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EP-4736851-A1 - LEVODOPA-BENSERAZIDE HYDROCHLORIDE COMPOSITION AND PREPARATION THEREFOR

EP4736851A1EP 4736851 A1EP4736851 A1EP 4736851A1EP-4736851-A1

Abstract

Provided in the present invention are a pharmaceutical composition used for treating Parkinson's disease and a preparation method therefor. Tablets prepared from the pharmaceutical composition have better stability, and involve a simple production process, thus facilitating commercial production.

Inventors

  • ZHU, Lulu
  • ZHANG, Zhengzan
  • LOU, Guichuan
  • SHEN, Jiaxu
  • JIANG, Shiyong
  • LU, Jinping
  • ZHAO, Zhouming
  • GUO, XIAODI

Assignees

  • Zhejiang Huahai Pharmaceutical Co., Ltd.

Dates

Publication Date
20260506
Application Date
20240618

Claims (10)

  1. A co-beneldopa composition comprising levodopa, benserazide hydrochloride, and calcium hydrogen phosphate, characterized in that the calcium hydrogen phosphate has a D50 ≤ 12 µm, preferably, the calcium hydrogen phosphate has a D50 of 8 to 12 µm.
  2. The composition according to claim 1, characterized in that the calcium hydrogen phosphate is anhydrous calcium hydrogen phosphate.
  3. The composition according to claim 1 or 2, characterized in that the composition comprises the following components by weight: 200 parts of levodopa, 57 parts of benserazide hydrochloride, and 55 to 275 parts of calcium hydrogen phosphate; preferably, 99 to 102 parts of calcium hydrogen phosphate.
  4. The composition according to any one of claims 1-3, characterized in that the composition further comprises one or more of a filler, a binder, a disintegrant, a solubilizer and a lubricant.
  5. The composition according to any one of claims 1-4, characterized in that : the filler is selected from one or more of microcrystalline cellulose, mannitol, lactose and corn starch, preferably selected from one or more of microcrystalline cellulose and mannitol; the binder can be selected from one or more of pregelatinized starch, ethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose and polyethylene glycol, preferably selected from one or more of pregelatinized starch and ethyl cellulose; the disintegrant can be selected from one or more of crospovidone, croscarmellose sodium, sodium carboxymethyl starch and sodium alginate, preferably crospovidone; the solubilizer is selected from one or more of docusate sodium and sodium dodecyl sulfate; the lubricant is selected from one or more of magnesium stearate, sodium stearyl fumarate, sodium stearate and colloidal silicon dioxide, preferably selected from one or more of magnesium stearate and colloidal silicon dioxide.
  6. The composition according to any one of claims 1-5, characterized in that the composition comprising the following components by weight: Levodopa 200 parts Benserazide Hydrochloride 57 parts Calcium Hydrogen Phosphate 55 to 275 parts Microcrystalline Cellulose 20 to 60 parts Mannitol 50 to 150 parts Pregelatinized Starch 10 to 30 parts Ethyl Cellulose 0 to 6 parts Crospovidone 5 to 25 parts Colloidal Silicon Dioxide 0 to 3 parts Magnesium Stearate 2 to 8 parts Docusate Sodium or Sodium Lauryl Sulfate 0 to 2 parts
  7. Use of the composition according to any one of claims 1-6 in the manufacture of a medicament for treating Parkinson's disease, Parkinson's syndrome, and restless legs syndrome.
  8. The use according to claim 7, characterized in that the medicament is a solid preparation, preferably a tablet or a capsule.
  9. A preparation method for a co-beneldopa tablet, characterized by comprising compressing the composition according to any one of claims 1-6 into a tablet.
  10. The preparation method according to claim 9, characterized in that the preparation method specifically comprises: (1) granulation: mixing levodopa, benserazide hydrochloride, calcium hydrogen phosphate, and one or more of a filler, a binder, a disintegrant, and a solubilizer to obtain granules for tableting; (2) tableting: mixing the granules with a lubricant and then tableting; optionally, a sieving treatment is performed before and after the granulation.

Description

The present application claims the priority of Chinese Patent Application No. CN202310766123.5, filed on June 27, 2023, which is incorporated herein by reference in its entirety. TECHNICAL FIELD The present application belongs to the field of pharmaceutical technology, in particular to a co-beneldopa pharmaceutical composition and preparation therefor. BACKGROUND Parkinson's disease (PD) is the second most common neurodegenerative disease in department of neurology, after Alzheimer's disease. It is estimated that there were up to 9.4 million patients worldwide in 2020. The main pathological changes are degeneration and death of midbrain substantia nigra dopaminergic neurons, a significant decrease of dopamine (DA) content in striatum, and an appearance of eosinophilic inclusion bodies, i.e. Lewy bodies, in the cytoplasm of residual neurons of the substantia nigra. Among the various treatment methods for Parkinson's disease, drug therapy is still the most effective. By maintaining the balance of the two neurotransmitters, dopamine and acetylcholine, in the striatum, the clinical symptoms are improved. The drugs mainly include levodopa, DA receptor agonists, MAO-B inhibitors, COMT inhibitors, and the like. Co-Beneldopa is a combination of levodopa and benserazide hydrochloride in a ratio of 4:1. It was first approved for marketing in Europe in 1973 and subsequently launched in many countries, including Japan and China. As a classic compound for the treatment of Parkinson's disease and Parkinson plus syndrome, it has been used clinically for many years with definite efficacy and low cost. Wherein the chemical name of benserazide hydrochloride is 2-[(2,3,4-trihydroxyphenyl)methyl]hydrazide-DL-serine hydrochloride. Its chemical structural formula is as follows: Benserazide hydrochloride is unstable under alkaline, light, and humidity-heat conditions, and is particularly unstable under humid-heat conditions. As temperature or humidity increases, the degradation of benserazide accelerates, primarily yielding the following two degradation impurities: Impurity A: (2RS)-2-amino-3-hydroxypropanehydrazide, and Impurity B: (2RS)-2-amino-3-hydroxy-N,N-bis(2,3,4-trihydroxybenzyl)propanehydrazide. Furthermore, the content of these two impurities increases significantly over time. Ma Guizhi et al. (Study on the Influencing Factors of Chemical Stability of Benserazide Hydrochloride [J], China Medical Herald, 2014, 11(35)) discloses the changes in the content of benserazide hydrochloride with temperature and humidity. The results are shown in Table 1 and Table 2. Table 1 Effect of Temperature on the Content of Benserazide HydrochlorideTemperature (°C)5d10d25100.02±0.97100.00±1.314097.89 ±1.5495.43 ±4.576094.33±5.5690.86±5.04Table 2 Effect of Humidity on the Content of Benserazide HydrochlorideRelative Humidity(%)5d10d0100.02±1.42100.00±1.196067.43±2.111.84±0.987532.11±1.130.00±0.00 CN101797144A discloses a co-beneldopa orally disintegrating tablet and preparation therefor. However, currently only conventional preparation of co-beneldopa tablets are available on the domestic market. The orally disintegrating tablets are not marketed and are not clinically available. CN101623278B discloses a pharmaceutical composition containing levodopa and benserazide hydrochloride. A carrier substance containing benserazide hydrochloride is obtained by spray drying, and then mixed uniformly with other excipients before being compressed into tablets. However, as it uses ethanol solution that is easily evaporated and explosive to prepare the drug-containing carrier via spray drying, which imposes high requirements on production equipment, production facilities, and production operations, it is not conducive to large-scale production. During the preparation of the co-beneldopa composition, the inventors found that the particle size of calcium hydrogen phosphate significantly affects the stability of the co-beneldopa composition and of the co-beneldopa tablets or capsules prepared therefrom. When the particle size of calcium hydrogen phosphate is too large, the degradation of benserazide hydrochloride accelerates, and the contents of Impurity A and Impurity B increase significantly, thereby adversely affecting the clinical efficacy and safety of the co-beneldopa preparation. Furthermore, none of the various prior art solutions discloses how to obtain a co-beneldopa composition that is easier to scale up for production and exhibits good stability. Therefore, it is necessary to develop a co-beneldopa composition that is easier to scale up for production and exhibits good stability, and a solid preparation prepared therefrom. SUMMARY OF THE INVENTION To solve the above problem, the present application provides a co-beneldopa composition comprising levodopa, benserazide hydrochloride, and calcium hydrogen phosphate, wherein the calcium hydrogen phosphate has a D50 ≤ 12 µm. According to an embodiment of the present application, the D50 of the calcium