Carbolevodopa sustained-release tablet and preparation method thereof

Abstract

The invention provides a carbidopa-levodopa sustained-release tablet and a preparation method thereof. The carbidopa-levodopa sustained-release tablet is prepared from the following pharmaceutical composition, the sustained-release tablet comprises the following components in percentage by weight: 13.0%-22.4% of carlevodopa, 63.7%-77.9% of levodopa, 0.1%-10.0% of a sustained-release material, 0.1%-15.0% of an adhesive, 0.1%-10.0% of a protective agent, 0.01%-10.0% of a coloring agent and 0.1%-10.0% of a lubricant. The carbidopa-levodopa sustained release tablet provided by the invention has an in-vitro dissolution curve similar to that of a reference preparation 'Ninine', in-vivo bioequivalence and equivalent quality stability, raw materials and auxiliary materials are easy to obtain, the preparation process is simple, the reproducibility is good, and commercial production is facilitated. Meanwhile, the possibility that the product is degraded in the storage process to generate a genotoxic substance-hydrazine is greatly reduced.

Description

Technical Field

[0001] This invention relates to the pharmaceutical field, specifically to a carbapenem / levodopa sustained-release tablet and its preparation method. Background Technology

[0002] Parkinson's disease (PD), also known as "tremor paralysis," is a common neurodegenerative disease in the elderly. Its main pathological change is the degeneration and death of dopamine neurons in the substantia nigra of the midbrain, leading to a significant reduction in striatal dopamine levels. Clinical manifestations are primarily resting tremor, increased muscle tone, sleep disturbances, and autonomic dysfunction. PD has a high disability rate, with a high proportion of patients in the middle and late stages. Treatment is expensive and often ineffective, requiring long-term care and placing a heavy burden on families. It is the third leading cause of death among the elderly. For early-stage PD, the recommended treatment is a combination of levodopa and carbidopa.

[0003] Carbidopa is a peripheral L-aromatic amino acid decarboxylase inhibitor that cannot cross the blood-brain barrier to enter the brain. Therefore, when used in combination with levodopa, it can inhibit the conversion of peripheral levodopa to dopamine, reduce peripheral dopamine production, and decrease side effects. At the same time, it increases the amount of levodopa entering the central nervous system, thereby increasing the levodopa content in the circulating blood. This allows more levodopa to reach the substantia nigra-striatum to exert its effect, thus improving the efficacy of levodopa, prolonging its half-life, and reducing the adverse reactions of levodopa in the periphery.

[0004] The original drug Sinemet, which is marketed in China, uses polyvinyl acetate-crotonic acid copolymer as a sustained-release material. This excipient is not available in China, which limits the commercial production of carbapenem-levodopa sustained-release tablets. Currently, China needs an alternative formulation that is available in terms of raw materials, excipients, and packaging, has a simple preparation process, is cost-controllable, and has the same quality as the original drug Sinemet.

[0005] Genotoxic impurities (GTIs) refer to compounds that directly or indirectly damage cellular DNA, causing gene mutations or in vivo mutagenesis, and thus have the potential or tendency to cause cancer. Hydrazine (N₂H₄), also known as hydrazine, is a multifunctional reducing agent. It is a strongly polar compound with weak basicity, only one-fifteenth that of ammonia, but it can react with acids to form salts. Furthermore, hydrazine is highly corrosive and has strong reducing properties, capable of reducing carbonyl, alkenes, alkynes, nitro compounds, and participating in acylation reactions or serving as a raw material for the synthesis of nitrogen-containing heterocyclic compounds. Hydrazine exhibits mutagenic and genotoxic effects both in vivo and in vitro. Hydrazine is classified as Group 2B by the IARC, meaning it is possibly carcinogenic to humans. The EPA considers hydrazine a Group B2 carcinogen or a possible human carcinogen. The CPBD cited seven studies on the carcinogenicity of hydrazine: three involving inhalation for one year, three involving oral administration, and one involving gavage administration. Of these seven studies, five reported that hydrazine is carcinogenic. Many pharmaceutical raw materials listed hydrazine residues in their impurity testing items in domestic and international pharmacopoeias, such as isoniazid, losartan potassium, dihydralazine sulfate, allopurinol, hydralazine, furacilin, hydralazine hydrochloride, carbidopa, and pyridoxal isoniazid.

[0006] Therefore, this invention provides a carbapenem-levodopa sustained-release tablet with the same quality as the original drug Sinemet and its preparation method, while also reducing the content of genotoxic impurities. Summary of the Invention

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to address the shortcomings of the prior art by providing a carbapenem-levodopa sustained-release tablet and its preparation method.

[0008] To solve the above-mentioned technical problems, the present invention discloses the following technical solution:

[0009] In a first aspect, the present invention discloses a carbapenem / levodopa pharmaceutical composition.

[0010] The composition contains the following components in weight percentage:

[0011] Cazodopa 13.0%–22.4%

[0012] Levodopa 63.7%–77.9%

[0013] Sustained-release material: 0.1%–10.0%

[0014] Adhesive 0.1% to 15.0%

[0015] Protective agent 0.1%–10.0%

[0016] Colorant 0.01% to 10.0%

[0017] Lubricant 0.1%–10.0%.

[0018] In some embodiments, the composition contains the following components by weight percentage:

[0019] Cazodopa 15.0%–20.4%

[0020] Levodopa 66.7%–74.9%

[0021] Sustained-release material: 1.0%–5.0%

[0022] Adhesive 1.0% to 10.0%

[0023] Protective agent 0.1%–2.0%

[0024] Colorant 0.1%–2.0%

[0025] Lubricant 0.5%–2.0%;

[0026] In some embodiments, the composition contains the following components by weight percentage:

[0027]

[0028] In some embodiments, the composition further includes a wetting agent, such as water; the amount of the wetting agent may be appropriate, such as 30% to 50% of the total mass of the prescription, preferably 40% to 45%.

[0029] The sustained-release material is hydroxypropyl methylcellulose.

[0030] The adhesive is hydroxypropyl cellulose.

[0031] The protective agent is cysteine ​​and / or sodium lactate, or a combination of lactic acid and an alkaline compound; the alkaline compound is preferably sodium hydroxide; when the protective agent is lactic acid and an alkaline compound, the alkaline compound is added to adjust the pH of the mixture of adhesive, protective agent and wetting agent to 4-8, preferably 4-6.

[0032] The colorant is any one or a combination of several of the following: yellow iron oxide, lemon yellow aluminum lake, and red iron oxide.

[0033] The lubricant is any one or a combination of several of stearic acid, sodium stearate fumarate, silicon dioxide, and magnesium stearate.

[0034] In a second aspect, the present invention discloses a carbapenem / levodopa formulation made from the pharmaceutical composition described in the first aspect above. Extended-release tablets.

[0035] In some embodiments, the manufacturing process of the carbapenem-levodopa extended-release tablet includes the following steps:

[0036] (1) Mix levodopa, levodopa, sustained-release material and colorant, and add to a fluidized bed for preheating;

[0037] (2) Granulation is carried out by adding a solution containing binders and protective agents to a fluidized bed;

[0038] (3) Drying and granulation;

[0039] (4) Add lubricant, mix well, compress into tablets, and obtain carbapenem-levodopa sustained-release tablets.

[0040] In step (1), the preheating is to preheat to 45-50°C.

[0041] In step (2), the solution includes a wetting agent, such as water; the amount of the wetting agent added is appropriate, such as 30% to 50% of the total mass of the prescription, preferably 40% to 45%.

[0042] In step (2), the temperature of the material in the fluidized bed is controlled to be 20-60°C, preferably 35-45°C, during the granulation process.

[0043] In step (3), the granulation screen is 0.6-1.2 mm, preferably 0.8-1.0 mm.

[0044] In some specific embodiments, the manufacturing process of the carbapenem-levodopa extended-release tablet includes the following steps:

[0045] Step 1. Mixing: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant until well combined;

[0046] Step 2. Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent, add an appropriate amount of wetting agent, and stir until dissolved.

[0047] Step 3. Granulation: The powder mixed evenly in Step 1 is added to a fluidized bed and preheated to a material temperature of 20-60℃. The binder solution prepared in Step 2 is then added to the fluidized bed for one-step granulation. During granulation, the material temperature is maintained at 20-60℃. After the binder solution is added, the material is put into drying mode to control the drying weight loss at 1.0-5.0%. The material is then taken out and granulated through a 0.6mm-1.2mm sieve for later use.

[0048] Step 4. Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0049] Thirdly, this invention discloses a method for preparing a carbapenem / levodopa sustained-release tablet, which is derived from the first aspect described above. The pharmaceutical composition described herein is prepared.

[0050] In some embodiments, the manufacturing process of the carbapenem-levodopa extended-release tablet includes the following steps:

[0051] (1) Mix levodopa, levodopa, sustained-release material and colorant, and add to a fluidized bed for preheating;

[0052] (2) Granulation is carried out by adding a solution containing binders and protective agents to a fluidized bed;

[0053] (3) Drying and granulation;

[0054] (4) Add lubricant, mix well, compress into tablets, and obtain carbapenem-levodopa sustained-release tablets.

[0055] In step (1), the preheating is to preheat to 45-50°C.

[0056] In step (2), the solution includes a wetting agent, such as water; the amount of the wetting agent added is appropriate, such as 30% to 50% of the total mass of the prescription, preferably 40% to 45%.

[0057] In step (2), the temperature of the material in the fluidized bed is controlled to be 20-60°C, preferably 35-45°C, during the granulation process.

[0058] In step (3), the granulation screen is 0.6-1.2 mm, preferably 0.8-1.0 mm.

[0059] In some specific embodiments, the preparation method of the carbapenem-levodopa sustained-release tablets includes the following steps:

[0060] Step 1. Mixing: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant until well combined;

[0061] Step 2. Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent, add an appropriate amount of wetting agent, and stir until dissolved.

[0062] Step 3. Granulation: The powder mixed evenly in Step 1 is added to a fluidized bed and preheated to a material temperature of 20-60℃. The binder solution prepared in Step 2 is then added to the fluidized bed for one-step granulation. During granulation, the material temperature is maintained at 20-60℃. After the binder solution is added, the material is put into drying mode to control the drying weight loss at 1.0-5.0%. The material is then taken out and granulated through a 0.6mm-1.2mm sieve for later use.

[0063] Step 4. Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0064] The levodopa / carbazide sustained-release tablets provided by this invention can reduce the content of genotoxic impurities by adding a protective agent that can control the pH of the formulation and has certain complexing and antioxidant effects. Specifically, the hydrazine content in the levodopa / carbazide sustained-release tablets is below 15 ppm; after being placed at 60℃±2℃ for 30 days, the hydrazine content in the levodopa / carbazide sustained-release tablets is below 40 ppm; after being placed at RH 90%±5% and 25℃±2℃ for 30 days, the hydrazine content in the levodopa / carbazide sustained-release tablets is below 350 ppm; and the hydrazine content in the levodopa / carbazide sustained-release tablets at 4500Lx±500Lx and 90μw / cm 2 After being placed for 14 days, the hydrazine content in the carbapenem-levodopa sustained-release tablets was below 120 ppm.

[0065] Beneficial effects:

[0066] This invention utilizes a one-step granulation technique to prepare carbidopa and levodopa sustained-release tablets, achieving a release profile similar to the original formulation, Sinemet. The sustained-release material used effectively controls the release of carbidopa and levodopa, overcoming the unavailability of excipients in the original formulation and enabling commercial production in China. Furthermore, by adding a protective agent to the formulation, this invention significantly reduces the possibility of degradation during storage, leading to the formation of genotoxic substances such as hydrazine. Detailed Implementation

[0067] The present invention can be better understood from the following embodiments. However, those skilled in the art will readily understand that the descriptions in the embodiments are for illustrative purposes only and should not, and will not, limit the invention as detailed in the claims.

[0068] In the following embodiments, unless otherwise specified, the experimental methods are conventional methods; and unless otherwise specified, the reagents and materials are commercially available.

[0069] In the following examples, the reference preparation is carbidopa-levodopa extended-release tablets (Sinemet), the main components of which are carbidopa 50mg and levodopa 200mg.

[0070] Example 1

[0071] Table 1. Prescription composition of Example 1

[0072] raw materials mg / tablet Carbidopa 50 Levodopa 200 Hydroxypropyl methylcellulose K15M 6 Hydroxypropyl cellulose L 16 Sodium lactate 4 Yellow iron oxide 0.75 Red iron oxide 0.25 Purified water Appropriate amount magnesium stearate 3 total 280

[0073] The preparation method of the above-mentioned carbolev-levodopa sustained-release tablets is as follows:

[0074] Step 1: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant thoroughly;

[0075] Step 2: Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent, add the prescribed amount of wetting agent, and stir until dissolved.

[0076] Step 3: Granulation: The powder from Step 1 is added to a fluidized bed. When the material is preheated to 45°C, the binder solution prepared in Step 2 is added to the fluidized bed for one-step granulation. During the granulation process, the material temperature is maintained at 35-40°C. After the binder solution is added, the material is put into drying mode to control the drying weight loss to less than 2.0%. The material is then taken out and granulated through a 0.8mm sieve for later use.

[0077] Step 4: Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0078] Example 2

[0079] Table 2. Prescription composition of Example 2

[0080]

[0081]

[0082] The preparation method of the above-mentioned carbolev-levodopa sustained-release tablets is as follows:

[0083] Step 1: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant thoroughly;

[0084] Step 2: Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent, add the prescribed amount of wetting agent, and stir until dissolved.

[0085] Step 3: Granulation: The powder from Step 1 is added to a fluidized bed. When the material is preheated to 45°C, the binder solution prepared in Step 2 is added to the fluidized bed for one-step granulation. During the granulation process, the material temperature is maintained at 35-40°C. After the binder solution is added, the material is put into drying mode to control the drying weight loss to less than 2.0%. The material is then taken out and granulated through a 0.8mm sieve for later use.

[0086] Step 4: Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0087] Example 3

[0088] Table 3. Prescription composition of Example 3

[0089] raw materials mg / tablet Carbidopa 50 Levodopa 200 Hydroxypropyl methylcellulose K4M 12 Hydroxypropyl cellulose L 16 Sodium lactate 4 Yellow iron oxide 0.75 Red iron oxide 0.25 Purified water Appropriate amount magnesium stearate 3 total 286

[0090] The preparation method of the above-mentioned carbolev-levodopa sustained-release tablets is as follows:

[0091] Step 1: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant thoroughly;

[0092] Step 2: Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent, add the prescribed amount of wetting agent, and stir until dissolved.

[0093] Step 3: Granulation: The powder from Step 1 is added to a fluidized bed. When the material is preheated to 50°C, the binder solution prepared in Step 2 is added to the fluidized bed for one-step granulation. During the granulation process, the material temperature is maintained at 40°C to 45°C. After the binder solution is added, the material is put into drying mode to control the drying weight loss to less than 2.0%. The material is then taken out and granulated through a 0.8mm sieve for later use.

[0094] Step 4: Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0095] Example 4

[0096] Table 4. Prescription composition of Example 4

[0097] raw materials mg / tablet Carbidopa 50 Levodopa 200 Hydroxypropyl methylcellulose K15M 6 Hydroxypropyl cellulose L 16 lactic acid 4 Sodium hydroxide Appropriate amount Yellow iron oxide 0.75 Red iron oxide 0.25 Purified water Appropriate amount magnesium stearate 3 total 280

[0098] The preparation method of the above-mentioned carbolev-levodopa sustained-release tablets is as follows:

[0099] Step 1: Mix the prescribed amounts of carbidopa, levodopa, sustained-release material, and colorant thoroughly;

[0100] Step 2: Adhesive preparation: Weigh the prescribed amount of adhesive and protective agent lactic acid; add the prescribed amount of wetting agent and stir until dissolved; add an alkaline compound and adjust the pH to 4.0-6.0, then set aside.

[0101] Step 3: Granulation: The powder from Step 1 is added to a fluidized bed. When the material is preheated to 45°C, the binder solution prepared in Step 2 is added to the fluidized bed for one-step granulation. During the granulation process, the material temperature is maintained at 35-40°C. After the binder solution is added, the material is put into drying mode to control the drying weight loss to less than 2.0%. The material is then taken out and granulated through a 0.8mm sieve for later use.

[0102] Step 4: Total mixing and tableting: Add lubricant to the material obtained in step 3, mix evenly, and compress into tablets to obtain the final product.

[0103] Experiment 1: In vitro dissolution curve determination

[0104] Method: The dissolution method was performed according to the import registration standard JX20210099. The dissolution conditions were 900 ml of 0.1 N hydrochloric acid as the dissolution medium and 50 rpm. The dissolution curves of samples from Examples 1 to 3 were investigated.

[0105] Table 1 Summary of Carbidopa Dissolution Curves

[0106]

[0107] Table 2 Summary of Levodopa Dissolution Curves

[0108]

[0109] As shown in Table 1-2, the sustained-release tablets prepared in Examples 1-3 have relatively stable sustained-release effects, good consistency with the dissolution curves of the reference formulation, and simple preparation process, making it easy to achieve large-scale commercial production.

[0110] Three batches of levodopa and carbapenem sustained-release tablets were prepared according to the formulation and preparation method of Example 2, and then the in vitro dissolution curves were detected according to the above dissolution method. The results are shown in Tables 3-4.

[0111] Table 3 Summary of carbapenem dissolution results for three batches of Sample 2 from Example 2

[0112]

[0113] Table 4 Summary of L-DOPA dissolution results for three batches of Samples from Example 2

[0114]

[0115] As shown in Tables 3-4, the process of preparing the carbapenem-levodopa sustained-release tablets of the present invention is stable and has good reproducibility.

[0116] Experiment 2: Stability Test

[0117] To investigate the stability of the levodopa / dopa sustained-release tablets prepared in the embodiments of the present invention, the reference formulation and the levodopa / dopa sustained-release tablets prepared in Example 2 were subjected to the following influencing factors: high temperature (60℃±2℃) for 30 days, high humidity (RH 90%±5% / 25℃±2℃) for 30 days, and light exposure (4500Lx±500Lx / 90μw / cm²). 2 The results of the accelerated test (40℃±2℃ / RH75%±5%)-3M) and the accelerated test (40℃±2℃ / RH75%±5%)-3M) are shown in Tables 5 and 6.

[0118] Table 5. Detection results of related substances and their contents under influencing factors.

[0119]

[0120] Note: THPA stands for 3-(3,4,6-trihydroxyphenyl)alanine; 3,4-DHBA stands for 3,4-dihydroxybenzaldehyde; 3,4-DHPA stands for 1-(3,4-dihydroxyphenyl)-2-propanone; ND indicates that the content is below the detection limit of 0.05% or not detected.

[0121] Table 6. Hydrazine detection results under influencing factors.

[0122]

[0123] Table 7. Detection results of related substances and their contents under accelerated conditions.

[0124]

[0125] Note: ND indicates that the content is below the detection limit of 0.05% or not detected.

[0126] As shown in Tables 5-7, compared with the reference formulation, the levodopa-dopa sustained-release tablets prepared in the embodiments of the present invention are relatively stable in terms of related substances and content under influencing factors and accelerated conditions, and the product quality is comparable to that of the reference formulation; the hydrazine content is significantly lower than that of the reference formulation.

[0127] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention. Therefore, the scope of protection of this patent should be determined by the appended claims.

Claims

1. A carbapenem / levodopa drug composition, characterized in that, It contains the following components by weight percentage:

2. The carbapenem / levodopa drug composition according to claim 1, characterized in that, It contains the following components by weight percentage: Preferably, it contains the following components in weight percentage:

3. The carbapenem / levodopa pharmaceutical composition according to claim 1 or 2, characterized in that, The sustained-release material is hydroxypropyl methylcellulose; the binder is hydroxypropyl cellulose; the protective agent is cysteine ​​and / or sodium lactate, or a combination of lactic acid and an alkaline compound; the alkaline compound is preferably sodium hydroxide.

4. The carbapenem / levodopa pharmaceutical composition according to claim 1 or 2, characterized in that, The colorant is any one or a combination of several of yellow iron oxide, lemon yellow aluminum lake, and red iron oxide; the lubricant is any one or a combination of several of stearic acid, sodium stearate fumarate, silicon dioxide, and magnesium stearate.

5. A carbapenem / levodopa extended-release tablet, characterized in that, Made from the pharmaceutical composition according to any one of claims 1 to 4; preferably, the preparation process of the carbapenem-levodopa extended-release tablet includes the following steps: (1) Mix levodopa, levodopa, sustained-release material and colorant, and add to a fluidized bed for preheating; (2) Add a solution containing binder and protectant to the fluidized bed for granulation.

6. A method for preparing a carbapenem / levodopa sustained-release tablet, characterized in that, Made from the pharmaceutical composition according to any one of claims 1 to 4; preferably, the preparation process of the carbapenem-levodopa extended-release tablet includes the following steps: (1) Mix levodopa, levodopa, sustained-release material and colorant, and add to a fluidized bed for preheating; (2) Add a solution containing binder and protectant to the fluidized bed for granulation.

7. The carbapenem / levodopa extended-release tablet according to claim 5 or the method according to claim 6, characterized in that, In step (1), the preheating is to preheat to 45-50°C.

8. The carbapenem / levodopa extended-release tablet according to claim 5 or the method according to claim 6, characterized in that, In step (2), the temperature of the material in the fluidized bed is controlled to be 20-60°C, preferably 35-45°C, during the granulation process.

9. The carbapenem / levodopa extended-release tablet according to claim 5 or the method according to claim 6, characterized in that, The method further includes the following steps after step (2): (3) Drying and granulation; (4) Add lubricant, mix well, compress into tablets, and obtain carbapenem-levodopa sustained-release tablets; Preferably, in step (3), the granulation screen in the granulation process is 0.6-1.2 mm, more preferably 0.8-1.0 mm.

10. The carbapenem / levodopa extended-release tablet according to claim 5, 7, 8, or 9, characterized in that, The hydrazine content in the carbapenem-levodopa sustained-release tablets is below 15 ppm; preferably, after being stored at 60℃±2℃ for 30 days, the hydrazine content in the carbapenem-levodopa sustained-release tablets is below 40 ppm, or after being stored at RH 90%±5% and 25℃±2℃ for 30 days, the hydrazine content in the carbapenem-levodopa sustained-release tablets is below 350 ppm, or at 4500Lx±500Lx and 90μw / cm 2 After being placed for 14 days, the hydrazine content in the carbapenem-levodopa sustained-release tablets was below 120 ppm.

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