Nicergoline pharmaceutical composition and preparation method thereof

Abstract

The invention provides a nicergoline pharmaceutical composition without calcium hydrophosphate and a preparation method thereof. The nicergoline pharmaceutical composition has good stability and dissolution rate, the production process is simple, and industrial production is easy.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a stable nicergoline pharmaceutical composition and a preparation method thereof. Background Art

[0002] Nicergoline is an ergot derivative used to treat Alzheimer's disease and other diseases with vascular origins. It has a receptor blocking effect and vasodilation effect. It can enhance the metabolism of brain cell energy, increase the utilization of oxygen and glucose, promote the conversion of neurotransmitter dopamine to enhance nerve conduction, strengthen brain protein biosynthesis, and improve brain function.

[0003] The structural formula of nicergoline is as follows:

[0004]

[0005] Nicergoline tablets were originally developed by Pharmacia & Upjohn and sold under the trade name The specifications are 5mg, 10mg and 30mg, and have been approved for sale in more than 50 countries. The prescription disclosed in the specification is composed of calcium hydrogen phosphate dihydrate, sucrose, microcrystalline cellulose, sodium carboxymethyl cellulose, magnesium carbonate, magnesium stearate, talc, gum arabic, sandalwood resin, titanium dioxide, rosin, kanab wax, and sunset yellow. Nicergoline tablets available on the market The product has poor stability and its ester bond is easily hydrolyzed. The following impurities I and II are its main degradation impurities:

[0006]

[0007] Patent CN102228450 discloses a nicergoline capsule and a production method thereof. The inventors add acidic excipients to improve product dissolution. During storage, the acid promotes the hydrolysis of the ester bond of nicergoline, resulting in very poor stability of the preparation.

[0008] Patent CN102949372 discloses a kind of Nicergoline tablet and its preparation method. The inventor separates Nicergoline and excipients into granules, and Nicergoline granules are dried at low temperature (below 40°C) to ensure product stability. However, too low drying temperature means that the slower the evaporation of water, the risk of Nicergoline hydrolysis will be further aggravated in a long-term high humidity environment. At the same time, API and excipients are granulated separately, and the production process is cumbersome, which is not conducive to commercial production.

[0009] Patent CN110051639 discloses a fast disintegrating nicergoline tablet and its preparation method. The inventor prepared a tablet with rapid dissolution and good stability by granulating microcrystalline cellulose and sodium carboxymethylcellulose, and then mixing and tableting with nicergoline, calcium hydrogen phosphate and magnesium stearate. On the one hand, the stability of the preparation is still poor; on the other hand, granulating microcrystalline cellulose and sodium carboxymethylcellulose together increases the complexity of the process, resulting in increased production costs.

[0010] The instability of drug preparations will affect the effectiveness and safety of the preparations, reduce the efficacy of the drug preparations or increase the side effects, etc. Therefore, it is necessary to study a nicer-stable drug composition. Summary of the invention

[0011] The first aspect of the present invention provides a novel nicergoline pharmaceutical composition comprising the following ingredients:

[0012] i) active ingredient nicergoline;

[0013] ii) a filler, wherein the filler comprises microcrystalline cellulose, and the content of the microcrystalline cellulose is 10-20% of the total weight of the composition; and

[0014] The composition does not contain calcium hydrogen phosphate.

[0015] In some embodiments of the present invention, the filler further comprises pregelatinized starch and lactose.

[0016] In some embodiments of the present invention, the content of the pregelatinized starch is 10%-20% of the total weight of the composition, and the content of lactose is 50%-70% of the total weight of the composition. The lactose can be anhydrous lactose or monohydrate lactose. According to an embodiment of the present invention, the lactose is monohydrate lactose.

[0017] In some embodiments of the present invention, the nicergoline pharmaceutical composition is a tablet, and the tablet is preferably coated to form a film-coated tablet.

[0018] In some embodiments of the present invention, the nicergoline pharmaceutical tablet is prepared by direct tableting.

[0019] In some embodiments of the present invention, the dosage range of the nicergoline contained in the nicergoline pharmaceutical composition is 4 mg-30 mg, more specifically, it can be 5 mg, 10 mg, 20 mg or 30 mg.

[0020] In some embodiments of the present invention, the content of nicergoline is 1%-10%, preferably 4%-6% of the total weight of the composition.

[0021] In some embodiments of the present invention, the nicergoline pharmaceutical composition further comprises iii) a disintegrant.

[0022] In some embodiments of the present invention, the disintegrant is cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, preferably cross-linked sodium carboxymethyl cellulose.

[0023] In some embodiments of the present invention, the content of the disintegrant is 2%-10% of the total weight of the composition, preferably 2%-6%, such as 2%, 3%, 4%, 5%, 6%.

[0024] In some embodiments of the present invention, the nicergoline pharmaceutical composition further comprises a lubricant; the lubricant may be selected from: magnesium stearate, sodium stearyl fumarate, zinc stearate, polyethylene glycol, glyceryl behenate. Preferably, the lubricant is magnesium stearate.

[0025] In some embodiments of the present invention, the content of the lubricant is 0.1-5%, preferably 0.2-2% by weight of the total weight of the composition.

[0026] In some embodiments of the present invention, the nicergoline pharmaceutical composition further comprises a glidant. The glidant may be selected from: colloidal silicon dioxide or talc. Preferably, the glidant is colloidal silicon dioxide, more preferably hydrophobic colloidal silicon dioxide.

[0027] In some embodiments of the present invention, the content of the glidant is 0.1-5%, preferably 0.2-2%, of the total weight of the composition.

[0028] In some embodiments of the present invention, the nicergoline pharmaceutical composition of the present invention comprises the following components: nicergoline, lactose monohydrate, pregelatinized starch, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose, hydrophobic colloidal silicon dioxide and magnesium stearate.

[0029] In some embodiments of the present invention, the present invention provides a nicergoline pharmaceutical composition comprising the following components, and the content of each component is calculated by weight percentage based on the total weight of the composition:

[0030] Components Possible content range Preferred content range Nicergoline 1％-10％ 4％-6％ Microcrystalline Cellulose 10％-20％ 10％-20％ Lactose Monohydrate 50％-70％ 50％-70％ Pregelatinized starch 10％-20％ 10％-20％ Croscarmellose Sodium 2％-10％ 2％-6％ Hydrophobic colloidal silica 0.1％-5％ 0.2％-2％ Magnesium Stearate 0.1％-5％ 0.2％-2％

[0031] In some embodiments of the present invention, the nicergoline pharmaceutical composition of the present invention is a tablet, and the tablet is preferably further coated to form a film-coated tablet. The coating material is a coating material conventionally used in the art, and its components include but are not limited to hypromellose, polyethylene glycol, titanium dioxide, talc, iron oxide, etc. Preferably, the coating material accounts for 1 to 6% of the total weight of the plain tablet, and more preferably 1 to 6% of the total weight of the plain tablet.

[0032] On the other hand, the present invention also provides a method for preparing the nicergoline pharmaceutical composition, comprising preparing it by a direct tableting method, specifically comprising the following steps:

[0033] 1) Mixing I: Nicergoline, microcrystalline cellulose, pregelatinized starch and cross-linked sodium carboxymethyl cellulose are sieved through a granulator, and then the sieved materials, hydrophobic colloidal silicon dioxide and lactose monohydrate are added into a hopper mixer for mixing;

[0034] 2) Sieving: The mixed material I is sieved through a granulator;

[0035] 3) Mixing II: Add the sieved materials into the hopper mixer for mixing;

[0036] 4) Mixing III: sieve magnesium stearate and add it into the mixing barrel and mix;

[0037] 5) Tableting: compressing the mixed III material into tablets;

[0038] 6) Optionally, the tablets are coated.

[0039] In some embodiments of the present invention, the sieve mesh specification of step 1) is 1.0 mm, the rotor speed is 500 rpm; the mixture is added into the hopper mixer and mixed for 60 turns;

[0040] The mesh size of the sieve in step 2) is 1.0 mm, and the rotor speed is 500 rpm;

[0041] The mixing II in step 3) is to add the sieved material into the mixing barrel and mix for 120 cycles;

[0042] In step 4), the mixing III is to add magnesium stearate through a 40-mesh sieve into a mixing barrel and mix for 60 cycles;

[0043] The tabletting in step 5) is to press the mixed material into 6.0 mm round tablets;

[0044] The coating in step 6) is to coat the plain tablets, and the coating weight gain is 3%.

[0045] Unless otherwise specified, the terms in this invention have the following meanings:

[0046] Plain tablets: tablets that are not coated during the preparation process.

[0047] “Content” refers to the percentage of the weight of each component in the total weight of the composition. When the composition is a tablet, the “total weight of tablets” refers to the weight of the plain tablet.

[0048] When lactose exists in the form of lactose monohydrate, its weight percentage is calculated as lactose monohydrate; when lactose exists in the form of anhydrous lactose, its weight percentage is calculated as anhydrous lactose.

[0049] Reference preparation: The drug whose licensee for marketing in the European Union is Upjohn EESV as specified in the announcement of the Reference Preparation Catalogue of Generic Drugs (the 44th batch of 10mg in the Reference Preparation Catalogue) issued by the State Food and Drug Administration.

[0050] RL: Reporting limit; “<RL” means below the detection limit.

[0051] A1 / A3 / A6: refers to the stability test period of 1 month / 3 months / 6 months respectively.

[0052] rpm: revolutions per minute.

[0053] The nicergoline composition provided by the present invention has good stability and solubility, and the production process is simple and easy to industrialize. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The dissolution curves of the nicergoline tablets prepared in the present invention, comparative example 1 and reference preparation (specification 10 mg) under the conditions of paddle method 50 rpm and 0.1 N HCl 500 ml. DETAILED DESCRIPTION

[0055] In order to make the purpose of the present invention and the technical scheme clearer, the present invention is further described in detail below in conjunction with the implementation case, so that those skilled in the art can fully understand the technical content of the present invention. It should be understood that the following examples are only used to further illustrate the present invention, but the content of the present invention is not limited thereto. Some non-essential improvements and adjustments made by those skilled in the art according to the technical scheme of the present invention all belong to the protection scope of the present invention. The specific process parameters in the following embodiments are also only a case in a suitable range, that is, those skilled in the art can make a suitable range selection through the description of this article, and are not limited to the specific numerical values ​​of the following embodiments. The materials and reagents used in the embodiments are all commercially available sources unless otherwise specified.

[0056] Related substance testing

[0057] According to the national drug standard for Nicergoline tablets (WS1-(X-256)-2004Z-2020), the sample was tested for related substances at 288nm. Detection instrument: High performance liquid chromatograph, model: Waters e2695. Detection method: Use strong cation exchange and reverse phase C18 mixed filler (mixing ratio of 1:4) as filler (CAPCELLPAK CR, 4.6mm×250mm, 5um or chromatographic column with equivalent performance). Use acetonitrile-phosphate buffer (60mmol / L potassium dihydrogen phosphate solution containing 0.5% triethylamine, pH adjusted to 2.1 with phosphoric acid) (30:70) as mobile phase; detection wavelength is 288nm. Injection volume 10μl.

[0058] Dissolution Testing

[0059] Dissolution method: paddle method (Chinese Pharmacopoeia 2020 Edition, Part IV, General Rules, 0931, Method 2), dissolution medium: 0.1N HCl 500ml, rotation speed 50rpm, sampling time: 10min, 15min, 20min, 30min, 45min and 60min; detection method: UV-visible spectrophotometry, absorbance is measured at a wavelength of 288nm; detection instrument: high performance liquid chromatograph, model: Waterse2695.

[0060] Example 1

[0061] According to the preparation method of the present invention, Nicergoline tablets are prepared, and the prescription list (Table 1) and the preparation method are as follows.

[0062] Table 1 List of prescriptions for Nicergoline tablets

[0063]

[0064] The specific preparation method is as follows:

[0065] Mixing I: Mix nicergoline, microcrystalline cellulose, pregelatinized starch and cross-linked sodium carboxymethyl cellulose by hand for 50 times, and sieve through a granulator with a screen size of 1.0 mm and a rotor speed of 500 rpm. Add the sieved materials, hydrophobic colloidal silicon dioxide and lactose monohydrate into the mixing barrel and mix for 60 turns.

[0066] Screening: The material obtained by mixing I was screened through a granulator with a screen size of 1.0 mm and a rotor speed of 500 rpm.

[0067] Mixing II: Add the sieved material into the mixing bucket and mix for 120 turns.

[0068] Mixing III: Pass magnesium stearate through a 40-mesh sieve and add it into the mixing barrel. Mix for 60 turns.

[0069] Tablet pressing: Press the mixed material into 6.0 mm round tablets.

[0070] Coating: The plain tablets were coated with coating, and the coating weight gain was 3%.

[0071] Example 2

[0072] According to the preparation method of the present invention, Nicergoline tablets are prepared, and the prescription list (Table 2) and the preparation method are as follows.

[0073] Table 2 List of prescriptions for Nicergoline tablets

[0074]

[0075]

[0076] The specific preparation method is the same as that in Example 1.

[0077] Example 3

[0078] According to the preparation method of the present invention, Nicergoline tablets are prepared, and the prescription list (Table 3) and the preparation method are as follows.

[0079] Table 3 List of prescriptions for Nicergoline tablets

[0080]

[0081] The specific preparation method is the same as that in Example 1.

[0082] Example 4

[0083] According to the preparation method of the present invention, Nicergoline tablets are prepared, and the prescription list (Table 4) and the preparation method are as follows.

[0084] Table 4 Prescription list of Nicergoline tablets

[0085]

[0086]

[0087] The specific preparation method is the same as that in Example 1.

[0088] Comparative Example 1

[0089] According to the preparation method of the present invention, the pregelatinized starch is removed and the amount of microcrystalline cellulose is increased. The prescription list (Table 5) and the preparation method are as follows.

[0090] Table 5 Prescription list of Nicergoline tablets

[0091]

[0092] The specific preparation method is the same as that in Example 1.

[0093] Comparative Example 2

[0094] Nicergoline tablets were prepared using a prescription containing calcium hydrogen phosphate dihydrate. The prescription list (Table 6) and preparation method are as follows.

[0095] Table 6 List of prescriptions for Nicergoline tablets

[0096]

[0097]

[0098] The specific preparation method is the same as that in Example 1.

[0099] Test Example 1: Stability Test

[0100] The Nicergoline tablets prepared in Examples 1 to 4 of the present invention were packaged in HDPE bottles and placed in a stability test chamber at 40°C / 75RH% for 1 / 3 / 6 months according to the National Drug Standard for Nicergoline Tablets (WS1-(X-256)

[0101] -2004Z-2020), and the related substances of each sample were detected at 288nm. The results are shown in Table 7. The results show that the stability of the Nicergoline tablets prepared by the present invention is significantly improved, and the toxic and side effects can be significantly reduced in clinical application.

[0102] The Nicergoline tablets prepared in Comparative Example 2 of the present invention were packaged in HDPE bottles and placed in a stability test box at 40°C / 75RH% for 1 month. According to the same detection method, the results showed that the Nicergoline tablets prepared in Comparative Example 2 had poor stability and a significant growth trend of hydrolysis impurities.

[0103] Table 7 Comparison of the results of testing related substances in Nicergoline tablets prepared by the present invention and Comparative Example 2

[0104]

[0105] Note: *RL=0.10%.

[0106] Test Example 2: Dissolution Test

[0107] The dissolution curves of the nicergoline tablets prepared by the present invention, comparative example 1, and the reference preparation (original drug, specification 10 mg) under the conditions of paddle method 50 rpm, 0.1 N HCl 500 ml are shown in FIG. Figure 1 The results show that the in vitro dissolution behavior of the preparation prepared by the present invention is consistent with that of the reference preparation; while the dissolution of the nicergoline tablets prepared in Comparative Example 1 is slower than that of the reference preparation, which is not similar.

Claims

1. A nicergoline pharmaceutical composition, characterized in that, Contains the following ingredients: i) Nicergoline; ii) a filler, wherein the filler comprises microcrystalline cellulose, and the content of the microcrystalline cellulose is 10-20% of the total weight of the composition; and The composition does not contain calcium hydrogen phosphate.

2. The pharmaceutical composition according to claim 1, characterized in that Also includes The filler also includes pregelatinized starch and lactose; Further, the content of the pregelatinized starch is 10%-20% of the total weight of the composition; Furthermore, the content of the lactose is 50%-70% of the total weight of the composition. Preferably, the lactose is lactose monohydrate.

3. The Nicergoline pharmaceutical composition according to claim 1, wherein the composition is a tablet, preferably obtained by direct tablet compression, and further preferably the tablet is coated to form a film-coated tablet.

4. The Nicergoline pharmaceutical composition according to claim 1, wherein the dosage range of Nicergoline is 4 mg-30 mg, preferably 5 mg, 10 mg, 20 mg or 30 mg; preferably the content of the Nicergoline is 1%-10% of the total weight of the composition, preferably 4%-6%.

5. The nicergoline pharmaceutical composition according to claim 1, characterized in that Also comprising iii) a disintegrant; Furthermore, the disintegrant is cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, sodium carboxymethyl starch, hydroxypropyl starch, low-substituted hydroxypropyl cellulose, preferably cross-linked sodium carboxymethyl cellulose; Furthermore, the content of the disintegrant is 2%-10% of the total weight of the composition; More preferably, it is 2%-6%.

6. The nicergoline pharmaceutical composition according to claim 1, characterized in that Also includes lubricant; Further, the lubricant is selected from: magnesium stearate, sodium stearyl fumarate, zinc stearate, polyethylene glycol or glyceryl behenate, preferably magnesium stearate; Furthermore, the content of the lubricant is 0.1-5% by weight of the total weight of the composition, preferably 0.2%-2%.

7. The nicergoline pharmaceutical composition according to claim 1, characterized in that It also contains a glidant; Furthermore, the glidant is selected from: colloidal silicon dioxide or talc, preferably colloidal silicon dioxide; further, the content of the glidant is 0.1-5% of the total weight of the composition, preferably 0.2%-2%.

8. The nicergoline pharmaceutical composition according to claim 1, characterized in that Contains the following ingredients: nicergoline, lactose monohydrate, pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, hydrophobic colloidal silicon dioxide and magnesium stearate.

9. The nicergoline pharmaceutical composition according to claim 1, characterized in that The composition comprises the following components, and the content of each component is calculated by weight percentage based on the total weight of the composition as shown below: Preferably, the composition comprises the following components, and the content of each component is calculated as weight percentage based on the total weight of the composition as shown below: 。 10. A method for preparing the nicergoline pharmaceutical composition according to claim 9, characterized in that: Prepared by direct compression method; Further comprising the following steps: 1) Mixing I: Nicergoline, microcrystalline cellulose, pregelatinized starch and cross-linked sodium carboxymethyl cellulose are sieved through a granulator, and then the sieved materials, hydrophobic colloidal silicon dioxide and lactose monohydrate are added into a hopper mixer for mixing; 2) Sieving: The mixed material I is sieved through a granulator; 3) Mixing II: Add the sieved materials into the hopper mixer for mixing; 4) Mixing III: sieve magnesium stearate and add it into the mixing barrel for mixing; 5) Tableting: compressing the mixed III material into tablets; 6) Optionally, coating the tablets; Furthermore, the sieve mesh specification of the sieving in step 1) is 1.0 mm, and the rotor speed is 500 rpm; the mixture is added into the hopper mixer and mixed for 60 cycles; The mesh size of the sieve in step 2) is 1.0 mm, and the rotor speed is 500 rpm; The mixing II in step 3) is to add the sieved material into the mixing barrel and mix for 120 cycles; In step 4), the mixing III is to add magnesium stearate through a 40-mesh sieve into a mixing barrel and mix for 60 cycles; The tabletting in step 5) is to press the mixed material into 6.0 mm round tablets; The coating in step 6) is to coat the plain tablets, and the coating weight gain is 3%.

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