Pharmaceutical composition and capsule containing pyrroloquinoline quinone trilithium salt nonahydrate compound, and method for producing the same

Abstract

The present invention discloses a pharmaceutical composition, a capsule and a method for preparing the same, which comprises: 1.0 part by weight of pyrroloquinoline quinone trilithium salt nonahydrate compound, and a pharma- ceutical acceptable excipient, and the pharma-ceutical acceptable excipient comprises: 0.16-0.48 parts by weight of colloidal silica. The pharmaceutical composition, the capsule and the method for preparing the same ensure that the crystalline form of the pyrroloquinoline quinone trilithium salt nonahydrate compound has good stability and dissolution effect, and ensure a high drug content per unit of the formulation while minimizing the dosage of the excipient, making it easy for the elderly to take and improving drug treatment compliance in the elderly.

Description

[Technical Field]

[0001] This application claims priority to Chinese Patent Application No. 202011573509.7, entitled "Pharmaceutical Compositions, Capsules Containing Pyrroloquinoline Quinone Trilithium Salt Nonahydrate Compounds, and Methods for Preparing the Same," filed with the State Intellectual Property Administration of China on December 28, 2020, the contents of which are incorporated herein by reference.

[0002] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a pharmaceutical composition containing a pyrroloquinoline quinone trilithium salt nonahydrate compound, as well as a capsule containing said composition and a method for producing the same. [Background technology]

[0003] The compound represented by formula (I) has the chemical name 4,5-dioxo-4,5-dihydro-1H-pyrrolo[2,3-f]quinoline-2,7,9-tricarboxylic acid lithium salt nonahydrate and the molecular formula C 14 It is a pyrroloquinoline quinone trilithium salt nonahydrate compound with H3Li3N2O8·9H2O and molecular weight of 510.14, and is a promising drug candidate for the treatment of various neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. [ka]

[0004] Chinese Patent Applications Nos. 200910048873.9 and 201310270885.2 disclose the lithium salt and nonahydrate crystalline forms of pyrroloquinoline quinone compounds, respectively. As described in Chinese Patent Application No. 201310270885.2, the crystalline form of the compound represented by Formula (I) exhibits characteristic diffraction peaks at angles of 2θ=6.2°±0.2°, 7.4°±0.2°, 7.9°±0.2°, and 23.6°±0.2° in powder X-ray diffraction (PXRD). Furthermore, the nonahydrate compound contains up to 31.8% water of crystallization and is temperature-sensitive, losing water of crystallization at 40°C and rapidly and irreversibly losing water above 60°C.

[0005] The active pharmaceutical ingredient, pyrroloquinoline quinone trilithium salt nonahydrate, is crystalline and prone to aggregation, low bulk density, poor flowability, and adhesion to equipment surfaces. Therefore, granulation is required to increase bulk density and flowability and ensure the accuracy of the subsequent capsule filling process. It has been found that the solvent removal process by drying in wet granulation can result in partial or complete loss of water of crystallization in pyrroloquinoline quinone trilithium salt nonahydrate, resulting in a change in crystalline morphology. Dry granulation does not require the use of solvents, thereby avoiding the risk of crystalline morphology changes due to heating. However, pyrroloquinoline quinone trilithium salt nonahydrate is a metal salt with a high percentage of water of crystallization, and like other metal salts, it tends to form a rigid structure after pressing. Dry granulation involves mixing the drug and excipients, rolling them into thin sheets, and then milling them to form granules. If the metal salt forms a thin, rigid sheet after rolling, not only does this make subsequent processing difficult and reduce production efficiency, but prolonged rolling and repeated milling also increase the temperature of the equipment, affecting the stability of the crystalline form of pyrroloquinoline quinone trilithium salt nonahydrate. Furthermore, forced granulation produces hard granules, which can slow the dissolution rate. Increasing the amount of excipients to reduce physical contact between the metal salt raw material particles and thereby reduce the formation of a hard structure can result in excessively large final product size, even with the same specifications, due to the excessive amount of excipients. For elderly patients with neurodegenerative diseases who have swallowing difficulties and require lifelong medication, this can easily lead to psychological and physiological barriers to medication administration.

[0006] Therefore, currently, there is no corresponding formulation containing the crystalline form of pyrroloquinoline quinone trilithium salt nonahydrate, and a method for producing the same, which ensures the stability and good dissolution profile of the crystalline form of pyrroloquinoline quinone trilithium salt nonahydrate, and ensures a high drug content in each unit of the formulation while minimizing the dosage of excipients, thereby making it easy for elderly patients to take and improving drug treatment compliance in elderly patients. Summary of the Invention

[0007] In order to solve the above-mentioned technical problems, the present invention provides a pharmaceutical composition containing a pyrroloquinoline quinone trilithium salt nonahydrate compound, as well as capsules containing the composition and a method for preparing the same. The pharmaceutical composition, capsules containing the composition and a method for preparing the same provided by the present invention ensure that the crystalline form of pyrroloquinoline quinone trilithium salt nonahydrate has a good stability and dissolution profile, and ensure a high drug content in each unit of the formulation while minimizing the amount of excipients, making it easier for elderly patients to take the drug, and improving drug treatment compliance in elderly patients.

[0008] The present invention provides a pharmaceutical composition comprising a pyrroloquinoline quinone trilithium salt nonahydrate compound, the pharmaceutical composition comprising: 1.0 part by weight of a pyrroloquinoline quinone trilithium salt nonahydrate compound; and a pharmaceutically acceptable excipient; The pharmaceutically acceptable excipient comprises: 0.16 parts by weight to 0.48 parts by weight of colloidal silica; The pyrroloquinoline quinone trilithium salt nonahydrate compound is in a crystalline form, and the pyrroloquinoline quinone trilithium salt nonahydrate compound has a powder X-ray diffraction pattern including characteristic diffraction peaks at 2θ diffraction angles of 6.2°±0.2°, 7.4°±0.2°, 7.9°±0.2°, and 23.6°±0.2°.

[0009] Optionally, the pharmaceutically acceptable excipient is: further comprising 1.0 parts by weight to 5.0 parts by weight of an additional pharmaceutically acceptable excipient; The additional pharmaceutically acceptable excipient may be selected from the group consisting of starch, pregelatinized starch, microcrystalline cellulose, lactose, lactose-starch complex, lactose-cellulose complex, mannitol, mannitol-starch complex, sorbitol, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, magnesium stearate, sodium stearyl fumarate, talcand stearic acid.

[0010] Optionally, the colloidal silica is 0.2 parts by weight to 0.4 parts by weight; and the additional pharmaceutically acceptable excipient is 2.0 parts by weight to 4.0 parts by weight.

[0011] Optionally, the additional pharmaceutically acceptable excipients are 0.6 to 4 parts by weight of pregelatinized starch; 0.36 to 0.96 parts by weight of microcrystalline cellulose; and 0 to 0.06 parts by weight of magnesium stearate.

[0012] Optionally, colloidal silica can be added by the internal addition method or the internal-external addition method; and additional pharmaceutically acceptable excipients can be added by the internal addition method or the internal-external addition method.

[0013] Optionally, when colloidal silica is added by the internal-external addition method, the internally added colloidal silica of Externally added colloidal silica against The weight ratio is 3 super : 1 in and when the additional pharmaceutically acceptable excipient is added by the internal-external addition method, the weight ratio of the internally added additional pharmaceutically acceptable excipient to the externally added additional pharmaceutically acceptable excipient is greater than 3:1.

[0014] Optionally, additional pharmaceutically acceptable excipients that may be added by internal addition are selected from one or more of starch, lactose, microcrystalline cellulose, mannitol, croscarmellose sodium, copovidone, and magnesium stearate; and additional pharmaceutically acceptable excipients that may be added by external addition are selected from one or more of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

[0015] The present invention further provides a capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound, and the capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound comprises the pharmaceutical composition of the present invention.

[0016] Optionally, the material of the capsule can be selected from any one of gelatin capsule, hydroxypropyl methylcellulose capsule, pullulan polysaccharide capsule and starch capsule.

[0017] Optionally, the capsule material is a hydroxypropyl methylcellulose capsule.

[0018] Optionally, in capsules, each capsule contains 5 mg to 100 mg of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

[0019] Optionally, each capsule contains 20 mg to 75 mg of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

[0020] Furthermore, the present invention provides a method for producing capsules containing the pyrroloquinoline quinone trilithium salt nonahydrate compound, which is used for producing capsules containing the pyrroloquinoline quinone trilithium salt nonahydrate compound of the present invention, and is a dry granulation method for producing capsules.

[0021] Optionally, when the pharmaceutically acceptable excipient is added by an internal addition method, the manufacturing method comprises: a step of weighing out a pyrroloquinoline quinone trilithium salt nonahydrate compound as an active pharmaceutical ingredient (API) and a pharmaceutically acceptable excipient according to a mixing ratio; mixing the API pyrroloquinoline quinone trilithium salt nonahydrate compound with a pharmaceutically acceptable excipient; subjecting the blended API pyrroloquinoline quinone trilithium salt nonahydrate compound and pharmaceutically acceptable excipients to dry granulation, first rolling the blend into a thin sheet and then granulating it into granules; and Filling the granules into capsules to obtain capsules. Includes.

[0022] Optionally, when the pharmaceutically acceptable excipient is added by the internal-external addition method, the preparation method is: weighing out the API pyrroloquinoline quinone trilithium salt nonahydrate compound and a pharmaceutically acceptable excipient according to a blending ratio; mixing the API pyrroloquinoline quinone trilithium salt nonahydrate compound with a pharmaceutically acceptable excipient; subjecting the blended API pyrroloquinoline quinone trilithium salt nonahydrate compound and pharmaceutically acceptable excipients to dry granulation, first rolling the blend into thin sheets and then granulating them into granules; Mixing the granules obtained by dry granulation with a pharmaceutically acceptable excipient; and A step of filling the granules mixed with pharmaceutically acceptable excipients into capsules to obtain capsules. Includes:

[0023] Compared with the prior art, the pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate compound, the capsule containing the composition and the preparation method thereof provided by the embodiments of the present invention have the following advantages:

[0024] The pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate compound provided by the present invention utilizes an appropriate proportion of colloidal silica and an appropriate proportion of additional pharmaceutically acceptable excipients. By utilizing the high specific surface area and low density (meaning a high proportion of air) of colloidal silica, along with the dilution effect of the additional pharmaceutically acceptable excipients, the composition effectively alleviates the drawback of pyrroloquinoline quinone trilithium salt nonahydrate compound's tendency to form hard, thin sheets that are difficult to granulate during dry granulation. The thin sheets produced by dry granulation are loose and easy to granulate, improving production efficiency and yield and enabling scale-up of commercial production. At the same time, the large specific surface area and strong anti-adhesion effect of colloidal silica solve the problems of its tendency to agglomerate and adhere to equipment surfaces.

[0025] Furthermore, capsules of pyrroloquinoline quinone trilithium salt nonahydrate prepared by the composition and method for preparing the capsules of the present invention can provide the crystalline form of the pyrroloquinoline quinone trilithium salt nonahydrate compound with good stability and dissolution profile. Experimental results showed that the capsules can be stored for a long period of time at 30°C and maintain a good dissolution profile in both long-term and accelerated tests at 25°C and 60% relative humidity and 30°C and 65% relative humidity for 6 months, with no related substances detected, and the characteristic peaks and geometric topology patterns of PXRD consistent with those on day 0, suggesting that capsules containing the pharmaceutical composition prepared by the method of the present invention have good chemical stability. Furthermore, the use of appropriate excipient proportions avoids excessive use of excipients, making the produced capsules easier for elderly patients to swallow and take, thereby improving drug treatment compliance in elderly patients. [Brief explanation of the drawings]

[0026] [Figure 1] FIG. 1 shows the results of a microscopic observation of the API, pyrroloquinoline quinone trilithium salt nonahydrate compound. [Figure 2] FIG. 2 shows the dissolution profiles of capsule numbers 1 to 4 in Example 1. [Figure 3] FIG. 3 shows the dissolution profiles of capsule numbers 5 to 8 of Example 2. [Figure 4] FIG. 4 shows the dissolution profiles of capsule numbers 9 to 12 of Example 3. [Figure 5] FIG. 5 shows the dissolution profiles of capsule numbers 13 to 16 of Example 4. [Figure 6] FIG. 6 shows the dissolution profiles of capsule numbers 1 and 2 in Comparative Example 1. [Figure 7] FIG. 7 shows the dissolution profiles of capsule numbers 3 to 6 of Comparative Example 2. [Figure 8] FIG. 8 shows the dissolution profiles of capsule numbers 7 to 10 of Comparative Example 3. [Figure 9] FIG. 9 shows the dissolution profiles of capsule number 3 of Example 1 and capsule number 7 of Example 2 before and after the 6-month stability study. [Figure 10] FIG. 10 shows the PXRD measurement results of capsule No. 3 of Example 1 and capsule No. 7 of Example 2 before and after the 6-month test. DETAILED DESCRIPTION OF THE INVENTION

[0027] As explained in the Background Art section, pyrroloquinoline quinone trilithium salt nonahydrate compound has a crystallization water content of 31.8% and is temperature-sensitive, losing crystallization water at temperatures above 40°C and rapidly and irreversibly losing water at temperatures above 60°C. The API, pyrroloquinoline quinone trilithium salt nonahydrate compound, has a short rod-like shape, and API particles are prone to aggregation (Figure 1 shows the results of microscopic observation; aggregated API particles are indicated by dotted circles). During formulation development, it has been discovered that the API has drawbacks such as low bulk density, poor flowability, and a tendency to adhere to equipment surfaces.

[0028] Upon further investigation, the inventors found that pyrroloquinoline quinone trilithium salt nonahydrate compound is prone to aggregation, requiring a high proportion of excipients for dilution and dispersion. However, too much excipient increases the volume of the formulation, potentially affecting swallowability (its indications are primarily for elderly patients). Pyrroloquinoline quinone trilithium salt nonahydrate compound is a metal lithium salt. If the proportion of excipients in the formulation is low and the drug is not sufficiently diluted and dispersed, the resulting thin sheets are hard and difficult to crush (a characteristic common to many metal salts). Repeated crushing of thin sheets at high speeds also affects the stability of the hydrate due to frictional heating.

[0029] To solve the above-mentioned technical problems, the present invention provides a pharmaceutical composition containing pyrroloquinoline quinone trilithium salt nonahydrate. The pharmaceutical composition utilizes an appropriate proportion of colloidal silica and an appropriate proportion of additional pharmaceutically acceptable excipients. By utilizing the high specific surface area and low density (meaning a high proportion of air) of colloidal silica, along with the dilution effect of the additional pharmaceutically acceptable excipients, the composition effectively alleviates the drawback of pyrroloquinoline quinone trilithium salt nonahydrate compound's tendency to form hard, thin sheets that are difficult to granulate during dry granulation. The thin sheets produced by dry granulation are loose and easy to granulate, improving production efficiency and yield and enabling scale-up of commercial production. At the same time, colloidal silica's large specific surface area and strong anti-adhesion effect solve the problem of its tendency to agglomerate and adhere to equipment surfaces.

[0030] Furthermore, the capsules of pyrroloquinoline quinone trilithium salt nonahydrate prepared by the composition and the method for preparing the capsules of the present invention can provide the crystalline form of the pyrroloquinoline quinone trilithium salt nonahydrate compound with good stability and dissolution profile. Experimental results showed that the capsules can be stored for a long period of time at 30°C, and maintained a good dissolution profile in both long-term and accelerated tests at 25°C and 60% relative humidity and 30°C and 65% relative humidity for 6 months, with no related substances detected, suggesting that the capsules containing the pharmaceutical composition prepared by the method of the present invention have good chemical stability. Furthermore, the use of an appropriate proportion of excipients avoids excessive use of excipients, making the produced capsules easier for elderly patients to swallow and take, thereby improving drug treatment compliance in elderly patients.

[0031] To make the above-mentioned objects, features and advantages of the present invention more apparent, the present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0032] Unless otherwise stated, the starting materials, samples, reagents and equipment used in the examples of this invention are commercially available.

[0033] 1. Starting Materials The API, pyrroloquinoline quinone trilithium salt nonahydrate crystals, can be prepared according to the manufacturing method described in Chinese Invention Patent Grant CN103351387B (Application No.: 201310270885.2, issued October 16, 2013), which will not be described in detail herein. The pyrroloquinoline quinone trilithium salt nonahydrate compound prepared by the above-described manufacturing method has a powder X-ray diffraction pattern including characteristic diffraction peaks at 2θ diffraction angles of 6.2°±0.2°, 7.4°±0.2°, 7.9°±0.2°, and 23.6°±0.2°.

[0034] 2. Excipients The specifications and supplier information for the excipients used in Examples 1 to 4 and Comparative Examples 1 to 3 are as follows: colloidal silica, pregelatinized starch (Starch 1500, manufactured by Colorcon), microcrystalline cellulose (VIVAPUR101, manufactured by JRS), magnesium stearate (MF2V, manufactured by Liaoning Aoda Co., Ltd.), lactose (granulac200, manufactured by MEGGLE), mannitol (160C, manufactured by ROQUETTE), anhydrous calcium hydrogen phosphate (Fujicalin-SG, manufactured by Fuji Chemical Industry Co., Ltd.), magnesium aluminum silicate (Neusilin UFL2, manufactured by Fuji Chemical Industry Co., Ltd.), croscarmellose sodium (Ac-Di-Sol, manufactured by FMC BioPolymer), copovidone (VA64 fine, manufactured by BASF), hollow capsule shell: hydroxypropyl methylcellulose hollow capsule (Vcaps Plus, manufactured by Capsugel), and gelatin hollow capsule (Coni-Snap, manufactured by Capsugel).

[0035] Among these, colloidal silica, also known as aerosil or fumed silica, is typically produced by reacting silicon tetrachloride in a flame with hydrogen and oxygen (Chinese Pharmacopoeia 2020, Part IV, Colloidal Silica, P719). Examples of colloidal silica in English include colloidal anhydrous silica, light anhydrous silicic acid, colloidal anhydrous silica, colloidal silicon dioxide, and fumed silica powder. Commercially available products for pharmaceutical use include the Aerosil series from Evonik Degussa, the HDK series from Wacker, the CAB-O-SIL series from CABOT, and the pharmaceutical-grade colloidal silica series from Hubei Huifu Nanomaterial Co., Ltd. in China. These products typically have a bulk density of 0.02 to 0.05 g / cm. 3 The tap density is in the range of 0.03 to 0.22 g / cm 3 Colloidal silica as a pharmaceutical excipient is commonly used as a lubricant (glidant), adsorbent, stabilizer, stabilizer, and thickener. In oral solid dosage forms, it is usually used as a glidant at a typical amount of 0.1% to 0.3% (Fang Liang, Pharmaceutics, 8th Edition, People's Medical Publishing House, p. 127). The amount used as a lubricant (glidant) ranges from 0.1% to 1.0% (Raymond C Rowe, Paul J Sheskey, Marian E Quinn, eds., Handbook of Pharmaceutical Excipients, 6th Edition, Pharmaceutical Press and the American Pharmacists Association, p. 186).

[0036] The above examples of excipient and capsule models and suppliers are intended only to better illustrate the ranges of proportions and effects of the examples, and are not intended to limit the types and suppliers of excipients and capsule shells of the present invention.

[0037] 3. Equipment TF-MINI dry granulator (manufacturer: Freund Corporation of Japan); HD-5 multi-directional motion mixer (manufacturer: Shanghai Tianxiang Jiantai); Z25 capsule filling machine (manufacturer: Shandong Xinma); DPP80 automatic blister packaging machine (manufacturer: Jiangnan Pharmaceutical Machinery Factory). The above-mentioned examples of equipment models and supplier information are intended only to better explain the implementation effects of the embodiments, and the equipment models and suppliers used in the manufacturing method of the present invention are not limited to these. [Example]

[0038] Examples 1-4: Compositions containing pyrroloquinoline quinone trilithium salt nonahydrate, capsules containing the compositions, and their preparation [Table 1]

[0039] [Table 2]

[0040] [Table 3]

[0041] [Table 4]

[0042] Preparation method: Example 1 (Formulation Nos. 1 to 4), Example 2 (Formulation Nos. 5 to 8), Example 3 (Formulation Nos. 9 to 12) and Example 4 (Formulation Nos. 13 and 15): (1) Pretreatment of starting materials: API pyrroloquinoline quinone trilithium salt nonahydrate compound was sieved through a 30 mesh sieve, and excipients were sieved through a 40 mesh sieve; (2) Preparation of starting materials: API pyrroloquinoline quinone trilithium salt nonahydrate compound and excipients are weighed according to the blending ratio; (3) Pre-mixing: The API pyrroloquinoline quinone trilithium salt nonahydrate compound and all excipients are placed in a multi-directional mixer and mixed at a speed of 20 rpm for 15 minutes to be uniformly mixed; (4) Dry granulation: The API pyrroloquinoline quinone trilithium salt nonahydrate compound and all excipients are uniformly mixed in a dry granulator, and dry granulated at a temperature of 15°C to 25°C and a relative humidity of 45% to 55% under the following granulation parameters: rolling pressure: 5.0 MPa ± 1.0 MPa, feed rate: 15 rpm to 30 rpm, roller speed: 4 rpm to 8 rpm, and granulated to a 20-mesh size using the built-in device of the dry granulator; (5) Intermediate assessment: After dry granulation, granule samples are collected and the content and other characteristics are tested. (6) Capsule filling: Calculate the actual filling amount based on the intermediate content and theoretical filling amount at a temperature of 15°C to 25°C and a relative humidity of 45% to 55%, and select the appropriate capsule specifications; place the appropriate materials and hollow capsules in the powder tray and capsule tray of the capsule filling machine, respectively, and fill the capsules at a rate of 18,000 capsules / hour, controlling the average capsule weight difference to be ≦±5.0% and the single capsule weight difference to be ≦±7.5%; (7) Packaging: Packing the filled capsules into double aluminum blister packages at a rate of 1,200 plates / hour in a DPP80 automatic blister packaging machine; and (8) Storage: Packaged capsules containing pyrroloquinoline quinone trilithium salt nonahydrate were stored at room temperature (below 30°C).

[0043] Preparation of Example 4 (Formulations Nos. 14 and 16) (1) Pretreatment of starting materials: API pyrroloquinoline quinone trilithium salt nonahydrate compound is sieved through a 30 mesh sieve, and excipients are sieved through a 40 mesh sieve; (2) Preparation of starting materials: API pyrroloquinoline quinone trilithium salt nonahydrate compound and excipients including internal and external excipients are weighed according to the blending ratio; (3) Pre-mixing: The API pyrroloquinoline quinone trilithium salt nonahydrate compound and the internally added excipients are placed in a multi-directional motion mixer and mixed at a speed of 20 rpm for 15 minutes to be uniformly mixed; (4) Dry granulation: The API pyrroloquinoline quinone trilithium salt nonahydrate compound and internal excipients are uniformly mixed and placed in a dry granulator, and dry granulated at a temperature of 15°C to 25°C and a relative humidity of 45% to 55% under the following granulation parameters: rolling pressure: 5.0 MPa ± 1.0 MPa, feed rate: 15 rpm to 30 rpm, roller speed: 4 rpm to 8 rpm, and granulated to a 20-mesh size using the built-in device of the dry granulator; (5) Total mixing: The granules obtained after dry granulation and externally added excipients are placed in a multi-directional motion mixer and mixed at a speed of 20 rpm for 15 minutes; (6) Intermediate judgment: After the whole mixture, the granules are sampled and the content and other characteristics are tested. (7) Capsule filling: Calculate the actual filling amount based on the intermediate content and theoretical filling amount at a temperature of 15°C to 25°C and a relative humidity of 45% to 55%, and select the appropriate capsule specifications; place the appropriate materials and hollow capsules in the powder tray and capsule tray of the capsule filling machine, respectively, and fill the capsules at a rate of 18,000 capsules / hour, controlling the average capsule weight difference to be ≦±5.0% and the single weight difference to be ≦±7.5%; (8) Packaging: Packing the filled capsules into double aluminum blister packages at a rate of 1,200 plates / hour in a DPP80 automatic blister packaging machine; and (9) Storage: Packaged capsules containing pyrroloquinoline quinone trilithium salt nonahydrate were stored at room temperature (below 30°C).

[0044] Comparative Examples 1 to 3 [Table 5]

[0045] [Table 6]

[0046] [Table 7]

[0047] Preparation method: The preparation methods of Comparative Example 1 (Formulation Nos. 1 and 2), Comparative Example 2 (Formulation Nos. 3 to 6) and Comparative Example 3 (Formulation Nos. 7 to 10) were the same as those in Example 1.

[0048] Comparison of preparation results between Examples 1 to 4 and Comparative Examples 1 to 3 By comparing the dry granulation of Comparative Example 2 Formulation No. 5 and Comparative Example 2 Formulation No. 6, it was found that due to the high proportion of added colloidal silica, the obtained thin sheet was too soft and the material was prone to sticking to the surface of the roller shaft, which prevented continuous pressing. However, during the dry granulation process, no obvious sticking phenomenon was observed on the surface of the roller shaft for the formulations of Examples 1 to 4 and the remaining formulations of Comparative Examples 1 to 3.

[0049] The difference in the granulation results after dry rolling into a thin plate is shown in Effect Example 1.

[0050] In Examples 1 to 4 and Comparative Examples 1 to 3, except for the dry granulation process, no abnormalities or problems that would affect subsequent scale-up or stability of the production were observed in the remaining manufacturing processes for the capsules of pyrroloquinoline quinone trilithium salt nonahydrate.

[0051] The advantages of the capsule preparation containing pyrroloquinoline quinone trilithium salt nonahydrate of the present invention and the method for producing the same will be further explained below by carrying out performance tests on the final products of Examples 1 to 4 and Comparative Examples 1 to 3.

[0052] Effect example 1 To compare and demonstrate the effect of colloidal silica on improving the granulation of pyrroloquinoline quinone trilithium salt nonahydrate, which is easily compressed into hard, thin sheets, 20 g ± 2 g of dry-granulated pyrroloquinoline quinone trilithium salt nonahydrate thin sheets (0.8 mm to 1.0 mm thick) prepared in Examples 1 to 4 and Comparative Examples 1 and 3 were each sampled and placed in a dry granulator. The sample was passed through a 20-mesh 316L stainless steel sieve at a constant speed (96 rpm, 0.2 kW motor output, unidirectional rotary granulation) set by the dry granulator. The granulation time was fixed at 15 minutes. After granulation, the material remaining on the sieve was collected and weighed to represent A (g), and the material passing through the sieve was collected and weighed to represent B (g). The granulation yield was calculated according to the formula: W = B / (A + B) × 100%.

[0053] [Table 8]

[0054] [Table 9]

[0055] Granulation Results: According to the results in Tables 8 and 9, the granulation yield of the capsules prepared with Formulation Nos. 1 to 16 in Examples 1 to 4 was always greater than 90%. The colloidal silica was preferably 0.2 to 0.4 parts by weight, and the additional pharmaceutically acceptable excipient was preferably 2.0 to 4.0 parts by weight. The granulation yield of the capsules prepared with Formulation Nos. 2 and 3 in Example 1, Formulation No. 7 in Example 2, Formulation Nos. 9 to 12 in Example 3, and Formulation Nos. 13 to 16 in Example 4 was always greater than 97%.

[0056] In Comparative Example 1, although the capsules of Formulation No. 1 contained colloidal silica, the addition of a certain proportion of other metal salts such as anhydrous calcium hydrogen phosphate made the material hard and difficult to process, and the yield after 15 minutes of granulation was only 46.1%. In Formulation No. 2 of Comparative Example 1, the colloidal silica of Formulation No. 7 of Example 2 was similarly added to a capsule of a granule having an extremely high specific surface area (300 m 2 / g), low bulk density (0.06~0.11g / cm 3 ) and tap density (0.10~0.17g / cm 3 ), resulting in a decrease in granulation yield from 99.5% to 50.1%. The reason for this difference is that the metal salt aluminum magnesium silicate can increase the rigidity of the granules, whereas colloidal silica can resist or decrease the rigidity.

[0057] In Comparative Example 2, the ratio of pyrroloquinoline quinone trilithium salt nonahydrate to the additional pharmaceutically acceptable excipient was fixed at 1:2.7, and the colloidal silica ratio was changed to less than 0.16. As shown by the results of Formulations Nos. 3 and 4, the yield after granulation was only 64.1% and 67.7%, respectively. As shown by Formulations Nos. 5 and 6, when the colloidal silica ratio was increased to more than 0.48, the material became looser and easier to granulate, and the yield reached 100.0%. However, due to the high colloidal silica ratio, the resulting thin sheet was too soft, and serious roller adhesion was observed during the dry granulation process.

[0058] In Comparative Example 3, as shown by Formulation Nos. 7 and 8, when the ratio of pyrroloquinoline quinone trilithium salt nonahydrate to colloidal silica was fixed at 1:0.16 and the ratio of the additional pharmaceutically acceptable excipient was changed to less than 1.0, the granulation yield was only 37.2% and 35.8%, respectively, suggesting that it is also important to maintain a constant ratio of the additional pharmaceutically acceptable excipient in addition to colloidal silica. As shown by Formulation Nos. 9 and 10, when the ratio of the additional pharmaceutically acceptable excipient increased to more than 5.0, the material became looser and easier to granulate, and the yield exceeded 99.0%; however, when the ratio of the additional pharmaceutically acceptable excipient increased, the ratio of the excipient in the content had to be significantly increased accordingly, and the capsule volume size had to be increased for the same drug specifications. For example, because of the large amount of material required for formulations 9 and 10 in Comparative Example 3, they had to be filled into capsules 1 and 0, with major axes of 18.5-19.5 mm and 20.7-21.7 mm, respectively; on the other hand, formulations 5-8 in Example 2, with similar specifications (50 mg), were filled into capsules 4 and 3, with major axes of 13.4-14.3 mm and 15.0-15.8 mm, respectively. The variation in capsule size described above can make swallowing difficult for elderly patients.

[0059] Effect example 2 Capsules of pyrroloquinoline quinone trilithium salt nonahydrate prepared in Examples 1 to 4 and Comparative Examples 1 to 3 were collected (6 capsules for each formulation), and the dissolution profile was determined by the following method.

[0060] Dissolution test conditions: 900 mL of aqueous hydrochloric acid solution (37±0.2°C, pH 1.2) was used as the dissolution medium, and the capsules were placed in a sedimentation basket at a rotation speed of 50 rpm, and then in a dissolution cup; samples were taken at predetermined time points and filtered through a 0.45 μm microporous membrane made of mixed cellulose ester, and the filtrate was used as the test solution.

[0061] Dissolution measurement method: Octadecylsilane-bonded silica gel (Welch Ultimate® XB-C18 A 4.6*150 mm, 5 μm, or equivalent chromatography column was used as the packing material, and 10 mM dipotassium hydrogen phosphate-15 mM tetrabutylammonium bromide (adjusted to pH 6.8 with phosphoric acid):acetonitrile (65:35) was used as the mobile phase. The flow rate was 1.0 mL / min, the column temperature was 30°C, and the detection wavelength was 250 nm. 20 μL of the standard solution and 20 μL of the test solution were accurately sampled and injected into the liquid chromatograph; the chromatograms were recorded, and the concentrations at each time point were calculated from the peak areas using the external standard method, and the cumulative dissolution rates at each time point were calculated.

[0062] Dissolution Results: As shown in Figures 2-5 and Tables 10-13, capsule formulations Nos. 1-16 prepared according to Examples 1-4 dissolved rapidly, with cumulative dissolution rates Q exceeding 80% after 20 minutes and cumulative dissolution rates Q exceeding 90% after 30 minutes.

[0063] According to the results in Table 14 and Figure 6, in Formulation No. 1 of Comparative Example 1, the additional pharmaceutically acceptable excipient of the composition contained a certain proportion of other metal salts (anhydrous calcium phosphate), which increased the hardness after dry granulation and decreased the dissolution rate of the resulting capsules, with the cumulative dissolution rates at 20 and 30 minutes decreasing to 58.3% and 84.5%, respectively. In Formulation No. 2 of Comparative Example 1, colloidal silica was replaced with UFL2 magnesium aluminum silicate, which also had an extremely high specific surface area (300 m 2 / g), low bulk density (0.06~0.11g / cm 3 ) and tap density (0.10~0.17g / cm 3 ), and as a result, the cumulative dissolution rates of the prepared capsules decreased to 78.3% and 87.7% after 20 and 30 minutes, respectively.

[0064] According to the results in Table 15 and Figure 7, in Comparative Example 2, when the weight ratio of the additional external excipient was fixed at 2.7, Formulations 3 to 6 containing low and high proportions of colloidal silica had cumulative dissolution rates exceeding 80% after 20 minutes and exceeding 90% after 30 minutes, indicating complete dissolution. However, from the perspective of processing, if the proportion of colloidal silica is low, the material becomes hard and difficult to grind (see Table 9 in Example 1), and if the proportion of colloidal silica is high, the material sticks to the roller surface (see the explanation of the preparation results in Comparative Example 2).

[0065] [Table 10]

[0066] [Table 11]

[0067] [Table 12]

[0068] [Table 13]

[0069] [Table 14]

[0070] [Table 15]

[0071] [Table 16]

[0072] Effect example 3 Capsules prepared with Formulation No. 3 in Example 1 and Formulation No. 2 in Example 2, packaged in double aluminum blisters, were tested in long-term and accelerated studies at 25° C. and 60% relative humidity and 30° C. and 65% relative humidity for 6 months. The dissolution profiles, related substances, and PXRD of the samples before and after testing were determined.

[0073] Dissolution test conditions: the same as in Effect Example 2.

[0074] Related substance determination method: Octadecylsilane-bonded silica (TCI Kaseisorb LC ODS 2000, 4.6*150 mm or equivalent efficiency chromatography column) was used as the packing material; 10 mM dipotassium hydrogen phosphate-15 mM tetrabutylammonium bromide buffer (preparation method: 2.28 g dipotassium hydrogen phosphate trihydrate and 4.84 g tetrabutylammonium bromide were taken, diluted with 1 L of water, and the pH value was adjusted to 7.4 with phosphoric acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Gradient elution was performed according to Table 9; flow rate: 1.0 mL / min, detection wavelength: 250 nm, and column temperature: 30 °C.

[0075] [Table 17]

[0076] The contents of the capsules were precisely weighed and ultrasonically diluted with 30% acetonitrile to prepare a solution containing approximately 0.2 mg of pyrroloquinoline quinone trilithium salt nonahydrate per mL. This solution was used as the test solution. The test solution was diluted 100 times with 30% acetonitrile to prepare the control solution. 20 μL of the test solution and 20 μL of the control solution were accurately injected into a liquid chromatograph, and the chromatograms were recorded. The related substances of pyrroloquinoline quinone trilithium salt nonahydrate were calculated using the control method. The reporting threshold for each impurity was 0.01 times the peak area of ​​the control solution.

[0077] PXRD measurement method: according to the Chinese Pharmacopoeia, 2015 edition, General Rule 0451, Part IV; conditions: CuKa40Kv 40mA, emission slit: 1.0mm, solar slit: 0.4°, continuous scan, step size: 0.02°, speed: 8° / min, detector: LynxEye, equipment model: Bruker D8 ADVANCE.

[0078] Results: The dissolution profile measurements are shown in Table 18 and Figure 9. After 6 months of long-term and accelerated testing at 25°C and 60% relative humidity and 30°C and 65% relative humidity (RH), the dissolution results of capsules prepared with Formulation No. 3 in Example 1 and Formulation No. 7 in Example 2 showed no significant changes, maintaining cumulative dissolution rates of over 80% after 20 minutes and over 90% after 30 minutes. Furthermore, no related substances were detected in the capsule samples before or after the stability testing, suggesting that the capsules containing pyrroloquinoline quinone trilithium salt nonahydrate prepared by the method of the present invention have good chemical stability. PXRD results are shown in Figure 10. These results indicate that the characteristic diffraction peak intensities and geometric topology of the contents of the capsules containing pyrroloquinoline quinone trilithium salt nonahydrate were consistent with those on day 0 after 6 months of long-term and accelerated testing, suggesting that the pyrroloquinoline quinone trilithium salt nonahydrate in the capsules has good crystalline stability.

[0079] [Table 18]

[0080] [Table 19]

[0081] Although the present invention has been disclosed above, the present invention is not limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the present invention, and therefore the scope of protection of the present invention should be limited by the claims.

Claims

1. 1. A pharmaceutical composition comprising a pyrroloquinoline quinone trilithium salt nonahydrate compound, 1.0 part by weight of a pyrroloquinoline quinone trilithium salt nonahydrate compound; and a pharmaceutically acceptable excipient; The pharmaceutically acceptable excipient comprises: containing 0.16 to 0.48 parts by weight of colloidal silica relative to 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound; the pyrroloquinoline quinone trilithium salt nonahydrate compound is in a crystalline form, and the pyrroloquinoline quinone trilithium salt nonahydrate compound has a powder X-ray diffraction pattern including characteristic diffraction peaks at 2θ diffraction angles of 6.2°±0.2°, 7.4°±0.2°, 7.9°±0.2°, and 23.6°±0.2°; A pharmaceutical composition comprising the pyrroloquinoline quinone trilithium salt nonahydrate compound.

2. The pharmaceutically acceptable excipient comprises: further comprising 1.0 to 5.0 parts by weight of an additional pharmaceutically acceptable excipient per 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound; 2. The pharmaceutical composition comprising the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 1, wherein the additional pharmaceutically acceptable excipient is selected from one or more of starch, pregelatinized starch, microcrystalline cellulose, lactose, lactose starch complex, lactose cellulose complex, mannitol, mannitol starch complex, sorbitol, povidone, copovidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, magnesium stearate, sodium stearyl fumarate, talc, and stearic acid.

3. 3. The pharmaceutical composition comprising the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 2, wherein the colloidal silica is present in an amount of 0.2 to 0.4 parts by weight relative to 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound; and the additional pharmaceutically acceptable excipient is present in an amount of 2.0 to 4.0 parts by weight relative to 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

4. The additional pharmaceutically acceptable excipient is 0.6 to 4 parts by weight of pregelatinized starch relative to 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound; 0.36 to 0.96 parts by weight of microcrystalline cellulose per 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound; and 4. The pharmaceutical composition according to claim 3, comprising 0 to 0.06 parts by weight of magnesium stearate per 1 part by weight of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

5. The method for producing the pharmaceutical composition according to claim 2, wherein the colloidal silica can be added by an internal addition method or an internal-external addition method; In the internal addition method, the pyrroloquinoline quinone trilithium salt nonahydrate compound and the colloidal silica are mixed before dry granulation; In the internal-external addition method, the pyrroloquinoline quinone trilithium salt nonahydrate compound and the colloidal silica for internal addition are mixed before dry granulation, and then the granules obtained by the dry granulation are mixed with the colloidal silica for external addition; and The additional pharmaceutically acceptable excipients may be added by internal or internal-external addition methods; In the internal addition method, the pyrroloquinoline quinone trilithium salt nonahydrate compound and the additional pharmaceutically acceptable excipients are mixed prior to dry granulation; In the internal-external addition method, the pyrroloquinoline quinone trilithium salt nonahydrate compound and the additional pharmaceutically acceptable excipient for internal addition are mixed before dry granulation, and then the granules obtained by the dry granulation are mixed with the additional pharmaceutically acceptable excipient for external addition. The manufacturing method.

6. 6. The method of claim 5, wherein, when the colloidal silica is added by an internal-external addition method, the weight ratio of the internally added colloidal silica to the externally added colloidal silica is greater than 3:1; and when the additional pharmaceutically acceptable excipients are added by an internal-external addition method, the weight ratio of the internally added additional pharmaceutically acceptable excipients to the externally added additional pharmaceutically acceptable excipients is greater than 3:

1.

7. 6. The manufacturing method according to claim 5, wherein the additional pharmaceutically acceptable excipient that can be added by the internal addition method is selected from one or more of starch, lactose, microcrystalline cellulose, mannitol, croscarmellose sodium, copovidone, and magnesium stearate; and the additional pharmaceutically acceptable excipient that can be added by the external addition method is selected from one or more of microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.

8. 5. A capsule comprising a pyrroloquinoline quinone trilithium salt nonahydrate compound, the capsule comprising the pyrroloquinoline quinone trilithium salt nonahydrate compound, comprising the pharmaceutical composition of any one of claims 1 to 4.

9. 9. A capsule comprising the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 8, wherein the material of the capsule is selected from any one of gelatin capsules, hydroxypropyl methylcellulose capsules, pullulan polysaccharide capsules, and starch capsules.

10. 10. A capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 9, wherein the capsule material is a hydroxypropyl methylcellulose capsule.

11. 9. The capsules containing pyrroloquinoline quinone trilithium salt nonahydrate of claim 8, wherein each capsule contains 5 mg to 100 mg of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

12. 12. The pyrroloquinoline quinone trilithium salt nonahydrate compound-containing capsules of claim 11, wherein each capsule contains 20 mg to 75 mg of the pyrroloquinoline quinone trilithium salt nonahydrate compound.

13. A method for producing a capsule containing a pyrroloquinoline quinone trilithium salt nonahydrate compound, the method being used for producing the capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 8, the method being a dry granulation method for producing the capsule.

14. A method for producing a capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 13, when a pharmaceutically acceptable excipient is added by an internal addition method, the method comprising: a step of weighing out the pyrroloquinoline quinone trilithium salt nonahydrate compound, which is an active pharmaceutical ingredient (API), and the pharmaceutically acceptable excipient according to a mixing ratio; mixing said API of pyrroloquinoline quinone trilithium salt nonahydrate compound with said pharmaceutically acceptable excipient; subjecting the blended API of pyrroloquinoline quinone trilithium salt nonahydrate compound and pharmaceutically acceptable excipients to dry granulation, first rolling the blend into thin sheets and then granulating them into granules; and Filling the granules into capsules to obtain the capsules. A method for producing a capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound, comprising:

15. A method for producing a capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound of claim 13, when a pharmaceutically acceptable excipient is added by an internal-external addition method, the method comprising: a step of weighing out the pyrroloquinoline quinone trilithium salt nonahydrate compound, which is an active pharmaceutical ingredient (API), and the pharmaceutically acceptable excipient according to a mixing ratio; mixing the pyrroloquinoline quinone trilithium salt nonahydrate compound, which is an API, with the pharmaceutically acceptable internal excipient; subjecting the blended API, pyrroloquinoline quinone trilithium salt nonahydrate compound and pharmaceutically acceptable internal excipients to dry granulation, first rolling the blend into thin sheets and then granulating them into granules; mixing the granules obtained by the dry granulation with the pharmaceutically acceptable excipient; and a step of filling the granules mixed with the pharmaceutically acceptable excipient into a capsule to obtain the capsule; A method for producing a capsule containing the pyrroloquinoline quinone trilithium salt nonahydrate compound, comprising:

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