Carbolevodopa sustained release tablet and preparation method thereof

Abstract

The invention relates to the technical field of pharmacy, and discloses a carbidopa-levodopa sustained release tablet and a preparation method thereof.The carbidopa-levodopa sustained release tablet is prepared from, by mass, 65.4%-68.0% of levodopa, 17.0%-18.5% of carbidopa, 0.1%-0.5% of an adhesive, 0.1%-0.5% of a lubricant and 0.1%-0.5% of a coloring agent. And the mass percentage of the sustained-release material is 8.0%-9.0%. According to the carbidopa-levodopa sustained-release tablet and the preparation method thereof, polyvinyl acetate-crotonic acid copolymer is selected as a sustained-release material, hydroxypropyl cellulose is selected as an adhesive, the defects existing in the prior art are overcome, the carbidopa-levodopa sustained-release tablet can well control slow release of carbidopa and levodopa, and the sustained-release effect is good. According to the present invention, the release curve is highly consistent with the release curve of the original development agent, such that the safety and the effectiveness of the medication can be significantly improved, the wet granulation process is adopted, the addition mode of the adhesive is adjusted, the granulation process problem that the granulation is not easily performed when the active component content is large is solved, the preparation process is simple, and the industrial production is easy.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and specifically relates to a carbidopa and levodopa sustained-release tablet and a preparation method thereof. Background Art

[0002] The carbidopa and levodopa sustained-release tablet, with a specification of 50mg / 200mg, is an original research formulation and is clinically used for the relief and treatment of Parkinson's symptoms. Carbidopa has a strong inhibitory effect on dopa decarboxylase. When carbidopa and levodopa are combined for use, it can inhibit the conversion of levodopa by dopa decarboxylase, increase the amount of levodopa entering the brain, reduce the clinical dosage of levodopa (standard maintenance dose 1.5 - 3.0g / day), and reduce the gastrointestinal reactions frequently caused by the large amount of levodopa used.

[0003] However, during the actual use, the inventor found that there are still the following problems: the active ingredients in the carbidopa and levodopa sustained-release tablet account for nearly 90% in the prescription, and the active ingredients are hydrophobic with poor granulation properties, which brings great challenges to the granulation process. In the existing preparation methods, hydrophilic gel matrices are often used as sustained-release materials, which have a high molecular weight and high viscosity, resulting in poor reproducibility of the preparation process and poor similarity of the in vitro dissolution rate with the original research formulation.

[0004] Based on this, the present invention provides a carbidopa and levodopa sustained-release tablet and a preparation method thereof. Summary of the Invention

[0005] The present invention provides a carbidopa and levodopa sustained-release tablet and a preparation method thereof, selects polyvinyl acetate-crotonic acid copolymer as the sustained-release material and hydroxypropyl cellulose as the binder, solves the defects existing in the prior art, realizes the stable and slow release of carbidopa and levodopa, and achieves a high degree of consistency with the in vitro release rate of the original research formulation.

[0006] The present invention provides the following technical solution: a carbidopa and levodopa sustained-release tablet and a preparation method thereof, including levodopa, carbidopa, a sustained-release material, a binder, a lubricant and a colorant. The mass percentage of levodopa is 65.4% - 68.0%, the mass percentage of carbidopa is 17.0% - 18.5%, the mass percentage of the sustained-release material is 8.0% - 9.0%, the mass percentage of the binder is 4.0% - 6.0%, the mass percentage of the lubricant is 0.9% - 1.1%, and the mass percentage of the colorant is 0.8% - 1.2%.

[0007] Preferably, the sustained-release material is a polyvinyl acetate-povidone mixture, and the mass ratio of polyvinyl acetate to povidone is 80% - 90%:10% - 20%.

[0008] Preferably, the binder is one of hydroxypropyl cellulose (ELF, EXF, EF, LXF, LF).

[0009] Preferably, the lubricant is magnesium stearate.

[0010] Preferably, the colorant is one or two of brilliant blue and allura red.

[0011] A preparation method of carbidopa and levodopa sustained release tablets comprises the following steps:

[0012] (1) Weigh each component according to the designed ratio, add levodopa, carbidopa, sustained release material, part of the binder, and colorant into a wet granulator for premixing to obtain a premix; wherein, the addition amount of part of the binder is 85% - 90% of the total mass of the binder.

[0013] (2) Prepare an aqueous solution of part of the binder; wherein part of the binder is 10% - 15% of the total mass of the binder, and the concentration of the aqueous binder solution is 5% - 8%.

[0014] (3) Add the aqueous binder solution to the premix, carry out wet granulation, screening, drying, and dry screening to obtain granules.

[0015] (4) Mix the granules and the lubricant evenly, and press tablets to obtain carbidopa and levodopa sustained release tablets.

[0016] Compared with the prior art, the present invention has the following beneficial effects:

[0017] The carbidopa and levodopa sustained release tablets and the preparation method thereof solve the defects existing in the prior art by selecting polyvinyl acetate - crotonic acid copolymer as the sustained release material and hydroxypropyl cellulose as the binder. The carbidopa and levodopa sustained release tablets in the present invention can well control the slow release of carbidopa and levodopa, have a high consistency with the release curve of the original research preparation, can significantly improve the safety and effectiveness of medication, and adopt a wet granulation process and adjust the addition method of the binder to solve the granulation process problem that it is not easy to granulate when the proportion of the active ingredient is relatively large. The preparation process is simple and easy for industrial production. Description of the Drawings

[0018] Figure 1 It is a comparison chart of the release curves of the embodiment of the present invention and the original research preparation in 0.1M hydrochloric acid medium (levodopa);

[0019] Figure 2 It is a comparison chart of the release curves of the embodiment of the present invention and the original research preparation in 0.1M hydrochloric acid medium (carbidopa);

[0020] Figure 3Release curve comparison diagram of the embodiment of the present invention and the original developed preparation in pH 4.5 acetate buffer solution (levodopa);

[0021] Figure 4 Release curve comparison diagram of the embodiment of the present invention and the original developed preparation in pH 4.5 acetate buffer solution (carbidopa);

[0022] Figure 5 Release curve comparison diagram of the embodiment of the present invention and the original developed preparation in pH 6.8 phosphate buffer solution (levodopa);

[0023] Figure 6 Release curve comparison diagram of the embodiment of the present invention and the original developed preparation in pH 6.8 phosphate buffer solution (carbidopa). Detailed implementation manners

[0024] Next, the technical solutions in the embodiments of the present invention will be clearly and completely described in conjunction with the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0025] Embodiment 1

[0026] Please refer to Figures 1-6 , a controlled-release tablet of carbidopa and levodopa and its preparation method, including levodopa, carbidopa, a sustained-release material, a binder, a lubricant, and a colorant. The mass percentage of levodopa is 65.4%-68.0%, the mass percentage of carbidopa is 17.0%-18.5%, the mass percentage of the sustained-release material is 8.0%-9.0%, the mass percentage of the binder is 4.0%-6.0%, the mass percentage of the lubricant is 0.9%-1.1%, and the mass percentage of the colorant is 0.8%-1.2%.

[0027] Among them; the sustained-release material is a polyvinyl acetate-povidone mixture, and the mass ratio of polyvinyl acetate to povidone is 80%-90%:10%-20%, and the preferred ratio is 80%:20%.

[0028] Among them; the binder is one of hydroxypropyl cellulose (ELF, EXF, EF, LXF, LF), and hydroxypropyl cellulose LXF is preferred.

[0029] Among them; the lubricant is magnesium stearate.

[0030] Among them; the colorant is one or two of brilliant blue and allura red.

[0031] The prescription composition of this embodiment (batch: 2000 tablets, unit: g):

[0032] Levodopa 400g Carbidopa 108g Polyvinyl acetate-povidone mixture 50g Hydroxypropyl cellulose LXF 30g Brilliant Blue 2g Allura Red 1g Magnesium stearate 6g

[0033] The preparation method of the above-mentioned co-careldopa is as follows: Weigh each component according to the designed ratio, add levodopa, carbidopa, polyvinyl acetate povidone mixture, partial hydroxypropyl cellulose, and colorant into a wet granulator for premixing to obtain a premix; among them, the addition amount of hydroxypropyl cellulose is 27 g, and partial hydroxypropyl cellulose is prepared into an aqueous solution; the dosage of hydroxypropyl cellulose is 3 g, and the preparation concentration is 5%. Add the 5% hydroxypropyl cellulose aqueous solution to the above-mentioned premix, carry out wet granulation, sizing, drying, and dry sizing to obtain granules. Mix the granules and magnesium stearate evenly, and press tablets to obtain co-careldopa sustained-release tablets, where magnesium stearate is added after being calculated according to the dry granule yield.

[0034] Example 2

[0035]

[0036]

[0037] The preparation method of the above-mentioned co-careldopa is as follows: Weigh each component according to the designed ratio, add levodopa, carbidopa, polyvinyl acetate povidone mixture, partial hydroxypropyl cellulose, and colorant into a wet granulator for premixing to obtain a premix; among them, the addition amount of hydroxypropyl cellulose is 23 g, and partial hydroxypropyl cellulose is prepared into an aqueous solution; the dosage of hydroxypropyl cellulose is 3 g, and the preparation concentration is 5%. Add the 5% hydroxypropyl cellulose aqueous solution to the above-mentioned premix, carry out wet granulation, sizing, drying, and dry sizing to obtain granules. Mix the granules and magnesium stearate evenly, and press tablets to obtain co-careldopa sustained-release tablets, where magnesium stearate is added after being calculated according to the dry granule yield.

[0038] When preparing the examples of the present invention, the inventors also studied other alternative sustained-release materials, which are specifically described as follows:

[0039] Comparative Example 1: This comparative example provides a co-careldopa sustained-release tablet and its preparation method. The difference from Example 1 is that the polyvinyl acetate povidone mixture is replaced with an equal amount of hypromellose K4M;

[0040] Comparative Example 2: This comparative example provides a co-careldopa sustained-release tablet and its preparation method. The difference from Example 1 is that the polyvinyl acetate povidone mixture is replaced with an equal amount of quaternary ammonium methyl methacrylate resin type A;

[0041] To investigate the in vitro dissolution of the co-careldopa sustained-release tablets prepared in Examples 1-2 and Comparative Examples 1-2 of the present invention, in vitro dissolution tests were carried out in 0.1 M hydrochloric acid medium, pH 4.5 acetate buffer solution, and pH 6.8 phosphate buffer solution.

[0042]

[0043] Table 1 Results of the dissolution curve determination of the samples in 0.1 M hydrochloric acid medium

[0044]

[0045] Table 2 Results of the dissolution curve determination of the samples in pH 4.5 acetate buffer

[0046]

[0047] Table 3 Results of the dissolution curve determination of the samples in pH 6.8 phosphate buffer

[0048] As can be seen from Tables 1 - 3, the sustained - release effect of the carbidopa - levodopa sustained - release tablets prepared in Examples 1 - 2 of the present invention is highly consistent with the in vitro release curve of the original research formulation in physiologically relevant media, enabling the replacement of the original research formulation. At the same time, the preparation process is simple, stable and controllable, and is easy to realize large - scale industrial production.

[0049] It should be noted that, in this article, relational terms such as first and second are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any actual relationship or order between these entities or operations. Moreover, the term "comprising", "including" or any other variant thereof is intended to cover non - exclusive inclusion, so that a process, method, article or device comprising a series of elements not only includes those elements, but also includes other elements not expressly listed, or further includes elements inherent to such process, method, article or device.

[0050] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions and variations can be made to these embodiments without departing from the principles and spirit of the present invention, and the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A carbendazim sustained-release tablet and a preparation method thereof, characterized in that: The invention comprises levodopa, carbidopa, a sustained-release material, an adhesive, a lubricant and a colorant, wherein the mass percentage of the levodopa is 65.4%-68.0%, the mass percentage of the carbidopa is 17.0%-18.5%, the mass percentage of the sustained-release material is 8.0%-9.0%, the mass percentage of the adhesive is 4.0%-6.0%, the mass percentage of the lubricant is 0.9%-1.1%, and the mass percentage of the colorant is 0.8%-1.2%.

2. A carbendazim sustained-release tablet and a preparation method thereof according to claim 1, characterized in that: The sustained-release material is a polyvinyl acetate-povidone mixture, and the mass ratio of the polyvinyl acetate to the povidone is 80%-90%:10%-20%.

3. A carbendazim sustained-release tablet and a preparation method thereof according to claim 1, characterized in that: The binder is one of hydroxypropyl cellulose (ELF, EXF, EF, LXF, LF).

4. A carbendazim sustained-release tablet and a preparation method thereof according to claim 1, characterized in that: The lubricant is magnesium stearate.

5. The sustained-release tablet of carbendazim and the preparation method thereof according to claim 1, characterized in that: The colorant is one or both of brilliant blue and allure red.

6. A method for preparing a carbocycline-containing sustained-release tablet according to claims 1-5, comprising the following steps: (1) Weighing each component according to the designed ratio, adding levodopa, carbidopa, sustained-release material, part of the binder, and colorant into a wet granulator for premixing to obtain a premix; wherein the amount of the part of the binder added is 85% to 90% of the total mass of the binder; (2) preparing a part of the adhesive into an aqueous solution; wherein the part of the adhesive accounts for 10% to 15% of the total mass of the adhesive, and the concentration of the adhesive aqueous solution is 5% to 8%; (3) adding a binder aqueous solution to the premix, performing wet granulation, granulation, drying and dry granulation to obtain granules; (4) Evenly mix the granules and lubricant, and compress the mixture into tablets to obtain Levodopa sustained-release tablets.

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