A combination of a container containing tiotropium bromide, olodaterol pharmaceutical preparation and an aldehyde-removing packaging material

Abstract

The application discloses a combination of tiotropium bromide, hydrochloric acid odatro medicine preparation and aldehyde-removing packaging material, which comprises the following components: hydrochloric acid odatro or a salt thereof, tiotropium bromide or a salt thereof, a pH regulator, the medicine hydrochloric acid odatro or a salt thereof, tiotropium bromide or a salt thereof, a pH regulator, a pharmaceutically acceptable additive, a solvent, and the combination is stored in an aldehyde-removing packaging material container. The combination of tiotropium bromide and hydrochloric acid odatro is stored in the aldehyde-removing packaging material container, so that the packaging material container can be used for a soft mist inhalation device and the quality of the medicine liquid is not affected.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a combination of a pharmaceutical preparation containing tiotropium bromide and olodaterol, and a formaldehyde-removing packaging container. Background Technology

[0002] In soft mist inhalation devices, a container holds the medication, and this container needs to meet the requirement of not affecting the quality of the medication. The published patent PCT / US20 / 439994 describes a single-layer plastic container for holding the medication. This type of container requires a flexible plastic material, such as low-density polyethylene. In practical applications, it has been found that when this type of plastic container is used to directly hold tiotropium bromide and olodaterol medication without special treatment, the amount of impurities in the medication increases significantly after a period of storage.

[0003] Why does this type of bottle affect the stability of the medicine solution? How to eliminate the influence of this material on the stability of the medicine solution is a technical problem that this application urgently needs to solve. Summary of the Invention

[0004] The finished plastic vials affected the medicine solution. We found that the vials were not clean or contained some kind of substance, so we decided to clean them.

[0005] Therefore, how to clean plastic containers in a way that ensures the quality of the solutions containing tiotropium bromide and olodaterol is not affected is an urgent problem to be solved.

[0006] Research has shown that plastic bottles processed through injection molding and blow molding may contain aldehydes and other impurities on their surface. These substances, such as aldehydes, can react with substances in the medicine, affecting the quality of the drug.

[0007] This invention provides a pharmaceutical preparation containing tiotropium bromide and olodaterol hydrochloride in a plastic packaging material, ensuring that the quality of the medicine is not affected by the packaging material when the medicine is stored in the plastic packaging material. This achieves the technical effect that the packaging material does not affect the quality of the medicine liquid contained in the container, and ensures that the stored quality of the medicine liquid meets the requirements.

[0008] A combination of a pharmaceutical preparation containing tiotropium bromide, olodaterol hydrochloride, and a formaldehyde-removing packaging container, comprising the following components:

[0009] Odaterol or its salt, tiotropium bromide or its salt, pH adjuster, pharmaceutically acceptable additive, solvent, the composition being stored in a formaldehyde-removed packaging container.

[0010] Preferably, the concentration of odoretrol or its salt is 1 μg / 100ml to 1000 mg / 100ml.

[0011] Preferably, the concentration of tiotropium bromide or its salt is 1 μg / 100ml to 1000 mg / 100ml.

[0012] Preferably, the pH adjuster is selected from citric acid, hydrochloric acid, and sodium hydroxide, and the pH range of the pharmaceutical preparation is 2 to 6.

[0013] Preferably, the additive is selected from one or more of benzalkonium chloride or its salts, EDTA or its salts.

[0014] Preferably, the solvent is water.

[0015] Preferably, the formaldehyde-removing packaging material is a plastic container that has undergone formaldehyde removal treatment.

[0016] Preferably, the method for treating the formaldehyde-removed plastic container includes the following steps:

[0017] (1) The plastic container was soaked in water;

[0018] (2) The plastic container after being soaked in water in step (1) is then rinsed with water;

[0019] (3) The plastic container washed in step (2) is vacuum dried.

[0020] Preferably, the method for treating the formaldehyde-removed plastic container includes the following steps:

[0021] (1) The plastic container is soaked in water at a temperature ≥40℃ for a time ≥1 day;

[0022] (2) The plastic container after being soaked in water in step (1) is then rinsed with water;

[0023] (3) The plastic containers washed in step (2) are vacuum dried at a temperature of ≥50℃ for a time of ≥1 day.

[0024] Preferably, the soaking temperature in step (1) is 50-90°C.

[0025] Preferably, the soaking time in step (1) is 1 to 14 days.

[0026] Preferably, the vacuum drying temperature in step (3) is 50℃~90℃.

[0027] Preferably, the vacuum drying time in step (3) is 1 to 14 days.

[0028] Preferably, the plastic container is a flexible plastic container.

[0029] Preferably, the pharmaceutical preparation is a soft mist.

[0030] Preferably, the soft mist is stored in a flexible plastic vial and administered via a soft mist device.

[0031] Beneficial effects:

[0032] The combination of tiotropium bromide and olodaterol pharmaceutical preparations and formaldehyde-removing packaging containers described in this invention allows the liquid medicine to be placed in formaldehyde-removing packaging materials, achieving the technical effect that the packaging materials do not affect the quality of the liquid medicine contained therein, and ensuring that the stored quality of the liquid medicine meets the requirements. Detailed Implementation

[0033] The present invention will be further described below with reference to the embodiments. These embodiments are merely typical descriptions of the present invention, but the present invention is not limited thereto. Unless otherwise specified, the experimental methods used in the following embodiments are conventional methods, and the raw materials and reagents used are commercially available from conventional markets unless otherwise specified.

[0034] PE: Polyethylene plastic; PP: Polypropylene plastic; PET: Polyterephthalic acid plastic; LDPE: Low-density polyethylene.

[0035] Example 1

[0036] Prepare a batch of tiotropium bromide and olodaterol hydrochloride soft spray solution, as follows:

[0037] Table 1. Formulation of Tiotropium bromide and Odaterol hydrochloride soft spray solution

[0038] TB 56mg OH 50mg EDTA 20mg 50% BAC 40mg Hydrochloric acid adjusts pH 2.85 Pure water weighing to 200g

[0039] TB stands for tiotropium bromide; OH stands for olodaterol hydrochloride; 50% BAC stands for 50% benzalkonium chloride; EDTA stands for disodium ethylenediaminetetraacetate.

[0040] Preparation method: Dissolve TB, OH and EDTA in 190g of pure water, adjust the pH to 2.85 with hydrochloric acid, sonicate until completely dissolved, and finally bring the volume to 200g with pure water.

[0041] The prepared sample 1 tiotropium bromide and olodaterol hydrochloride soft spray solutions were dispensed into different bottles, and the bottle handling information is as follows:

[0042] Table 2 Different Packaging Materials and Packaging Processing Methods

[0043]

[0044] Different packaged forms of liquid medicine were placed at 60℃ for 0 days, 5 days, and 10 days, and samples were tested for impurities and aldehydes. The test results are as follows:

[0045] Table 3. Impurity results of soft spray solutions containing tiotropium bromide and olodaterol hydrochloride on day 0:

[0046] OLO-14 (%) 0.07

[0047] As mentioned above, the impurities are publicly known impurities, and specific information is as follows:

[0048]

[0049]

[0050] Table 4. Impurity results of tiotropium bromide and olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 5 days:

[0051] OLO-14 (%) 0.07 0.13

[0052] Table 5. Impurity results of tiotropium bromide and olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 10 days:

[0053]

[0054]

[0055] Table 6. Formaldehyde detection results of tiotropium bromide and olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 10 days:

[0056]

[0057] As can be seen from the impurity results in Tables 3 to 5, the OLO-14 impurities in the liquid medicine contained in the vials treated by the method of the present invention are significantly less than those in the liquid medicine contained in the untreated vials. The results in Table 6 show that the formaldehyde content in the liquid medicine contained in the treated plastic vials is significantly lower than that in the untreated liquid medicine. This indicates that the bottle treatment method described in the present invention can effectively remove formaldehyde impurities from the bottles, thereby reducing the impact of the plastic bottles on the stability of the liquid medicine.

[0058] Example 2

[0059] The effects of different soaking temperatures and soaking times on the formaldehyde removal effect of plastic vials and the stability of the solution were investigated.

[0060] Sample 1 from Example 1 was dispensed into bottles treated under different conditions. The bottle treatment information is as follows:

[0061] Table 7 Different methods for treating vials containing pharmaceutical solutions

[0062] Experiment 3 LDPE Soak in 50℃ pure water for 14 days, then rinse with pure water and dry at 60℃. Experiment 4 LDPE Soak in 60℃ pure water for 7 days, then rinse with pure water, and finally dry at 60℃. Experiment 5 LDPE Soak in 70℃ pure water for 1 day, then rinse with pure water, and finally dry at 60℃. Experiment 6 LDPE Soak in 80℃ pure water for 1 day, then rinse with pure water, and finally dry at 60℃. Experiment 7 LDPE Soak in 90℃ pure water for 1 day, then rinse with pure water, and finally dry at 60℃. Experiment 8 LDPE Untreated soft spray vials

[0063] The vials obtained from different processing methods were filled with the drug solution. Sample 1 was placed at 60℃ for 0 days, 5 days, and 10 days. The samples were tested for impurities and aldehydes.

[0064] The test results are as follows:

[0065] Table 8. Impurity results for Sample 1 after 0 days of storage.

[0066]

[0067] Table 9 shows the impurity results of Sample 1 after being placed in different vials at 60°C for 5 days (conditions: 60°C, 5 days).

[0068]

[0069] Table 10 shows the impurity results of samples placed at 60℃ for 10 days (conditions: 60℃, 10 days).

[0070]

[0071] Table 11. Formaldehyde detection results of small bottles obtained from different experiments after placing the medicine solution (conditions: 60℃, 5 days).

[0072]

[0073] Table 12. Formaldehyde detection results of small bottles obtained from different experiments after placing the medicine solution (conditions: 60℃, 10 days).

[0074]

[0075]

[0076] The experimental results in Tables 9-12 show that the formaldehyde content in the liquid medicine was significantly lower in LDPE plastic vials soaked in pure water at 50℃~90℃ compared to untreated vials. Untreated vials had a significant impact on the OLO-14 impurity, while treated LDPE vials showed significantly lower levels of OLO-14 impurities. Table 12 indicates that soaking vials in pure water at 50℃~90℃ can significantly remove formaldehyde from LDPE plastic vials, reducing the impact of the vials on the liquid medicine and ensuring the quality of the stored medicine.

[0077] Comparative Experiment 1

[0078] A batch of tiotropium bromide and olodaterol hydrochloride soft spray solution was prepared, with the same formulation as sample 1 in Example 1, and was packaged into bottles treated by the following four different methods:

[0079] Table 13 Packaging Material Treatment Methods

[0080]

[0081] Bottles treated with different packaging methods in experiments 9-12 were placed in containers filled with the liquid medicine at 60℃ for 0, 5, and 10 days, and at 40℃ for 1 and 2 months. Impurities and aldehydes were then tested in each sample. The results are as follows:

[0082] Table 14 Impurity Results for Sample 1 on Day 0

[0083]

[0084] Table 15. Impurity results of tiotropium bromide and olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 5 days.

[0085] OLO-14 (%) 0.27 0.24 0.26 0.28

[0086] Table 16. Results of impurities in tiotropium bromide and olodaterol hydrochloride soft spray solutions from different bottles after 10 days at 60℃.

[0087] OLO-14 (%) 0.43 0.49 0.48 0.48

[0088] Table 17. Impurity results of tiotropium bromide and olodaterol hydrochloride soft spray solutions in different bottles after being stored at 40°C for 1 month.

[0089] OLO-14 (%) 0.33 0.35 0.37 0.39

[0090] Table 18. Results of impurities in soft spray solutions containing tiotropium bromide and olodaterol hydrochloride from different bottles after being stored at 40°C for 2 months.

[0091] OLO-14 (%) 0.52 0.55 0.59 0.67

[0092] As can be seen from the results in Table 14-18, the treatment method described in Experiment 9-12, due to its failure to effectively remove impurities from the bottle, will accelerate the generation of drug impurities and seriously affect the stability of the drug solution.

[0093] The bottles in Experiments 9 and 10 were not soaked in water, resulting in substandard bottle quality. The treatment method in Experiment 11 involved insufficient water soaking temperature and time, and insufficient vacuum drying temperature, leading to substandard bottle quality. The bottles in Experiment 12 were untreated and also failed to meet quality standards.

[0094] Table 19. Aldehyde Detection Results of Tiotropium Bromide and Odaterol Hydrochloride Soft Foam Solution in Different Bottles

[0095]

[0096]

[0097] Note: TDI: Daily Intake, μg / day

[0098] As shown in Table 19, soaking is a necessary step in removing formaldehyde. Furthermore, the soaking temperature and time, as well as the vacuum drying temperature and time, must reach specific levels to effectively remove formaldehyde. Experiments 9 and 10, which involved direct vacuum drying without soaking, failed to effectively remove formaldehyde. Similarly, the soaking temperature and time in the small bottle described in Experiment 11 were insufficient, and the vacuum drying temperature was too low, also preventing effective formaldehyde removal.

[0099] Comparative Experiment 2

[0100] The plastic bottle described in Experiment 2 is an untreated plastic bottle, while the plastic bottle described in Experiment 1 is a plastic bottle obtained by the preferred treatment conditions and method of the present invention.

[0101] Sample 1 from Example 1 was placed in plastic vials treated in Experiments 1 and 2, respectively. Stability tests were conducted by placing the vials in a 40°C incubator for 6 months. Samples were taken at 0, 1, 3, and 6 months to measure impurities and formaldehyde content. The results are as follows:

[0102] Table 20 shows the results of impurities in the plastic vials containing sample 1 obtained from Experiment 1 (condition: 40℃).

[0103] OLO-14 Not detected 0.09％ 0.29％ 0.61％

[0104] Table 21 Results of impurities in sample 1 contained in the plastic vials obtained from Experiment 2 (condition: 40℃)

[0105] OLO-14 Not detected 0.37％ 0.88％ 1.89％

[0106] Table 22 shows the formaldehyde detection results of sample 1 in the plastic bottles obtained from Experiment 1 (condition: 40℃).

[0107]

[0108]

[0109] Table 23 shows the formaldehyde detection results of sample 1 in the plastic bottles obtained from Experiment 2 (condition: 40℃).

[0110]

[0111] The pharmacopoeia stipulates that after a 6-month stability test, the impurity content of the sample must be less than 1.0%. Comparative data from Tables 20 and 21 show that the sample 1 solution stored in vials treated by the method described in this invention meets the pharmacopoeia requirement for OLO-14 impurity. However, after 6 months of storage, the untreated plastic vials showed an OLO-14 impurity content of 1.89%, exceeding the pharmacopoeia's upper limit of 1.0%. Therefore, untreated plastic vials will result in the drug solution failing to meet pharmacopoeia requirements. This comparative experiment demonstrates that storing tiotropium bromide and olodaterol hydrochloride soft spray solutions in treated plastic vials meets quality requirements. It also proves that the bottle washing method described in this experiment can effectively reduce the amount of formaldehyde released from plastic vials.

[0112] The above embodiments are used to illustrate the present invention. Those skilled in the art will understand that these embodiments are for illustrative purposes only and do not limit the scope of the invention in any way. Furthermore, it should be understood that after reading the teachings herein, those skilled in the art can make various alterations or modifications to the invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A combination of a pharmaceutical preparation containing tiotropium bromide and olodaterol, and a formaldehyde-removing packaging container; The pharmaceutical formulation is an inhalation soft fog containing olodaterol or its salt, tiotropium bromide or its salt, and also contains a pH adjuster, a pharmaceutically acceptable additive, and a water solvent; The packaging container is a low-density polyethylene flexible plastic container adapted to a soft mist inhalation device, and the flexible plastic container is treated to remove formaldehyde. The formaldehyde removal process includes the following steps: (1) Plastic containers are soaked in water at ≥40℃ for ≥1 day; (2) The soaked plastic container is then rinsed with water; (3) The washed plastic containers are vacuum dried at ≥50℃ for ≥1 day; The combination is used to reduce formaldehyde leaching from plastic containers, inhibit the formation of OLO-14 impurity in the medication solution, and improve the long-term storage stability of the compound inhalation soft fog.

2. The combination according to claim 1, characterized in that, The concentration of odorol or its salt is 1 μg / 100ml to 1000 mg / 100ml.

3. The combination according to claim 1, characterized in that, The concentration of tiotropium bromide or its salt is 1 μg / 100ml to 1000 mg / 100ml.

4. The combination according to claim 1, characterized in that, The pH adjuster is selected from citric acid, hydrochloric acid, and sodium hydroxide, and the pH range of the pharmaceutical preparation is 2 to 6.

5. The combination according to claim 1, characterized in that, The additive is selected from one or more of benzalkonium chloride or its salts, EDTA or its salts.

6. The combination according to claim 1, characterized in that, The solvent is pure water or water for injection.

7. The combination according to claim 1, characterized in that, Step (1) Soaking temperature is 50-90℃.

8. The combination according to claim 1, characterized in that, Step (1) Soaking time is 1 to 14 days.

9. The combination according to claim 1, characterized in that, Step (3) Vacuum drying temperature is 50-90℃.

10. The combination according to claim 1, characterized in that, Step (3) Vacuum drying time is 1 to 14 days.

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