CN114259498A - Pharmaceutical composition containing desogestrel and ethinylestradiol, and preparation method and application thereof - Google Patents
Pharmaceutical composition containing desogestrel and ethinylestradiol, and preparation method and application thereof Download PDFInfo
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- CN114259498A CN114259498A CN202111458849.XA CN202111458849A CN114259498A CN 114259498 A CN114259498 A CN 114259498A CN 202111458849 A CN202111458849 A CN 202111458849A CN 114259498 A CN114259498 A CN 114259498A
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Abstract
The invention provides a pharmaceutical composition containing desogestrel and ethinylestradiol, which is prepared from raw materials including desogestrel, ethinylestradiol, sulfite, a lubricant, a disintegrant and a diluent. The pharmaceutical composition containing desogestrel and ethinylestradiol, provided by the invention, is prepared by a dry mixing and direct tabletting process, so that the oxidative degradation of desogestrel and ethinylestradiol can be effectively controlled, and the stability of the pharmaceutical composition containing desogestrel and ethinylestradiol is improved; the pharmaceutical composition containing desogestrel and ethinylestradiol provided by the invention has the advantages that the impurities are measured by high performance liquid chromatography, the total amount of the impurities is lower than 0.1 percent of the total peak area of the active drug within 24 months, the content of the active drug component is effectively maintained, and the medication safety and effectiveness of patients are ensured.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a pharmaceutical composition containing desogestrel and ethinylestradiol, and a preparation method and application thereof.
Background
Desogestrel is a third generation progestogen developed by Olgan, Netherlands, and is mainly used for compounding with estrogen (such as ethinyl estradiol) to prepare compound oral contraceptives. Compared with the first-generation and second-generation oral contraceptives consisting of other progestagens and estrogens, the contraceptive has higher effect and lower toxic and side effect. Since desogestrel and ethinylestradiol are very easy to be oxidized and degraded, the difficulty of developing the product is increased due to the stability problem of the drug.
US5527543A discloses a process for the preparation of pharmaceutical particles containing one or more steroids which is a primary research product
The method of preparing the drug-containing particles of (a) includes the steps of: dissolving one or more steroids and a lubricant in an organic solvent to obtain a drug-containing solution, wherein the drug-containing solution comprises an antioxidant; mixing the medicine-containing solution with a diluent, and heating to remove the organic solvent to obtain medicine-containing particles; the steroid medicine comprises one or more of desogestrel, ethinylestradiol, norgestrel and norethindrone; the organic solvent comprises one or more mixed solvents of acetone, dichloromethane, ethanol, methanol and isopropanol. According to the preparation method of the medicine particles, an organic solvent is used for preparing a medicine-containing solution, and then the organic solvent is removed in a heating mode; the preparation process is complex, the time consumption is long, the requirement on equipment is high, and meanwhile, residual solvent exists in the product, so that the safety of taking medicine by a patient is influenced. In addition, the chemical stability of desogestrel and ethinylestradiol may be affected by the heating process.
According to the original grinding product
As can be seen in the description, the antioxidant alpha-tocopherol is added into the original product to improve the stability of the product; because alpha-tocopherol is oily liquid, the alpha-tocopherol can be added into the drug-containing particles only by dissolving the alpha-tocopherol in an organic solvent, which indicates that the original grinding product cannot avoid using the organic solvent. Therefore, how to develop a stable pharmaceutical composition containing desogestrel and ethinylestradiol, which can ensure desogestrel and ethinylene simultaneously in a longer timeStability of estradiol; and how to develop a simple and easily-controlled production process of the pharmaceutical composition containing desogestrel and ethinylestradiol, so that the process time is shortened, and the use of an organic solvent and a heating process are avoided, which becomes a problem to be solved at present.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a pharmaceutical composition containing desogestrel and ethinylestradiol, and a preparation method and application thereof. The pharmaceutical composition containing desogestrel and ethinylestradiol, provided by the invention, can control the oxidative degradation of desogestrel and ethinylestradiol, and improve the stability of the pharmaceutical composition containing desogestrel and ethinylestradiol; according to the pharmaceutical composition containing desogestrel and ethinylestradiol, provided by the invention, the impurities are measured by HPLC, and the total amount of the impurities is lower than 0.1% of the total peak area of the active drug within 24 months, so that the content of the active drug component is effectively maintained, and the medication safety and effectiveness of patients are ensured; the pharmaceutical composition containing desogestrel and ethinylestradiol provided by the invention can adopt a simple and easily-controlled production process, shorten the process time, and simultaneously avoid the use of organic solvents and a heating process.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a pharmaceutical composition containing desogestrel and ethinylestradiol, and the pharmaceutical composition containing desogestrel and ethinylestradiol is prepared from raw materials including desogestrel, ethinylestradiol, sulfite, a disintegrant and a diluent.
In the present invention, the active pharmaceutical ingredients include desogestrel and ethinylestradiol.
In the present invention, oxidative degradation of desogestrel and ethinylestradiol may be controlled by the addition of sulfites, thereby improving the overall stability of pharmaceutical compositions comprising desogestrel and ethinylestradiol.
In the present invention, the structural formulae of desogestrel and ethinylestradiol are as follows:
in the present invention, the desogestrel related impurities include desogestrel european pharmacopoeia impurity D, having the following structural formula:
in the invention, the impurities related to the ethinylestradiol mainly comprise 6 alpha-hydroxy ethinylestradiol, 6 beta-hydroxy ethinylestradiol, 6-oxo-ethinylestradiol and delta 9, 11-ethinylestradiol, and the structural formula is shown as follows:
in the invention, the pharmaceutical composition containing desogestrel and ethinylestradiol comprises the following raw materials in percentage by weight:
in the present invention, the content of desogestrel may be 0.01 to 0.5% by weight, for example, 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5% or the like.
In the present invention, the content of ethinylestradiol may be, for example, 0.001% to 0.05% by weight, such as 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05% by weight.
In the present invention, the content of the sulfite is 0.05 to 0.1% by weight, and may be, for example, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 0.1%, or the like.
In the present invention, the content of the lubricant is 0.2 to 1% by weight, and may be, for example, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, or the like.
In the present invention, the content of the disintegrant is 2 to 10% by weight, and may be, for example, 2%, 4%, 6%, 8%, 10%, etc
In the present invention, the sulfite includes a potassium sulfite salt and/or a sodium sulfite salt.
In the present invention, the potassium sulfite salt includes any one of potassium metabisulfite, potassium sulfite, or potassium bisulfite, or a combination of at least two thereof.
Preferably, the sodium sulfite salt comprises any one or a combination of at least two of sodium metabisulfite, sodium sulfite or sodium bisulfite, preferably sodium metabisulfite.
In the present invention, the lubricant comprises any one of magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, glyceryl behenate, polyethylene glycol or sodium stearyl fumarate or a combination of at least two thereof, preferably stearic acid.
In the present invention, the disintegrant comprises any one or a combination of at least two of crospovidone, croscarmellose sodium, croscarmellose calcium, or sodium starch glycolate, preferably crospovidone.
In the present invention, the diluent includes any one or a combination of at least two of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, starch, pregelatinized starch, or corn starch, preferably lactose.
In the present invention, the weight of the pharmaceutical composition comprising desogestrel and ethinylestradiol is 90-110 mg/tablet, and may be, for example, 90 mg/tablet, 92 mg/tablet, 94 mg/tablet, 96 mg/tablet, 98 mg/tablet, 100 mg/tablet, 102 mg/tablet, 104 mg/tablet, 106 mg/tablet, 108 mg/tablet, 110 mg/tablet, etc.
In a second aspect, the present invention provides a process for the preparation of a pharmaceutical composition comprising desogestrel and ethinylestradiol according to the first aspect; the method comprises the steps of mixing desogestrel, ethinylestradiol, sulfite, a lubricant, a disintegrant and a diluent by adopting a dry mixing and direct tabletting process, and then directly tabletting to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
In the invention, the dry mixing and direct tabletting process is adopted, so that the process is simple and easy to control, and the process time can be shortened; and simultaneously, the use of organic solvents and a heating process can be avoided.
In the present invention, the preparation method of the pharmaceutical composition comprising desogestrel and ethinylestradiol comprises the following steps:
(1) sieving desogestrel, ethinylestradiol, sulfite and diluent;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and diluent accounting for 25-35% (for example, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, and the like) of the total weight of the diluent to obtain a mixture 1;
(3) mixing the mixture 1 obtained in step (2) with a diluent accounting for 25-35% (for example, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, etc.) of the total weight of the diluent to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
In the present invention, in the step (1), the mesh number of the mesh through which desogestrel, ethinylestradiol and sulfite are sieved is 40 to 60 meshes, for example, 40 meshes, 50 meshes, 60 meshes, and the like; the mesh number of the screen through which the diluent is sieved is 20-30 meshes, for example, 20 meshes, 25 meshes, 30 meshes and the like can be adopted.
In the present invention, in the step (2), the mixing time is 14-20min, for example, 14min, 16min, 18min, 20min, etc.; the rotation speed of the mixing is 15 to 25rpm, and may be, for example, 15rpm, 17rpm, 19rpm, 21rpm, 23rpm, 25rpm, or the like.
In the present invention, in step (3), the mixing time is 14-20min, for example, 14min, 16min, 18min, 20min, etc.; the rotation speed of the mixing is 15 to 25rpm, and may be, for example, 15rpm, 17rpm, 19rpm, 21rpm, 23rpm, 25rpm, or the like.
In the present invention, in step (4), the mixing time is 14-20min, for example, 14min, 16min, 18min, 20min, etc.; the rotation speed of the mixing is 15 to 25rpm, and may be, for example, 15rpm, 17rpm, 19rpm, 21rpm, 23rpm, 25rpm, or the like.
In the present invention, in the step (5), the mixing time is 3 to 7min, for example, 3min, 5min, 7min, etc.; the rotation speed of the mixing is 15 to 25rpm, and may be, for example, 15rpm, 17rpm, 19rpm, 21rpm, 23rpm, 25rpm, or the like.
As a preferred technical solution of the present invention, the preparation method of the pharmaceutical composition comprising desogestrel and ethinylestradiol comprises the following steps:
(1) sieving desogestrel, ethinylestradiol and sulfite with a 40-60 mesh sieve, and sieving the diluent with a 20-30 mesh sieve;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and a diluent accounting for 25-35% of the total weight of the diluent, and mixing for 14-20min at the rotating speed of 15-25rpm to obtain a mixture 1;
(3) mixing the mixture 1 obtained in the step (2) with a diluent accounting for 25-35% of the total weight of the diluent, and mixing for 14-20min at the rotating speed of 15-25rpm to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent, and mixing for 14-20min at the rotating speed of 15-25rpm to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent, and mixing for 3-7min at the rotating speed of 15-25rpm to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
In a third aspect, the present invention provides the use of a pharmaceutical composition comprising desogestrel and ethinylestradiol according to the first aspect, for the manufacture of a medicament for female contraception.
Compared with the prior art, the invention has the following beneficial effects:
(1) the pharmaceutical composition containing desogestrel and ethinylestradiol, provided by the invention, can control the oxidative degradation of desogestrel and ethinylestradiol, and improve the stability of the pharmaceutical composition containing desogestrel and ethinylestradiol;
(2) according to the pharmaceutical composition containing desogestrel and ethinylestradiol, provided by the invention, the impurities are measured by HPLC, and the total amount of the impurities is lower than 0.1% of the total peak area of the active drug within 24 months, so that the content of the active drug component is effectively maintained, and the medication safety and effectiveness of patients are ensured;
(3) the pharmaceutical composition containing desogestrel and ethinylestradiol provided by the invention can adopt a simple and easily-controlled production process, shorten the process time, and simultaneously avoid the use of organic solvents and a heating process.
Drawings
FIG. 1 is a high performance liquid chromatogram of the pharmaceutical composition comprising desogestrel and ethinylestradiol as described in example 1 for 24 months stored at 25 ℃/60% RT of the relevant impurities;
wherein 8 is an unknown impurity 3.
FIG. 2 is a high performance liquid chromatogram of the pharmaceutical composition comprising desogestrel and ethinylestradiol as described in comparative example 1 of the relevant impurities stored for 24 months at 25 ℃/60% RT;
wherein 1 is 6 alpha-hydroxy ethinylestradiol, 2 is 6 beta-hydroxy ethinylestradiol, 3 is 6-oxo ethinylestradiol, 4 is delta 9, 11-ethinylestradiol, 5 is unknown impurity 1, 6 is unknown impurity 2, 7 is desogestrel European pharmacopoeia impurity D, 8 is unknown impurity 3, and 9 is unknown impurity 4.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
The sources of the components in the following examples are as follows:
| name (R) | Specification or manufacturer |
| Desogestrel | Micronization |
| Ethinyl estradiol | Micronization |
| Sodium metabisulfite | Spectrum |
| Stearic acid | Hunan Erkang |
| Lactose | Kerry |
| Cross-linked polyvidone | Ashland |
Example 1
The embodiment provides a pharmaceutical composition containing desogestrel and ethinylestradiol, which is prepared from the following raw materials in percentage by weight:
the preparation method of the pharmaceutical composition containing desogestrel and ethinylestradiol comprises the following steps:
(1) sieving desogestrel, ethinylestradiol and sulfite with a 40-mesh sieve, and sieving the diluent with a 20-mesh sieve;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and a diluent accounting for 30% of the total weight of the diluent, and mixing at the rotating speed of 15rpm for 14min to obtain a mixture 1;
(3) mixing the mixture 1 obtained in the step (2) with a diluent accounting for 30% of the total weight of the diluent, and mixing for 14min at the rotating speed of 15rpm to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent, and mixing for 14min at the rotating speed of 15rpm to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent, and mixing for 3min at the rotating speed of 15rpm to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
As shown in fig. 1, the high performance liquid chromatogram of the pharmaceutical composition comprising desogestrel and ethinylestradiol described in example 1 for 24 months at 25 ℃/60% RT for the relevant impurities; the unknown impurity 3 is 8, and the peak-off time of the unknown impurity 3 is 28.248 min.
Example 2
The embodiment provides a pharmaceutical composition containing desogestrel and ethinylestradiol, which is prepared from the following raw materials in percentage by weight:
the preparation method of the pharmaceutical composition containing desogestrel and ethinylestradiol comprises the following steps:
(1) sieving desogestrel, ethinylestradiol and sulfite with a 50-mesh sieve, and sieving the diluent with a 25-mesh sieve;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and a diluent accounting for 25% of the total weight of the diluent, and mixing at the rotating speed of 20rpm for 18min to obtain a mixture 1;
(3) mixing the mixture 1 obtained in the step (2) with a diluent accounting for 25% of the total weight of the diluent, and mixing at the rotating speed of 20rpm for 18min to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent, and mixing for 18min at the rotating speed of 20rpm to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent, and mixing for 5min at the rotating speed of 20rpm to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
Example 3
The embodiment provides a pharmaceutical composition containing desogestrel and ethinylestradiol, which is prepared from the following raw materials in percentage by weight:
the preparation method of the pharmaceutical composition containing desogestrel and ethinylestradiol comprises the following steps:
(1) sieving desogestrel, ethinylestradiol and sulfite with a 60-mesh sieve, and sieving the diluent with a 30-mesh sieve;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and a diluent accounting for 35% of the total weight of the diluent, and mixing at the rotating speed of 25rpm for 20min to obtain a mixture 1;
(3) mixing the mixture 1 obtained in the step (2) with a diluent accounting for 35% of the total weight of the diluent, and mixing at the rotating speed of 25rpm for 20min to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent, and mixing for 20min at the rotating speed of 25rpm to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent, and mixing for 7min at the rotating speed of 25rpm to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
Example 4
This example provides a pharmaceutical composition comprising desogestrel and ethinylestradiol that differs from example 1 only in that the sodium metabisulfite is present in an amount of 0.2% by weight; other preparation materials and preparation methods were the same as example 1.
Example 5
This example provides a pharmaceutical composition comprising desogestrel and ethinylestradiol that differs from example 1 only in that the sodium metabisulfite is present in an amount of 0.03% by weight; other preparation materials and preparation methods were the same as example 1.
Example 6
This example provides a pharmaceutical composition comprising desogestrel and ethinylestradiol that differs from example 1 only by replacing sodium metabisulfite with an equivalent weight percent of sodium sulfite; other preparation materials and preparation methods were the same as example 1.
Comparative example 1
This comparative example provides a pharmaceutical composition comprising desogestrel and ethinylestradiol that differs from example 1 only in that sodium metabisulfite is not present and in that the other starting materials and methods of preparation are the same as in example 1.
FIG. 2 is a high performance liquid chromatogram of the pharmaceutical composition comprising desogestrel and ethinylestradiol as described in comparative example 1 of the relevant impurities stored for 24 months at 25 ℃/60% RT;
wherein 1 is 6 alpha-hydroxy ethinylestradiol, and the retention time is 6.984 min; 2 is 6 beta-hydroxy ethinyl estradiol, and the retention time is 7.583 min; 3 is 6-oxo-ethinylestradiol, and the retention time is 11.505 min; 4 is delta 9, 11-ethinylestradiol, and the retention time is 20.369 min; 5 is unknown impurity 1, the retention time is 25.646min, 6 is unknown impurity 2, the retention time is 27.991 min; 7 is desogestrel European pharmacopoeia impurity D, and the retention time is 28.262 min; 8 is unknown impurity 3, and the retention time is 28.646 min; 9 is unknown impurity 4, retention time is 29.732 min.
Comparative example 2
This comparative example provides a pharmaceutical composition comprising desogestrel and ethinylestradiol that differs from example 1 only in that sodium metabisulfite is replaced with vitamin C in an equivalent weight percent, and other manufacturing raw materials and manufacturing methods are the same as example 1.
Test example
Stability testing of pharmaceutical compositions comprising desogestrel and ethinylestradiol
Testing a sample: examples 1-6 and comparative examples 1-2 provide pharmaceutical compositions comprising desogestrel and ethinylestradiol;
the test method comprises the following steps: storing a pharmaceutical composition comprising desogestrel and ethinylestradiol for 24 months at 25 ℃ and a relative humidity of 60% (25 ℃/60% RT) in an aluminum plastic package, and measuring the amounts of the relevant substances in the samples for 0 day and 24 months, respectively, using High Performance Liquid Chromatography (HPLC);
the HPLC chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; taking acetonitrile and water in a ratio of 1:3 as a mobile phase A, acetonitrile and water in a ratio of 3:1 as a mobile phase B, and acetonitrile and water in a ratio of 98:2 as a mobile phase C, and carrying out linear gradient elution according to the following table; UV 210 nm; column temperature: 50 ℃; sample introduction volume: 25 μ L.
Among the single unknown impurities:
unknown impurity 1: the retention time relative to ethinyl estradiol is 1.19 +/-0.02; unknown impurity 2: the retention time relative to ethinyl estradiol is 1.30 +/-0.02; unknown impurity 3: the retention time relative to ethinyl estradiol is 1.33 +/-0.02; unknown impurity 4: the retention time relative to ethinyl estradiol is 1.38 plus or minus 0.02;
the test results are shown in table 1, where the amount of impurities is given as a percentage (%) of the total peak area of the active drug, and the total amount of impurities is rounded to retain one decimal:
TABLE 1
Where "BQL" indicates that the amount of impurities is below the limit of quantitation and "-" indicates no detection.
As can be seen from the data in Table 1, the pharmaceutical compositions comprising desogestrel and ethinylestradiol provided by the present invention (examples 1-6) have 6 α -hydroxyethinylestradiol always below the limit of quantitation after 24 months of storage, 6 β -hydroxyethinylestradiol in an amount of BQL-0.14%, 6-oxoethinylestradiol in an amount of BQL-0.20%, Δ 9, 11-ethinylestradiol in an amount of BQL-0.11%, desogestrel European pharmacopoeia impurity D in an amount of BQL-0.34%, unknown impurity 1 in an amount of 0-0.09%, unknown impurity 2 in an amount of 0-0.12%, unknown impurity 3 in an amount of 0.05-0.11%, unknown impurity 4 in an amount of 0-0.20%, and total impurity in an amount of 0.1-1.3%.
As can be seen from the data in table 1, after 24 months of storage, the pharmaceutical composition containing desogestrel and ethinylestradiol provided by the preferred embodiment of the present invention (examples 1-3) has the amount of ethinylestradiol-related impurities and the amount of desogestrel-related impurities below the quantitative limit, no unknown impurities 1, 2, and 4 are detected, the amount of unknown impurity 3 is only 0.05%, and the total amount of impurities is controlled to 0.1%, indicating that the formation of degradation products can be controlled by adding a certain amount of sodium metabisulfite to the composition.
As can be seen by comparing example 1 with examples 4-5, the ability to maintain the stability of a pharmaceutical composition comprising desogestrel and ethinylestradiol is not enhanced when the sulfite content is higher by weight percentage; when the weight percentage of sulfite is low, the effect of maintaining the stability of the pharmaceutical composition comprising desogestrel and ethinylestradiol is reduced.
As is clear from a comparison between example 1 and example 6, the effect of maintaining the stability of the pharmaceutical composition containing desogestrel and ethinylestradiol was deteriorated by replacing sodium metabisulfite with sodium sulfite.
As can be seen from a comparison of example 1 and comparative example 1, when the pharmaceutical composition comprising desogestrel and ethinylestradiol was stored for 24 months without the addition of sulfite, both ethinylestradiol and desogestrel underwent oxidative degradation and the amount of unknown impurities increased, and the total impurities reached 3.3%.
As can be seen from a comparison of example 1 and comparative example 2, the effect of maintaining the stability of the pharmaceutical composition comprising desogestrel and ethinylestradiol was reduced when sodium metabisulfite was replaced with vitamin C in an equivalent weight percentage content.
The applicant states that the present invention is illustrated by the above examples, but the present invention is not limited to the above examples, i.e. it does not mean that the present invention must be implemented by the above examples. It is obvious to those skilled in the art that any modification of the present invention, equivalent substitution of each raw material and addition of auxiliary components, selection of specific modes, etc., of the product of the present invention fall within the protection scope and disclosure of the present invention.
Claims (10)
1. The pharmaceutical composition containing desogestrel and ethinylestradiol is characterized in that raw materials for preparing the pharmaceutical composition containing desogestrel and ethinylestradiol comprise desogestrel, ethinylestradiol, sulfite, a lubricant, a disintegrant and a diluent.
2. The pharmaceutical composition containing desogestrel and ethinylestradiol according to claim 1, wherein the pharmaceutical composition containing desogestrel and ethinylestradiol comprises the following raw materials in percentage by weight:
3. pharmaceutical composition comprising desogestrel and ethinylestradiol according to claim 1 or 2, characterized in that the sulphite comprises a potassium sulphite salt and/or a sodium sulphite salt.
4. The pharmaceutical composition comprising desogestrel and ethinylestradiol according to any of claims 1-3, wherein the potassium sulfite salt comprises any one or a combination of at least two of potassium metabisulfite, potassium sulfite, or potassium bisulfite;
preferably, the sodium sulfite salt comprises any one or a combination of at least two of sodium metabisulfite, sodium sulfite or sodium bisulfite, preferably sodium metabisulfite.
5. A pharmaceutical composition comprising desogestrel and ethinylestradiol according to any of claims 1 to 4, wherein said lubricant comprises any one or a combination of at least two of magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, glyceryl behenate, polyethylene glycol or sodium stearyl fumarate, preferably stearic acid.
6. The pharmaceutical composition comprising desogestrel and ethinylestradiol according to any of claims 1 to 5, wherein the disintegrant comprises any one or a combination of at least two of crospovidone, croscarmellose sodium, croscarmellose calcium or carboxymethyl starch sodium, preferably crospovidone.
7. The pharmaceutical composition comprising desogestrel and ethinylestradiol according to any of claims 1 to 6, wherein said diluent comprises any one or a combination of at least two of lactose, sucrose, microcrystalline cellulose, mannitol, sorbitol, starch, pregelatinized starch, or corn starch, preferably lactose;
preferably, the weight of the pharmaceutical composition comprising desogestrel and ethinylestradiol is 90-110 mg/tablet.
8. A preparation method of the pharmaceutical composition containing desogestrel and ethinylestradiol according to any one of claims 1 to 7, characterized by adopting a dry mixing and direct tabletting process, mixing desogestrel, ethinylestradiol, sulfite, a lubricant, a disintegrant and a diluent, and then directly tabletting to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
9. The method of preparing a pharmaceutical composition comprising desogestrel and ethinyl estradiol according to claim 8, wherein the method of preparing the pharmaceutical composition comprising desogestrel and ethinyl estradiol comprises the steps of:
(1) sieving desogestrel, ethinylestradiol, sulfite and diluent;
(2) mixing the sieved desogestrel obtained in the step (1), ethinylestradiol, sulfite and a diluent accounting for 25-35% of the total weight of the diluent to obtain a mixture 1;
(3) mixing the mixture 1 obtained in the step (2) with a diluent accounting for 25-35% of the total weight of the diluent to obtain a mixture 2;
(4) mixing the mixture 2 obtained in the step (3) with the rest of the diluent to obtain a mixture 3;
(5) mixing the mixture 3 obtained in the step (4), a lubricant and a disintegrating agent to obtain a mixture 4;
(6) and (4) tabletting the mixture 4 obtained in the step (5) to obtain the pharmaceutical composition containing desogestrel and ethinylestradiol.
10. Use of a pharmaceutical composition comprising desogestrel and ethinylestradiol according to any one of claims 1 to 7 for the preparation of a female contraceptive medicament.
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Citations (7)
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| CN1672685A (en) * | 2004-03-26 | 2005-09-28 | 董可娟 | New contraception medicine |
| US20090269403A1 (en) * | 2008-04-24 | 2009-10-29 | Shaked Ze Ev | Oral contraceptive dosage forms and methods of making such dosage forms |
| CN101987082A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Solid preparation and preparation method thereof |
| CN103271928A (en) * | 2013-05-31 | 2013-09-04 | 南通联亚药业有限公司 | Prescription technique for improving stability of desogestrel |
| CN103271927A (en) * | 2013-05-31 | 2013-09-04 | 南通联亚药业有限公司 | Technique of three-stage dilution method for improving content uniformity of oral contraceptive |
| CN103957899A (en) * | 2011-11-04 | 2014-07-30 | 敏捷治疗公司 | Dermal delivery compositions and methods |
| US20190343770A1 (en) * | 2018-05-09 | 2019-11-14 | Hemant N. Joshi | Hard Capsule Shell Compositions for the Oral Contraceptive Formulations |
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2021
- 2021-12-02 CN CN202111458849.XA patent/CN114259498B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1672685A (en) * | 2004-03-26 | 2005-09-28 | 董可娟 | New contraception medicine |
| US20090269403A1 (en) * | 2008-04-24 | 2009-10-29 | Shaked Ze Ev | Oral contraceptive dosage forms and methods of making such dosage forms |
| CN101987082A (en) * | 2010-07-16 | 2011-03-23 | 钟术光 | Solid preparation and preparation method thereof |
| CN103957899A (en) * | 2011-11-04 | 2014-07-30 | 敏捷治疗公司 | Dermal delivery compositions and methods |
| CN103271928A (en) * | 2013-05-31 | 2013-09-04 | 南通联亚药业有限公司 | Prescription technique for improving stability of desogestrel |
| CN103271927A (en) * | 2013-05-31 | 2013-09-04 | 南通联亚药业有限公司 | Technique of three-stage dilution method for improving content uniformity of oral contraceptive |
| US20190343770A1 (en) * | 2018-05-09 | 2019-11-14 | Hemant N. Joshi | Hard Capsule Shell Compositions for the Oral Contraceptive Formulations |
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| CN114259498B (en) | 2023-04-28 |
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Address after: 226009 No. 1, Guangxing Road, comprehensive free trade zone, economic and Technological Development Zone, Nantong City, Jiangsu Province Applicant after: Nantong Lianya Pharmaceutical Co.,Ltd. Address before: 226009 No. 1, Guangxing Road, comprehensive free trade zone, economic and Technological Development Zone, Nantong City, Jiangsu Province Applicant before: NOVAST LABORATORIES (CHINA) Ltd. |
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