Solid selexipag preparation

Abstract

The invention aims to provide a selexipag solid preparation which comprises an active substance selexipag and a filler, the filler is mannitol and one or a combination of more of polyethylene glycol, microcrystalline cellulose, starch, lactose and sorbitol, and the mannitol accounts for 19-40% of the total weight of a prescription. The selexipag solid preparation has the advantages that the quality is stable, the impurity content is low, and the specific surface area of mannitol does not need to be limited during preparation.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical preparations, and in particular to a solid preparation of Celecoxib and a preparation method thereof. Background Art

[0002] Selexipag is the first selective oral prostacyclin receptor agonist. Compared with other drugs that target the prostacyclin channel and must be inhaled or intravenously injected, it is more convenient to use. As a new oral long-acting PGI2 receptor agonist, its active metabolite is highly selective for human PGI2 receptors. Compared with beraprost or epoprostenol, it has a stronger vasodilator effect and greatly reduces adverse reactions compared with PGI2 analogs. Selexipag was approved by the U.S. FDA on December 21, 2015 for the treatment of pulmonary arterial hypertension in adults. It has been granted orphan drug status in Europe, Japan, and Australia, and is currently on the market in China. The structural formula of Selexipag is shown in Formula I below,

[0003]

[0004] Patent ZL201680068849.X reported that the solid preparation of Celexa contained D-mannitol, which caused Celexa in the solid preparation to decompose and reduce its content. In this regard, it proposed to control the specific surface area of ​​D-mannitol to 0.2 m 2 / g~0.7m 2 / g of the technical solution, reducing the contact area between celecoxib and D-mannitol in the celecoxib solid preparation, inhibiting the decomposition of celecoxib, and reducing the generation of decomposition products, i.e., related substances. However, the D-mannitol in the prescription disclosed in the patent limits the specific surface area, and different specific surface areas correspond to different mannitol types, which causes inconvenience to the preparation of the preparation.

[0005] Based on the above situation, at present, there is a need to develop a solid preparation of Celecoxib with stable quality, low impurity content and no restrictions on the specific surface area of ​​the auxiliary material mannitol. Summary of the invention

[0006] The purpose of the present invention is to solve the above technical problems and provide a solid preparation of celecoxib with celecoxib as an active substance, stable quality, low impurity content and no restriction on the specific surface area of ​​the auxiliary material mannitol.

[0007] The first object of the present invention is to provide a solid preparation of celecoxib, which comprises celecoxib and a filler, wherein the filler comprises mannitol, wherein the content of mannitol accounts for 19% to 40% of the total weight of the prescription.

[0008] In a preferred embodiment of the present invention, the filler is a combination of mannitol and one or more selected from polyethylene glycol, microcrystalline cellulose, starch, lactose, sorbitol, and refined white sugar, and the filler accounts for 89% to 93% of the total weight of the prescription.

[0009] As a preferred embodiment of the present invention, the filler is a combination of mannitol, polyethylene glycol and microcrystalline cellulose.

[0010] As a preferred embodiment of the present invention, the solid preparation further comprises a binder, and the binder is selected from one of copovidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose.

[0011] As a preferred embodiment of the present invention, the solid preparation further comprises a disintegrant and a lubricant, wherein the disintegrant is selected from one of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose, and the lubricant is selected from one of magnesium stearate, sodium stearyl fumarate, calcium stearate, and stearic acid.

[0012] As a preferred embodiment of the present invention, the disintegrant is cross-linked polyvinylpyrrolidone, accounting for 3.5% to 4.5% of the total weight of the prescription, the binder is copolyvinylpyrrolidone, accounting for 1.5% to 2.5% of the total weight of the prescription, and the lubricant is magnesium stearate, accounting for 0.1% to 0.2% of the total weight of the prescription.

[0013] As a preferred embodiment of the present invention, the solid preparation is a granule or a tablet, more preferably a tablet.

[0014] As a preferred embodiment of the present invention, the solid preparation comprises the following components:

[0015] Components Weight Percent Celexa 0.4％～0.9％ Mannitol 19％～40％ Polyethylene glycol 6.0％～13％ Microcrystalline Cellulose 40％～64％ Crospovidone 3.5％～4.5％ Copolyvidone 1.5％～2.5％ Magnesium Stearate 0.1％～0.2％

[0016] The second object of the present invention is to provide a method for preparing the solid preparation of Celecoxib described in the first object of the present invention, comprising the following steps: placing the main drug Celecoxib, the filler and the disintegrant in a fluidized bed granulation desiccant according to the prescribed amount and mixing them, spraying a 1-10% aqueous solution of a binder while mixing to prepare granules, mixing a prescribed amount of a lubricant into the obtained granules, and pressing them into tablets to prepare tablets.

[0017] The third object of the present invention is to provide the use of the solid preparation of Celecoxib described in the first object of the present invention and the solid preparation prepared by the preparation method of the second object of the present invention in the preparation of drugs for preventing and / or treating the following diseases: diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, chronic arterial occlusive disease, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease or symptoms associated with spinal stenosis.

[0018] The positive effects of the present invention are:

[0019] The amount of mannitol used in the solid preparation of the present invention is reduced, and the reduction in the amount of mannitol reduces the total contact area between celecoxib and mannitol in the solid preparation, reduces the decomposition of celecoxib in the solid preparation during storage and transportation, reduces the generation of decomposition products, ensures stable quality, and in the process of preparing the celecoxib preparation, the selection of the auxiliary material mannitol does not need to limit its specific surface area or type. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 : The HPLC spectrum of the raw material of Seroxip (SJ032) shows that the main peak content is 99.863% and the total impurity content is 0.137%;

[0021] Figure 2A : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-1 were placed in an open environment at 40°C / 75%RH for one month. The HPLC spectrum showed that the total impurity content was 0.4518%;

[0022] Figure 2B : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-1 were placed in an open environment at 60°C for one month. The HPLC spectrum showed that the total impurity content was 1.13%;

[0023] Figure 3A : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-1 were placed in an open environment at 40°C / 75%RH for one month. The HPLC spectrum showed that the total impurity content was 0.5275%;

[0024] Figure 3B : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-1 were placed in an open environment at 60° C. for one month, and the HPLC spectrum measured showed that the total impurity content was 1.61%;

[0025] Figure 4A : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-2 were placed under 40°C / 75%RH and open conditions for one month. The HPLC spectrum showed that the total impurity content was 0.471%;

[0026] Figure 4B : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-2 were placed in an open environment at 60°C for one month. The HPLC spectrum showed that the total impurity content was 1.3587%;

[0027] Figure 5A : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-2 were placed in an open environment at 40°C / 75%RH for one month. The HPLC spectrum showed that the total impurity content was 0.5313%;

[0028] Figure 5B : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-2 were placed in an open environment at 60° C. for one month, and the HPLC spectrum measured showed that the total impurity content was 1.7187%;

[0029] Fig. 6A : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-3 were placed under 40°C / 75%RH and open conditions for one month. The HPLC spectrum measured showed that the total impurity content was 0.7632%;

[0030] Figure 6B : The tablets using mannitol Pearlitol 160C as an excipient in Example 1-3 were placed in an open environment at 60°C for one month. The HPLC spectrum showed that the total impurity content was 1.9258%;

[0031] Fig. 7A : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-3 were placed in an open environment at 40°C / 75%RH for one month. The HPLC spectrum showed that the total impurity content was 0.839%;

[0032] Figure 7B : The tablets using mannitol Pearlitol 100SD as an excipient in Example 1-3 were placed in an open environment at 60° C. for one month. The HPLC spectrum measured showed that the total impurity content was 1.9688%. DETAILED DESCRIPTION

[0033] The above contents of the present invention are further described in detail below through specific implementation modes, but this should not be construed as limiting the present invention.

[0034] Mannitol Pearlitol 160C in the present invention is purchased from Roquette Freres, and mannitol Pearlitol 100SD is purchased from Roquette Freres.

[0035] The reagents and instruments required in the present invention, unless otherwise specified, are all commercially available conventional models. Celexa was prepared by Puji Biotechnology (Taizhou) Co., Ltd.

[0036] High performance liquid chromatography analysis method in the present invention:

[0037] 1. Preparation of reference solution:

[0038] Reference stock solution: Accurately weigh about 30.0 mg of CELEX API reference into a 50 mL volumetric flask, add diluent to dissolve and dilute to the mark.

[0039] Reference solution: Pipette 1.0 mL of the reference stock solution into a 50 mL volumetric flask, dilute to volume with diluent, and mix. Pipette 1.0 mL of the above solution into a 20 mL volumetric flask, dilute to volume with diluent.

[0040] 2. Sample solution preparation:

[0041] Take 0.2mg and 0.4mg of Celexa tablets and weigh them accurately, place them in a stoppered conical flask, put them into the stoppered conical flask recommended in the table below, add the diluent specified in the table below, and shake for 15 minutes. Filter the above solution using a 0.45μm filter membrane (Φ13mm, hydrophobic PTFE, Amplex), discard at least the initial 2mL, and use the subsequent filtrate.

[0042] Sample Specifications 0.2mg 0.4mg Conical flask 25mL 50mL Thinner 10mL 20mL

[0043] 3. Chromatographic conditions:

[0044] Chromatographic column: C18, 4.6mm×250mm, 5μm

[0045] Flow rate: 1.0mL / min

[0046] Column temperature: 35°C

[0047] Wavelength: 300nm

[0048] Injection volume: 40 μL

[0049] Diluent: 5mmol phosphate buffer: acetonitrile (50:50, v / v)

[0050] Mobile phase A: ammonium acetate buffer: acetonitrile (90:10, v / v)

[0051] Mobile phase B: acetonitrile

[0052] Sample chamber temperature: 5°C

[0053] Mixer assembly: 675uL

[0054] Gradient Program:

[0055] Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 3 70 30 18 10 90 23 10 90 24 70 30 36 70 30

[0056] Example 1

[0057] (1) Preparation of tablets

[0058] The main drug Celexipa is mixed with mannitol, polyethylene glycol, microcrystalline cellulose and cross-linked polyvinylpyrrolidone in a fluidized bed granulation desiccant according to the prescribed amount, and a 5% copolyvinylpyrrolidone aqueous solution is sprayed while mixing to prepare granules. The prescribed amount of magnesium stearate is mixed into the obtained granules, and tablets are pressed to prepare tablets.

[0059] The ingredients and contents of the tablets are shown in Table 1:

[0060] Table 1

[0061]

[0062] (2) Evaluation experimental methods and results

[0063] Referring to the evaluation method of patent ZL201680068849.X, the mannitol in the prescriptions of Example 1-1, Example 1-2, and Example 1-3 was prepared into tablets using models Pearlitol 160C and Pearlitol 100SD (i.e., different specific surface areas), and the tablets were placed in an open container and placed under open conditions of 40°C / 75%RH and 60°C for one month. The total content of related substances at the beginning of the test was evaluated, and the total content of related substances in the tablets after storage was determined using a high performance liquid chromatograph, see Table 2 and Figure 1 to Figure 7B .

[0064] Table 2

[0065]

[0066] The specific surface area of ​​mannitol model Pearlitol 160C is less than 0.7 m2 / g, and the specific surface area of ​​mannitol model Pearlitol 100SD is greater than 1.0 m2 / g. The increase in related substances of tablets made of these two types of mannitol in Table 3 of Patent ZL201680068849.X is relatively high, such as 1.38% and 2.29% at 40°C / 75%RH, and 2.22% and 3.19% at 60°C, respectively. The total content of related substances in Table 2 of the present invention is less than the increase reported in Patent ZL201680068849.X. Compared with the patent, not only the amount of mannitol used in the formulation of the present invention is reduced, but also the amount of impurities generated under the same conditions is reduced. Moreover, the preparation of the present invention can achieve the beneficial effect of reducing the increase in impurities without limiting the specific surface area of ​​mannitol.

[0067] Equivalent programs and scope

[0068] Some non-limiting preferred embodiments of the present invention have been described above. Those skilled in the art may make various changes and modifications to the description without departing from the essential scope of the present invention as defined in the claims. These changes and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A solid preparation of Celexa, characterized in that: The solid preparation comprises celecoxib and a filler, wherein the filler comprises mannitol, wherein the content of mannitol accounts for 19% to 40% of the total weight of the prescription.

2. The solid preparation according to claim 1, characterized in that The filler is a combination of mannitol and one or more selected from polyethylene glycol, microcrystalline cellulose, starch, lactose, sorbitol, and refined white sugar, and the filler accounts for 89% to 93% of the total weight of the prescription.

3. The solid preparation according to claim 1 or 2, characterized in that The filler is a combination of mannitol, polyethylene glycol and microcrystalline cellulose.

4. The solid preparation according to any one of claims 1 to 3, characterized in that The solid preparation further comprises a binder, and the binder is selected from one of copovidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, and carboxymethyl cellulose.

5. The solid preparation according to any one of claims 1 to 4, characterized in that The solid preparation further comprises a disintegrant and a lubricant, wherein the disintegrant is selected from one of cross-linked polyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and cross-linked sodium carboxymethyl cellulose, and the lubricant is selected from one of magnesium stearate, sodium stearyl fumarate, calcium stearate, and stearic acid.

6. The solid preparation according to claim 5, characterized in that The disintegrant is cross-linked polyvinylpyrrolidone, accounting for 3.5% to 4.5% of the total weight of the prescription; the binder is copolyvinylpyrrolidone, accounting for 1.5% to 2.5% of the total weight of the prescription; and the lubricant is magnesium stearate, accounting for 0.1% to 0.2% of the total weight of the prescription.

7. The solid preparation according to any one of claims 1 to 6, characterized in that The solid preparation is granules or tablets, preferably tablets.

8. The solid preparation according to any one of claims 5 to 7, characterized in that The solid preparation comprises the following components:

9. Use of the solid preparation according to any one of claims 1 to 8 in the preparation of a medicament for preventing and / or treating diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, chronic arterial occlusive disease, intermittent claudication, scleroderma, thrombosis, pulmonary hypertension, myocardial infarction, angina pectoris, glomerulonephritis, diabetic nephropathy, chronic renal failure, bronchial asthma, interstitial pneumonia (pulmonary fibrosis), chronic obstructive pulmonary disease, tubulointerstitial nephritis, inflammatory bowel disease or concomitant spinal stenosis.

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