Dopamine hydrochloride tablet, preparation method and application thereof

Abstract

The application relates to the technical field of medicine preparation, and particularly discloses a levodopa-benserazide tablet, a preparation method and application thereof, which comprises levodopa granules, benserazide hydrochloride granules, cross-linked polyvinylpyrrolidone and magnesium stearate; the levodopa granules are composed of levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, cross-linked polyvinylpyrrolidone, red iron oxide and sodium docusate; and the benserazide hydrochloride granules are composed of benserazide hydrochloride, mannitol, microcrystalline cellulose, colloidal silicon dioxide, red iron oxide and ethyl cellulose. The related substances and the friability of the levodopa-benserazide tablet meet the production requirements, the stability is high, and the tablet is suitable for large-scale production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of medicine preparation, and particularly relates to a levodopa / benserazide tablet and a preparation method and application thereof. BACKGROUND

[0002] The compound levodopa / benserazide preparation can effectively treat Parkinson's disease, especially the bradykinesia and rigidity symptoms caused by Parkinson's disease. The drug not only has no neurotoxicity, but also has a neuroprotective effect, and can delay and control the motor complications in the later stage of Parkinson's disease. The basal ganglia of Parkinson's disease patients lacks dopamine, and levodopa can pass through the blood-brain barrier into the central nervous system to replace dopamine. However, levodopa is rapidly decarboxylated into dopamine in the periphery, only a small amount of which enters the brain, which can cause adverse reactions. Benserazide is a peripheral decarboxylase inhibitor, and when combined with levodopa, it can effectively treat Parkinson's syndrome, and the symptoms of postencephalitic or combined with cerebral arteriosclerosis.

[0003] Benserazide hydrochloride is a white or white crystalline powder, easily soluble in water, slightly soluble in ethanol, and insoluble in acetone. The structure of benserazide hydrochloride determines that the material is extremely sensitive to air, light, temperature, humidity, etc. Not only will the color change, but the related substances will also increase significantly. Benserazide hydrochloride and levodopa directly contact each other, and will also interact with each other. Stability is one of the basic properties of drugs, and therefore, it is very important to use a suitable approach to ensure the stability of the drug.

[0004] The main drug in the compound levodopa / benserazide hydrochloride preparation is unstable to moisture or heat. Dry granulation can be used for the preparation. However, the raw materials of benserazide hydrochloride and levodopa have poor adhesion and flowability. The granules prepared by dry granulation have poor strength, become powder after slight shaking, and are not conducive to production. Wet granulation is widely used in pharmaceutical production. Wet granulation is a process in which a binder is added to the powder to produce adhesion, and then the powder is aggregated together by the bridge of the binder or the adhesion under the action of the liquid bridge and external mechanical force. The solvent of the binder is evaporated and removed during drying. The remaining binder is finally solidified in the form of a solid bridge to form granules with certain strength, good compression molding property, and good production. For example, patent CN116549408A discloses a composition containing levodopa and benserazide hydrochloride. The composition is prepared by granulating levodopa and benserazide hydrochloride into granules A and granules B, coating the granules, and double-layer tabletting process. Granules A contain levodopa, anhydrous calcium hydrogen phosphate, mannitol, and a binder. Granules B contain benserazide hydrochloride and microcrystalline cellulose. Alternatively, granules B contain benserazide hydrochloride, anhydrous calcium hydrogen phosphate, mannitol, and microcrystalline cellulose. However, because benserazide hydrochloride is sensitive to air, light, temperature, and humidity, it is a raw material with poor stability. Using the conventional wet granulation process, benserazide hydrochloride has already been degraded, resulting in problems such as excessive impurities in the prepared solid preparation, failure to meet the standard in the accelerated long-term test, and lower bioavailability than the original product on the market.

[0005] Therefore, there is a need for a preparation method of dopa carbidopa tablets that does not affect the stability of benserazide hydrochloride and meets the production requirements for the stability and friability of dopa carbidopa tablets. SUMMARY

[0006] The present application provides a dopa carbidopa tablet and a preparation method and application thereof. The stability and friability of the dopa carbidopa tablet meet the production requirements and are suitable for large-scale production.

[0007] To achieve the above-mentioned object, the technical scheme adopted by the present application is as follows:

[0008] In one aspect, the present application provides a dopa carbidopa tablet, which comprises levodopa granules, benserazide hydrochloride granules, cross-linked polyvinylpyrrolidone, and magnesium stearate. The levodopa granules are composed of levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, cross-linked polyvinylpyrrolidone, red iron oxide, and sodium docusate. The benserazide hydrochloride granules are composed of benserazide hydrochloride, mannitol, microcrystalline cellulose, colloidal silicon dioxide, red iron oxide, and ethyl cellulose.

[0009] Preferably, the mass ratio of the levodopa granules to the benserazide hydrochloride granules is 1.5-1.8:1.

[0010] Preferably, the levodopa granules are composed of 200-220 parts of levodopa, 80-120 parts of anhydrous calcium hydrogen phosphate, 15-25 parts of pregelatinized starch, 8-15 parts of crosslinked polyvidone, 0.5-1.0 parts of red iron oxide and 0.2-0.3 parts of sodium docusate, by weight.

[0011] Further preferably, the levodopa granules are composed of 200-220 parts of levodopa, 100-120 parts of anhydrous calcium hydrogen phosphate, 20-25 parts of pregelatinized starch, 10-15 parts of crosslinked polyvidone, 0.8-1.0 parts of red iron oxide and 0.2-0.3 parts of sodium docusate, by weight.

[0012] Preferably, the weight ratio of levodopa to sodium docusate is 200-220:0.2-0.3.

[0013] Preferably, the benserazide hydrochloride granules are composed of 55-65 parts of benserazide hydrochloride, 85-120 parts of mannitol, 35-45 parts of microcrystalline cellulose, 0.8-1.5 parts of colloidal silicon dioxide, 0.5-1.0 parts of red iron oxide and 3-5 parts of ethyl cellulose, by weight.

[0014] Further preferably, the benserazide hydrochloride granules are composed of 57-65 parts of benserazide hydrochloride, 103-120 parts of mannitol, 38-45 parts of microcrystalline cellulose, 1.0-1.5 parts of colloidal silicon dioxide, 0.7-1.0 parts of red iron oxide and 3-5 parts of ethyl cellulose, by weight.

[0015] Preferably, the weight ratio of benserazide hydrochloride to mannitol is 57-65:100-120.

[0016] Mannitol can increase the stability and activity of drugs and plays a good role in drug preparations. Through mechanisms such as water absorption, liquid maintenance, evaporation inhibition, etc., the moisture content in the drug preparation is maintained, and the activity of the drug is maintained.

[0017] The present application also provides a preparation method of the above-mentioned levodopa and benserazide tablet, comprising the following steps:

[0018] S1, preparing levodopa granules: premixing the formula amount of levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, crosslinked polyvidone and red iron oxide, then adding the formula amount of sodium docusate, wet granulating after adding ethanol and water, and then drying and dry granulating to obtain levodopa granules;

[0019] S2, preparing benserazide hydrochloride granules: premixing the formula amount of microcrystalline cellulose, colloidal silicon dioxide and red iron oxide, then adding the formula amount of ethyl cellulose, wet granulating after adding ethanol, drying and then dry granulating, then adding the formula amount of benserazide hydrochloride and mannitol mixture to obtain benserazide hydrochloride granules;

[0020] S3, premixing levodopa granules, benserazide hydrochloride granules and cross-linked polyvinylpyrrolidone, then total mixing with magnesium stearate, then tabletting and inner packaging to obtain the said dopa benserazide tablet.

[0021] Preferably, the drying in step S1 is drying to a moisture content of not more than 3.0%.

[0022] Further preferably, the drying in step S1 is drying to a moisture content of not more than 0.8%.

[0023] Preferably, the particle size of the wet granulation in step S1 is 0.8mm-1.0mm, and the particle size of the dry granulation is 0.3mm-0.5mm; the particle size of the wet granulation in step S2 is 0.8mm-1.0mm, and the particle size of the dry granulation is 0.3mm-0.5mm.

[0024] Preferably, the drying in step S2 is drying to a moisture content of not more than 3.0%.

[0025] Further preferably, the drying in step S2 is drying to a moisture content of not more than 0.8%.

[0026] In another aspect, the present application provides a use of the above-mentioned dopa benserazide tablet or the dopa benserazide tablet prepared by the above-mentioned preparation method in the preparation of a drug for treating Parkinson's disease.

[0027] Specifically, the dopa benserazide tablet can be used as a raw material for preparing a drug for treating Parkinson's disease.

[0028] Preferably, a flavoring agent can also be added when preparing the drug for treating Parkinson's disease.

[0029] Compared with the prior art, the present application has the following beneficial effects:

[0030] The preparation method of the dopa benserazide tablet of the present application is simple, the types of raw materials used are few and easy to obtain, and has great economic value; the dopa benserazide tablet of the present application has specific components and specific amounts, and the benserazide hydrochloride is not wet granulated, which can significantly reduce the influence of moisture and temperature on benserazide hydrochloride, reduce the degradation of benserazide hydrochloride, and improve the stability and friability of the dopa benserazide tablet. DETAILED DESCRIPTION

[0031] The present application will be described in detail below with specific examples, so that the technical solutions of the present application are easier to understand and master, but the present application is not limited to this, the described examples are only a part of the examples of the present application, not all examples.

[0032] The endpoints of the ranges and any values described herein are not limited to the precise values stated. The endpoints of the ranges are included in the range, as are intermediate values not explicitly stated (i.e., the stated ranges are not inclusive of the endpoints, unless the context clearly dictates otherwise). The endpoints of the ranges of values are included in the ranges, as are the individual values (i.e., the range is inclusive of the endpoints, unless the context clearly dictates otherwise). All values and subranges within the ranges stated are intended to be specifically included.

[0033] All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present application without creative labor should belong to the scope of protection of the present application. The experimental methods described in the following examples are all conventional methods, unless otherwise specified. The reagents and materials described, unless otherwise specified, can be obtained commercially. The % in the present application, unless otherwise specified, means volume percent.

[0034] Example 1

[0035] The prescription of each tablet contains the following ingredients:

[0036] Table 1 Prescription of levodopa tablets in Example 1

[0037]

[0038]

[0039] After the ingredients are prepared according to the prescription of Example 1, levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, cross-linked povidone and red iron oxide are premixed, then sodium docusate is added, 100 ml of 95% ethanol is added for wetting, 900 ml of purified water is added, and a high-efficiency wet granulator is used for wet granulation, then wet granulation, drying to a moisture content of about 0.8%, dry granulation, and levodopa granules are obtained; the wet granulation particle size is 1.0 mm, and the dry granulation particle size is 0.5 mm.

[0040] After the ingredients are prepared according to the prescription of Example 1, the microcrystalline cellulose, colloidal silicon dioxide and red iron oxide are premixed, then the ethyl cellulose is added, wet granulation is carried out in a high efficiency wet granulator with 500 ml 95% ethanol, then wet sizing, drying to a moisture content of 0.8% and dry sizing are carried out, then the mixture of benserazide hydrochloride and mannitol is added, to obtain benserazide hydrochloride granules; wherein the wet sizing particle size is 1.0 mm and the dry sizing particle size is 0.5 mm.

[0041] After the levodopa granules, benserazide hydrochloride granules and 10 mg cross-linked polyvidone are premixed, total mixing is carried out with 5.5 mg magnesium stearate, then tabletting and inner packaging are carried out to obtain the dopa-sine tablet.

[0042] Example 2

[0043] Prescription: the content of each tablet is as follows:

[0044] Table 2 Prescription of dopa-sine tablet of Example 2

[0045]

[0046]

[0047] The preparation method is the same as that of Example 1.

[0048] Example 3

[0049] Prescription: the content of each tablet is as follows:

[0050] Table 3 Prescription of dopa-sine tablet of Example 3

[0051]

[0052]

[0053] The preparation method is the same as that of Example 1.

[0054] Comparative Example 1

[0055] Compared with Example 1, the only difference is that the prescription is different.

[0056] Prescription: the content of each tablet is as follows:

[0057] Table 4 Prescription of dopa-sine tablet of Comparative Example 1

[0058]

[0059]

[0060] After the ingredients in the prescription of Comparative Example 1 are mixed, levo-dopa, anhydrous dibasic calcium phosphate, pregelatinized starch, cross-linked polyvidone, mannitol, colloidal silicon dioxide and red ferric oxide are premixed, then sodium docusate is added, 100 ml of 95% ethanol is added for wetting, 900 ml of purified water is added, and a high-efficiency wet granulator is used for wet granulation, then wet granulation, drying to a moisture content of about 0.8%, and dry granulation are performed, to obtain levo-dopa granules; the wet granulation particle size is 1.0 mm, and the dry granulation particle size is 0.5 mm.

[0061] After the ingredients in the prescription of Comparative Example 1 are mixed, microcrystalline cellulose, colloidal silicon dioxide and red ferric oxide are premixed, then ethyl cellulose is added, 500 ml of 95% ethanol is added in a high-efficiency wet granulator for wet granulation, then wet granulation, drying to a moisture content of about 0.8%, and dry granulation are performed, then a mixture of benserazide hydrochloride and mannitol is added, to obtain benserazide hydrochloride granules; the wet granulation particle size is 1.0 mm, and the dry granulation particle size is 0.5 mm.

[0062] After levo-dopa granules, benserazide hydrochloride granules and 10 mg of cross-linked polyvidone are premixed, 5.5 mg of magnesium stearate is added for total mixing, then tabletting and inner packaging are performed, to obtain the dopa-sine tablet.

[0063] Comparative Example 2

[0064] Compared with Example 1, the only difference is that the prescription is different.

[0065] Prescription: the content of each tablet is as follows:

[0066] Table 5 Prescription of dopa-sine tablet in Comparative Example 2

[0067]

[0068] The preparation method is the same as that in Example 1.

[0069] Comparative Example 3

[0070] Compared with Example 1, the prescription is the same, and only the preparation method is different, specifically:

[0071] After the ingredients in Table 1 are mixed, levo-dopa, anhydrous dibasic calcium phosphate, pregelatinized starch, cross-linked polyvidone and red ferric oxide are premixed, then sodium docusate is added, 100 ml of 95% ethanol is added for wetting, 900 ml of purified water is added, and a high-efficiency wet granulator is used for wet granulation, then wet granulation, drying to a moisture content of about 1%, and dry granulation are performed, to obtain levo-dopa granules; the wet granulation particle size is 1.0 mm, and the dry granulation particle size is 0.5 mm.

[0072] After the ingredients in Table 1 are prepared, the levodopa granules, the carbidopa granules, and 10 mg of crospovidone are premixed, and then mixed with 5.5 mg of magnesium stearate, and then tableting and inner packaging to obtain the carbidopa / levodopa tablet.

[0073] After the levodopa granules, the carbidopa granules, and 10 mg of crospovidone are premixed, and then mixed with 5.5 mg of magnesium stearate, and then tableting and inner packaging to obtain the carbidopa / levodopa tablet.

[0074] Comparative Example 4

[0075] The prescription is as follows: each tablet contains the following ingredients:

[0076] Table 6 Prescription of the carbidopa / levodopa tablet of Comparative Example 4

[0077]

[0078]

[0079] After the ingredients in Table 6 are prepared, the levodopa, the anhydrous calcium hydrogen phosphate, the pregelatinized starch, the crospovidone, and the red iron oxide and the microcrystalline cellulose and the colloidal silicon dioxide are premixed, and then sodium docusate is added, and then wetting is performed with 600 ml of 95% ethanol, and then wet granulation is performed in a high-efficiency wet granulator after 900 ml of purified water is added, and then wet sizing, drying to a moisture content of about 1%, and dry sizing are performed, and then the mixture of carbidopa and mannitol and crospovidone is premixed, and then mixed with magnesium stearate, and then tableting and inner packaging to obtain the carbidopa / levodopa tablet; wherein the wet sizing particle size is 1.0 mm, and the dry sizing particle size is 0.5 mm.

[0080] Effect Example 1 Stability Test

[0081] The carbidopa / levodopa tablets of Examples 1-3 and Comparative Examples 1-4 are placed in a light of 4500±500 lx, high temperature of 60°C, and high humidity of 75% RH for 14 days, and the content of the related substances, including the maximum single impurity and the total impurities, of the carbidopa / levodopa tablets is detected, so as to investigate the stability of the carbidopa / levodopa tablets under light, high temperature, and high humidity, and to provide a scientific basis for the production, packaging, storage, and transportation conditions of the drug. The test results are shown in Table 7.

[0082] Table 7 Stability results of each group under light, high temperature, and high humidity

[0083]

[0084]

[0085] From the results of the above table, it can be seen that the levodopa and benserazide tablets of the embodiments of the present application have no obvious change in related substances under light, high temperature and high humidity conditions, and have higher stability.

[0086] Effect Example 2: friability detection

[0087] According to the friability detection method (general rule 0923) in the Chinese Pharmacopoeia 2020 edition, the friability of the levodopa and benserazide tablets of Examples 1-3 and Comparative Examples 1-4 was detected.

[0088] Take several tablets, and make the total weight 6.5g. Blow off the powder falling off the tablets with a hair dryer, accurately weigh, put in a cylinder, and rotate 100 times. Take out, remove the powder in the same way, accurately weigh, and the loss weight should not be more than 1%, and no broken, cracked and crushed tablets should be detected. This test is generally only 1 time. If the loss weight exceeds 1%, it should be retested 2 or 3 times, the average loss weight should not be more than 1%, and no broken, cracked and crushed tablets should be detected.

[0089] The results are shown in Table 8 below,

[0090] Table 8: friability results of levodopa and benserazide tablets of each group

[0091] Group Friability (%) Example 1 0.12 Example 2 0.14 Example 3 0.15 Comparative Example 1 0.25 Comparative Example 2 0.39 Comparative Example 3 0.71 Comparative Example 4 0.63

[0092] From the above table data, it can be seen that the levodopa and benserazide tablets of the embodiments of the present application are not easy to be friable, and have high tablet stability. The levodopa and benserazide tablets of the comparative examples are high in friability, which will cause the tablets to be broken when taken, thereby affecting the curative effect of the drug.

[0093] Finally, it should be noted that the above content is only used to explain the technical solutions of the present application, and is not a limitation on the protection scope of the present application. Simple modifications or equivalent replacements of the technical solutions of the present application made by those skilled in the art do not deviate from the essence and scope of the technical solutions of the present application.

Claims

1. A benserazide tablet, characterized by: The levodopa granules, benserazide hydrochloride granules, cross-linked polyvinylpyrrolidone and magnesium stearate; The levodopa granules are composed of 200-220 parts of levodopa, 80-120 parts of anhydrous calcium hydrogen phosphate, 15-25 parts of pregelatinized starch, 8-15 parts of cross-linked polyvinylpyrrolidone, 0.5-1.0 parts of red iron oxide and 0.2-0.3 parts of sodium docusate; The benserazide hydrochloride granules are composed of 55-65 parts of benserazide hydrochloride, 85-120 parts of mannitol, 35-45 parts of microcrystalline cellulose, 0.8-1.5 parts of colloidal silicon dioxide, 0.5-1.0 parts of red iron oxide and 3-5 parts of ethyl cellulose; The preparation method of the dopa benserazide tablet comprises the following steps: S1, preparing the levodopa granules: premixing the formula amount of levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, cross-linked polyvinylpyrrolidone and red iron oxide, then adding the formula amount of sodium docusate, wet granulating after adding ethanol and water, drying and then dry granulating to obtain the levodopa granules; S2, preparing the benserazide hydrochloride granules: premixing the formula amount of microcrystalline cellulose, colloidal silicon dioxide and red iron oxide, then adding the formula amount of ethyl cellulose, wet granulating after adding ethanol, drying and then dry granulating, and then adding the formula amount of a mixture of benserazide hydrochloride and mannitol to obtain the benserazide hydrochloride granules; S3, premixing the levodopa granules, benserazide hydrochloride granules and cross-linked polyvinylpyrrolidone, then total mixing with magnesium stearate, and then tabletting and inner packaging to obtain the dopa benserazide tablet.

2. The benserazide tablet according to claim 1, characterized by: The weight ratio of the levodopa to sodium docusate is 200-220:0.2-0.

3.

3. The benserazide tablet according to claim 1, wherein: The weight ratio of the benserazide hydrochloride to mannitol is 57-65:100-120.

4. A process for the preparation of the benserazide tablet according to any one of claims 1 to 3, characterized in that: The preparation method comprises the following steps: S1, preparing the levodopa granules: premixing the formula amount of levodopa, anhydrous calcium hydrogen phosphate, pregelatinized starch, cross-linked polyvinylpyrrolidone and red iron oxide, then adding the formula amount of sodium docusate, wet granulating after adding ethanol and water, drying and then dry granulating to obtain the levodopa granules; S2, preparing the benserazide hydrochloride granules: premixing the formula amount of microcrystalline cellulose, colloidal silicon dioxide and red iron oxide, then adding the formula amount of ethyl cellulose, wet granulating after adding ethanol, drying and then dry granulating, and then adding the formula amount of a mixture of benserazide hydrochloride and mannitol to obtain the benserazide hydrochloride granules; S3, premixing the levodopa granules, benserazide hydrochloride granules and cross-linked polyvinylpyrrolidone, then total mixing with magnesium stearate, and then tabletting and inner packaging to obtain the dopa benserazide tablet.

5. The method of claim 4, wherein: The drying in step S1 is drying to a moisture content of not more than 3.0%.

6. The method of claim 4, wherein: The particle size of the wet granulation in step S1 is 0.8mm-1.0mm, and the particle size of the dry granulation is 0.3mm-0.5mm; the particle size of the wet granulation in step S2 is 0.8mm-1.0mm, and the particle size of the dry granulation is 0.3mm-0.5mm.

7. The method of claim 4, wherein: The drying in step S2 is drying to a moisture content of not more than 3.0%.

8. The dopa benserazide tablet of any one of claims 1-3 or prepared by the preparation method of any one of claims 4-7 for use in the preparation of a drug for treating Parkinson's disease.

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