrenol tablet of claim 1, wherein:
the filler is selected from one or more of microcrystalline cellulose, anhydrous lactose, sucrose, pregelatinized starch, mannitol, sorbitol and xylitol;
the disintegrating agent is selected from one or more of crospovidone, sodium carboxymethyl starch, croscarmellose sodium, hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose and microcrystalline cellulose;
the adhesive is selected from one or more of povidone, starch slurry, hydroxypropyl methyl cellulose and hydroxypropyl cellulose;
the lubricant is selected from one or more of magnesium stearate and stearic acid;
the glidant is selected from one or more of silicon dioxide and talcum powder.
6. The allylestrenol tablet of claim 1, wherein said additional excipients are microcrystalline cellulose, crospovidone, povidone, magnesium stearate, and silicon dioxide.
7. The allylestrenol tablet according to claim 6, wherein the allylestrenol tablet comprises, by weight, 0.5-5% of allylestrenol, 10-50% of polyethylene glycol carrier material, 1-5% of crospovidone, 1-5% of povidone, 20-80% of microcrystalline cellulose, 0.1-2% of magnesium stearate, and 0.1-2% of silicon dioxide.
8. The allylestrenol tablet according to any one of claims 1 to 7, wherein said heating temperature is controlled to be 100-120 ℃.
9. The allylestrenol tablet according to any one of claims 1 to 7, wherein said exit rate is adjusted so that the residence time of the material in the warming part of the apparatus is between 30 and 50 seconds.
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| CN105120899A (en) * | 2012-12-06 | 2015-12-02 | Hra医药实验室 | Solid dispersion of a selective modulator of the progesterone receptor |
| CN106860406A (en) * | 2016-12-26 | 2017-06-20 | 上海市计划生育科学研究所 | Progestational hormone solid dispersion pellets and preparation method thereof |
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2018
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| CN1180521A (en) * | 1997-10-09 | 1998-05-06 | 海南诚成药业有限公司 | Medicinal composite containing megestrol acetate |
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| WO2011018482A1 (en) * | 2009-08-12 | 2011-02-17 | Bayer Schering Pharma Aktiengesellschaft | Stabilised particles comprising 5-methyl-(6s)-tetrahydrofolate |
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Effective date of registration: 20190426 Address after: 213018 Wudao 567, Tianning District, Changzhou City, Jiangsu Province Applicant after: Changzhou City No.4 Pharmaceutical Factory Co., Ltd. Applicant after: Pharmaceutical Co., Ltd., Changzhou Pharmaceutical Factory No.4 Address before: 213018 No. 567 Zhongwu Avenue, Changzhou City, Jiangsu Province Applicant before: Changzhou City No.4 Pharmaceutical Factory Co., Ltd. |
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Effective date of registration: 20201125 Address after: 213018 middle Wu Avenue, Tianning District, Changzhou, Jiangsu Province, No. 567 Applicant after: CHANGZHOU SIYAO PHARMACEUTICALS Co.,Ltd. Address before: 213018 middle Wu Avenue, Tianning District, Changzhou, Jiangsu Province, No. 567 Applicant before: CHANGZHOU SIYAO PHARMACEUTICALS Co.,Ltd. Applicant before: CHANGZHOU SIYAO PHARMACY Co.,Ltd. |
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Effective date of registration: 20210918 Address after: 213018 Wudao 567, Tianning District, Changzhou City, Jiangsu Province Patentee after: CHANGZHOU SIYAO PHARM Co.,Ltd. Patentee after: CHANGZHOU SIYAO PHARMACY Co.,Ltd. Address before: 213018 Wudao 567, Tianning District, Changzhou City, Jiangsu Province Patentee before: CHANGZHOU SIYAO PHARM Co.,Ltd. |
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