Pharmaceutical composition containing desloratadine as active ingredient

Abstract

To provide a pharmaceutical composition containing desloratadine as an active ingredient, which has good dissolution properties and excellent storage stability (photostability, temperature and humidity stability).SOLUTION: The present invention relates to a pharmaceutical composition containing desloratadine and polyvinyl alcohol (partially saponified product), and more specifically to a film-coated tablet containing desloratadine, anhydrous calcium hydrogen phosphate and polyvinyl alcohol (partially saponified product) in an uncoated tablet portion and polyvinyl alcohol (partially saponified product) in a coating portion.SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition containing desloratadine as an active ingredient. [Background technology]

[0002] Desloratadine is an active metabolite of loratadine, has a sustained histamine H1 receptor antagonistic effect, and is widely used as a treatment for allergic rhinitis, urticaria, and itching associated with skin diseases (eczema, dermatitis, cutaneous pruritus) (Patent Document 1, Non-Patent Document 1). Non-Patent Document 1 states that when bulk desloratadine powder was subjected to a light stress test using a transparent quartz container, slight discoloration was observed, while when a formulation containing desloratadine as an active ingredient was subjected to a long-term storage test and an accelerated storage test in PTP packaging, an increase in related substances and an increase in moisture was observed, and further, an increase in related substances was observed in a light stability test both unpackaged and in PTP packaging. Patent Document 2 also finds that desloratadine discolors and decomposes in the presence of an acidic excipient, and discloses a pharmaceutical composition that is substantially free of acidic excipients and contains a pharma- ceutically acceptable basic salt (such as a calcium phosphate salt) and a pharma- ceutically acceptable disintegrant. Patent Document 2 also describes that the main decomposition product is N-formyldesloratadine. Patent Document 3 proposes to avoid incompatibility between desloratadine and reactive excipients such as lactose and other mono- or disaccharides, since in the presence of lactose, desloratadine is not stable and decomposes. Furthermore, Patent Document 4 discloses a stable pharmaceutical composition that does not discolor even under accelerated stability testing and is substantially free of desloratadine decomposition products (N-formyldesloratadine), and contains 50 to 80% by weight of a polyol, 5 to 15% by weight of a disintegrant, and 0.01 to 0.5% by weight of an antioxidant and / or a chelating agent. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] Patent No. 4237822 [Patent Document 2] Patent No. 3224379 [Patent Document 3] Special table 2001-511184 [Patent Document 4] Special table 2008-506679 [Non-patent literature]

[0004] [Non-Patent Document 1] Drug Interview Form for Desalex Tablets 5mg (Revised January 2023 (8th edition)) Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a pharmaceutical composition containing desloratadine as an active ingredient, which has good dissolution properties and excellent storage stability (light stability, temperature and humidity stability). [Means for solving the problem]

[0006] In tablet production, water-soluble polymers are commonly used as binders or film-coating bases. Desloratadine is poorly compatible with commonly used water-soluble polymers, but the inventors' research has revealed that by using polyvinyl alcohol (partially saponified), it is possible to formulate the drug without compromising storage stability. Furthermore, although Patent Document 2 recommends not using acidic excipients, we unexpectedly found that anhydrous calcium hydrogen phosphate, whose 10% suspension is on the acidic side, exhibits good dissolution and storage stability, and thus completed the present invention. That is, (1) The present invention relates to a pharmaceutical composition containing desloratadine and polyvinyl alcohol (partially saponified). (2) The present invention also relates to a pharmaceutical composition comprising desloratadine, anhydrous calcium hydrogen phosphate and polyvinyl alcohol (partially saponified). (3) The present invention also relates to the pharmaceutical composition according to the above (1) or (2), wherein the polyvinyl alcohol (partially saponified product) has a degree of saponification of 86.5 to 89.0 mol% and a viscosity of 4.5 to 6.1 mPa s. (4) The present invention also relates to the pharmaceutical composition according to the above (2), wherein the pH of a 10% suspension of anhydrous calcium hydrogen phosphate is 5.5 to 6.5. (5) The present invention also relates to the pharmaceutical composition according to the above (2), wherein the bulk density of the anhydrous calcium hydrogen phosphate is 0.6 g / mL or less. (6) The present invention also relates to the pharmaceutical composition according to the above (2), which further contains a disintegrant. (7) The present invention also relates to the pharmaceutical composition according to the above (6), wherein the disintegrant is sodium starch glycolate. (8) The present invention also relates to the pharmaceutical composition according to (2) above, which further contains an excipient. (9) The present invention also relates to the pharmaceutical composition according to the above (8), wherein the excipient is selected from the group consisting of crystalline cellulose and partially pregelatinized starch. (10) The present invention also relates to the pharmaceutical composition according to the above (1) or (2), wherein the average particle size of desloratadine is 100 µm or less. (11) The present invention also relates to the pharmaceutical composition according to the above (1) or (2), wherein the average particle size of desloratadine is 40 μm or less. (12) The present invention also relates to the pharmaceutical composition according to the above (2), wherein the pharmaceutical composition is in the form of a tablet. (13) The present invention also relates to the tablet according to (12) above, which is produced by direct compression. (14) The present invention also relates to the film-coated tablet described in (12) above, which has a coating layer. (15) The present invention also relates to the film-coated tablet according to the above (14), wherein the coating agent is polyvinyl alcohol (partially saponified). (16) The present invention also relates to the film-coated tablet according to the above (14), further comprising a plasticizer in the coating layer. (17) The present invention also relates to the film-coated tablet according to the above (16), wherein the plasticizer is polyethylene glycol. (18) The present invention also relates to the film-coated tablet according to the above (14), wherein the coating agent is hypromellose and the plasticizer is triethyl citrate. (19) The present invention also relates to the film-coated tablet according to the above (14), wherein the coating layer further contains a colorant. (20) Furthermore, the present invention relates to the pharmaceutical composition according to (1) or (2) above, which contains less than 0.5% by weight of N-formyldesloratadine. Effect of the Invention

[0007] According to an embodiment of the present invention, it is possible to provide a pharmaceutical composition containing desloratadine as an active ingredient, which has good dissolution properties and excellent storage stability (photostability, temperature and humidity stability). [Brief description of the drawings]

[0008] [Figure 1] 4 shows the results of a photostability test using hypromellose as a coating agent. [Diagram 2] The results of a photostability test using hypromellose as the coating agent and triethyl citrate as the plasticizer are shown. [Diagram 3]The results of a photostability test using polyvinyl alcohol (partially saponified) as the coating agent are shown below. [Figure 4] 1 shows the results of a temperature and humidity stability test using hypromellose as a coating agent. [Diagram 5] The results of a temperature and humidity stability test using hypromellose as a coating agent and triethyl citrate as a plasticizer are shown. [Figure 6] The results of a temperature and humidity stability test using polyvinyl alcohol (partially saponified) as the coating agent are shown below. [Figure 7] The results of a dissolution test for different grades of calcium hydrogen phosphate are shown. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The pharmaceutical composition of the present invention is described in detail below. The active ingredient, desloratadine, can be prepared by the methods described in JP-B-5-72910 and other known publications. Desloratadine having an average particle size of 100 μm or less, preferably 40 μm or less, can be used. As the polyvinyl alcohol, polyvinyl alcohol (partially saponified product) is preferable. More preferred is polyvinyl alcohol (partially saponified) having a degree of saponification of 86.5 to 89.0 mol % and a viscosity of 4.5 to 6.1 mPa·s. As the anhydrous calcium hydrogen phosphate, one having a pH of 5.5 to 6.5 in a 10% suspension and a bulk density of 0.6 g / mL or less is preferred. Examples of the disintegrant include sodium starch glycolate, carboxymethylcellulose, croscarmellose sodium, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, crospovidone, and hydroxypropylstarch, and preferably sodium starch glycolate. Examples of excipients include celluloses such as crystalline cellulose, ethyl cellulose, and low-substituted hydroxypropyl cellulose; starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, and hydroxypropyl starch; and inorganic salts such as magnesium aluminometasilicate, synthetic hydrotalcite, calcium triphosphate, calcium carbonate, precipitated calcium carbonate, calcium silicate, calcium lactate, and sodium bicarbonate, with crystalline cellulose and partially pregelatinized starch being preferred. In addition, known lubricants and flow agents can be used. The pharmaceutical composition of the present invention includes granules, capsules, and tablets, and preferably includes tablets. Tablets are preferably manufactured by direct powder compression (direct compression). The tablets are preferably film-coated tablets. Each tablet contains 2.5 mg or 5 mg of the active ingredient, desloratadine. The pharmaceutical composition of the present invention may contain other active ingredients. The anhydrous calcium hydrogen phosphate is contained in the uncoated tablet in an amount of 20 to 95%. The polyvinyl alcohol (partially saponified) is contained in the uncoated tablet in an amount of 1 to 10%. The above excipients are contained in the uncoated tablet in an amount of 5 to 70%. The above disintegrant is contained in an amount of 0.5 to 10% in the uncoated tablet. Examples of coating agents for film-coated tablets include polyvinyl alcohol (partially saponified), polyvinyl alcohol-polyethylene glycol graft copolymer, polyvinyl alcohol-acrylic acid-methyl methacrylate copolymer, hypromellose, methylcellulose, and hydroxypropylcellulose, and preferably polyvinyl alcohol (partially saponified). Examples of plasticizers for film-coated tablets include polyethylene glycol, triethyl citrate, glycerin, triacetin, castor oil, propylene glycol, and glycerin monostearate, and preferably polyethylene glycol. Examples of colorants for film-coated tablets include titanium oxide, talc, ferric oxide, yellow ferric oxide, black ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Blue No. 1 Aluminum Lake, Food Blue No. 2 Aluminum Lake, Food Yellow No. 4 Aluminum Lake, Food Yellow No. 5 Aluminum Lake, Food Red No. 2 Aluminum Lake, Food Red No. 3 Aluminum Lake, and Food Red No. 102 Aluminum Lake, and preferably titanium oxide, talc, and ferric oxide. The coating layer contains the above coating agent in an amount of 10 to 95%. The coating layer contains the plasticizer in an amount of 1 to 40%. The coating layer contains the colorant in an amount of 0.01 to 50%. Methods for producing film-coated tablets include the following. <First step> Desloratadine, microcrystalline cellulose, partially pregelatinized starch and light anhydrous silicic acid are mixed in a mixer. <Second process> The mixture produced in the first step and crystalline cellulose are mixed in a mixer. Anhydrous calcium hydrogen phosphate, polyvinyl alcohol (partially saponified), and sodium starch glycolate are added and mixed. Furthermore, magnesium stearate is added and mixed. <Third step> The granules produced in the second step are compressed into tablets using a tablet press. <Fourth step> Coating step The tablets produced in the third step are placed in a coating machine and coated with a coating liquid. The additives used in the present invention are Ceolus UF-702 (registered trademark) for crystalline cellulose, PCS PC-10 (registered trademark) for partially pregelatinized starch, Adsolider 101 (registered trademark) for light anhydrous silicic acid, Fujicalin SG (registered trademark), FF-100 (manufactured by Kyowa Chemical Industry Co., Ltd.), and GS Carica (manufactured by Kyowa Chemical Industry Co., Ltd.) for calcium hydrogen phosphate, Gohsenol EG-05PW (registered trademark) for polyvinyl alcohol (partially saponified product), EXPLOTAB Type A (registered trademark) for sodium starch glycolate, TC-5E (registered trademark) for hypromellose, Citroflex 2 SC-60 (registered trademark) for triethyl citrate, PEG-6000SP (trade name) for macrogol 6000, Crown Talc (trade name) for talc, and Polishing Wax 105 (trade name) for carnauba wax. The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. EXAMPLES

[0010] Compatibility test (Test Method) 75 mg of desloratadine and 1,500 mg of water-soluble polymer were mixed uniformly in an agate mortar. The mixture was then placed in an open glass bottle and stored at 40°C and 75% RH using an accelerated tester. The amount of related substances was measured at the start of the test, in the samples stored for one week, and in the samples stored for two weeks. Related substances were measured using the following HPLC. The measurements of related substances described in other Examples were also carried out in the same manner. Test conditions Detector: Ultraviolet spectrophotometer (measurement wavelength: 280 nm) Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 25 cm is packed with 5 μm octylsilanized silica gel for liquid chromatography. Column temperature: constant temperature around 30℃ Mobile phase A: pH 2.5 phosphate buffer / methanol / acetonitrile (80:15:5) Mobile phase B: acetonitrile / buffer / tetrahydrofuran (70:30:5) Mobile phase delivery: The concentration gradient is controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows: Flow rate: 1.0mL per minute

[0011] [Table 1] Retention time: Desloratadine is about 31 minutes, and analogue K is about 40 minutes (relative retention time is 1.32). Analogue K is N-formyldesloratadine (Test Results) The test results are shown in Table 2.

[0012] [Table 2] Verdict: Compatibility with desloratadine ×: Bad △: Somewhat bad 〇: Good As can be seen from Table 2, desloratadine has poor compatibility with commonly used water-soluble polymers, but has good compatibility with polyvinyl alcohol (saponified product). EXAMPLES

[0013] (Stability test of film-coated tablets) Manufacturing method of film-coated tablets <First step> Drug substance tri-dispersion sieving step Put desloratadine, crystalline cellulose, partially pregelatinized starch, and light anhydrous silicic acid into a plastic bag and mix for 1 minute. Pass this through a No. 42 sieve to obtain the drug substance trituration product. <Second process> Mixing granule process The drug substance trituration product and crystalline cellulose produced in the first step are placed in a diffusion mixer (V-20) and mixed for 15 minutes. Anhydrous calcium hydrogen phosphate, polyvinyl alcohol (partially saponified), and sodium starch glycolate are added and mixed for 15 minutes. Magnesium stearate is then added and mixed for 1 minute. <Third step> Tableting process The granules produced in the second step are compressed into tablets using a rotary tablet press (HT-X12) with a 6.35 mm diameter punch and die to give tablets with an average weight of 100 mg and a thickness of 2.85 mm. <Fourth step> Coating step The tablets produced in the third step are placed in a coating machine (HC-LABO) and coated with a coating liquid so that the average tablet weight becomes 107 mg. Next, carnauba wax is added to give it a glossy finish. Preparation of the above coating solution Hypromellose or polyvinyl alcohol (partially saponified) and macrogol 6000 or triethyl citrate are added to purified water and stirred until dissolved. Talc, titanium oxide and ferric oxide are added to a separate portion of purified water and ultrasonically dispersed. These liquids are mixed and stirred, then sieved to make the coating liquid. For the preparations A, B, and C shown in Table 3 produced by the above method, a light stability test and a temperature and humidity stability test were carried out. Photostability Test Method The obtained tablets are placed in a glass petri dish and stored at an illumination intensity of 2000 lux / hr using a photostability tester. The samples were removed at total illuminances of 300,000 lux·hr, 600,000 lux·hr, and 1.2 million lux·hr, and the amount of related substances was quantified. Temperature and humidity stability test method The obtained tablets are placed in a brown glass bottle (open) and stored at 40°C / 75% RH using an accelerated testing machine. After 2 and 4 weeks of storage, the samples are taken out and the amount of related substances is quantified.

[0014] [Table 3] (Photostability test results) The stability test results are shown in Figures 1 to 3. From FIG. 3, it is clear that formulation C, which uses polyvinyl alcohol (partially saponified) as a coating agent, has excellent photostability effect. As shown in Figure 1, formulation C, which used hypromellose as a coating agent, showed an increase in related substances. Furthermore, Figure 2 reveals that formulation B also has a good photostability effect. (Temperature and humidity stability test results) The stability test results are shown in Figures 4 to 6. From FIG. 6, it is clear that preparation C, which uses polyvinyl alcohol (partially saponified) as a coating agent, has an excellent temperature and humidity stabilizing effect. As shown in Figure 4, formulation C, which used hypromellose as a coating agent, showed an increase in related substances. Furthermore, as shown in Figure 5, formulation B also showed good temperature and humidity stabilization effects. EXAMPLES

[0015] Dissolution test for different grades of calcium hydrogen phosphate (Test Method) The film-coated tablets shown in Table 4 were obtained by the same manufacturing method as described in Example 2. The grade of calcium hydrogen phosphate in Table 5 was changed and a dissolution test was performed.

[0016] [Table 4]

[0017] [Table 5] Dissolution test method Dissolution was evaluated according to the Japanese Pharmacopoeia General Test Method Dissolution Test Method 2 (paddle method) using water as the test liquid at a paddle rotation speed of 75 rpm. Desloratadine had a mean particle size of 77.3 μm. Dissolution test results As shown in FIG. 7, anhydrous calcium hydrogen phosphate C, whose 10% suspension had an acidic pH, showed better dissolution than the other two types. EXAMPLES

[0018] (Manufacturing of film-coated tablets) The film-coated tablets shown in Table 6 can be obtained by the same manufacturing method as described in Example 2.

[0019] [Table 6] EXAMPLES

[0020] (Manufacturing of film-coated tablets) The film-coated tablets in Table 7 can be obtained by a method similar to that described in Example 2.

[0021] [Table 7] EXAMPLES

[0022] (Manufacturing of film-coated tablets) The film-coated tablets shown in Table 8 were obtained in the same manner as in Example 2.

[0023] [Table 8] The above film-coated tablets (average particle size of desloratadine: 29.2 μm) were subjected to the dissolution test described in Example 2, and showed a dissolution rate of 85% or more in 45 minutes. [Industrial Applicability]

[0024] The pharmaceutical composition of the present invention containing desloratadine as an active ingredient can ensure stability over a long period of time during production, storage and distribution.

Claims

1. A pharmaceutical composition comprising desloratadine and polyvinyl alcohol (partially saponified).

2. A pharmaceutical composition comprising desloratadine, anhydrous calcium hydrogen phosphate and polyvinyl alcohol (partially saponified).

3. 3. The pharmaceutical composition according to claim 1, wherein the polyvinyl alcohol (partially saponified product) has a degree of saponification of 86.5 to 89.0 mol % and a viscosity of 4.5 to 6.1 mPa·s.

4. 3. The pharmaceutical composition according to claim 2, wherein the pH of a 10% suspension of anhydrous calcium hydrogen phosphate is 5.5 to 6.

5.

5. 3. The pharmaceutical composition according to claim 2, wherein the bulk density of the anhydrous calcium hydrogen phosphate is 0.6 g / mL or less.

6. The pharmaceutical composition according to claim 2, further comprising a disintegrant.

7. 7. The pharmaceutical composition according to claim 6, wherein the disintegrant is sodium starch glycolate.

8. The pharmaceutical composition according to claim 2, further comprising an excipient.

9. 9. The pharmaceutical composition according to claim 8, wherein the excipient is selected from the group consisting of microcrystalline cellulose and partially pregelatinized starch.

10. 3. The pharmaceutical composition according to claim 1, wherein the average particle size of desloratadine is 100 μm or less.

11. 3. The pharmaceutical composition according to claim 1, wherein the average particle size of desloratadine is 40 μm or less.

12. 3. The pharmaceutical composition according to claim 2, which is in the form of a tablet.

13. 13. The tablet of claim 12 which is produced by direct compression.

14. The film-coated tablet according to claim 12, which has a coating layer.

15. 15. The film-coated tablet according to claim 14, wherein the coating agent is polyvinyl alcohol (partially saponified).

16. The film-coated tablet according to claim 14, further comprising a plasticizer in the coating layer.

17. 17. The film-coated tablet according to claim 16, wherein the plasticizer is polyethylene glycol.

18. 15. The film-coated tablet according to claim 14, wherein the coating agent is hypromellose and the plasticizer is triethyl citrate.

19. 15. The film-coated tablet according to claim 14, further comprising a colorant in the coating layer.

20. 3. The pharmaceutical composition according to claim 1 or 2, containing less than 0.5% by weight of N-formyldesloratadine.

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