Pharmaceutical composition containing vortioxetine
Patent Information
- Authority / Receiving Office
- WO · WO
- Patent Type
- Applications
- Current Assignee / Owner
- WHANIN PHARMA CO LTD
- Filing Date
- 2026-02-02
- Publication Date
- 2026-08-06
Smart Images
Figure KR2026001933_06082026_PF_FP_ABST
Abstract
Description
Medicinal composition containing vortioxetine
[0001] The present invention relates to a pharmaceutical composition containing vortioxetine or a pharmaceutically acceptable salt thereof.
[0002] Vortioxetine is a compound having the structure of Chemical Formula 1 below, and is used as a treatment for major depressive disorder.
[0003] [Chemical Formula 1]
[0004]
[0005] N-nitroso impurities may be generated during the manufacturing and distribution of pharmaceutical compositions containing vortioxetine. These N-nitroso impurities are potential genotoxic substances and are managed by pharmaceutical regulatory agencies in various countries. Vortioxetine is listed on the nitrosamines list of regulatory agencies such as MDFS, EMA, and FDA; it is classified as CPCA Class 3, and its acceptable daily intake (ng / day) is 400. Therefore, it is necessary to reduce the generation of N-nitroso impurities and develop high-quality pharmaceuticals that meet domestic and international standards.
[0006] The present invention is to provide a pharmaceutical composition comprising vortioxetine with reduced N-nitroso-vortioxetine (NNVt) impurities or a pharmaceutically acceptable salt thereof.
[0007] The inventors conducted research in various aspects to reduce the NNVt of vortioxetine formulations and completed the present invention by confirming that the NNVt is reduced when an alkalizing agent is used as an additive.
[0008] Accordingly, the present invention relates to a pharmaceutical composition comprising one or more additives selected from the group consisting of vortioxetine or a pharmaceutically acceptable salt thereof; and an alkalizing agent.
[0009] The pharmaceutical composition according to the present invention inhibits the formation of impurities (particularly, N-nitroso-vortioxetine).
[0010] In the present invention, the content of an additive selected from the group consisting of the alkalizing agent may range from 0.1 to 20 weight% with respect to the total weight of the pharmaceutical composition, but is not limited thereto. Preferably, the content of the alkalizing agent may be 0.1 to 10 weight% with respect to the total weight of the pharmaceutical composition, and more preferably 0.1 to 5 weight%.
[0011] In the present invention, one or more alkalizing agents selected from the group consisting of L-arginine, meglumine, magnesium oxide, sodium bicarbonate, sodium carbonate, and calcium hydroxide may be used.
[0012] The pharmaceutical composition according to the present invention has a pH of 7.0 or higher in a 50% (w / w) slurry state.
[0013] In the present invention, the pharmaceutically acceptable salt of vortioxetine may be any pharmaceutically acceptable acidic salt of vortioxetine, preferably vortioxetine hydrochloride or vortioxetine hydrobromide.
[0014] 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, excipients, binders, disintegrants, lubricants, etc., as needed.
[0015] For example, the excipient may be D-mannitol, lactose, microcrystalline cellulose, calcium hydrogen phosphate, starch, or sugar alcohols, and the disintegrant may be sodium starch glycolate, sodium croscarmellose, crospovidone, or calcium carboxymethylcellulose, and the lubricant may be talc, magnesium stearate, sodium stearyl fumarate, or stearic acid.
[0016] For example, the pharmaceutical composition according to the present invention is,
[0017] (i) a step of preparing a mixture using vortioxetine or a pharmaceutically acceptable salt thereof and one or more additives selected from the group consisting of excipients and alkalizing agents;
[0018] (ii) a step of preparing a mixture by adding a disintegrant and a lubricant to the above mixture; and
[0019] (iii) Step of tableting and coating the above mixture
[0020] It can be manufactured into a coated tablet by a manufacturing method including
[0021] The pharmaceutical composition containing vortioxetine prepared according to the present invention significantly reduced the NNVt content.
[0022] FIGS. 1 to 4 are drawings showing the NNVt evaluation results of compositions and tablets according to embodiments and comparative examples of the present invention.
[0023] 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.
[0024] Preparation of the mixture of Comparative Example 1 and Examples 1 to 5
[0025] The compositions of Comparative Example 1 and Examples 1 to 5, having the components and content according to Table 1 below, were prepared according to the following process.
[0026] Comparative Example 1
[0027] 1) Put vortioxetine hydrochloride, D-mannitol, and microcrystalline cellulose into a mixer and mix.
[0028] 2) Prepare a compound by adding a binding solution (hydroxypropylcellulose + an appropriate amount of purified water) to the mixture of 1).
[0029] 3) After drying and settling the mixture of 2), mix it with sodium starch glycolate (sieved through 30 mesh).
[0030] 4) Add magnesium stearate (sieved through 30 mesh) to the mixture of 3) and mix.
[0031] Examples 1 to 5
[0032] 1) Put vortioxetine hydrochloride, D-mannitol, and microcrystalline cellulose into a mixer and mix.
[0033] 2) Prepare a compound by adding a binding solution (hydroxypropylcellulose + an appropriate amount of purified water) to the mixture of 1).
[0034] 3) After drying and settling the compound of 2), mix it with a stabilizer (ascorbic acid, magnesium oxide, sodium bicarbonate, L-arginine, or meglumine) and sodium starch glycolate (sieved through 30 mesh).
[0035] 4) Add magnesium stearate (sieved through 30 mesh) to the mixture of 3) and mix.
[0036] [Table 1]
[0037]
[0038] In this example and subsequent examples, the pH of each composition is the value measured after mixing the pharmaceutical composition and purified water at 50% (w / w) to form a slurry based on the Slurry pH Method.
[0039] Preparation of tablets in Comparative Example 2 and Examples 6 to 9
[0040] Tablets of Comparative Example 2 and Examples 6 to 9 having the components and content according to Table 2 below were prepared according to the following process.
[0041] Comparative Example 2
[0042] 1) Put vortioxetine hydrochloride, lactose monohydrate, and microcrystalline cellulose into a mixer and mix.
[0043] 2) Prepare a compound by adding a binding solution (hypromellose + an appropriate amount of purified water) to the mixture of 1).
[0044] 3) After drying and settling the mixture of 2), mix in sodium starch glycolate (sieved through 30 mesh).
[0045] 4) Add sodium stearyl fumarate (sieved through 30 mesh) to the mixture of 3).
[0046] 5) The mixture of 4) is compressed and coated to produce a coated tablet.
[0047] Examples 6 to 9
[0048] 1) Put vortioxetine hydrochloride, lactose monohydrate, microcrystalline cellulose, and a stabilizer (L-arginine, sodium bicarbonate, sodium carbonate, or calcium hydroxide) into a mixer and mix.
[0049] 2) Prepare a compound by adding a binding solution (hypromellose + an appropriate amount of purified water) to the mixture of 1).
[0050] 3) After drying and settling the mixture of 2), mix in sodium starch glycolate (sieved through 30 mesh).
[0051] 4) Add sodium stearyl fumarate (sieved through 30 mesh) to the mixture of 3).
[0052] 5) The mixture of 4) is compressed and coated to produce a coated tablet.
[0053] [Table 2]
[0054]
[0055] Preparation of tablets in Comparative Example 3 and Examples 10 to 15
[0056] Tablets of Comparative Example 3 and Examples 10 to 15 having the components and content according to Table 3 below were prepared according to the following process.
[0057] Comparative Example 3
[0058] 1) Put vortioxetine hydrochloride, D-mannitol, and microcrystalline cellulose into a mixer and mix.
[0059] 2) Prepare a compound by adding a binding solution (hydroxypropylcellulose + an appropriate amount of purified water) to the mixture of 1).
[0060] 3) After drying and settling the mixture of 2), mix in sodium starch glycolate (sieved through 30 mesh).
[0061] 4) Add magnesium stearate (sieved through 30 mesh) to the mixture of 3).
[0062] 5) The mixture of 4) is compressed and coated to produce a coated tablet.
[0063] Examples 10 to 15
[0064] 1) Put vortioxetine hydrochloride, D-mannitol, microcrystalline cellulose, and a stabilizer (L-arginine, sodium bicarbonate, sodium carbonate, magnesium oxide, meglumine, or calcium hydroxide) into a mixer and mix.
[0065] 2) Prepare a compound by adding a binding solution (hydroxypropylcellulose + an appropriate amount of purified water) to the mixture of 1).
[0066] 3) After drying and settling the mixture of 2), mix in sodium starch glycolate (sieved through 30 mesh).
[0067] 4) Add magnesium stearate (sieved through 30 mesh) to the mixture of 3).
[0068] 5) The mixture of 4) is compressed and coated to produce a coated tablet.
[0069] [Table 3]
[0070]
[0071] Example 16 Preparation of Tablets
[0072] Tablets of Example 16 having the ingredients and content according to Table 4 below were prepared according to the following process.
[0073] Example 16
[0074] 1) Put vortioxetine hydrochloride, D-mannitol, microcrystalline cellulose, and L-arginine into a mixer and mix.
[0075] 2) Prepare a compound by adding a binding solution (hydroxypropylcellulose + an appropriate amount of purified water) to the mixture of 1).
[0076] 3) After drying and settling the mixture of 2), mix in sodium starch glycolate (sieved through 30 mesh).
[0077] 4) Add magnesium stearate (sieved through 30 mesh) to the mixture of 3).
[0078] 5) The mixture of 4) is compressed and coated to produce a coated tablet.
[0079] [Table 4]
[0080]
[0081] Stability Evaluation 1
[0082] The mixtures obtained according to Examples 1 to 5 and Comparative Example 1 were each stored in glass vials under accelerated conditions (40°C, relative humidity 75%), removed at specified periods (initial and after 2 weeks), and the amount of NNVt in the samples was measured using LC-MS / MS. The results are shown in Table 5 and Figure 1 below.
[0083] [Table 5]
[0084]
[0085] Based on the results in Table 5, the effects of four alkalizing agents and one antioxidant were confirmed.
[0086] Experimental results confirmed that the generation of impurities was improved when an alkalizing agent was added compared to Comparative Example 1 and Examples 2 to 5.
[0087] Stability Evaluation 2
[0088] The tablets obtained for Examples 6 and 9 and Comparative Example 2 were each stored in an HDPE bottle under accelerated conditions (40°C, relative humidity 75%), removed after a specified period (initial, after 2 weeks), and the amount of NNVt in the sample was measured using LC-MS / MS. The results are shown in Table 6 and Figure 2 below.
[0089] [Table 6]
[0090]
[0091] Based on the results in Table 6, the degree of impurity generation due to the addition of a stabilizer was confirmed.
[0092] The packaging was conducted in an HDPE bottle, and the experimental results confirmed that the occurrence of impurities was improved in all tablets of Examples 6 to 9.
[0093] Stability Evaluation 3
[0094] For the purification of Examples 10 to 15 and Comparative Example 3, each was stored in an HDPE bottle under accelerated conditions (40°C, relative humidity 75%) [initial, 2 weeks, 4 weeks] and long-term conditions (25°C, relative humidity 60%) [4 weeks]. After removal, the amount of NNVt in the sample was measured using LC-MS / MS. The results are shown in Table 7 and Figure 3 below.
[0095] [Table 7]
[0096]
[0097] Based on the results of Table 7, it was confirmed that selecting and using one type from the group of alkalizing agents in Comparative Example 3 has the effect of reducing the formation of impurities.
[0098] Stability Evaluation 4
[0099] For Example 16 and Comparative Example 3, the amount of NNVt of the samples was measured using LC-MS / MS under accelerated conditions (40°C, relative humidity 75%) after being stored in an HDPE bottle. The results are shown in Figure 4 below.
[0100] Based on the results of Figure 4, improvement in impurity generation due to the addition of 0.3% arginine was confirmed. The experimental results confirmed that impurity generation was improved at 0.3% arginine.
[0101] The pharmaceutical composition of the present invention has a significant effect of reducing NNVt impurities.
Claims
1. A pharmaceutical composition comprising vortioxetine or a pharmaceutically acceptable salt thereof; and an alkalizing agent.
2. A pharmaceutical composition according to claim 1, wherein the alkalizing agent is selected from one or more of the group consisting of L-arginine, meglumine, magnesium oxide, sodium bicarbonate, sodium carbonate, and calcium hydroxide.
3. A pharmaceutical composition according to claim 1, wherein the content of the alkalizing agent is in the range of 0.1 to 20 weight% with respect to the total weight of the pharmaceutical composition.
4. A pharmaceutical composition according to claim 1, wherein the excipient is D-mannitol, lactose, microcrystalline cellulose, calcium hydrogen phosphate, starch, or sugar alcohol.
5. A pharmaceutical composition according to claim 1, wherein the disintegrant is sodium starch glycolate, sodium croscarmellose, crospovidone, or calcium carboxymethylcellulose.
6. A pharmaceutical composition according to claim 1, characterized in that the lubricant is talc, magnesium stearate, sodium stearyl fumarate, or stearic acid.
7. The pharmaceutical composition according to claim 1, wherein the pH of the slurry state of 50% (w / w) of the pharmaceutical composition is 7.0 or higher.
8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition inhibits the formation of N-nitroso-vortioxetine.
9. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt of vortioxetine is vortioxetine hydrochloride or vortioxetine hydrobromide.