Slexipag pharmaceutical composition and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition and a preparation method thereof. The pharmaceutical composition comprises selexipag, a diluent containing mannitol, an alkaline substance, an adhesive and a lubricant. The alkaline substance is added into the pharmaceutical composition, so that the degradation / hydrolysis of the selepag can be obviously inhibited, and the stability of the pharmaceutical composition is obviously improved; the technical scheme does not depend on strict control of the specific surface area of the auxiliary material mannitol, overcomes the limitation of the prior art, has good universality, and is more beneficial to industrial production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical preparations, and relates to a selipag drug composition and a preparation method thereof. BACKGROUND

[0002] Selipag (Compound I) is the first selective oral prostacyclin receptor agonist. Selipag tablets were approved for marketing in the United States on December 21, 2015, and have been approved by the National Medical Products Administration and marketed in China.

[0003]

[0004] The chemical structure of selipag makes it prone to degradation in the solid state, especially during the preparation process and storage, which may generate specific degradation / hydrolysis impurities (such as Impurity I described in the present application), affecting the stability and safety of the product.

[0005]

[0006] The prior art CN108289890A discloses a selipag solid preparation, which inhibits the generation of Impurity I by strictly controlling the specific surface area of the D-mannitol used (which must be below 1.0 m 2 / g). This method has strict requirements for the source and specifications of the excipients and is not universal.

[0007] Therefore, there is an urgent need to develop a new selipag drug composition that can effectively inhibit the degradation / hydrolysis of selipag without relying on strict physical parameter limitations on specific excipients (mannitol), improve the stability of the preparation, and have universality. SUMMARY

[0008] The present inventors have unexpectedly found that by adding an appropriate alkaline substance to the selipag (selipag) drug composition, the degradation / hydrolysis of selipag can be significantly inhibited, and the stability of selipag in the drug composition can be improved; the drug composition does not need to control the specific surface area of mannitol, has universality, and is more conducive to industrial production.

[0009] The technical solutions of the present application are as follows:

[0010] In one aspect of the present application, a drug composition is provided, which comprises selipag, a diluent containing mannitol, an alkaline substance, a binder, and a lubricant, and optionally further comprises a film coating premix.

[0011] In some embodiments, the basic substance is selected from one or more of inorganic basic substances and / or organic basic substances; preferably, the basic substance is selected from one or more of carbonates (such as magnesium carbonate, calcium carbonate), bicarbonates (such as sodium bicarbonate), basic oxides (such as magnesium oxide), disodium hydrogen phosphate, trisodium phosphate; more preferably, the basic substance is selected from one or more of heavy magnesium carbonate, heavy calcium carbonate, heavy magnesium oxide, anhydrous disodium hydrogen phosphate, anhydrous trisodium phosphate, sodium bicarbonate; further more preferably, the basic substance is selected from one or more of anhydrous disodium hydrogen phosphate, anhydrous trisodium phosphate;

[0012] In some embodiments, the basic substance accounts for 1-10% of the total weight of the pharmaceutical composition; preferably 2-8%, more preferably 4-6%;

[0013] In some embodiments, the weight ratio of the selitogepa to the basic substance is 1:10-1:50;

[0014] In some embodiments, the mannitol-containing diluent is selected from one or more of mannitol in combination with corn starch, lactose, mannitol, microcrystalline cellulose, maltitol, sorbitol; preferably, the mannitol-containing diluent is a combination of mannitol and corn starch;

[0015] In some embodiments, the specific surface area of the mannitol in the pharmaceutical composition is not particularly limited, preferably ≥ 1 m 2 / g, more preferably 1.0-4.0 m 2 / g, such as 3.683 m 2 / g, 1.111 m 2 / g, etc.

[0016] In some embodiments, the binder is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone, preferably hydroxypropyl cellulose;

[0017] In some embodiments, the lubricant is one or more of magnesium stearate, sodium stearyl fumarate, talc, more preferably magnesium stearate.

[0018] In some embodiments, the selitogepa accounts for 0.1-1.5% of the total weight of the pharmaceutical composition, preferably 0.1-0.6%, more preferably 0.1-0.2%;

[0019] In some embodiments, the mannitol-containing diluent accounts for 80-90% of the total weight of the pharmaceutical composition, preferably 80-88%;

[0020] In some embodiments, the mannitol accounts for 40-60% of the total weight of the pharmaceutical composition, preferably 45-55%, more preferably 50-55%;

[0021] In some embodiments, the adhesive comprises 2-10% of the total weight of the pharmaceutical composition, preferably 2-6%, more preferably 4-6%;

[0022] In some embodiments, the lubricant accounts for 1-5% of the total weight of the pharmaceutical composition, preferably 1-3%, more preferably 1-2%.

[0023] In some embodiments, the pharmaceutical composition further includes a disintegrant;

[0024] Preferably, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, and crospovidone sodium carboxymethyl cellulose, and more preferably low-substituted hydroxypropyl cellulose;

[0025] Preferably, the disintegrant accounts for 0-10% of the total weight of the pharmaceutical composition, more preferably 3-8%, and even more preferably 4-6%; in some embodiments, the pharmaceutical composition comprises the following components by weight percentage:

[0026]

[0027] Preferably, the pharmaceutical composition comprises the following components by weight percentage:

[0028]

[0029] More preferably, the pharmaceutical composition comprises the following components by weight percentage:

[0030]

[0031] More preferably, the pharmaceutical composition comprises the following components by weight percentage:

[0032]

[0033] In some embodiments, the pharmaceutical composition is a tablet.

[0034] In another aspect, the present invention provides a method for preparing the above-described pharmaceutical composition, comprising the following steps:

[0035] (1) Mix the prescribed amount of selepag, an alkaline substance, a mannitol-containing diluent and optionally a disintegrant to obtain a mixed powder;

[0036] (2) The binder and the mixed powder obtained in step (1) are subjected to fluidized bed granulation to obtain particles;

[0037] (3) After granulating the particles obtained in (2), mix them evenly with the lubricant to obtain total mixed particles;

[0038] (4) Compress the total mixed particles obtained in step (3) into tablets; optionally, it further includes:

[0039] (5) Coat the tablets obtained in step (4) with a film.

[0040] In some implementations, the mixing in step (1) is carried out in a wet granulator for 3-5 minutes.

[0041] In some of these embodiments, the tablets compressed in step (4) have a hardness of 4-8 kg;

[0042] In some implementations, the sheet bed temperature is controlled at 38-50°C during step (5) of the film coating process, and / or the weight gain after coating is 3-5%.

[0043] In another aspect of the present invention, the pharmaceutical composition described above or the pharmaceutical composition prepared by the above preparation method is provided, wherein the content of impurity 1 is not greater than 2% and the content of total impurities is not greater than 3%.

[0044] In some embodiments, when the alkaline substance is anhydrous disodium hydrogen phosphate or anhydrous trisodium phosphate, the content of impurity 1 in the pharmaceutical composition is not greater than 1%, and the content of total impurities is not greater than 2%.

[0045] In another aspect, the present invention provides a packaging article comprising the above-described pharmaceutical composition and the pharmaceutical composition prepared by the above-described method.

[0046] In some embodiments, the packaging is blister packaging, which involves packaging a pharmaceutical composition containing selexipag using a flat blister packaging machine, placing the packaging in an aluminum bag, optionally adding a desiccant, and then sealing it with a heat sealer.

[0047] In another aspect, the present invention provides a packaging product comprising the above-described packaging, and further comprising a pharmaceutical instruction manual and / or a desiccant.

[0048] In another aspect, the present invention provides the use of the above-described pharmaceutical composition, the pharmaceutical composition prepared by the above-described preparation method, the above-described packaging article, or the above-described packaged product in the preparation of a medicament for treating the following diseases, which are selected from: diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, chronic arterial occlusion, 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 spinal stenosis.

[0049] Compared with the prior art, the present invention has the following beneficial technical effects:

[0050] 1. Significantly Improved Stability: The applicant unexpectedly discovered that the pharmaceutical composition of the present invention, with the addition of an alkaline substance, can significantly reduce impurities (such as impurity 1) generated by the degradation / hydrolysis of selexipag during storage. Practice has proven that the pharmaceutical compositions of the present invention all meet the following requirements: the content of impurity 1 is not greater than 2%, and the content of total impurities is not greater than 3%, which can significantly improve the stability of the pharmaceutical composition. In particular, when the alkaline substance is disodium hydrogen phosphate (such as anhydrous disodium hydrogen phosphate) or trisodium phosphate (such as anhydrous trisodium phosphate), the content of impurity 1 is not greater than 1%, and the content of total impurities is not greater than 2%.

[0051] 2. High applicability: The technical effect of this invention does not depend on the stringent physical parameters such as the specific surface area of ​​mannitol. It can use pharmaceutical excipients of conventional sources and specifications, which reduces the cost of raw material screening and supply chain risks, and is more conducive to industrial production.

[0052] 3. Good formulation performance: While ensuring stability, the pharmaceutical composition of the present invention can still maintain good dissolution characteristics and compressibility, and is easy to formulate into solid dosage forms (such as tablets) that meet quality requirements.

[0053] 4. Simple process suitable for industrial production: The preparation method adopts conventional fluidized bed granulation and tableting process, which is simple to operate, the parameters are easy to control, and the reproducibility is good, making it suitable for large-scale industrial production. Detailed Implementation

[0054] The method of the present invention will be described below through specific embodiments to make the technical solution of the present invention easier to understand and master, but the present invention is not limited thereto. Unless otherwise specified, the experimental methods described in the following embodiments are conventional methods; unless otherwise specified, the reagents and materials are commercially available.

[0055] In this invention, the specific surface area is a value determined by the BET method;

[0056] This invention relates to the determination of related substances:

[0057] Testing instrument: High Performance Liquid Chromatography (HPLC)

[0058] Chromatographic column: Waters CORTECS C18 (4.6 × 150 mm, 2.7 μm)

[0059] Column temperature: 35℃

[0060] Sample chamber temperature: 25℃

[0061] Injection volume: 20ul

[0062] Mobile phase A: 0.1% trifluoroacetic acid solution

[0063] Mobile phase B: Acetonitrile

[0064] Flow rate: 1.0 ml / min

[0065] Detection wavelength: 302nm

[0066] The flow elution procedure is as follows:

[0067] Time (min) Mobile phase A (%) Mobile phase B (%) 0 70 30 8 40 60 14 35 65 17 10 90 30 10 90 31 70 30 40 70 30

[0068] Diluent: Acetonitrile-water-phosphoric acid (700:300:1)

[0069] Test solution: Weigh 5 tablets of this product accurately, place them in a stoppered Erlenmeyer flask, and accurately add 10 ml or 40 ml of diluent (10 ml for 0.2 mg tablets; 40 ml for 0.8 mg tablets). Shake for 15 minutes, centrifuge, and filter the supernatant through a 0.45 μm filter membrane. Use the filtrate as the test solution.

[0070] Comparative Examples 1-2: Preparation of tablets without alkaline substances

[0071] Table 1: Prescription dosage per tablet

[0072]

[0073] Table 2: Mannitol Information

[0074] Example Mannitol grade Mannitol manufacturer Specific surface area (m 2 / g) Comparative Example 1 M100 Merc·k KGaA 3.683 Comparative Example 2 200 SD Roquette Freres 1.111

[0075] Preparation method: 50% mannitol and 50% corn starch (as per the prescription) are poured into a pot. Then, micronized selepag, low-substituted hydroxypropyl cellulose (as per the prescription), the remaining 50% mannitol, and the remaining 50% corn starch are added and mixed in a wet granulator. After mixing, the resulting mixture is transferred to a fluidized bed for preheating. After preheating, a 10% hydroxypropyl cellulose aqueous solution (preperformed according to the prescription) is prepared with purified water and sprayed into the mixture. Granulation and drying are then performed. After drying, the material is collected and granulated. The granulated granules are transferred to a mixer and the prescribed amount of magnesium stearate is added and mixed evenly to obtain tableting granules. The tablets are then compressed using a rotary tablet press (circular die, 7mm in diameter) to a target tablet hardness of 6kg. A film coating premix (gastric-soluble type) is prepared into a coating solution with a solid content of 10%. After tableting, the solution is transferred to a coating machine for coating to obtain the target coated tablets. The tablets are then packaged using a flat blister packaging machine to obtain packaged products. The packaged products are placed in aluminum bags and desiccant is added. The bags are then sealed using a heat sealer to obtain the target aluminum bag packaged products.

[0076] Examples 1-9: Preparation of tablets containing different types of alkaline substances and mannitol

[0077] Table 3: Prescription dosage per tablet

[0078]

[0079] Table 4: Information on alkaline substances and mannitol

[0080]

[0081] Preparation method: 50% mannitol and 50% corn starch (as per the prescription) are poured into a pot. Then, micronized selepag, an alkaline substance, low-substituted hydroxypropyl cellulose, the remaining 50% mannitol, and the remaining 50% corn starch are added and mixed in a wet granulator. After mixing, the resulting mixture is transferred to a fluidized bed for preheating. After preheating, a 10% hydroxypropyl cellulose aqueous solution is prepared by mixing the prescribed amount of hydroxypropyl cellulose and purified water and sprayed into the mixture. Granulation and drying are then performed. After drying, the material is collected and processed... Granulation is performed, and the granulated granules are transferred to a mixer. The prescribed amount of magnesium stearate is added and mixed evenly to obtain tableting granules. Tableting is performed using a rotary tablet press (circular die, 7mm diameter) to achieve a target tablet hardness of 6kg. A film coating premix (gastric-soluble type) is prepared into a coating solution with a solid content of 10%. After tableting, the solution is transferred to a coating machine for coating to obtain the target coated tablets. The tablets are packaged using a flat blister packaging machine to obtain packaged products. The packaged products are placed in aluminum bags, and a desiccant is added. The bags are then sealed using a heat sealer to obtain the target aluminum bag packaged products.

[0082] Example 9: Preparation of tablets with low alkaline content

[0083] Table 5: Prescription dosage per tablet

[0084]

[0085] Table 6: Information on alkaline substances and mannitol

[0086] Example Alkaline substance name Alkaline substance manufacturer Mannitol specific surface area (m 2 / g) Mannitol grade Mannitol manufacturer Example 9 Anhydrous trisodium phosphate National Pharmaceutical Group 3.683 M100 Merc·k KGaA

[0087] Preparation method: Example 9 was prepared according to the prescriptions in Tables 5 and 6, referring to the methods of Examples 1-8.

[0088] Example 10 Stability Study:

[0089] The tablets obtained in Comparative Examples 1-2 and Examples 1-9 were stored at a high temperature of 60°C for 1 month, and the amount of related substances generated in the formulation was evaluated. The results are shown in Table 7.

[0090] Table 7: Amounts of related substances formed (Storage conditions: 60℃)

[0091]

[0092]

[0093] According to the results of Comparative Examples 1-2, without the addition of alkaline substances in the formulation, the specific surface area of ​​mannitol is ≥1m². 2 At / g, the formulation has poor stability. After being stored at 60℃ for 1 month, the impurity 1 is not less than 3% and the total impurity is greater than 5%.

[0094] The tablets containing alkaline substances in Examples 1-9, when stored at 60°C for 1 month, showed impurity 1 ≤ 2% and total impurities ≤ 3%; in particular, the tablets obtained in Examples 3, 4, 8, and 9, when stored at 60°C for 1 month, showed impurity 1 ≤ 1% and total impurities ≤ 2%, which were far superior to those in Comparative Examples 1-2.

[0095] Examples 1-9 illustrate that, after the addition of alkaline substances, the different specific surface areas of mannitol have no significant effect on the amount of related substances in the composition, demonstrating good universality.

Claims

1. A pharmaceutical composition, characterized in that, It contains sleipag, a mannitol-containing diluent, an alkaline substance, an adhesive, and a lubricant, and optionally, a film-coating premix.

2. The pharmaceutical composition according to claim 1, characterized in that: The alkaline substance is selected from inorganic alkaline substances and / or organic alkaline substances; preferably, the alkaline substance is selected from one or more of carbonates (such as magnesium carbonate, calcium carbonate), bicarbonates (such as sodium bicarbonate), alkaline oxides (such as magnesium oxide), disodium hydrogen phosphate, and trisodium phosphate; more preferably, the alkaline substance is selected from one or more of heavy magnesium carbonate, heavy calcium carbonate, heavy magnesium oxide, anhydrous disodium hydrogen phosphate, anhydrous trisodium phosphate, and sodium bicarbonate; even more preferably, the alkaline substance is selected from one or more of anhydrous disodium hydrogen phosphate and anhydrous trisodium phosphate. And / or, the alkaline substance accounts for 1-10% of the total weight of the pharmaceutical composition; preferably 2-8%, more preferably 4-6%; And / or, the weight ratio of the sleipag and the alkaline substance is 1:10 to 1:

50.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The mannitol-containing diluent is selected from one or more combinations of mannitol with corn starch, lactose, mannitol, microcrystalline cellulose, maltitol, and sorbitol. Preferably, the mannitol-containing diluent is a combination of mannitol and corn starch. And / or, the specific surface area of ​​the mannitol is 1.0-4.0 m². 2 / g; And / or, the adhesive is selected from one or more of hydroxypropyl cellulose, hydroxypropyl methylcellulose, and povidone, preferably hydroxypropyl cellulose; And / or, the lubricant is selected from one or more of magnesium stearate, sodium stearate fumarate, and talc, preferably magnesium stearate.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that: Selepag comprises 0.1-1.5% of the total weight of the pharmaceutical composition, preferably 0.1-0.6%, more preferably 0.1-0.2%; And / or, the mannitol-containing diluent accounts for 80-90% of the total weight of the pharmaceutical composition, preferably 80-88%; And / or, the mannitol constitutes 40-60% of the total weight of the pharmaceutical composition, preferably 45-55%, more preferably 50-55%; And / or, the adhesive accounts for 2-10% of the total weight of the pharmaceutical composition, preferably 2-6%, more preferably 4-6%; And / or, the lubricant accounts for 1-5% of the total weight of the pharmaceutical composition, preferably 1-3%, more preferably 1-2%.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition also includes a disintegrant; Preferably, the disintegrant is selected from one or more of crospovidone, low-substituted hydroxypropyl cellulose, and crospovidone sodium carboxymethyl cellulose, more preferably low-substituted hydroxypropyl cellulose; and / or, the disintegrant accounts for 0-10% of the total weight of the pharmaceutical composition, preferably 3-8%, more preferably 4-6%.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, Each component is expressed as a percentage by weight in the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that, The pharmaceutical composition is a tablet.

8. A method for preparing a pharmaceutical composition according to any one of claims 1-7, characterized in that, Includes the following steps: (1) Mix the prescribed amount of selepag, an alkaline substance, a mannitol-containing diluent and optionally a disintegrant to obtain a mixed powder; (2) The binder and the mixed powder obtained in step (1) are subjected to fluidized bed granulation to obtain particles; (3) After granulating the particles obtained in (2), mix them with the lubricant to obtain total mixed particles; (4) Compress the total granules obtained in step (3) into tablets; optionally, it further includes: (5) Coat the tablets obtained in step (4) with a film.

9. A pharmaceutical composition according to any one of claims 1-7 or a pharmaceutical composition prepared by the preparation method of claim 8, characterized in that, The content of impurity 1 in the pharmaceutical composition is no more than 2%, and the content of total impurities is no more than 3%.

10. A package comprising the pharmaceutical composition according to any one of claims 1-7 and 9, or the pharmaceutical composition prepared by the preparation method of claim 8.

11. A packaging product comprising the packaging of claim 9, further comprising a pharmaceutical instruction manual and / or a desiccant.

12. Use of a pharmaceutical composition according to any one of claims 1-7, 9, a pharmaceutical composition prepared by the method of claim 8, a packaging article according to claim 9, or a packaging product according to claim 10 in the preparation of a medicament for treating diseases selected from: diabetic neuropathy, diabetic gangrene, peripheral circulatory disorders, chronic arterial occlusion, 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 spinal stenosis.

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