Suspension containing selepag and preparation method thereof

Abstract

The invention provides a suspension containing selepag and a preparation method of the suspension, and relates to the technical field of pharmaceutical preparations. The suspension comprises the following components: selexipag, hydroxypropyl methylcellulose, a diluent, a lubricant and a preservative. According to the present invention, the components and the formula are optimized to prepare the selexipag-containing suspension, and under the specific components, the specific ratio and the specific preparation method, the selexipag-containing suspension prepared by the present invention has characteristics of good stability, good fluidity and high dissolution rate, and can be easily taken by children, old people and other patients with dysphagia.

Description

Technical Field

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

[0002] Selexipag, chemical name is 2-{4-[(5,6-diphenylpyrazin-2-yl)(2-propyl)amino]butoxy}-N-(methylsulfonyl)acetamide, and its structural formula is as follows:

[0003]

[0004] Selexipag is an oral, highly selective prostacyclin receptor agonist that inhibits contraction and proliferation of pulmonary artery smooth muscle cells (“Application of Selexipag in the Treatment of Pulmonary Hypertension”, Wang Zhiwei, Han Yu, Cheng Jiangtao). Its structure is different from that of prostacyclin. Selexipag is hydrolyzed by carboxylesterase 1 into active metabolites, which are about 37 times more potent than selexipag. Selexipag and its active metabolites selectively act on IP receptors, but have no effect on other prostaglandin receptors (EP1-4, DP, FP and TP). It can improve endothelium-dependent relaxation of damaged pulmonary arteries and may inhibit proliferation of human pulmonary smooth muscle cells and thickening of pulmonary vascular walls. Compared with other prostacyclin drugs, Selexipag tablets are the first oral preparation that can improve patient compliance. The drug is easy to use, avoiding injection site reactions of intravenous administration and throat irritation reactions and coughing of inhaled dosage forms.

[0005] The pharmaceutical preparations of Selexipag disclosed in the prior art include: Chinese patent CN112220770A provides a pharmaceutical composition of Selexipag, which is a coated tablet containing a core and a coating layer, and the coating layer is a double-layer coating; Chinese patent CN115887399A provides a Selexipag tablet and a preparation method thereof, which is composed of a quick-release coating layer and a controlled-release core, and the quick-release coating layer and the controlled-release core both contain the active ingredient Selexipag. Chinese patent CN116392491A provides a pharmaceutical composition of Selexipag and a preparation method thereof, involving various components of the pharmaceutical composition, and the pharmaceutical composition includes: Selexipag, lactose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, starch, silicon dioxide, magnesium stearate, and the dosage form is a tablet. The above-mentioned preparations are mainly tablets.

[0006] As mentioned above, the pharmaceutical preparations disclosed in the prior art are all in tablet dosage form, which is not conducive to medication for children and has poor medication compliance. Suspensions are formed by dispersing insoluble solid drug particles in a liquid medium. Suspensions are superior to tablets in terms of onset speed, dosage flexibility, improved taste and applicability to special populations, and are particularly suitable for children, the elderly and patients with dysphagia.

[0007] Based on this, developing a selexipag suspension dosage form that is more suitable for pediatric patients while ensuring its efficacy and stability is the research focus of researchers in this field. Summary of the invention

[0008] In view of the above problems, the present invention provides a suspension containing selexipag and a preparation method thereof. By optimizing the components and their ratios and optimizing the preparation method, a suspension that is easy for children to take and has high stability is obtained.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] In one aspect, the present invention provides a suspension containing selexipag, comprising the following components: selexipag, hypromellose, a diluent, a lubricant and a preservative.

[0011] Preferably, the diluent is selected from at least one of lactose, microcrystalline cellulose, mannitol, corn starch, pregelatinized starch, dextrin and calcium carbonate.

[0012] More preferably, the diluent is selected from at least one of lactose and corn starch.

[0013] More preferably, the diluent is a mixture of corn starch and lactose.

[0014] Preferably, the mass ratio of the corn starch to lactose is 1.4-1.8; further preferably, the mass ratio of the corn starch to lactose is 1.48-1.68.

[0015] Preferably, the lubricant is selected from at least one of colloidal silicon dioxide, magnesium stearate and talc.

[0016] More preferably, the lubricant is colloidal silicon dioxide.

[0017] Preferably, the preservative is selected from at least one of sorbic acid and its salts, benzoic acid and its salts, and parahydroxybenzoates.

[0018] Further preferably, the preservative is selected from benzoic acid and its salts.

[0019] More preferably, the preservative is selected from benzoates.

[0020] Most preferably, the preservative is selected from sodium benzoate.

[0021] Preferably, the selexipag-containing suspension may further comprise at least one of a flavoring agent, an essence and a pigment.

[0022] Preferably, the flavoring agent is selected from at least one of xylitol, maltitol, erythritol, sorbitol, steviol glycosides, licorice extract, monk fruit extract, neohesperidin dihydrochalcone, sucralose, cyclamate, aspartame, saccharin, glucose and fructose.

[0023] More preferably, the flavoring agent is selected from at least one of neohesperidin dihydrochalcone, sucralose, cyclamate, and glucose.

[0024] More preferably, the flavoring agent is neohesperidin dihydrochalcone.

[0025] Preferably, the flavor is selected from natural flavors or artificial flavors.

[0026] Preferably, the flavor is selected from at least one of strawberry flavor, lemon flavor, banana flavor, grape flavor, and orange flavor.

[0027] Further preferably, the flavor is selected from natural strawberry flavor.

[0028] Preferably, the pigment is selected from at least one of red iron oxide, titanium dioxide, carotene, lutein and chlorophyll.

[0029] Further preferably, the pigment is selected from red iron oxide.

[0030] Preferably, the suspension comprises the following raw materials in parts by mass:

[0031] 150-250 parts of Selexipag, 10-70 parts of Hydroxypropyl Methylcellulose, 650-800 parts of diluent, 1-20 parts of lubricant and 1-5 parts of preservative.

[0032] Further preferably, the suspension comprises the following raw materials in parts by mass:

[0033] 150-250 parts of Selexipag, 10-70 parts of Hydroxypropyl Methylcellulose, 650-800 parts of diluent, 1-20 parts of lubricant, 1-5 parts of preservative, 5-12 parts of flavoring agent, 8-15 parts of flavor and 0.1-2 parts of pigment.

[0034] More preferably, the suspension comprises the following raw materials in parts by mass:

[0035] 150-200 parts of Selexipag, 12.5-65 parts of Hydroxypropyl Methylcellulose, 700-760 parts of diluent, 5-15 parts of lubricant, 1-3.5 parts of preservative, 5-8 parts of flavoring agent, 8-12 parts of flavor and 0.1-1 part of pigment.

[0036] In another aspect, the present invention provides a method for preparing the suspension described above, comprising the following steps:

[0037] S1: pre-treat selexipag to control the particle size D90≤40μm;

[0038] S2: Mixing hypromellose, selexipag and water to obtain granulation liquid;

[0039] S3: diluent, preservative and pigment are mixed to obtain a mixture;

[0040] S4: the granulation liquid obtained in S2 is mixed with the mixture obtained in S3, granulated, and dried to obtain granules;

[0041] S5: The granules obtained in S4 are mixed with a lubricant, a flavoring agent and an essence.

[0042] Preferably, in S1, the particle size D90 is ≤35 μm.

[0043] Preferably, in S2, the water is selected from at least one of purified water, deionized water and distilled water; further preferably, in S2, the water is purified water.

[0044] Preferably, in S4, the drying temperature is 50-75°C.

[0045] Compared with the prior art, the present invention has the following beneficial effects:

[0046] The present invention prepares a suspension containing selexipag by optimizing components and formulas. Under the specific components, proportions and preparation methods of the present invention, the suspension containing selexipag prepared by the present invention has good stability, good fluidity and high solubility, which is beneficial for children, the elderly and other patients with dysphagia to take the medicine. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 The dissolution graphs of the suspensions prepared in Example 1, Example 9, Example 10, Comparative Example 7 and Comparative Example 8. DETAILED DESCRIPTION

[0048] In order to make the technical means, creative features, purpose and effect of the present invention easy to understand, the present invention is further explained below in conjunction with specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all. Based on the embodiments in the implementation mode, other embodiments obtained by those skilled in the art without making creative work all belong to the protection scope of the present invention. It is worth noting that the raw materials used in the present invention are all common commercial products, and their sources are not specifically limited. The technology and scientific terms used in the embodiments have the meanings commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0049] raw material:

[0050] Selexipag was purchased from Zhejiang Huayi Pharmaceutical Co., Ltd.

[0051] Corn starch was purchased from Anhui Shanhe Pharmaceutical Excipients Co., Ltd.

[0052] Lactose was purchased from Metz-Levosberg Milk House GmbH & Co. KG, model number flowlac 90.

[0053] Hydroxypropyl methylcellulose was purchased from Nutrition&Biosciences, model: 5 cP.

[0054] Colloidal silicon dioxide was purchased from Evonik Operations GmbH, model AEROSIL 200Pharma.

[0055] Sodium benzoate was purchased from Merck KGaA.

[0056] Neohesperidin dihydrochalcone was purchased from HealthTech Bio Actives SLU.

[0057] The strawberry-flavored natural flavor was purchased from Mann's (Shanghai) Flavors and Fragrances Co., Ltd.

[0058] Red iron oxide was purchased from Shanghai Yipin Pigment Co., Ltd.

[0059] Example 1

[0060] A suspension containing selexipag, the components of which are shown in Table 1:

[0061] Table 1. Components (mg)

[0062] Component / mg Dosage Sleipag 200 Corn starch 445 lactose 290 Hydroxypropyl methylcellulose 32.5 Colloidal Silica 10 Sodium Benzoate 1.5 Neohesperidin dihydrochalcone 8 Strawberry natural flavor 12 Red Iron Oxide 1 Total amount / mg 1000

[0063] The preparation method is:

[0064] (1) Pretreatment: micronizing Selexipag to control the particle size D90 to 7.9 μm; sieving the raw and auxiliary materials for later use;

[0065] (2) Preparation of granulation liquid: Add the prescribed amount of HPMC to purified water, stir to dissolve, then add the prescribed amount of API and disperse evenly;

[0066] (3) Mixing: Mix corn starch, lactose, sodium benzoate, and red iron oxide in a mixing device;

[0067] (4) Granulation: The mixed excipients are made into wet granules using a granulation liquid;

[0068] (5) Drying: Dry the wet granules at 60°C;

[0069] (6) Total mixing: uniformly mix the granules with colloidal silicon dioxide, neohesperidin dihydrochalcone and flavor.

[0070] Embodiment 2-8

[0071] A suspension containing selexipag, compared with Example 1, only the dosage of each component is changed, as shown in Table 2.

[0072] Table 2. Components (mg)

[0073]

[0074]

[0075] The preparation method is the same as that in Example 1.

[0076] Examples 9-10

[0077] A suspension containing selexipag, compared with Example 1, only the particle size of selexipag in step (1) is changed, as shown in Table 3.

[0078] Table 3. Particle size (μm)

[0079]

[0080] The rest is the same as Example 1.

[0081] Comparative Examples 1-6

[0082] A suspension containing selexipag, compared with Example 1, only the dosage of each component is different, as shown in Table 4.

[0083] Table 4. Components (mg)

[0084]

[0085] The preparation method is the same as that in Example 1.

[0086] Comparative Examples 7-8

[0087] A suspension containing selexipag, compared with Example 1, only the particle size of selexipag in step (1) is changed, as shown in Table 5.

[0088] Table 5. Particle size (μm)

[0089]

[0090] The rest is the same as Example 1.

[0091] Comparative Example 9

[0092] A suspension containing selexipag, compared with Example 1, only corn starch is replaced by lactose, and the rest is the same as Example 1.

[0093] Comparative Example 10

[0094] A suspension containing selexipag, compared with Example 1, only lactose is replaced by corn starch, and the rest is the same as Example 1.

[0095] Comparative Example 11

[0096] A suspension containing selexipag, compared with Example 1, only the hypromellose is replaced with pregelatinized starch, and the rest is the same as Example 1.

[0097] Comparative Example 12

[0098] A suspension containing selexipag, compared with Example 1, only the colloidal silicon dioxide is replaced by polyethylene glycol, and the rest is the same as Example 1.

[0099] Comparative Example 13

[0100] A suspension containing selexipag, compared with Example 1, only sodium benzoate is replaced by butylated hydroxytoluene, and the rest is the same as Example 1.

[0101] Test Example 1

[0102] Liquidity evaluation:

[0103] The repose angle of the suspension of the present invention is mainly used to evaluate fluidity, and the determination method is:

[0104] Slowly add the powder from the top of the funnel. The inclination angle of the material leaking out from the bottom of the funnel to form a cone-shaped accumulation on the horizontal plane is the angle of repose.

[0105] The judgment limit is that an angle of repose of less than 30° indicates good fluidity, and an angle of repose of more than 40° indicates poor fluidity. The smaller the angle of repose, the better the fluidity. The angle of repose of the suspensions prepared in Examples 1-3 and Comparative Examples 1-2, 6, 10, and 12 was tested, and the results are shown in Table 6.

[0106] Table 6. Angle of repose

[0107]

[0108] It can be seen from the data in Table 6 that the fluidity of the suspensions prepared in Examples 1-3 is good and can meet the production requirements. After reducing the amount of colloidal silicon dioxide used in Comparative Example 1-2, the fluidity of the suspension is significantly poor, which is not conducive to production; although the amount of colloidal silicon dioxide is significantly increased in Comparative Example 6, the fluidity of the product is not significantly improved compared with Examples 1-3; in Comparative Example 10, after lactose is replaced by corn starch, the fluidity of the prepared suspension is significantly deteriorated, which is not conducive to production; in Comparative Example 12, colloidal silicon dioxide is replaced by polyethylene glycol, and the fluidity of the prepared suspension is slightly reduced, but it can still meet the production requirements.

[0109] Test Example 2

[0110] Sedimentation volume ratio and redispersibility test:

[0111] The sedimentation ratio detection method of the dry suspension of the present invention is:

[0112] Refer to the 2020 edition of the Chinese Pharmacopoeia and proceed as follows: Take the test sample, measure it with a 50mL stoppered measuring cylinder, seal it tightly, shake it vigorously for 1 minute, and record the starting height H of the suspension. 0 , let it stand for 3 hours, and record the final height H of the suspension:

[0113] Sedimentation volume ratio = H / H 0 .

[0114] Redispersibility detection method of the dry suspension of the present invention:

[0115] The sedimentation suspension that has been left for 3 days is placed in a 100 mL measuring cylinder, and the measuring cylinder is rotated and inverted at 180°C, inverted once, and left for 5 seconds, which is counted as one shaking.

[0116] The number of rotations required for redispersion was recorded and evaluated as "good", "good", "fair", and "poor"; among them, "good" was defined as uniform dispersion within 12 rotations or less, "good" was defined as uniform dispersion requiring 12 to 60 rotations, "fair" was defined as uniform dispersion exceeding 60 rotations but still being uniformly dispersed, and "poor" was defined as non-uniform dispersion. The sedimentation volume ratio and redispersion of the suspensions prepared in Examples 1, 4-6 and Comparative Examples 3, 6, 9, and 11 were tested, and the results are shown in Table 7.

[0117] Table 7. Results

[0118]

[0119] From the data in Table 7, it can be seen from the above table that the selexipag suspension prepared using hydroxypropyl methylcellulose as a suspending agent has a better suspending effect, among which Example 1 has the best suspending effect, and changing the components of the diluent will also affect its dispersibility. In Comparative Example 9, replacing all corn starch with lactose is not conducive to its physical stability and dispersibility.

[0120] Test Example 3

[0121] Stability test:

[0122] The samples prepared in Examples 7-8 and Comparative Examples 4-6 and 13 were placed under accelerated conditions (40°C ± 2°C, 75% RH ± 5% RH) for 3 months, and the related substances, selexipag content, and sodium benzoate content were investigated. The results are shown in Table 8.

[0123] Table 8. Stability test

[0124]

[0125] It can be seen from the data in Table 8 that the use of the specific preservative sodium benzoate of the present invention is beneficial to improving the stability of the selexipag suspension, especially under the specific component ratio of the present invention, the stability is significantly improved.

[0126] Test Example 4

[0127] Dissolution behavior:

[0128] Test method: pH 6.8 phosphate buffer-paddle method-50rpm-900mL;

[0129] The dissolution of the suspensions prepared in Examples 1, 9-10 and Comparative Examples 7-8 was tested. The results are shown in Tables 9 and Figure 1 shown.

[0130] Table 9. Dissolution

[0131]

[0132]

[0133] From Table 9 and Figure 1 The data show that the particle size of selexipag will affect the solubility of the product. The particle size of selexipag obtained by the specific micronization treatment of the present invention can achieve better solubility.

[0134] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A suspension containing selexipag, characterized in that: Contains the following ingredients: selexipag, hypromellose, diluent, lubricant and preservative.

2. The suspension according to claim 1, characterized in that The diluent is selected from at least one of lactose, microcrystalline cellulose, mannitol, corn starch, pregelatinized starch, dextrin and calcium carbonate.

3. The suspension according to claim 2, characterized in that The diluent is selected from at least one of lactose and corn starch.

4. The suspension according to claim 3, characterized in that The diluent is a mixture of corn starch and lactose; the mass ratio of the corn starch to lactose is 1.4-1.

8.

5. The suspension according to claim 1, characterized in that The lubricant is selected from at least one of colloidal silicon dioxide, magnesium stearate, and talc; the preservative is selected from at least one of sorbic acid and its salts, benzoic acid and its salts, and parabens.

6. The suspension according to claim 5, characterized in that The lubricant is colloidal silicon dioxide; the preservative is selected from benzoic acid and its salts.

7. The suspension according to claim 1, characterized in that The selexipag-containing suspension may further comprise at least one of a flavoring agent, an essence and a pigment.

8. The suspension according to claim 7, characterized in that The flavoring agent is selected from at least one of xylitol, maltitol, erythritol, sorbitol, steviol glycoside, licorice extract, monk fruit extract, neohesperidin dihydrochalcone, sucralose, sodium cyclamate, aspartame, saccharin, glucose, and fructose; the flavor is selected from natural flavors or artificial flavors; the pigment is selected from at least one of red iron oxide, titanium dioxide, carotene, lutein, and chlorophyll.

9. The suspension according to claim 1, characterized in that The suspension comprises the following raw materials in parts by mass: 150-250 parts of Selexipag, 10-70 parts of Hydroxypropyl Methylcellulose, 650-800 parts of diluent, 1-20 parts of lubricant and 1-5 parts of preservative.

10. The method for preparing the suspension according to any one of claims 1 to 9, characterized in that: The following steps are involved: S1: pre-treat selexipag to control the particle size D90≤40μm; S2: Mixing hypromellose, selexipag and water to obtain granulation liquid; S3: diluent, preservative and pigment are mixed to obtain a mixture; S4: the granulation liquid obtained in S2 is mixed with the mixture obtained in S3, granulated, and dried to obtain granules; S5: The granules obtained in S4 are mixed with a lubricant, a flavoring agent and an essence.

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