A pharmaceutical composition for treating diabetic peripheral neuropathy and a preparation method thereof

Abstract

The application relates to a preparation method of a medicine composition for treating diabetic peripheral neuropathy, in particular to the following steps: mixing sodium citicoline, a binder, a filling agent, a disintegrating agent and a lubricant to obtain sodium citicoline mixed powder; mixing methylcobalamin, a binder, a filling agent, a disintegrating agent and a lubricant to obtain methylcobalamin mixed powder; compressing the sodium citicoline mixed powder and the methylcobalamin mixed powder on a double-layer tablet press to obtain double-layer double-release tablets; and coating the double-layer double-release tablets with light-shielding coating agent. The medicine composition for treating diabetic peripheral neuropathy prepared by the application is prepared into double-layer tablets by using sodium citicoline and methylcobalamin, which effectively guarantees the content uniformity of the medicinal components, the distribution uniformity in the tablets and the medicinal stability, reduces the medicine taking frequency and the auxiliary material intake amount of patients, and improves the use compliance of the patients.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a pharmaceutical composition for treating diabetic peripheral neuropathy and its preparation method. Background Technology

[0002] Peripheral neuropathy (DPN) is the most common type of diabetic neuropathy and one of the most common chronic complications of diabetes. Diabetic patients experience symptoms related to peripheral nerve dysfunction, clinically manifesting as symmetrical pain and sensory abnormalities, with lower limb symptoms being more common than upper limb symptoms. It has a high incidence rate and is a major risk factor for diabetic foot ulcers and lower limb amputations, and has now become a leading cause of disability and death in diabetic patients.

[0003] Mecobalamin is commonly used to treat diabetic peripheral neuropathy. Mecobalamin repairs damaged nerve tissue by promoting nucleic acid and protein synthesis, as well as the synthesis of lecithin from phospholipids in the brain, thereby promoting myelin formation and axonal regeneration. Meanwhile, citicoline sodium tablets, through the synthesis of phosphatidylcholine, can repair nerve cell membranes, increase blood perfusion in the blood vessels supplying nerves, and improve peripheral nerve pathological damage. It is mainly used for acute traumatic brain injury and post-brain surgery-related disturbances of consciousness. These two drugs are currently used in different disease areas, but studies have shown that the combined use of citicoline sodium and mecobalamin has a synergistic effect on improving diabetic peripheral neuropathy, showing better efficacy than mecobalamin alone. Therefore, formulating them into a combination preparation can reduce the frequency of dosing and increase patient compliance. Summary of the Invention

[0004] The purpose of this invention is to provide a pharmaceutical composition for treating diabetic peripheral neuropathy. The invention uses sodium citicoline and methylcobalamin to form a bilayer tablet pharmaceutical composition, which solves the problem of uneven drug content and distribution in compound preparations and ensures the stability of drug efficacy.

[0005] Another object of the present invention is to provide a method for preparing the above-mentioned pharmaceutical composition.

[0006] The objective of this invention is achieved through the following technical solution:

[0007] A pharmaceutical composition for treating diabetic peripheral neuropathy, characterized in that: the pharmaceutical composition has a bilayer sheet structure, specifically a sodium citicoline layer and a methylcobalamin layer, wherein the sodium citicoline layer includes sodium citicoline, a binder, a filler, a disintegrant, and a lubricant; and the methylcobalamin layer includes methylcobalamin, a binder, a filler, a disintegrant, and a lubricant.

[0008] Furthermore, in the sodium cytidine diphosphate choline layer, the binder is at least one of sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose; the filler is at least one of microcrystalline cellulose, mannitol, sorbitol, lactose, and corn starch; the disintegrant is crospovidone; and the lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate.

[0009] Furthermore, according to parts by weight, the sodium citicoline layer contains 50-200 parts sodium citicoline, 10-100 parts binder, 50-200 parts filler, 20-50 parts disintegrant, and 1-10 parts lubricant.

[0010] Furthermore, in the methylcobalamin layer, the adhesive is at least one of polyoxyethylene, polyethylene glycol, polyvinyl alcohol, and povidone; the filler is at least one of microcrystalline cellulose, mannitol, sorbitol, lactose, and corn starch; the disintegrant is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, or croscarmellose; and the lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate.

[0011] More preferably, the filler is composed of mannitol and lactose in a mass ratio of 2:1.

[0012] More preferably, the adhesive is polyethylene glycol 4000.

[0013] Furthermore, based on parts by weight, the methylcobalamin layer contains 0.5 to 1 part methylcobalamin, 5 to 10 parts binder, 20 to 60 parts filler, 5 to 30 parts disintegrant, and 0.1 to 0.3 parts lubricant.

[0014] Furthermore, the pharmaceutical composition is prepared by mixing sodium citicoline, binder, filler, disintegrant, and lubricant to obtain sodium citicoline mixed powder, and mixing methylcobalamin, binder, filler, disintegrant, and lubricant to obtain methylcobalamin mixed powder; then pressing the sodium citicoline mixed powder and methylcobalamin mixed powder on a double-layer tablet press to obtain double-layer double-release tablets, and finally coating them with a light-shielding coating agent.

[0015] Furthermore, when the filler is composed of mannitol and lactose in a mass ratio of 2:1, first mix methylcobalamin with lactose and 30% of the disintegrant, then add mannitol and 30% of the disintegrant and mix, and finally add the remaining components and mix.

[0016] A pharmaceutical composition for treating diabetic peripheral neuropathy and its preparation method, characterized in that:

[0017] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder;

[0018] S2) Preparation of Methylcobalamin mixed powder: Methylcobalamin, binder, filler, disintegrant and lubricant are mixed to obtain Methylcobalamin mixed powder;

[0019] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0020] S4) Coat the double-layered double-release tablets from step S3 with a light-shielding coating agent.

[0021] Furthermore, the preparation of the methylcobalamin powder involves mixing methylcobalamin with 30% disintegrant and 30% filler evenly, and then adding the remaining disintegrant, remaining filler, binder, disintegrant and lubricant for further mixing.

[0022] Furthermore, in the sodium cytidine diphosphate choline layer, the binder is at least one of sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose; the filler is at least one of microcrystalline cellulose, mannitol, sorbitol, lactose, and corn starch; the disintegrant is crospovidone; and the lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate.

[0023] Furthermore, according to parts by weight, the sodium citicoline layer contains 50-200 parts sodium citicoline, 10-100 parts binder, 50-200 parts filler, 20-50 parts disintegrant, and 1-10 parts lubricant.

[0024] Furthermore, in the methylcobalamin layer, the adhesive is at least one of polyoxyethylene, polyethylene glycol, polyvinyl alcohol, and povidone; the filler is at least one of microcrystalline cellulose, mannitol, sorbitol, lactose, and corn starch; the disintegrant is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, or croscarmellose; and the lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate.

[0025] More preferably, the filler is composed of mannitol and lactose in a mass ratio of 2:1.

[0026] More preferably, the adhesive is polyethylene glycol 4000.

[0027] Furthermore, based on parts by weight, the methylcobalamin layer contains 0.5 to 1 part methylcobalamin, 5 to 10 parts binder, 20 to 60 parts filler, 5 to 30 parts disintegrant, and 0.1 to 0.3 parts lubricant.

[0028] Furthermore, the coating agent is a coating agent containing dark iron oxide.

[0029] Most specifically, a method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy is characterized by proceeding according to the following steps:

[0030] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder. By weight, sodium citicoline is 50-200 parts, binder is 10-100 parts, filler is 50-200 parts, disintegrant is 20-50 parts and lubricant is 1-10 parts.

[0031] S2) Preparation of Methylcobalamin mixed powder: Methylcobalamin is mixed evenly with 30% disintegrant, and then mixed with the remaining disintegrant, binder, filler and lubricant to obtain Methylcobalamin mixed powder. By weight, Methylcobalamin is 0.5-1 parts, binder is 5-10 parts, filler is 20-60 parts, disintegrant is 5-30 parts and lubricant is 0.1-0.3 parts;

[0032] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0033] S4) Coat the double-layered double-release tablets from step S3 with a light-shielding coating agent.

[0034] More preferably, when the filler is composed of mannitol and lactose in a mass ratio of 2:1, methylcobalamin is first stirred and mixed with lactose and 30% of the disintegrant, then mannitol and 30% of the disintegrant are added and mixed, and finally the remaining components are added and mixed.

[0035] This invention reduces the side effects of drugs on the human body by preparing citicoline sodium and methylcobalamin into tablets. Specifically, the two drug components are made into bilayer tablets to solve the release interference between them. However, during the preparation of the bilayer tablets, it was found that because the amount of methylcobalamin in the two drugs is extremely small, the content difference between it and that of citicoline sodium and excipients is large. This results in poor uniformity of the distribution of the active ingredient in the prepared tablets, leading to differences in the content of drug components between the tablet compositions, poor drug efficacy stability, poor uniformity of the distribution of the active ingredient within the tablets, and inconsistent drug release in the bilayer tablets, making it difficult to guarantee the efficacy of the tablets.

[0036] In this invention, by adjusting the types and ratios of excipients in the sodium cytidine diphosphate choline layer and the mecobalamin layer, the mecobalamin exhibits excellent uniformity of distribution within the layers. Furthermore, when mixed with sodium cytidine diphosphate choline, the disintegration, release, and dissolution of the two active pharmaceutical ingredients achieve consistency, thereby ensuring drug efficacy stability. In particular, during the preparation of the mecobalamin layer, a filler composed of mannitol and lactose in a 2:1 mass ratio is selected, and the powder is prepared by stepwise mixing with the disintegrant. This effectively improves the uniformity of mecobalamin distribution within the tablet. Combined with the selection of the disintegrant in the sodium cytidine diphosphate choline layer, this enhances the consistency of active ingredient release in the double-layer tablet.

[0037] The present invention has the following technical effects:

[0038] The pharmaceutical composition for treating diabetic peripheral neuropathy prepared in this invention reduces the frequency of medication and excipient intake, thereby improving patient compliance. By preparing citicoline sodium and methylcobalamin into a bilayer tablet, the uniformity of the active ingredient content and its distribution in the tablet is effectively improved, thus effectively enhancing the efficacy stability of the bilayer tablet. Detailed Implementation

[0039] The present invention will be specifically described below through embodiments. It should be noted that the following embodiments are only used to further illustrate the present invention and should not be construed as limiting the scope of protection of the present invention. Those skilled in the art can make some non-essential improvements and adjustments to the present invention based on the above description.

[0040] Example 1

[0041] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 1:

[0042]

[0043] Prepare according to the following steps:

[0044] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder;

[0045] S2) Preparation of Methylcobalamin mixed powder: Methylcobalamin is mixed evenly with 30% disintegrant and 30% filler, and then the remaining disintegrant, binder, remaining filler and lubricant are added and mixed to obtain Methylcobalamin mixed powder;

[0046] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0047] S4) Coat the double-layer dual-release tablets from step S3 with a light-shielding coating agent to obtain a double-layer tablet composition.

[0048] Example 2

[0049] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 2:

[0050] Table 2

[0051]

[0052] Prepare according to the following steps:

[0053] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder;

[0054] S2) Preparation of methylcobalamin mixed powder: First, mix methylcobalamin with lactose and 30% disintegrant, then add mannitol and 30% disintegrant and mix, and finally add the remaining disintegrant, binder, disintegrant and lubricant and mix to obtain methylcobalamin mixed powder;

[0055] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0056] S4) Coat the double-layered dual-release tablets from step S3 with a light-shielding coating agent to obtain a double-layered tablet composition.

[0057] Performance testing:

[0058] (1) By preparing bilayer tablets of sodium citicoline and mecobalamin in each scheme, with a sample size of 10, the content of the drug components inside was determined, and the average calculated content of sodium citicoline and mecobalamin in each bilayer tablet was 100%.

[0059] (2) The release assay was performed according to Method I of the 2015 edition of the Chinese Pharmacopoeia, using 0.01 mol / L hydrochloric acid solution as the dissolution medium. The volume of the dissolution medium was 900 mL, and the rotation speed was 100 r / min. Samples were taken every 10 min to detect the dissolution rate of cytidine diphosphate choline sodium and methylcobalamin. The test results are shown in Table 1. Eight samples were randomly selected, and the test results are shown in Table 3.

[0060] Table 3:

[0061]

[0062] In the bilayer composition prepared in Example 1, the content of sodium cytidine diphosphate choline was uniformly distributed, ranging from 98% to 102%, while the distribution range of methylcobalamin was slightly larger, ranging from 90% to 106%, still showing good uniformity. In Example 2, the content distributions of sodium cytidine diphosphate choline and methylcobalamin were 98% to 101% and 98% to 102%, respectively, and the uniformity of methylcobalamin distribution was further improved compared to Example 1.

[0063] Comparative Example 1:

[0064] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 4, and the preparation method is the same as in Example 2.

[0065] Table 4:

[0066]

[0067] Comparative Example 2

[0068] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 5, and the preparation method is the same as in Example 2.

[0069] Table 5:

[0070]

[0071] The content uniformity and disintegration time of the bilayer tablet compositions prepared in Comparative Example 1 and Comparative Example 2 are shown in Table 6.

[0072] Table 6:

[0073]

[0074] Compared to Example 1, Comparative Example 1 replaced the disintegrant crospovidone in the sodium cytidine diphosphate choline layer with low-substituted hydroxypropyl cellulose. Comparative Example 2, compared to Example 2, replaced the binder in the sodium cytidine diphosphate choline layer with polyvinyl alcohol. The final test results showed that when the disintegrant and binder in the sodium cytidine diphosphate choline layer were replaced with the same low-substituted hydroxypropyl cellulose and polyvinyl alcohol as in the methylcobalamin layer, the disintegration rate of the bilayer composition decreased to varying degrees.

[0075] Comparative Example 3

[0076] All component ratios are the same as in Example 2, and the preparation steps are as follows:

[0077] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder;

[0078] S2) Preparation of methylcobalamin mixed powder: First, mix methylcobalamin with a filler consisting of 30% disintegrant, 30% mannitol and lactose in a 2:1 ratio, and then add the remaining disintegrant, remaining filler, binder and lubricant to obtain methylcobalamin mixed powder;

[0079] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0080] S4) Coat the double-layered dual-release tablets from step S3 with a light-shielding coating agent to obtain a double-layered tablet composition.

[0081] Comparative Example 4

[0082] All component ratios are the same as in Example 2, and the preparation steps are as follows:

[0083] S1) Preparation of sodium citicoline mixed powder: Sodium citicoline, binder, filler, disintegrant and lubricant are mixed to obtain sodium citicoline mixed powder;

[0084] S2) Preparation of Methylcobalamin mixed powder: First, mix Methylcobalamin with 30% disintegrant, then add the remaining disintegrant, filler, binder, disintegrant and lubricant and mix to obtain Methylcobalamin mixed powder;

[0085] S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets.

[0086] S4) Coat the double-layered dual-release tablets from step S3 with a light-shielding coating agent to obtain a double-layered tablet composition.

[0087] The results of the content uniformity, disintegration time, and other performance tests of the bilayer tablet compositions prepared in Comparative Examples 3 and 4 are shown in Table 7.

[0088] Table 7:

[0089]

[0090] Compared to Example 2, the method of adding disintegrants and fillers in Comparative Example 3 was different, but consistent with the method of adding them in Example 1. The content of sodium cytidine diphosphate choline ranged from 98% to 102%, the same as in Example 1, while the content of methylcobalamin ranged from 89% to 106%, showing a decrease in content uniformity compared to Example 1. Compared to Example 2, the method of adding disintegrants in Comparative Example 4 was different. The content ranges of sodium cytidine diphosphate choline and methylcobalamin in the prepared bilayer tablet composition were 98% to 103% and 70% to 113%, respectively, with extremely poor content uniformity, and the disintegration time was significantly prolonged compared to Example 2.

[0091] Example 3

[0092] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 8.

[0093] Table 8:

[0094]

[0095] The average disintegration time of the bilayer tablet composition prepared in this embodiment is 11 s, the content of sodium citicoline is between 99.1% and 101.8%, and the content of methylcobalamin is between 97.9% and 102.7%.

[0096] Example 4

[0097] A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, wherein the components of the pharmaceutical composition are shown in Table 9.

[0098] Table 9:

[0099]

[0100] The average disintegration time of the bilayer tablet composition prepared in this embodiment is 11 s, the content of sodium cytidine diphosphate choline is between 98.4% and 101.5%, and the content of methylcobalamin is between 98.2% and 102.8%.

[0101] In the process of testing dissolution consistency, tablets prepared according to each scheme with cytidine diphosphate choline sodium and methylcobalamin contents between 99% and 101% were selected for release assay. The test results are shown in Table 10.

[0102] Table 10:

[0103]

[0104] As can be seen from the table above, the release rates of sodium citicoline and methylcobalamin in Comparative Examples 1-4 showed different degrees of variation throughout the entire release process. This is because the distribution uniformity of the active ingredients in the bilayer tablets was poor, resulting in a significant deviation in the consistency of drug release at the same time.

Claims

1. A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy, characterized in that: S1) Preparation of sodium citicoline powder: Sodium citicoline, binder, filler, disintegrant, and lubricant are mixed to obtain sodium citicoline powder. The binder is at least one of sodium carboxymethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose. The filler is at least one of microcrystalline cellulose, mannitol, sorbitol, lactose, and corn starch. The disintegrant is crospovidone. The lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate. S2) Preparation of Methylcobalamin Powder: Methylcobalamin, binder, filler, disintegrant, and lubricant are mixed to obtain Methylcobalamin powder. The binder is at least one of polyoxyethylene, polyethylene glycol, polyvinyl alcohol, and povidone. The filler is composed of mannitol and lactose in a mass ratio of 2:

1. The disintegrant is sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, or croscarmellose. The lubricant is any one of magnesium stearate, calcium stearate, and sodium stearate fumarate. Specifically, Methylcobalamin is first stirred and mixed with lactose and 30% of the disintegrant, then mannitol and 30% of the disintegrant are added and mixed, and finally the remaining components are added and mixed to obtain Methylcobalamin powder. S3) The sodium citicoline mixture from step S1 and the methylcobalamin mixture from step S2 are pressed together on a double-layer tablet press to obtain double-layer dual-release tablets. S4) Coat the double-layered double-release tablets from step S3 with a light-shielding coating agent.

2. The method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy as described in claim 1, characterized in that: By weight, the sodium citicoline layer contains 50-200 parts sodium citicoline, 10-100 parts binder, 50-200 parts filler, 20-50 parts disintegrant, and 1-10 parts lubricant.

3. A method for preparing a pharmaceutical composition for treating diabetic peripheral neuropathy as described in claim 1 or 2, characterized in that: By weight, the methylcobalamin layer contains 0.5 to 1 part methylcobalamin, 5 to 10 parts binder, 20 to 60 parts filler, 5 to 30 parts disintegrant, and 0.1 to 0.3 parts lubricant.

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