Stable pharmaceutical composition

Abstract

The invention discloses a stable pharmaceutical composition, and belongs to the technical field of medicines. The stable pharmaceutical composition comprises the following components: a content: a lornoxicam pharmaceutical composition; the container is used for containing the lornoxicam pharmaceutical composition; and the rubber plug is buckled with the container and is used for sealing the lornoxicam pharmaceutical composition. The Mooney viscosity of the halogenated butyl rubber in the rubber plug and the types of the filler, the vulcanizing agent and the vulcanization accelerator are controlled, so that all the components interact with one another, and after the prepared rubber plug is buckled with a container, a solution is clear and meets the requirement of clarity under the test, high-temperature condition and acceleration condition, and the rubber plug has a good application prospect. The problems that in the prior art, the clarity of a product exceeds the limit, and the stability is poor under the high-temperature and acceleration conditions are solved.

Description

Technical Field

[0001] The present application relates to a stable pharmaceutical composition, belonging to the field of medical technology. Background Art

[0002] Lornoxicam is a nonsteroidal anti-inflammatory drug used to relieve various types of acute and chronic pain and inflammation. Lornoxicam injection is usually packaged in glass bottles and rubber stoppers to ensure that the drug does not react with the packaging material and affect the stability and efficacy of the drug, ensuring the stability and safety of the drug.

[0003] The reference preparation was tested and its solution clarity exceeded the limit, and the reference reagent was tested for stability. After 10 days of high temperature, 10 days of nakedness, and 1 month of acceleration, its clarity was greater than that of turbidity solution No. 1. In addition, after 10 days of high temperature, the related substances increased rapidly and exceeded the quality standard.

[0004] Therefore, the research on its packaging material is particularly important, and there is no report on the relevant research on lornoxicam packaging material in the prior art. Summary of the invention

[0005] According to one aspect of the present application, a stable pharmaceutical composition is provided, the Mooney viscosity of the halogenated butyl rubber in the rubber stopper, as well as the types of fillers, vulcanizers and vulcanization accelerators are controlled so that the components interact with each other. After the prepared rubber stopper is buckled with the container, after testing, the solution is clarified under high temperature conditions and accelerated conditions, meeting the clarity requirements, thereby solving the problems of excessive clarity of products in the prior art and poor stability under high temperature and accelerated conditions.

[0006] The stable pharmaceutical composition described in the present application comprises:

[0007] Contents: Lornoxicam pharmaceutical composition;

[0008] Container: used to contain the lornoxicam pharmaceutical composition;

[0009] Rubber stopper: snapped with the container to seal the lornoxicam pharmaceutical composition;

[0010] The rubber stopper is halogenated butyl rubber.

[0011] Optionally, the lornoxicam pharmaceutical composition comprises lornoxicam and pharmaceutically acceptable excipients.

[0012] Optionally, the pharmaceutically acceptable excipients include one or more of fillers, cosolvents, and chelating agents.

[0013] Optionally, the pharmaceutically acceptable excipients include fillers, co-solvents and chelating agents.

[0014] Optionally, the lornoxicam pharmaceutical composition comprises 8-9 parts of lornoxicam, 110-120 parts of filler, 10-20 parts of cosolvent, and 0.1-0.5 parts of chelating agent in parts by weight.

[0015] Specifically, by weight, the lornoxicam pharmaceutical composition includes 8 parts of lornoxicam, 116 parts of filler, 15 parts of cosolvent, and 0.3 parts of chelating agent.

[0016] The filler described in the present application is not particularly limited, and those skilled in the art can make conventional selections, and examples thereof include mannitol, gelatin, lactose, etc. Optionally, the filler is mannitol.

[0017] The cosolvent described in the present application is not particularly limited, and those skilled in the art can make a conventional selection. Optionally, the cosolvent is tromethamine.

[0018] The chelating agent described in the present application is not particularly limited, and those skilled in the art can make a conventional selection. Optionally, the chelating agent is disodium edetate.

[0019] Optionally, the preparation method of the lornoxicam pharmaceutical composition comprises: mixing water for injection, pharmaceutically acceptable excipients and lornoxicam at 65° C., stirring, filtering and freeze-drying to obtain the lornoxicam pharmaceutical composition; wherein the water for injection is 240 times the weight of lornoxicam;

[0020] The freeze-drying conditions were as follows:

[0021] Pre-freezing: enter the box at 0℃, cool to -40℃ at 5℃ / min, keep warm for 150min;

[0022] Raise the temperature to -10°C at 0.5°C / min and keep warm for 60 min;

[0023] Cool down to -40°C at 5°C / min and keep warm for 150 min;

[0024] Drying I: Raise the temperature to -10°C at 5°C / min, keep warm for 960min, vacuum gauge pressure 20Pa;

[0025] Heat up to 10℃ at 5℃ / min, keep warm for 120min, the air gauge pressure is 20Pa;

[0026] Drying II: Raise the temperature to 35°C at 10°C / min, keep warm for 240min, vacuum gauge pressure 5Pa;

[0027] Drying III: cool down to 25°C at 2°C / min, keep warm for 120 min, vacuum gauge pressure 5Pa.

[0028] Optionally, the container is made of medium borosilicate glass.

[0029] Optionally, the halogenated butyl rubber is brominated butyl rubber.

[0030] Optionally, the raw materials for preparing the rubber stopper include, by weight, 80-90 parts of brominated butyl rubber, 70-80 parts of filler, 2.6-3.6 parts of vulcanizing agent, 3-3.5 parts of vulcanization accelerator, and 1-2 parts of processing aid.

[0031] Optionally, the raw materials for preparing the rubber stopper include, by weight, 85 parts of brominated butyl rubber, 75 parts of filler, 3 parts of vulcanizing agent, 3.2 parts of vulcanization accelerator, and 1.5 parts of processing aid.

[0032] Optionally, the Mooney viscosity of the brominated butyl rubber at 125° C. is 40-50; preferably, the Mooney viscosity of the brominated butyl rubber at 125° C. is 46.

[0033] Optionally, the grade of the brominated butyl rubber is brominated butyl rubber X2.

[0034] Optionally, the filler is selected from one or more of kaolin, talc, carbon black, calcium carbonate, and calcium silicate.

[0035] Optionally, the carbon black meets at least one of the following conditions:

[0036] 1) Iodine absorption value is 30-49 mg / g;

[0037] 2) CTAB specific surface area is (35-49)*10 3 m 2 / Kg;

[0038] 3) Nitrogen adsorption specific surface area is (34-46)*10 3 m 2 / Kg.

[0039] Optionally, the carbon black includes carbon black A and carbon black B.

[0040] Optionally, the carbon black A is N550.

[0041] Optionally, the carbon black B is N660.

[0042] Optionally, the weight ratio of carbon black A to carbon black B is 1:(0.1-0.5); preferably, the weight ratio of carbon black A to carbon black B is 1:0.3.

[0043] Optionally, the filler includes calcined kaolin, calcium carbonate and carbon black.

[0044] Optionally, the weight ratio of the calcined kaolin, calcium carbonate and carbon black is (14-16):(2-6):1; preferably, the weight ratio of the calcined kaolin, calcium carbonate and carbon black is 15:4:1.

[0045] Optionally, the vulcanizing agent is selected from any one or more of sulfur, zinc oxide, peroxide, and phenolic resin.

[0046] Optionally, the vulcanizing agent is zinc oxide and sulfur.

[0047] Optionally, the weight ratio of zinc oxide to sulfur is (1-3):1; preferably, the weight ratio of zinc oxide to sulfur is 2:1.

[0048] Optionally, the vulcanization accelerator is magnesium oxide.

[0049] Optionally, the processing aid is PE wax.

[0050] The preparation method of the rubber stopper of the present application is not particularly limited, and those skilled in the art can make conventional selections.

[0051] Optionally, the method for preparing the rubber stopper comprises: mixing the raw materials of various components, kneading, calendering, cutting into pieces, vulcanizing, punching and cooling.

[0052] The temperature and time in the preparation process of the present application can be routinely selected by those skilled in the art.

[0053] The beneficial effects of this application include:

[0054] 1. This application uses carbon black N550 and carbon black N660. Through the differences in specific surface area and structure, the uniform dispersion of filler powder between the rubber bodies is promoted, the performance of the rubber stopper is improved, the interaction between the rubber stopper and the lornoxicam pharmaceutical composition is reduced, and the stability is improved.

[0055] 2. The mixture of calcined kaolin, calcium carbonate and carbon black in the present application forms a complementary effect, and has good compatibility with brominated butyl rubber of a specific viscosity, effectively improving fluidity, and improving the processing performance, tensile strength, wear resistance and dimensional stability of the rubber stopper, providing a basis for the stability between the rubber and the drug composition after vulcanization.

[0056] 3. The present application controls the Mooney viscosity of the halogenated butyl rubber in the rubber stopper, as well as the types of fillers, vulcanizers and vulcanization accelerators, so that the components interact with each other. After the prepared rubber stopper is buckled with the container, after testing, the solution is clear under high temperature and accelerated conditions, meeting the clarity requirements, thus solving the problems of excessive clarity of products in the prior art and poor stability under high temperature and accelerated conditions.

[0057] 4. The contents stored in the container and rubber stopper of the present application were tested for relevant substances on day 0, at high temperature and under accelerated conditions. The relevant substances met the quality standards. Among them, the tests under high temperature and accelerated conditions showed that the content of impurity B was within 0.03%, the content of impurity I was within 0.02%, the content of impurity K was within 0.07%, the content of impurity H was within 0.05%, and the maximum unknown single impurity was within 0.03%.

[0058] 5. The present application optimizes the preparation process of the lornoxicam pharmaceutical composition, shortens the entire process, and improves production efficiency. The lornoxicam pharmaceutical composition prepared by the short-time preparation process can still ensure the stability of the pharmaceutical composition by using the container and rubber stopper of the present application. BRIEF DESCRIPTION OF THE DRAWINGS

[0059] Figure 1 This is a diagram showing the clarity test results of the solution after 5 days of high temperature in Example 1-8;

[0060] Figure 2 This is a diagram showing the clarity test results of the solution after 10 days of high temperature in Example 1-8;

[0061] Figure 3 This is a diagram showing the clarity test results of the solution after 30 days of high temperature in Example 1-8;

[0062] Figure 4 This is a graph showing the results of the solution clarity test of Examples 1-8 accelerated for one week. DETAILED DESCRIPTION

[0063] The present application is described in detail below with reference to embodiments, but the present application is not limited to these embodiments.

[0064] Unless otherwise specified, the raw materials in the examples of this application were purchased through commercial channels.

[0065] The preparation method of the lornoxicam pharmaceutical composition described in the embodiment comprises: mixing water for injection, pharmaceutically acceptable excipients and lornoxicam at 65° C., stirring, filtering and freeze-drying to obtain the lornoxicam pharmaceutical composition; wherein the water for injection is 240 times the weight of lornoxicam;

[0066] The freeze-drying conditions were as follows:

[0067] Pre-freezing: enter the box at 0℃, cool to -40℃ at 5℃ / min, keep warm for 150min;

[0068] Raise the temperature to -10°C at 0.5°C / min and keep warm for 60 min;

[0069] Cool down to -40°C at 5°C / min and keep warm for 150 min;

[0070] Drying I: Raise the temperature to -10°C at 5°C / min, keep warm for 960min, vacuum gauge pressure 20Pa;

[0071] Heat up to 10℃ at 5℃ / min, keep warm for 120min, the air gauge pressure is 20Pa;

[0072] Drying II: Raise the temperature to 35°C at 10°C / min, keep warm for 240min, vacuum gauge pressure 5Pa;

[0073] Drying III: cool down to 25°C at 2°C / min, keep warm for 120 min, vacuum gauge pressure 5Pa.

[0074] Example 1

[0075] A stable freeze-dried powder composition comprising:

[0076] Contents: Lornoxicam pharmaceutical composition, including 8 mg of lornoxicam, 116 mg of mannitol, 15 mg of tromethamine, and 0.3 mg of edetate disodium;

[0077] Container: Made of medium borosilicate glass, used to contain the lornoxicam pharmaceutical composition;

[0078] A rubber stopper, which is engaged with the container and is used to seal the lornoxicam pharmaceutical composition;

[0079] The rubber stopper is brominated butyl rubber;

[0080] The preparation method of the rubber stopper comprises: mixing, by weight, 80 parts of brominated butyl rubber X2, 70 parts of fillers (calcined kaolin, calcium carbonate and carbon black, with a weight ratio of 14:2:1, and carbon black N550 and N660, with a weight ratio of 1:0.1), 1.5 parts of vulcanizing agent zinc oxide, 1.5 parts of vulcanizing agent sulfur, 3 parts of vulcanization accelerator magnesium oxide, and 1 part of processing aid PE wax; kneading; calendering; cutting; vulcanization at 195°C and 22MPa; punching; and cooling.

[0081] Example 2

[0082] A stable freeze-dried powder composition comprising:

[0083] Contents: 8 mg lornoxicam, 116 mg mannitol, 15 mg tromethamine, 0.3 mg edetate disodium;

[0084] Container: Made of medium borosilicate glass, used to contain the lornoxicam pharmaceutical composition;

[0085] A rubber stopper, which is engaged with the container and is used to seal the lornoxicam pharmaceutical composition;

[0086] The rubber stopper is brominated butyl rubber;

[0087] The preparation method of the rubber stopper comprises: mixing, by weight, 90 parts of brominated butyl rubber X2, 80 parts of filler (calcined kaolin, calcium carbonate and carbon black, with a weight ratio of 16:6:1, and carbon black N550 and N660, with a weight ratio of 1:0.5), 2.2 parts of vulcanizing agent zinc oxide, 0.8 parts of vulcanizing agent sulfur, 3.5 parts of vulcanization accelerator magnesium oxide, and 2 parts of processing aid PE wax, kneading, calendering, cutting, vulcanizing at 195°C and 22MPa, punching, and cooling.

[0088] Example 3

[0089] A stable freeze-dried powder composition comprising:

[0090] Contents: 8 mg lornoxicam, 116 mg mannitol, 15 mg tromethamine, 0.3 mg edetate disodium;

[0091] Container: Made of medium borosilicate glass, used to contain the lornoxicam pharmaceutical composition;

[0092] A rubber stopper, which is engaged with the container and is used to seal the lornoxicam pharmaceutical composition;

[0093] The rubber stopper is brominated butyl rubber;

[0094] The preparation method of the rubber stopper comprises: mixing, by weight, 85 parts of brominated butyl rubber X2, 75 parts of fillers (calcined kaolin, calcium carbonate and carbon black, with a weight ratio of 15:4:1, and carbon black N550 and N660, with a weight ratio of 1:0.3), 2 parts of vulcanizing agent zinc oxide, 1 part of vulcanizing agent sulfur, 3.2 parts of vulcanization accelerator magnesium oxide, and 1.5 parts of processing aid PE wax, kneading, calendering, cutting, vulcanizing at 195°C and 22MPa, punching, and cooling.

[0095] Example 4

[0096] A freeze-dried powder composition, the specific implementation manner of which is the same as that of Example 3, except that the brominated butyl rubber is brominated butyl rubber 2030, and the Mooney viscosity at 125° C. is 32±4.

[0097] Example 5

[0098] A freeze-dried powder composition, the specific implementation manner of which is the same as that of Example 3, except that the brominated butyl rubber is butyl rubber 2222, and the Mooney viscosity at 125° C. is 32±5.

[0099] Example 6

[0100] A freeze-dried powder composition, the specific implementation of which is the same as that of Example 3, except that the carbon black is N660 and the vulcanization accelerator is 2,2'-dibenzothiazole disulfide.

[0101] Example 7

[0102] A freeze-dried powder composition, the specific implementation manner of which is the same as that of Example 3, except that the carbon black is N330 and N660, the weight ratio is 1:0.3, and the vulcanization accelerator is 2,2'-dibenzothiazole disulfide.

[0103] Example 8

[0104] A freeze-dried powder composition, the specific implementation manner of which is the same as that of Example 3, except that the filler is calcined kaolin and carbon black, with a weight ratio of 15:1; and the vulcanizing agent is tert-butyl phenolic resin.

[0105] The freeze-dried powder compositions in Examples 1-8 were inverted and placed at 50° C. to perform a high temperature stability test with reference to C HP2020.

[0106] The freeze-dried powder compositions in Examples 1-8 were respectively subjected to accelerated tests with reference to CHP2020, and the accelerated conditions were 40° C.±2° C. and RH75%±5%.

[0107] The test results are shown in Table 1 below.

[0108] Table 1

[0109]

[0110]

[0111] See the figure for clarity of the solution tested at high temperature for 5 days. Figure 1 , Figure 1 From left to right in the figure are the test diagrams of Example 8, Example 2, Example 4, Example 1, Example 7, Example 3, Example 5, and Example 6.

[0112] See the figure for clarity of the solution tested at high temperature for 10 days. Figure 2 , Figure 2 From left to right in the figure are the test diagrams of Example 8, Example 2, Example 4, Example 1, Example 7, Example 3, Example 5, and Example 6.

[0113] See the figure for clarity of the solution tested at high temperature for 30 days. Figure 3 , Figure 3 From left to right in the figure are the test diagrams of Example 8, Example 2, Example 4, Example 1, Example 7, Example 3, Example 5, and Example 6.

[0114] See the figure for the clarity of the solution in the accelerated 1-month test. Figure 4 , Figure 4 From left to right in the figure are the test diagrams of Example 8, Example 2, Example 4, Example 1, Example 7, Example 3, Example 5, and Example 6.

[0115] The product of Example 3 was tested for related substances. The test method was based on CHP2020, where the high temperature condition was 50°C, the light condition was 5000lx, and the accelerated condition was 40°C±2°C, RH75%±5%.

[0116] Table 2

[0117]

[0118]

[0119] Table 3

[0120]

[0121] After testing, the test results of Example 1 and Example 2 are similar to the test results of Example 3.

[0122] The above are only a few embodiments of the present application and do not constitute any form of limitation to the present application. Although the present application is disclosed as above with preferred embodiments, it is not intended to limit the present application. Any technician familiar with the profession, without departing from the scope of the technical solution of the present application, using the technical content disclosed above to make slight changes or modifications are equivalent to equivalent implementation cases and fall within the scope of the technical solution.

Claims

1. A stable pharmaceutical composition, characterized in that: include: Contents: Lornoxicam pharmaceutical composition; Container: used to contain the lornoxicam pharmaceutical composition; Rubber stopper: snapped with the container to seal the lornoxicam pharmaceutical composition; The rubber stopper is halogenated butyl rubber.

2. The stable pharmaceutical composition according to claim 1, characterized in that The lornoxicam pharmaceutical composition comprises lornoxicam and pharmaceutically acceptable excipients.

3. The stable pharmaceutical composition according to claim 2, characterized in that: By weight, the lornoxicam pharmaceutical composition comprises 8-9 parts of lornoxicam, 110-120 parts of filler, 10-20 parts of cosolvent and 0.1-0.5 parts of chelating agent.

4. The stable pharmaceutical composition according to any one of claims 1 to 3, characterized in that The container is made of medium borosilicate glass.

5. The stable pharmaceutical composition according to claim 4, characterized in that: The halogenated butyl rubber is brominated butyl rubber.

6. The stable pharmaceutical composition according to claim 5, characterized in that: The raw materials for preparing the rubber stopper include 80-90 parts of brominated butyl rubber, 70-80 parts of filler, 2.6-3.6 parts of vulcanizing agent, 3-3.5 parts of vulcanization accelerator, and 1-2 parts of processing aid in parts by weight.

7. The stable pharmaceutical composition according to claim 6, characterized in that: The Mooney viscosity of the brominated butyl rubber at 125° C. is 40-50.

8. The stable pharmaceutical composition according to claim 6, characterized in that: The filler is selected from one or more of kaolin, talc, carbon black, calcium carbonate and calcium silicate.

9. The stable pharmaceutical composition according to claim 8, characterized in that The carbon black meets at least one of the following conditions: 1) Iodine absorption value is 30-49 mg / g; 2) CTAB specific surface area is (35-49)*10 3 m 2 / Kg; 3) Nitrogen adsorption specific surface area is (34-46)*10 3 m 2 / Kg.

10. The stable pharmaceutical composition according to claim 9, characterized in that: The carbon black includes carbon black A and carbon black B; The weight ratio of the carbon black A to the carbon black B is 1:(0.1-0.5).

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