Pharmaceutical composition with improved stability

Abstract

Disclosed is a pharmaceutical composition with improved stability.

Description

Pharmaceutical composition with improved stability

[0001] The present invention relates to a pharmaceutical composition containing atomoxetine or a pharmaceutically acceptable salt thereof.

[0002] Atomoxetine is a compound having the structure of Chemical Formula 1 below, and is used as a treatment for ADHD (Attention Deficit Hyperactivity Disorder):

[0003] [Chemical Formula 1]

[0004]

[0005] N-nitroso impurities may be generated during the manufacturing and distribution of pharmaceutical compositions containing atomoxetine, and N-nitroso impurities are controlled by pharmaceutical regulatory agencies in each country as potential genotoxic substances.

[0006] In particular, in July 2023, the EMA (European Medicines Agency) released guidelines on the control range for N-nitroso-atomoxetine (NNA), an N-nitroso impurity in atomoxetine.

[0007] Accordingly, the Ministry of Food and Drug Safety of Korea is also expected to establish guidelines for NNA. Therefore, it is necessary to develop high-quality pharmaceuticals that meet domestic and international standards.

[0008] The present invention is intended to provide a pharmaceutical composition comprising atomoxetine with reduced NNA impurities or a pharmaceutically acceptable salt thereof.

[0009] The inventors conducted research in various aspects to reduce the NNA of atomoxetine preparations and completed the present invention by confirming that NNA is reduced when alkalizing agents, moisture inhibitors, or antioxidants are used as additives.

[0010] Accordingly, the present invention relates to a pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof; and one or more additives selected from the group consisting of alkalizing agents, moisture barriers and antioxidants.

[0011] In the present invention, among the alkalizing agent, moisture inhibitor, and antioxidant, the preferred agent is the alkalizing agent.

[0012] The pharmaceutical composition according to the present invention inhibits the formation of impurities (particularly, N-nitroso-atomoxetine).

[0013] In the present invention, the content of one or more additives selected from the group consisting of alkalizing agents, moisture inhibitors, and antioxidants may be in the range of 0.1 to 15 weight% with respect to the total weight of the pharmaceutical composition, but is not limited thereto.

[0014] In the present invention, one or more alkalizing agents selected from the group consisting of L-arginine, magnesium oxide, calcium hydroxide, magnesium carbonate, and magnesium hydroxide may be used.

[0015] In the present invention, one or more types selected from the group consisting of hardened oil and dimethicone may be used as the moisture inhibitor.

[0016] In the present invention, BHT may be used as the antioxidant.

[0017] In the present invention, the pharmaceutically acceptable salt of atomoxetine may be any pharmaceutically acceptable acidic salt of atomoxetine, preferably atomoxetine hydrochloride.

[0018] In addition, the present invention relates to a pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof; and an alkalizing agent. The pharmaceutical composition according to the present invention inhibits the formation of impurities (particularly N-nitroso-atomoxetine).

[0019] In the present invention, one or more alkalizing agents selected from the group consisting of L-arginine, magnesium oxide, and calcium hydroxide may be used.

[0020] The above pharmaceutical composition of the present invention may further include one or more additives selected from the group consisting of moisture inhibitors and antioxidants.

[0021] Here, hydrogenated oil or dimethicone may be used as the moisture inhibitor, and BHT may be used as the antioxidant.

[0022] In the present invention, the pharmaceutically acceptable salt of atomoxetine may be any pharmaceutically acceptable acidic salt of atomoxetine, preferably atomoxetine hydrochloride.

[0023] In addition, the present invention relates to a method for preparing a pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof, comprising the step of adding one or more additives selected from the group consisting of alkalizing agents, moisture inhibitors, and antioxidants to suppress the formation of impurities (particularly, N-nitroso-atomoxetine).

[0024] In the present invention, one or more selected from the group consisting of L-arginine, magnesium oxide, and calcium hydroxide may be used as the alkalizing agent, one or more selected from the group consisting of hydrogenated oil and dimethicone may be used as the moisture inhibitor, and BHT may be used as the antioxidant.

[0025] In the present invention, the pharmaceutically acceptable salt of atomoxetine may be any pharmaceutically acceptable acidic salt of atomoxetine, preferably atomoxetine hydrochloride.

[0026] The pharmaceutical composition according to the present invention may be a solid formulation, for example, a tablet, granule, or capsule formulation. The pharmaceutical composition according to the present invention may additionally include pharmaceutically acceptable additives, for example, a diluent, a binder, a disintegrant, a lubricant, etc., as needed.

[0027] For example, the pharmaceutical composition according to the present invention is,

[0028] (i) mixing atomoxetine or a pharmaceutically acceptable salt thereof, and (ii) one or more additives selected from the group consisting of alkalizing agents, moisture barriers, and antioxidants;

[0029] (ii) a step of preparing a mixture by adding a diluent to the above mixture; and

[0030] (iii) Step of filling the above mixture into a capsule

[0031] It can be manufactured into a capsule by a manufacturing method including

[0032] In addition, for example, the pharmaceutical composition according to the present invention is,

[0033] (i) mixing atomoxetine or a pharmaceutically acceptable salt thereof, and (ii) one or more additives selected from the group consisting of alkalizing agents, moisture barriers, and antioxidants;

[0034] (ii) a step of preparing a mixture by adding one or more selected from the group consisting of a diluent, a disintegrant, a binder, and a lubricant to the above mixture; and

[0035] (iii) Step of compressing the above mixture into tablets

[0036] It can be manufactured into a tablet by a manufacturing method including.

[0037] The atomoxetine-containing pharmaceutical composition prepared according to the present invention significantly reduced the NNA content.

[0038] Figures 1 to 5 are drawings showing the NNA evaluation results of capsules and tablets according to examples and comparative examples of the present invention.

[0039] Hereinafter, the present invention will be described in detail based on embodiments to aid in understanding the invention. However, the following embodiments are merely illustrative of the content of the present invention, and the spirit or scope of the present invention is not limited in any way by the following embodiments. The embodiments of the present invention are provided to more completely explain the invention to those with average knowledge in the art.

[0040] Preparation of capsules in Examples 1 to 5

[0041] Capsule formulations of Examples 1 to 5 having the ingredients and contents shown in Table 1 below were manufactured according to the following process:

[0042] 1) Add atomoxetine hydrochloride, L-arginine, magnesium oxide, hydrogenated oil, dimethicone or BHT to the mixer and mix.

[0043] 2) Add lactose monohydrate to the mixture in 1) and mix.

[0044] 3) A capsule filling is prepared by mixing talc into the mixture of 2).

[0045] 4) Fill 230 mg of the mixture of 3) into a hard capsule.

[0046] [Table 1]

[0047]

[0048] Preparation of capsules in Examples 6 to 7

[0049] Capsule formulations of Examples 6 to 7 having the ingredients and contents shown in Table 2 below were manufactured according to the following process.

[0050] 1) Add atomoxetine hydrochloride and magnesium oxide to the mixer and mix.

[0051] 2) Add lactose monohydrate and light anhydrous silicic acid to the mixture in 1) and mix.

[0052] 3) Prepare a capsule filling by mixing crospovidone and talc into the mixture of 2).

[0053] 4) Fill 230 mg of the mixture of 3) into a hard capsule.

[0054] [Table 2]

[0055]

[0056] Preparation of capsules in Examples 8 to 11

[0057] Capsule formulations of Examples 8 to 11 having the ingredients and content according to Table 3 below were prepared according to the following process.

[0058] 1) Select two types from the group consisting of atomoxetine hydrochloride, L-arginine, magnesium oxide, hydrogenated oil, and dimethicone, add them to a mixer, and mix.

[0059] 2) Add lactose monohydrate and crospovidone to the mixture of 1) in a mixer and mix.

[0060] 3) A capsule filling is prepared by mixing talc into the mixture of 2).

[0061] 4) Fill 230 mg of the mixture of 3) into a hard capsule.

[0062] [Table 3]

[0063]

[0064] Preparation of capsules in Examples 12 to 13

[0065] Capsule formulations of Examples 12 to 13 having the ingredients and content according to Table 4 below were prepared according to the following process.

[0066] 1) Put atomoxetine hydrochloride and calcium hydroxide into a mixer and mix.

[0067] 2) Add lactose monohydrate and crospovidone to the mixture of 1) and mix.

[0068] 3) A capsule filling is prepared by mixing talc into the mixture of 2).

[0069] 4) Fill 230 mg of the mixture of 3) into a hard capsule.

[0070] [Table 4]

[0071]

[0072] Preparation of tablets of Examples 14 to 16

[0073] The tablet formulations of Examples 14 to 16 having the ingredients and contents shown in Table 5 below were manufactured according to the following process.

[0074] 1) Mix atomoxetine hydrochloride, L-arginine, magnesium oxide, calcium hydroxide, microcrystalline cellulose, and sodium starch glycolate in a mixer.

[0075] 2) Add mannitol to the mixture of 1) and mix.

[0076] 3) Add talc and magnesium stearate to the mixture in 2) and mix.

[0077] 4) 300 mg of the mixture of 3) is compressed into tablets using a tablet press.

[0078] [Table 5]

[0079]

[0080] Comparative Examples 1 to 3 Preparation of capsules

[0081] Capsule formulations according to Comparative Examples 1 to 3 having the ingredients and contents shown in Table 6 below were manufactured according to the process below.

[0082] Comparative Example 1

[0083] 1) Add atomoxetine hydrochloride, lactose monohydrate, and light anhydrous silicic acid to a mixer and mix.

[0084] 2) Prepared by mixing crospovidone and talc into the mixture of 1).

[0085] 3) Fill 230 mg of the mixture of 2) into a hard capsule.

[0086] Comparative Example 2

[0087] 1) Add atomoxetine hydrochloride and lactose monohydrate to a mixer and mix.

[0088] 2) It is manufactured by mixing talc into the mixture of 1).

[0089] 3) Fill 230 mg of the mixture of 2) into a hard capsule.

[0090] Comparative Example 3

[0091] 1) Add atomoxetine hydrochloride and lactose monohydrate to a mixer and mix.

[0092] 2) Prepared by mixing crospovidone and talc into the mixture of 1).

[0093] 3) Fill 230 mg of the mixture of 2) into a hard capsule.

[0094] [Table 6]

[0095]

[0096] Comparative Example 4 Preparation of Tablets

[0097] A tablet formulation according to Comparative Example 4 having the ingredients and contents shown in Table 7 below was manufactured according to the process below.

[0098] Comparative Example 4

[0099] 1) Mix atomoxetine hydrochloride, microcrystalline cellulose, and sodium starch glycolate.

[0100] 2) Add mannitol to the mixture of 1) and mix.

[0101] 3) Add talc and magnesium stearate to the mixture in 2) and mix.

[0102] 4) 300 mg of the mixture of 3) is made into tablets using a tablet press.

[0103] [Table 7]

[0104]

[0105] Stability Assessment 1

[0106] Each of the capsules obtained according to Examples 1 to 5 and Comparative Examples 1 and 2 was stored in a glass vial under accelerated conditions (40°C, 75% relative humidity) and removed after a specified period (initial and after 1 week). Then, an amount corresponding to 80 mg of atomoxetine was precisely weighed, and the amount of NNA of the sample was measured using LC-MS / MS. The results are shown in Table 8 and Figure 1 below.

[0107] [Table 8]

[0108]

[0109] Based on the results of Table 8, the effects of two types of alkalizing agents, two types of moisture inhibitors, and one type of antioxidant were confirmed.

[0110] Experimental results confirmed that the occurrence of impurities was improved when an alkalizing agent, moisture inhibitor, or antioxidant was added compared to Comparative Example 1 and Comparative Example 2.

[0111] Stability Assessment 2

[0112] Each of the capsules obtained for Examples 6 and 7 and Comparative Example 1 was stored in an HDPE bottle under accelerated conditions (40°C, 75% relative humidity) and removed after a specified period (initial, after 2 weeks). Then, an amount corresponding to 80 mg of atomoxetine was precisely weighed, and the amount of NNA of the sample was measured using LC-MS / MS. The results are shown in Table 9 and Figure 2 below.

[0113] [Table 9]

[0114]

[0115] Based on the results in Table 9, the degree of impurity generation according to the magnesium oxide addition ratio was confirmed.

[0116] The packaging was conducted using an HDPE bottle, and the experimental results confirmed that the occurrence of impurities was improved at both 2% and 5% magnesium oxide.

[0117] Stability Assessment 3

[0118] The amount of NNA was measured for the capsules of Examples 8 to 11 and Comparative Examples 1 and 3 in substantially the same manner as Stability Evaluation 2, and the results are shown in Table 10 and Figure 3 below.

[0119] [Table 10]

[0120]

[0121] Based on the results of Table 10, two types of magnesium oxide, arginine, dimethicone, and hydrogenated oil were selected for Comparative Examples 1 and 3 to check for improvement when used in combination.

[0122] The packaging was conducted using an HDPE bottle, and the experimental results confirmed that the combined use of an alkalizing agent or a moisture barrier had the effect of reducing the formation of impurities.

[0123] Stability Assessment 4

[0124] For Examples 12 and 13 and Comparative Example 3, the amount of NNA was measured in substantially the same way as in Stability Evaluation 2, and the results are shown in Table 11 and Figure 4 below.

[0125] [Table 11]

[0126]

[0127] Based on the results of Table 11, the degree of impurity generation according to the calcium hydroxide addition ratio was confirmed.

[0128] The packaging was conducted in an HDPE bottle, and the experimental results confirmed that the occurrence of impurities was improved at both 0.5% and 2% calcium hydroxide.

[0129] Stability Assessment 5

[0130] The amount of NNA was measured for the tablets of Examples 14 to 16 in substantially the same manner as in Stability Evaluation 2, and the results are shown in Table 12 and Figure 5 below.

[0131] [Table 12]

[0132]

[0133] Based on the results in Table 12, it was confirmed that using L-arginine, magnesium oxide, and calcium hydroxide has the effect of reducing the formation of impurities.

[0134] The pharmaceutical composition of the present invention has a significant effect of reducing NNA impurities.

Claims

1. Atomoxetine or a pharmaceutically acceptable salt thereof; and An additive selected from the group consisting of an alkalizing agent, a moisture-repelling agent, and an antioxidant. A pharmaceutical composition comprising:

2. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition suppresses the production of impurities.

3. A pharmaceutical composition according to claim 2, wherein the impurity is N-nitroso-atomoxetine.

4. A pharmaceutical composition according to claim 1, wherein the content of one or more additives selected from the group consisting of alkalizing agents, moisture-retaining agents, and antioxidants is 0.1 to 15 weight% based on the total weight of the pharmaceutical composition.

5. A pharmaceutical composition according to claim 1, wherein the alkalizing agent is one or more selected from the group consisting of L-arginine, magnesium oxide, calcium hydroxide, magnesium carbonate, and magnesium hydroxide.

6. A pharmaceutical composition according to claim 1, wherein the moisture barrier is at least one selected from the group consisting of hardened oil and dimethicone.

7. A pharmaceutical composition according to claim 1, wherein the antioxidant is BHT.

8. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of atomoxetine is atomoxetine hydrochloride.

9. Atomoxetine or a pharmaceutically acceptable salt thereof; and alkalizing agent A pharmaceutical composition comprising:

10. A pharmaceutical composition according to claim 9, wherein the alkalizing agent is one or more selected from the group consisting of L-arginine, magnesium oxide, calcium hydroxide, magnesium carbonate, and magnesium hydroxide.

11. A pharmaceutical composition according to claim 9, further comprising at least one additive selected from the group consisting of a moisture-preventing agent and an antioxidant.

12. A pharmaceutical composition according to claim 11, wherein the moisture barrier is a hardened oil or dimethicone, and the antioxidant is BHT.

13. A pharmaceutical composition according to claim 9, wherein the pharmaceutically acceptable salt of atomoxetine is atomoxetine hydrochloride.

14. A method for producing a pharmaceutical composition comprising atomoxetine or a pharmaceutically acceptable salt thereof, A method for producing a pharmaceutical composition, characterized in that it comprises a step of adding at least one additive selected from the group consisting of an alkalizing agent, a moisture-preventing agent, and an antioxidant to suppress the production of N-nitroso-atomoxetine.

15. In paragraph 14, The above alkalizing agent is at least one selected from the group consisting of L-arginine, magnesium oxide, calcium hydroxide, magnesium carbonate and magnesium hydroxide, The above moisture-preventing agent is at least one selected from the group consisting of hardened oil and dimethicone, A method for producing a pharmaceutical composition wherein the antioxidant is BHT.

16. A pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable salt of atomoxetine is atomoxetine hydrochloride.

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