A combination of an olodaterol-containing pharmaceutical formulation and an aldehyde-removing packaging material container

Abstract

The application discloses a combination of an olodaterol-containing medicine preparation and an aldehyde-removed packaging material container, and is characterized in that the combination comprises the following components: olodaterol or a salt thereof, a pH regulator, a pharmaceutically acceptable additive, a solvent, and the preparation is stored in an aldehyde-removed container. The olodaterol hydrochloride-containing preparation is stored in an aldehyde-removed plastic bottle, so that the technical effect that the plastic container can be used for a soft mist inhalation device and does not affect the quality of the medicine liquid is achieved.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a combination of an olodaterol-containing pharmaceutical preparation 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 olodaterol hydrochloride solution without special treatment, the amount of impurities in the solution increases significantly after a period of storage.

[0003] The reason why this type of bottle affects the stability of the medicine solution, and how to eliminate the influence of this material on the stability of the medicine solution, are the technical problems 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 to ensure that the quality of the solution containing olodaterol hydrochloride 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 combination of a container for olodaterol hydrochloride and a formaldehyde-removing pharmaceutical preparation to ensure that the quality of the drug is not affected by the packaging material when storing olodaterol-containing liquid in plastic packaging. This achieves the technical effect that the packaging material does not affect the quality of the contained liquid, ensuring that the stored liquid meets the required quality standards.

[0008] A combination of an olodaterol pharmaceutical preparation and a formaldehyde-removing packaging container comprises the following components:

[0009] Odaterol or its salts, pH adjusters, pharmaceutically acceptable additives, solvents, the composition being stored in formaldehyde-removed packaging.

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

[0011] Preferably, the olodaterol is olodaterol hydrochloride.

[0012] Preferably, the pH adjuster is selected from citric acid, hydrochloric acid, and sodium hydroxide, and the pH range of the pH adjuster in 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 formaldehyde-removing plastic container.

[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 flexible plastic is selected from one or more of low-density polyethylene plastic, polyethylene plastic, polypropylene plastic, and polyterephthalic acid plastic.

[0030] Preferably, the flexible plastic is low-density polyethylene plastic.

[0031] Preferably, the flexible plastic container is a flexible plastic bottle.

[0032] Preferably, the formulation is a soft mist.

[0033] Preferably, the soft mist is stored in a flexible plastic vial and administered via a soft mist device.

[0034] Beneficial effects:

[0035] The combination of the olodaterol-containing pharmaceutical preparation and the formaldehyde-removing packaging container described in this invention allows the liquid medicine to be placed in the formaldehyde-removing packaging material, achieving the technical effect that the packaging material does 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

[0036] 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.

[0037] PE: Polyethylene plastic; PP: Polypropylene plastic; PET: Polyterephthalic acid plastic; LDPE: Low-density polyethylene.

[0038] Example 1

[0039] Prepare a batch of olodaterol hydrochloride soft spray solution, as follows:

[0040] Table 1. Formula for Odaterol Hydrochloride Soft Mist Solution

[0041] OH 50mg EDTA 20mg 50% BAC 40mg Anhydrous citric acid 6mg Pure water weighing to 200g

[0042] OH represents olodaterol hydrochloride; 50% BAC represents 50% benzalkonium chloride; EDTA represents disodium ethylenediaminetetraacetate.

[0043] Preparation method: Weigh the prescribed amounts of EDTA and anhydrous citric acid into a beaker according to Table 1, dissolve them in part of pure water, add the prescribed amount of 50% BAC, dissolve, then add the prescribed amount of OH, and add water to a net weight of 200g. After stirring and dissolving evenly, measure the pH to be 3.94.

[0044] The prepared sample 1 olodaterol hydrochloride soft spray solution was dispensed into different soft spray plastic bottles. Bottle handling information is as follows:

[0045] Table 2 Different Packaging Materials and Packaging Processing Methods

[0046]

[0047]

[0048] The soft fog bottle described in this embodiment is a low-density polyethylene bottle.

[0049] Bottles prepared using different packaging methods were filled with the drug solution and placed at 60℃ for 0, 5, and 10 days. The samples were then tested for impurities and aldehydes. The test results are as follows:

[0050] Table 3. Impurity results of soft spray solutions containing olodaterol hydrochloride on day 0:

[0051]

[0052] Table 4 Formaldehyde Results of Soft Foam Solution Containing Odaterol Hydrochloride on Day 0

[0053]

[0054] The OLO-14 impurity is a publicly known impurity, and specific information is as follows:

[0055]

[0056] Table 5. Impurity results of olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 5 days:

[0057]

[0058] Table 6. Impurity results of olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 10 days:

[0059]

[0060] Table 7. Formaldehyde test results of olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 5 days:

[0061]

[0062]

[0063] Table 8. Formaldehyde test results of olodaterol hydrochloride soft spray solutions in different bottles after being placed at 60℃ for 10 days:

[0064]

[0065] As can be seen from the impurity results in Tables 3 to 8, 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 Tables 7 and 8 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 plastic bottles on the stability of the liquid medicine.

[0066] Comparative Experiment 1

[0067] Investigating the effects of different soaking temperatures and soaking times on formaldehyde removal from small plastic bottles.

[0068] Sample 1 from Example 1 was dispensed into bottles treated under different conditions. The processing information for the plastic bottles is as follows:

[0069] Table 9. Different methods for processing vials containing pharmaceutical solutions

[0070] Experiment 7 Soak in 60℃ pure water for 7 days, then wash, and then vacuum dry at 60℃ for 72 hours in a soft mist vial. Experiment 8 Vacuum drying of soft mist vials at 60℃ for 72 hours Experiment Nine Soak in purified water at 25°C, then rinse with pure water, and finally vacuum dry at 40°C for 48 hours in soft mist vials. Experiment 10 Soft mist vials dried twice under vacuum at 30℃ for 48 hours and 60℃ for 72 hours

[0071] Sample 1 solution was prepared in vials obtained from different processing methods and placed at 60℃ for 0 days, 5 days, and 10 days. The samples were then analyzed by HPLC for impurities and aldehydes.

[0072] The test results are as follows:

[0073] Table 10 Impurity Results for Sample 1 After 0 Days of Storage Table 10

[0074]

[0075] Table 11 Formaldehyde Results of Sample 1 After 0 Days of Storage Table 11

[0076]

[0077] Table 12 shows the impurity results of Sample 1 after being placed in different vials at 60°C for 5 days (conditions: 60°C, 5 days).

[0078]

[0079] Table 13 shows the impurity results of Sample 1 after being stored at 60℃ for 10 days (conditions: 60℃, 10 days).

[0080]

[0081] Table 14. Formaldehyde detection results of small vials obtained from different experiments after placing the medicine solution (conditions: 60℃, 5 days).

[0082]

[0083] Table 15. Formaldehyde detection results of small vials obtained from different experiments after placing the medicine solution (conditions: 60℃, 10 days).

[0084]

[0085] The results of the comparative experiments, from Experiment 7 to Experiment 10, on impurities and aldehydes show that soaking is a key step in removing formaldehyde, and that the soaking temperature and time, as well as the vacuum drying temperature and time, affect the formaldehyde removal effect.

[0086] Comparative Experiment 2

[0087] Sample 1 from Example 1 was placed in plastic vials treated in Experiments 6 and 7, 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:

[0088] Table 16 shows the results of impurities in the plastic vials containing sample 1 obtained from Experiment 6 (condition: 40℃).

[0089] OLO-14 0.02％ 0.75％ 1.65％ 2.19％

[0090] Table 17 Results of impurities in sample 1 contained in the plastic vials obtained from Experiment 7 (condition: 40℃)

[0091] OLO-14 0.02％ 0.32％ 0.69％ 0.93％

[0092] Table 18 shows the formaldehyde detection results of sample 1 in the plastic bottles obtained from Experiment 6 (condition: 40℃).

[0093]

[0094] Table 19 shows the formaldehyde detection results of sample 1 in the plastic bottles obtained from Experiment 7 (condition: 40℃).

[0095]

[0096] Experiment 6 describes untreated plastic vials, while Experiment 7 describes plastic vials treated under the preferred treatment conditions described in this invention. The pharmacopoeia stipulates that after a 6-month stability test, the impurity content of the sample must be less than 1.0%. Comparative data in Tables 16 and 17 show that the vials treated with the method described in this invention, containing sample 1, have a single impurity OLO-14 content that meets pharmacopoeia requirements. However, the untreated plastic vials, after 6 months, have an OLO-14 content of 2.19%, exceeding the upper limit of 1.0% required by the pharmacopoeia. Therefore, untreated plastic vials will result in a drug solution that does not meet pharmacopoeia requirements. This comparative experiment demonstrates that treating plastic vials for olodaterol hydrochloride soft spray solution meets quality requirements. It also proves that the bottle washing method described in this experiment can effectively reduce the amount of formaldehyde released from the plastic vials.

[0097] 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 an odoraterol pharmaceutical preparation and a formaldehyde-removing packaging container; The pharmaceutical formulation is an inhalation soft fog containing olodaterol or its salts, and also contains a pH adjuster, pharmaceutically acceptable additives, and a water-soluble agent; 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 inhaled soft fogging agent.

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

4. 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.

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

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

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

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

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

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