Carbidopa-levodopa pharmaceutical composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, and particularly discloses a carbidopa-levodopa pharmaceutical composition and a preparation method thereof.The carbidopa-levodopa pharmaceutical composition is composed of carbidopa, levodopa, a sustained-release material, an adhesive, a coloring agent and magnesium stearate, the sustained-release material is selected from one or a combination of two of hydroxypropyl cellulose MF and hydroxypropyl cellulose LF, and the adhesive is cellulose; in percentage by weight, the dosage of the slow-release material hydroxypropyl cellulose MF is 0.1-20.0%; and in percentage by weight, the dosage of the slow-release material hydroxypropyl cellulose LF is 0.1-20.0%. According to the carbidopa-levodopa sustained-release tablet disclosed by the invention, original and auxiliary bags in the prescription are accessible, the cost is low, the preparation process is simple and controllable, commercialized mass production can be realized, and the quality of the prepared product is consistent with that of the Ninning.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, in particular to a carbendazim-levodopa pharmaceutical composition and a preparation method thereof. Background Art

[0002] Parkinson's disease, also known as tremor paralysis, is a common degenerative disease of the nervous system in the elderly. Its clinical manifestations are mainly resting tremor as the first symptom, muscle rigidity, bradykinesia, and postural balance disorders.

[0003] The existing composition for treating Parkinson's disease mainly consists of levodopa and carbidopa. Levodopa is the key drug ingredient for treating Parkinson's disease. It can be converted into dopamine in the brain to supplement the dopamine deficiency in Parkinson's patients, thereby alleviating the symptoms of Parkinson's disease, such as tremor, muscle stiffness and bradykinesia. Carbidopa can inhibit the decomposition of levodopa in peripheral tissues, increase the amount of levodopa entering the brain, improve its therapeutic effect, and reduce the occurrence of side effects.

[0004] Xining (Carbodiol sustained-release tablets) uses polyvinyl acetate-crotonic acid copolymer as a pharmaceutical carrier. This excipient is not available in China, which limits the commercial production of Carbodiol sustained-release tablets. There are very few Carbodiol sustained-release tablets generic drugs on the market in China. At present, there is an urgent need for an alternative preparation with accessible raw materials and excipients, simple and controllable preparation process, low cost, and the same quality as Xining (Carbodiol sustained-release tablets). For this purpose, a Carbodiol pharmaceutical composition and a preparation method thereof are provided. Summary of the invention

[0005] The purpose of the present invention is to provide a carbendazim-levodopa pharmaceutical composition and a preparation method thereof in view of the defects of the prior art, so as to solve the problems raised by the above-mentioned background technology.

[0006] To achieve the above object, the present invention provides the following technical solution: a carbidopa-levodopa pharmaceutical composition and a preparation method thereof, comprising carbidopa, levodopa, a sustained-release material, a binder, a colorant, and magnesium stearate, wherein the sustained-release material is selected from one or a combination of hydroxypropylcellulose MF and hydroxypropylcellulose LF, and the binder is cellulose.

[0007] As a preferred technical solution of the present invention, the amount of the sustained-release material hydroxypropylcellulose MF is 0.1-20.0% by weight.

[0008] As a preferred technical solution of the present invention, the amount of the sustained-release material hydroxypropyl cellulose LF is 0.1-20.0% by weight.

[0009] As a preferred technical solution of the present invention, the adhesive is one or a combination of two of hypromellose and hydroxypropyl cellulose.

[0010] As a preferred technical solution of the present invention, the colorant is red iron oxide and quinoline yellow aluminum lake.

[0011] As a preferred technical solution of the present invention, in terms of weight percentage, the amount of carbidopa is 10.0-30.0%, the amount of levodopa is 60.0-80.0%, the amount of sustained-release material is 0.1-40.0%, the amount of binder is 0.1-20.0%, the amount of colorant is 0.05-10.0%, and the amount of magnesium stearate is 0.5-10.0%.

[0012] A method for preparing a carboplatin-containing pharmaceutical composition, comprising the following specific steps:

[0013] Step 1: Pre-treat carbidopa and levodopa to control particle size. 90 Control 10~150μm, L-dopa D 90 10~125μm;

[0014] Step 2: adding carbidopa, levodopa, sustained-release material, binder, and colorant into a wet granulator for mixing;

[0015] Step 3: Add a binder and a wetting agent to the material in step 2 to granulate and dry;

[0016] Step 4: The granules in step 3 are sized, magnesium stearate is added for overall mixing, and tableting is performed.

[0017] As a preferred technical solution of the present invention, the wetting agent is selected from water or ethanol solution.

[0018] Compared with the prior art, the present invention has the following beneficial effects: the carbocycline-levodopa sustained-release tablets of the present invention have accessible excipients in the prescription and low cost, and the preparation process is simple and controllable, and commercial mass production can be achieved. The prepared product has the same quality as that of Sinime, and the problem that the existing Sinime adopts polyvinyl acetate-crotonic acid copolymer as a pharmaceutical carrier, and the excipient is not available in China, which limits the commercial production of carbocycline-levodopa sustained-release tablets, and therefore there are very few generic carbocycline-levodopa sustained-release tablets on the market in China is solved. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 This is a graph of the blood concentration of carbidopa (before meal) of the present invention;

[0020] Figure 2 This is a graph of levodopa blood concentration (before meal) of the present invention;

[0021] Figure 3 This is a graph of carbidopa blood concentration (after meal) of the present invention;

[0022] Figure 4 This is a graph of the levodopa blood concentration (after meal) of the present invention. DETAILED DESCRIPTION

[0023] The preferred embodiments of the present invention are described in detail below in conjunction with the accompanying drawings so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention.

[0024] Embodiment 1:

[0025] Prescription composition:

[0026]

[0027] Preparation method: Weigh the prescribed amount of raw and auxiliary materials and mix them in a wet granulator. After mixing evenly, add a wetting agent for wet granulation. After granulation, dry and granulate, add magnesium stearate for total mixing, and press into tablets after mixing evenly.

[0028] Embodiment 2:

[0029] Prescription composition:

[0030]

[0031] Preparation method: Weigh the prescribed amount of raw and auxiliary materials and mix them in a wet granulator. After mixing evenly, add a wetting agent for wet granulation. After granulation, dry and granulate, add magnesium stearate for total mixing, and press into tablets after mixing evenly.

[0032] Embodiment 3:

[0033] Prescription composition:

[0034]

[0035]

[0036] Preparation method: Weigh the prescribed amount of raw and auxiliary materials and mix them in a wet granulator. After mixing evenly, add a wetting agent for wet granulation. After granulation, dry and granulate, add magnesium stearate for total mixing, and press into tablets after mixing evenly.

[0037] Verification example:

[0038] Dissolution curve determination:

[0039] Referring to the dissolution method of the import registration standard for Carbidopa-Levodopa sustained-release tablets (standard number: JX20210099), "the dissolution conditions are 900 mL of 0.1 mol / L hydrochloric acid as the dissolution medium, the rotation speed is 50 revolutions per minute, and the operation is carried out in accordance with the law. Sampling is carried out after 30, 60 and 150 minutes." The dissolution curves of batches 1 to 15 of the prescription were investigated.

[0040] Dissolution Summary

[0041]

[0042] Summary of carbidopa dissolution curves

[0043]

[0044] Summary of Levodopa dissolution curves

[0045]

[0046]

[0047] Content, related substances:

[0048]

[0049]

[0050] Conclusion: The dissolution curves of the preparations granulated with purified water / ethanol solution using hydroxypropylcellulose MF and LF as sustained-release materials and hydroxypropyl methylcellulose as a binder can be similar to that of Sinimelast (Carbopol sustained-release tablets) (f2>50). However, stability tests showed that the increase trend of related substances in prescriptions 8-10 and 13-14 granulated with ethanol was slightly faster than that in prescriptions 1-7 and 11-12 granulated with water, and the content of prescription 15 showed a decreasing trend.

[0051] Objective: To investigate the effects of a single oral dose of carbidopa 50 mg, levodopa 200 mg and a reference preparation of Sinimetin (carbidopa 50 mg, levodopa 200 mg, Licensee: MSDSharp&Dohme GmbH) to evaluate the pharmacokinetic (PK) characteristics of carbidopa and levodopa in healthy Chinese subjects after oral administration in fasting and fed states, and to evaluate the bioequivalence of the two preparations after oral administration in fasting and fed states. To evaluate the safety of the test preparation carbidopa-levodopa sustained-release tablets and the reference preparation carbidopa-levodopa sustained-release tablets after a single oral administration in healthy Chinese subjects in fasting and fed states.

[0052] Experimental design: 12 subjects were enrolled in the fasting trial, and 12 subjects were enrolled in the postprandial trial. Both trials adopted a single-center, randomized, open, two-drug, two-cycle, double-crossover design, with a washout period of 7 days between cycles.

[0053] Blood collection time points: fasting blood collection time points: before administration (0h) and 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 7h, 8h, 10h, 14h, 24h, 36h after administration, a total of 20 blood collection points, and about 4mL of venous blood was collected at each time;

[0054] Postprandial blood collection time points: before administration (0h) and 0.25h, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 7h, 8h, 9h, 10h, 14h, 24h, and 36h after administration, a total of 21 blood collection points, and approximately 4mL of venous blood was collected at each time.

[0055] like Figure 1-4 As shown, the blood concentration-time curves of the study preparation and Sinime are basically consistent, and the geometric mean ratios of AUC0-t, AUC0-∞, and Cmax before and after meals and their 90% confidence intervals are in the range of 80.00 to 125.00%, indicating that the study preparation is bioequivalent to Sinime.

[0056] The above embodiments only express the implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention.

Claims

1. A carbendazim-levodopa pharmaceutical composition, characterized in that: The invention is composed of carbidopa, levodopa, a sustained-release material, a binder, a colorant and magnesium stearate. The sustained-release material is selected from one or a combination of hydroxypropylcellulose MF and hydroxypropylcellulose LF, and the binder is cellulose.

2. The carbocycline-levodopa pharmaceutical composition according to claim 1, characterized in that: Calculated by weight percentage, the dosage of the sustained-release material hydroxypropylcellulose MF is 0.1-20.0%.

3. The carbendazim pharmaceutical composition according to claim 1, characterized in that: Calculated by weight percentage, the dosage of the sustained-release material hydroxypropylcellulose LF is 0.1-20.0%.

4. The carbendazim-levodopa pharmaceutical composition according to claim 1, characterized in that: The binder is one or a combination of hydroxypropyl methylcellulose and hydroxypropyl cellulose.

5. The carbendazim-levodopa pharmaceutical composition according to claim 1, characterized in that: The colorants are red iron oxide and quinoline yellow aluminum lake.

6. The carbendazim-levodopa pharmaceutical composition according to claim 1, characterized in that: In terms of weight percentage, the amount of carbidopa is 10.0-30.0%, the amount of levodopa is 60.0-80.0%, the amount of sustained-release material is 0.1-40.0%, the amount of binder is 0.1-20.0%, the amount of colorant is 0.05-10.0%, and the amount of magnesium stearate is 0.5-10.0%.

7. A method for preparing the carbocycline-levodopa pharmaceutical composition according to any one of claims 1 to 6, characterized in that: The specific steps are as follows: Step 1: Pre-treat carbidopa and levodopa to control particle size. 90 Control 10~150μm, L-dopa D 90 10~125μm; Step 2: adding carbidopa, levodopa, sustained-release material, binder, and colorant into a wet granulator for mixing; Step 3: Add a binder and a wetting agent to the material in step 2 to granulate and dry; Step 4: The granules in step 3 are sized, magnesium stearate is added for overall mixing, and tableting is performed.

8. The method for preparing the carbocycline-levodopa pharmaceutical composition according to claim 7, characterized in that: The wetting agent is selected from water or ethanol solution.

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