Levodopa and benserazide hydrochloride composition and preparation method thereof

Abstract

The invention relates to a levodopa and benserazide hydrochloride composition and a novel preparation process thereof, the pharmaceutical active ingredients of the composition are levodopa and benserazide hydrochloride, and the process comprises the following steps: separately granulating the two active ingredients, and then mixing and tabletting. The preparation process is simple and convenient, fluidized bed coating and double-layer tabletting processes are avoided, the production cost is reduced, the dissolution amount is obviously higher than that of a mode of granulating the composition together, the dissolution amount is closer to that of a control preparation, and the product quality is better.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a combination of levodopa and benserazide hydrochloride, a new preparation process thereof, and the resulting Madopar tablets. Background Art

[0002] Madopar tablets are a compound preparation of levodopa and benserazide (commonly benserazide hydrochloride), developed by F. Hoffmann-La Roche of Switzerland. Levodopa is a prodrug of dopamine (DA), which has no pharmacological activity itself. It enters the central nervous system through the blood-brain barrier and is converted into DA by the action of dopa decarboxylase to exert its pharmacological effect. Direct use has relatively large side effects and many adverse reactions, which are difficult to avoid due to the long medication time. This is mainly caused by excessive dopamine produced peripherally. Appropriate adjustment of the dose can reduce the adverse reactions. Since benserazide is a peripheral decarboxylase inhibitor, it can inhibit the decarboxylation of levodopa outside the brain and increase the amount of levodopa in the brain. Therefore, the dosage of levodopa can be reduced, thereby reducing the adverse reactions caused by it and enhancing the patient's tolerance. It has been proven that adding benserazide to levodopa can reduce the levodopa dose in patients with Parkinson's disease, reduce side effects and enhance the efficacy, and is useful in double-blind comparative studies of patients with Parkinson's disease.

[0003] Currently, the common production processes for compound solid preparations include direct compression tableting, wet granulation process, and dry granulation. It has been found that the conventional production processes for the combination of levodopa and benserazide hydrochloride, such as wet granulation or dry granulation after mixing, are difficult to achieve the same in vitro release as the control preparation, which affects the absorption and efficacy in vivo. Patents CN113081994A and CN116549408A both adopt a fluidized bed coating process and a double-layer compression tableting process during production, with complex production processes and high production costs. Summary of the Invention

[0004] The present invention provides a combination of levodopa and benserazide hydrochloride and a new preparation process thereof, in which the two active ingredients are granulated separately and then mixed and tabletted.

[0005] In one aspect of the embodiments of the present invention, the present invention provides a composition containing levodopa and benserazide hydrochloride, wherein the drug active ingredients of the composition are levodopa and benserazide hydrochloride, and they are prepared by separately granulating and mixing levodopa and benserazide hydrochloride; wherein, levodopa is granulated with anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch to obtain granule A; benserazide hydrochloride is granulated with microcrystalline cellulose, ethyl cellulose and sodium docusate to obtain granule B; the granule A, the granule B, crospovidone, colloidal silicon dioxide and magnesium stearate are mixed. In some embodiments, the granule A and granule B further include pigments of different colors, and the pigment is any one of red iron oxide and yellow iron oxide, preferably red iron oxide.

[0006] In some embodiments, the composition containing levodopa and benserazide hydrochloride is a tablet.

[0007] In some embodiments, the weight ratio of the granule A to the granule B is 4.3:1

[0008] In some embodiments, in the composition containing levodopa and benserazide hydrochloride,

[0009] Levodopa 36.36 parts by weight Mannitol 20 parts by weight Anhydrous calcium hydrogen phosphate 18 parts by weight Pregelatinized starch 4 parts by weight Benserazide hydrochloride 10.36 parts by weight Microcrystalline cellulose 7 parts by weight Ethylcellulose 0.5 parts by weight Sodium docusate 0.05 parts by weight Crospovidone 2.28 parts by weight Colloidal silicon dioxide 0.25 parts by weight Magnesium stearate 1 part by weight

[0010] Optionally, the granule A and granule B further include 0.1 part by weight of pigment.

[0011] In another aspect of the present invention, the present invention provides a preparation process of a composition of levodopa and benserazide hydrochloride, including the steps of separately granulating the two active ingredients of levodopa and benserazide hydrochloride and then mixing and tableting them.

[0012] The specific steps are as follows:

[0013] S1: Weigh the formula amount of levodopa, anhydrous calcium hydrogen phosphate and mannitol into a wet granulator, mix them evenly, and add pregelatinized starch slurry for wet granulation;

[0014] S2: Add the granules obtained in S1 into a fluidized bed for drying to obtain granule A;

[0015] S3: Weigh the formula amount of benserazide hydrochloride and microcrystalline cellulose into a wet granulator, mix them evenly, and add ethyl cellulose and anhydrous ethanol solution of sodium docusate for wet granulation;

[0016] S4: Add the granules obtained in S3 into a fluidized bed for drying to obtain granule B;

[0017] S5: Mix granule A and granule B, add crospovidone and colloidal silicon dioxide for mixing, and then add magnesium stearate for overall mixing to obtain overall mixed granules;

[0018] S6: Compress the total mixed granules obtained in S5 using a rotary tablet press.

[0019] Further, the weight ratio of granule A to granule B in S5 is 4.3:1.

[0020] Further, in S1 and / or S3 and / or S5, different colored pigments are added during granulation, and the pigment is any one of red iron oxide and yellow iron oxide.

[0021] Further, in the composition, the weight parts of each raw material are as follows: levodopa 36.36 parts, mannitol 20 parts, anhydrous calcium hydrogen phosphate 18 parts, pregelatinized starch 4 parts, benserazide hydrochloride 10.36 parts, microcrystalline cellulose 7 parts, ethyl cellulose 0.5 part, sodium docusate 0.05 part, red iron oxide 0.15 part, crospovidone 2.28 parts, colloidal silicon dioxide 0.25 part, magnesium stearate 1 part.

[0022] Further, in S1, when adding the pregelatinized starch slurry, the stirring paddle speed of the wet granulator is 100 - 180 rpm, the cutter speed is 500 - 1500 rpm, and the slurry adding duration is 1 - 5 min; after the slurry adding is completed, set the wet granulator to a stirring paddle speed of 100 - 180 rpm, a cutter speed of 500 - 1500 rpm, and a granulation time of 2 - 8 min.

[0023] Further, in S2, set the inlet air temperature to 80 ± 5 °C, dry until the material temperature reaches 40 - 60 °C, stop the machine to detect the moisture content of the material, and the moisture content does not exceed 1.2%.

[0024] Further, in S3, when adding the ethyl cellulose and sodium docusate anhydrous ethanol solution, start the stirring speed at 50 - 150 rpm, the cutter speed at 500 - 1500 rpm, and the liquid adding duration at 2 - 6 min. After the liquid adding is completed, set the wet granulator to a stirring speed of 80 - 120 rpm, a cutter speed of 1100 - 1300 rpm, and a granulation time of 1 - 5 min.

[0025] Further, in S4, set the inlet air temperature to 50 ± 5 °C, dry until the material temperature reaches 30 - 40 °C, stop the machine to detect the moisture content of the material, and the moisture content does not exceed 2.0%.

[0026] Further, in S5, first place granule A, granule B, crospovidone, colloidal silicon dioxide, and magnesium stearate in a sieving machine for sieving. The sieve mesh of the sieving machine is a Φ1.0 mm round hole sieve, and the sieving speed is 200 - 800 rpm; then transfer them to a mixer for mixing. The mixing speed is 15 rpm, and the mixing time is 10 min - 20 min; in S6, the tablet press die is 12.0 mm with a cross notch, and the tablet hardness is 5.0 - 12.0 KG.

[0027] In another aspect of the present invention, the present invention provides a levodopa and benserazide hydrochloride composition prepared according to the above preparation method.

[0028] Beneficial effects:

[0029] The present invention prepares tablets of levodopa and benserazide hydrochloride by separately granulating the two active components and then mixing and tableting them. The preparation process is simple, avoiding the use of fluidized bed coating and double-layer tableting processes, reducing production costs. Moreover, its dissolution amount is significantly higher than that of the method of granulating the composition together, closer to the control preparation, and the product quality is better. Brief description of the drawings

[0030] Figure 1 It shows the dissolution data of levodopa in different examples.

[0031] Figure 2 It shows the dissolution data of benserazide hydrochloride in different examples.

[0032] Figure 3 It shows the situation of benserazide hydrochloride impurity B in different examples. Detailed description of the invention

[0033] The examples are given to better illustrate the present invention, but the content of the present invention is not limited to the given examples only. Therefore, those skilled in the art who make non-essential improvements and adjustments to the implementation solutions based on the above invention content still fall within the protection scope of the present invention.

[0034] Example 1

[0035] 1. Formulation of the preparation

[0036]

[0037] 2. Preparation process

[0038] 1) Add the formulated amounts of levodopa, mannitol, red iron oxide, and anhydrous calcium hydrogen phosphate to a wet mixing granulator for mixing;

[0039] 2) Add the pregelatinized starch paste to the above wet granulation pot for wet granulation; turn on the stirring paddle speed at 120 rpm, the cutter speed at 1000 rpm, and the liquid addition time for 1 - 5 min; after the addition of the paste is completed, set the wet granulator to a stirring paddle speed of 150 rpm, a cutter speed of 1000 rpm, and a granulation time of 3 - 5 min to prepare the granules.

[0040] 3) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 80 ± 5 °C, dry until the material temperature reaches 50 °C, stop the machine to detect the moisture content of the material, and the moisture content should not exceed 1.2%. The preparation of levodopa granules is completed.

[0041] 4) Add the formula amounts of benserazide hydrochloride, microcrystalline cellulose, and red iron oxide into a wet granulator for mixing; 5) Dissolve sodium docusate in absolute ethanol, and add the sodium docusate absolute ethanol solution into the above wet granulation pot for wet granulation; start the stirring speed at 50 - 150 rpm and the cutter speed at 500 - 1500 rpm when adding the binder ethanol solution, with the liquid addition time of 2 - 6 min. After the binder solution is completely added, set the wet granulator to a stirring speed of 80 - 120 rpm and a cutter speed of 1100 - 1300 rpm, and the granulation time of 1 - 5 min to prepare the granules.

[0042] 6) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 50 ± 5 °C, dry until the material temperature reaches 35 °C, stop the machine to detect the moisture content of the material, and the moisture content should not exceed 2.0%. The preparation of benserazide hydrochloride granules is completed.

[0043] 7) Place the levodopa granules, the external excipient crospovidone, colloidal silicon dioxide, magnesium stearate, and the benserazide hydrochloride granules in a granulating machine for granulation, with a screen mesh size of Φ1.0 mm round hole screen, and the granulating speed of 200 - 800 rpm. Then transfer them to a mixer for mixing, with a mixing speed of 15 rpm and a mixing time of 10 min - 20 min.

[0044] 8) Compress the total mixed granules into tablets, with a tablet press die of 12.0 mm with a cross notch, and the tablet hardness of 5.0 - 12.0 KG.

[0045] Example 2

[0046] 1. Preparation formula

[0047]

[0048]

[0049] 1) Add the formula amounts of levodopa, mannitol, red iron oxide, and anhydrous calcium hydrogen phosphate into a wet granulator for mixing;

[0050] 2) Add the pregelatinized starch paste into the above wet granulation pot for wet granulation; start the stirring paddle speed at 120 - 150 rpm and the cutter speed at 900 - 1100 rpm, with the addition time of 1 - 3 min; after the addition of the paste is completed, set the wet granulator to a stirring paddle speed of 120 - 150 rpm and a cutter speed of 1100 - 1300 rpm, and the granulation time of 3 - 5 min to prepare the granules.

[0051] 3) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 80 ± 5 °C, dry until the material temperature reaches 50 °C, stop the machine to detect the moisture content of the material, and the moisture content shall not exceed 1.2%. The preparation of levodopa granules is completed.

[0052] 4) Add the formulated amount of benserazide hydrochloride, microcrystalline cellulose, and red iron oxide into the wet granulator for mixing; 5) Dissolve sodium docusate in absolute ethanol, and add the sodium docusate absolute ethanol solution into the above wet granulation pot for wet granulation; start the stirring speed at 80 - 100 rpm and the cutter speed at 900 - 1100 rpm when adding the binder solution, control the liquid addition time at 3 - 5 min, until the binder solution is completely added, then stop stirring and the cutter; set the wet granulator at a stirring speed of 80 - 120 rpm, a cutter speed of 1100 - 1300 rpm, and a granulation time of 1 - 3 min to prepare the granules.

[0053] 6) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 50 ± 5 °C, dry until the material temperature reaches 35 °C, stop the machine to detect the moisture content of the material, and the moisture content shall not exceed 2.0%. The preparation of benserazide hydrochloride granules is completed.

[0054] 7) Place the levodopa granules, additional excipients, and benserazide hydrochloride granules in the granulator for granulation, with a screen mesh size of Φ1.0 mm round hole screen, a granulation speed of 400 - 600 rpm, then transfer them to the mixer for mixing, with a mixing speed of 15 rpm and a mixing time of 10 min - 20 min.

[0055] 8) Compress the total mixed granules into tablets, with a tablet press die of 12.0 mm with cross marks, and a tablet hardness of 7.0 - 10.0 KG.

[0056] Example 3

[0057] 1. Preparation formula

[0058]

[0059]

[0060] 2. Preparation process

[0061] 1) Add the formulated amount of levodopa, mannitol, red iron oxide, and anhydrous calcium hydrogen phosphate into the wet granulator for mixing;

[0062] 2) Add the pregelatinized starch paste into the above wet granulation pot for wet granulation; start the stirring paddle speed at 130 rpm, the cutter speed at 1000 rpm, and the addition time at 2 - 3 min; after the addition of the paste, set the wet granulator at a stirring paddle speed of 130 rpm, a cutter speed of 1200 rpm, and a granulation time of 3 - 5 min to prepare the granules.

[0063] 3) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 80 ± 5 °C, dry until the material temperature reaches 50 °C, stop the machine to detect the moisture content of the material, and the moisture content does not exceed 1.2%. The preparation of levodopa granules is completed.

[0064] 4) Add the formulated amounts of benserazide hydrochloride, microcrystalline cellulose, and red iron oxide into a wet granulator for mixing.

[0065] 5) Dissolve sodium docusate in absolute ethanol, and add the sodium docusate absolute ethanol solution into the above-mentioned wet granulation pot for wet granulation; when adding the binder solution, turn on the stirring speed at 90 rpm and the cutter speed at 1000 rpm, control the liquid addition time for 3 - 5 min, until the binder solution is completely added, then stop stirring and the cutter; set the wet granulator to a stirring speed of 100 rpm and a cutter speed of 1200 rpm, and the granulation time is 1 - 3 min to prepare the granules.

[0066] 6) Add the prepared soft material into the fluidized bed for drying; set the inlet air temperature at 50 ± 5 °C, dry until the material temperature reaches 35 °C, stop the machine to detect the moisture content of the material, and the moisture content does not exceed 2.0%. The preparation of benserazide hydrochloride granules is completed.

[0067] 7) Place the levodopa granules, additional excipients, and benserazide hydrochloride granules in a granulating machine for granulation, with a screen mesh size of Φ1.0 mm round hole screen, and the granulating speed is 400 - 600 rpm, then transfer them to a mixer for mixing, with a mixing speed of 15 rpm and a mixing time of 15 min.

[0068] 8) Compress the total mixed granules into tablets, with a tablet press die of 12.0 mm with a cross notch, and the tablet hardness is 7.0 - 10.0 KG.

[0069] Comparative Example 1

[0070] 1. Preparation formula

[0071] Levodopa 36.36 parts Benserazide hydrochloride 10.36 parts Mannitol 20 parts Anhydrous calcium hydrogen phosphate 18 parts Pregelatinized starch 4 parts Red iron oxide 0.2 parts Microcrystalline cellulose 7 parts Ethylcellulose 0.5 parts Sodium docusate 0.05 parts Purified water Removed by drying during the preparation process Crospovidone 2.28 parts Colloidal silicon dioxide 0.25 parts Magnesium stearate 1 part

[0072] 2. Preparation process

[0073] 1) Add the formulated amounts of levodopa, benserazide hydrochloride, mannitol, anhydrous calcium hydrogen phosphate, red iron oxide, microcrystalline cellulose, ethyl cellulose, sodium docusate, and red iron oxide into a wet granulator for mixing.

[0074] 2) Add the pregelatinized starch paste into the above-mentioned wet granulation pot for wet granulation, turn on the stirring paddle speed at 130 rpm and the cutter speed at 1000 rpm, and the addition time is 2 - 3 min; after the addition of the paste is completed, set the wet granulator to a stirring paddle speed of 130 rpm and a cutter speed of 1200 rpm, and the granulation time is 3 - 5 min to prepare the granules.

[0075] 3) Add the prepared soft material into a fluidized bed for drying;

[0076] 4) Add the external excipients cross-linked povidone, colloidal silicon dioxide and magnesium stearate for overall mixing

[0077] 5) Compress the overall mixed granules into tablets

[0078] Example 4

[0079] Content uniformity

[0080] Take tablets prepared by granulating the two active ingredients separately and together for the content uniformity test of benserazide hydrochloride.

[0081] Table 1: Results of content uniformity of levodopa in the levodopa and benserazide hydrochloride composition

[0082] Sample A + 2.2S ≤ 15 Example 1 A + 2.2S = 4.5, meeting the requirements Example 2 A + 2.2S = 5.2, meeting the requirements Example 3 A + 2.2S = 6.6, meeting the requirements Control Example 1 A + 2.2S = 15.8, not meeting the requirements Control preparation A + 2.2S = 7.6, meeting the requirements

[0083] As can be seen from Table 1, for the two granulation methods of the levodopa and benserazide hydrochloride composition, the content uniformity of granulating separately meets the requirements, is basically the same as that of the control preparation, and the product quality is qualified.

[0084] Example 5

[0085] Dissolution

[0086] Take tablets prepared by granulating the two active ingredients separately and together for in vitro dissolution comparison. Use 1000 ml of pH 4.5 phosphate buffer solution as the dissolution medium, and the rotation speed of the basket method is 75 revolutions per minute. Operate according to the law and measure the cumulative dissolution at each time point.

[0087] Table 2: Dissolution data of levodopa in the levodopa and benserazide hydrochloride composition

[0088]

[0089]

[0090] Table 3: Dissolution data of benserazide hydrochloride in the levodopa and benserazide hydrochloride composition

[0091]

[0092] As can be seen from Table 2 and Table 3, for the two granulation methods of the levodopa and benserazide hydrochloride composition, the cumulative dissolution amount of granulating separately is significantly higher than that of granulating the composition together, is closer to the control preparation, and the product quality is better.

[0093] Example 6

[0094] Stability

[0095] Tablets prepared by separately granulating and co-granulating two active ingredients were compared for stability. After packaging, the samples were placed at a temperature of 40°C ± 2°C and a relative humidity of 75% ± 5% RH to investigate the growth of related substance impurity B (%) of benserazide hydrochloride over 3 months and 6 months.

[0096] Table 4: Growth of related substance impurity B (%) of benserazide hydrochloride

[0097]

[0098]

[0099] As can be seen from Table 4, for the two granulation methods of the levodopa and benserazide hydrochloride combination, the growth trend of related substance impurity B of benserazide hydrochloride in the separately granulated form was significantly lower than that in the co-granulated form of the combination, closer to the reference preparation, and the product quality was better.

Claims

1. A composition containing levodopa and benserazide hydrochloride, characterized in that: The pharmaceutical active ingredients of the composition are levodopa and benserazide hydrochloride, which are obtained by granulating levodopa and benserazide hydrochloride separately and mixing them; wherein levodopa is granulated with anhydrous calcium hydrogen phosphate, mannitol and pregelatinized starch to obtain granules A; benserazide hydrochloride is granulated with microcrystalline cellulose, ethyl cellulose and docusate sodium to obtain granules B; and the granules A, the granules B, cross-linked polyvinylpyrrolidone, colloidal silicon dioxide and magnesium stearate are mixed.

2. The composition containing levodopa and benserazide hydrochloride according to claim 1, characterized in that: The particles A and B also include pigments of different colors, and the pigment is any one of red iron oxide and yellow iron oxide.

3. The composition containing levodopa and benserazide hydrochloride according to claim 1 or 2, characterized in that: The composition containing levodopa and benserazide hydrochloride is a tablet.

4. The composition containing levodopa and benserazide hydrochloride according to any one of claims 1 to 3, characterized in that: In the composition containing levodopa and benserazide hydrochloride, 5. Optionally, the particles A and B further include 0.1 parts by weight of a pigment.

6. The method for preparing the composition containing levodopa and benserazide hydrochloride according to any one of claims 1 to 4, characterized in that: The following steps are involved: S1: Mix the formulated amount of levodopa, anhydrous calcium hydrogen phosphate and mannitol in a wet mixer granulator, mix them evenly, and add pregelatinized starch slurry for wet granulation; S2: Add the granules obtained in S1 into a fluidized bed for drying to obtain granules A; S3: Add the formulated amount of benserazide hydrochloride and microcrystalline cellulose into a wet mixing granulator, mix evenly, and add ethyl cellulose and docusate sodium anhydrous ethanol solution for wet granulation; S4: adding the granules obtained in S3 to a fluidized bed for drying to obtain granules B; S5: mixing granules A and B, adding cross-linked polyvinylpyrrolidone and colloidal silicon dioxide, and then adding magnesium stearate to obtain mixed granules; S6: The total mixed granules obtained in S5 are tableted using a rotary tablet press.

7. The method for preparing the composition containing levodopa and benserazide hydrochloride according to claim 5, characterized in that: In S1, when adding pregelatinized starch slurry, the stirring paddle speed of the wet granulator is 100-180rpm, the cutting knife speed is 500-1500rpm, and the slurry adding time is 1-5min; after the slurry adding is completed, the wet granulator is set to a stirring paddle speed of 100-180rpm, a cutting knife speed of 500-1500rpm, and a granulation time of 2-8min.

8. The method for preparing the composition containing levodopa and benserazide hydrochloride according to claim 5 or 6, characterized in that: In S2, the air inlet temperature is set at 80±5°C, and the material is dried to a temperature of 40-60°C. The machine is stopped to detect the moisture content of the material, which is no more than 1.2%.

9. The method for preparing the composition containing levodopa and benserazide hydrochloride according to any one of claims 5 to 7, characterized in that: In S3, when adding ethyl cellulose and docusate sodium anhydrous ethanol solution, the stirring speed is 50-150 rpm, the cutting speed is 500-1500 rpm, and the liquid addition time is 2-6 minutes. After the liquid addition is completed, the wet granulator is set to a stirring speed of 80-120 rpm, a cutting speed of 1100-1300 rpm, and a granulation time of 1-5 minutes.

10. The method for preparing the composition containing levodopa and benserazide hydrochloride according to any one of claims 5 to 8, characterized in that: In S4, the air inlet temperature is set at 50±5°C, and the material is dried to a temperature of 30-40°C. The machine is stopped to detect the moisture content of the material, which is not more than 2.0%.

11. The method for preparing the composition containing levodopa and benserazide hydrochloride according to any one of claims 5 to 9, characterized in that: In the S5, firstly, the particles A, particles B, cross-linked polyvinylpyrrolidone, colloidal dioxide and magnesium stearate are placed in a granulator for granulation, the sieve of the granulator has a mesh size of Φ1.0mm round hole sieve, and the granulation speed is 200-800rpm; then they are transferred to a mixer for mixing, the mixing speed is 15rpm, and the mixing time is 10min~20min; in the S6, the tableting die is 12.0mm with a cross notch, and the tablet hardness is 5.0-12.0KG.

12. A composition containing levodopa and benserazide hydrochloride prepared by the preparation method according to any one of claims 5 to 10.

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