CN111701024B

CN111701024B - Levodopa preparation and preparation method and application thereof

Info

Publication number: CN111701024B
Application number: CN202010455930.1A
Authority: CN
Inventors: 陈琰; 刘烁华; 鹿月; 侯建
Original assignee: Shanghai Jingxin Biological Medical Co ltd
Current assignee: Shanghai Jingxin Biological Medical Co ltd
Priority date: 2020-05-26
Filing date: 2020-05-26
Publication date: 2022-05-24
Anticipated expiration: 2040-05-26
Also published as: CN111701024A

Abstract

The invention discloses a levodopa preparation which comprises the following components: 13-36 wt% of levodopa, a dopa decarboxylase inhibitor with a weight ratio of levodopa to levodopa of 1: 4-10, arginine with a molar sum of levodopa and dopa decarboxylase inhibitor of 0.3-1.0: 1, meglumine with a molar sum of levodopa and dopa decarboxylase inhibitor of 0.05-0.8: 1, a pH regulator for regulating the pH of the solution to 9.6-10, 0.01-1 wt% of an antioxidant, 0.01-0.5 wt% of EDTA, and the balance of water. The levodopa preparation is a high-concentration solution preparation, the volume of a unit preparation can be reduced to 3mL, and the levodopa preparation can be used together with a second-generation patch pump, so that the use convenience and the medication compliance of patient treatment are improved. The invention also discloses a preparation method and application of the levodopa preparation.

Description

Levodopa preparation and preparation method and application thereof

Technical Field

The invention belongs to the technical field of medicines, relates to a compound composition, and particularly relates to a levodopa preparation and a preparation method and application thereof.

Background

First, Parkinson's disease incidence and medication requirement

Parkinson is a nervous system degenerative disease, and the incidence of the disease is high in the elderly over 65 years old. According to the estimation, the number of Parkinson patients in China is nearly 300 million at present, the number of Parkinson patients accounts for 50% of the number of Parkinson patients in the world, and with the serious aging and the prolonged life of the people in China, 500 million Parkinson patients are predicted to exist in 2030.

Levodopa drugs have been considered as milestone drugs for treating parkinson's disease, and as intermediate metabolic precursors of dopamine, levodopa drugs can penetrate the blood brain barrier and restore the concentration of dopamine in the brain. However, it is known that levodopa is catalyzed by an aromatic L-amino acid decarboxylase to realize conversion to dopamine, which is commonly present in intestinal mucosa, liver, brain and cerebral capillaries and has a high concentration, so that levodopa needs to be used in a large dose to obtain high-concentration dopamine in the brain, which causes nausea and other toxic and side effects after some patients take levodopa. Therefore, in general, when levodopa is orally taken, a dopa decarboxylase inhibitor such as carbidopa is also taken at the same time, so that the dosage of the levodopa can be reduced, and the generation of side effects can be avoided. However, after a patient takes levodopa medicine for a long time, a serious and difficult-to-cure delayed side effect is caused, and the effect is named as an 'on-off' phenomenon. The 'off effect' phenomenon is mainly caused by wave troughs in drug effect fluctuation after the levodopa drugs are orally taken, and the 'on-off effect' drug effect concentration range of severe Parkinson patients is narrowed, so that the wave trough time of the required blood concentration is prolonged, and the 'off effect' patients at the wave troughs of the blood concentration can not move at all, thereby seriously affecting the life quality. There is therefore a clinical need for a means of continuously delivering dopamine to the brain, thereby maintaining blood levels and ameliorating the "off-effect" phenomenon.

Second, the formulation on the market and development progress of levodopa and carbidopa

Levodopa (LD) and Carbidopa (CD) are the most commonly used pharmaceutical combinations for the treatment of Parkinson's disease, and various preparations are currently on the market, for example

And

and the like, as a rapid release oral tablet, it is difficult to maintain the blood concentration stably for a long period of time. Application publication CN 135809A discloses an oral solid composition of levodopa/carbidopa/entacapone for treating Parkinson's disease, which uses three drugsFixed dose compositions are prepared instead of taking individual tablets, and are administered as needed when the dose is "almost exhausted". Although the situation of taking two tablets for multiple times is improved, the composition still needs to be taken for multiple times every day, the dosage can reach 8-10 times a day, the compliance of a patient is not high, and continuous dopamine stimulation cannot be provided. Application publication CN 1901879 a provides an oral controlled delivery dosage structure for controllably delivering levodopa and carbidopa contained within the controlled delivery dosage structure at an effective rate to maintain a desired plasma drug concentration. The invention of application publication CN 101910113A relates to a controlled release preparation containing levodopa, decarboxylase inhibitor and carboxylic acid, and the drug is controlled to release by adding controlled release excipient, so as to maintain the plasma and serum concentration of levodopa to be relatively stable. The existing controlled release tablets comprise permeation equipment, coating tablets and the like, and the existing controlled release tablets comprise polymers or polymer coating materials for controlling release rate so as to control the release of levodopa or carbidopa, the preparation process is complex, the price of raw materials is expensive, the controlled release preparation needs large dose to realize long-acting effect, and the drug release is unpredictable; in addition, oral drugs need to be absorbed through intestines and stomach and then reach the brain, and the onset process is easy to change. Therefore, the conventional oral preparation or the sustained and controlled release preparation has obvious limitation on maintaining stable blood concentration for a long time, and the 'off effect' effect on the severe Parkinson disease is not ideal.

The application laid-open patent CN 104940224A relates to an inhalation type pharmaceutical composition for treating Parkinson's disease and a preparation method thereof, the inhalation type pharmaceutical composition comprises a first gas (containing atomized liquid medicine) and a second gas, the inhalation type administration mode is convenient for patients to take, hydrogen is taken as the first gas, malignant free radicals in the bodies of the patients can be removed, and the drug absorption curative effect of the patients is improved through the atomized liquid medicine (levodopa and the like); in the end of 2018, Acorda's pharmaceutical announcements that, based on the clinical phase 3 efficacy key trial, safety and tolerability assessment by INBRUA, which is an inhaled levodopa that is convenient for the patient to self-administer and is intended to provide precise doses of levodopa dry powder formulations to the lungs, the FDA approved INBRUA for intermittent treatment during the "off" period of parkinson's disease receiving carbidopa/levodopa. The inhalant overcomes the defects of the traditional oral preparation, can directly enter the body through the lung, reduces the first-pass effect of the medicine, directly reaches the brain, has quick response, can effectively improve the 'off' stage symptoms of Parkinson patients by INBRUA, and has important therapeutic significance for the late-stage Parkinson disease. However, the preparation is mainly used for rapidly improving the 'off effect', and cannot provide a continuous blood concentration to continuously exert the drug effect; medication needs to be synergistic, which is more complex for elderly patients; the cost of the inhalation device is high, the bioavailability of the pulmonary administration has large individual difference, and the long-term use of auxiliary materials is easy to cause local inflammatory reaction.

Commercial enema

(Levodopa/carbidopa enteric gels) are used to treat advanced Parkinson's disease. The conventional drug combination can not obviously inhibit the motor fluctuation or the dyskinesia, so a permanent entry catheter is firstly inserted through the abdominal wall percutaneous endoscopic gastrostomy and then CADD-Legacy is utilized

The pump delivers the drug directly to the duodenum or jejunum.

The preparation has good response in the market at present, can realize continuous dopamine administration, has good effect on improving the 'switch' phenomenon, and can reduce the severity of dyskinesia compared with the standard oral preparation. However, this mode of administration is quite inconvenient for the patient, firstly because of the surgical trauma caused by the insertion into the fistula and secondly because of the risk of sedimentation of the drug particles during storage and administration of the gel.

Therefore, a medicine suitable for the patients with the advanced Parkinson disease is needed clinically, can maintain a stable blood concentration level, continuously take effect, reduce toxic and side effects and solve the problems of 'switching phenomenon' and dyskinesia of the patients with the advanced Parkinson disease. Patent CN 102338587B/CN 103442693A et al discloses a composition for continuous administration of a dopa decarboxylase inhibitor, using continuous subcutaneous injection of carbidopa and simultaneous oral administration of levodopa and carbidopa, thereby achieving the purpose of reducing the number of oral administrations or the dose of levodopa, thereby achieving the treatment of parkinson's disease, including carbidopa and levodopa a salts and compositions comprising, for example, carbidopa a salts or optionally also entacapone or tolcapone or pharmaceutically acceptable compositions thereof; the invention can provide stable blood concentration, is non-invasive and convenient to use, but still needs to be combined with oral medicines, so the use is still troublesome. Application publication CN 105209029 a invented a composition for parenteral administration of carbidopa and levodopa or their pharmaceutically acceptable salts with 2-3 oral daily COMT inhibitors, causing inconvenience for patients in use.

Most injections adopt a physiologically acceptable pH range of pH 4-9, and the patent (CN 102338587B/CN 103442693A/CN 105209029A) emphasizes that the content of levodopa in a solution is not more than 12%, and the pH value is 8-10, so that on one hand, the pH value of the solution is improved to increase the solubility of levodopa, but the overhigh pH value can generate irritation to the organism; therefore, in order to completely dissolve levodopa, the injection preparations in the above patents are about 6mL, and thus there is a problem that the solution volume is large in use, and it is inconvenient to carry around, and it is not possible to use them with the second-generation patch-type infusion pump having a volume of about 2-4 mL. The patch type infusion pump is small in size, can be directly attached to the skin of a patient, and a retention needle can be directly inserted into the subcutaneous part, so that the first generation infusion pump is free from being bound by an externally-hung infusion tube, the patch type infusion pump is convenient for the patient to use, and the medication compliance of the patient is improved. The patch type infusion pump can continuously inject the micro preparation into a patient body for 24 hours, but because the volume is greatly reduced, in order to achieve 24 hours of continuous administration dosage (the LD dosage of 24 hours is 720mg, the CD dosage is 90mg), the patch type infusion pump is adopted on the premise that the concentrations of LD and CD in the injection respectively need to reach 180-360 mg/mL and 22.5-45 mg/mL. However, the existing prescription formulations do not achieve such high solubility and maintain stability of the formulation and therefore cannot be used with second generation patch-type infusion pumps.

Technical problems to be solved by combining levodopa preparation with second generation patch type infusion pump

1. Low solubility

LD and CD are only slightly soluble in water, and the saturated solubility in pure water is 3.7mg/mL and 1.4mg/mL, respectively. In addition, the applicant finds that the dissolution promoting effect of common surfactants, propylene glycol and other organic solvents is not obvious in earlier research, the saturated solubility of the drug is improved when the pH value is increased, but the saturated solubility is still far lower than the target solubility, and the experimental results are shown in the following table 1; meanwhile, the applicant also conducts experiments according to the prescription of the application published patent CN 103442693A, and although the LD solubility is greatly improved, the demand of the second generation patch type infusion pump is still difficult to meet.

TABLE 1 solubility of levodopa and carbidopa in different media

2. Poor stability

Molecular structures of LD and CD have phenolic hydroxyl groups, so that the LD and CD are easy to oxidize, oxidation products are complex and various, and complex compounds such as p-benzoquinone and the like generally exist. LD and CD are sensitive to oxygen and are very prone to darkening when exposed to air. Even under the condition of keeping out of the sun, the content of the LD aqueous solution is reduced by more than 7 percent after the LD aqueous solution is placed for 4 days at room temperature, and the color is changed from light yellow to reddish brown; whereas the CD content decreased by as much as 44% and the color changed from colorless to dark brown.

The oxidative degradation chain reaction mechanism of CD is described in the document "Oxidation of cardiovascular by tyrosine and its effect on microorganism melanoma", and is specifically shown in the following reaction formula.

In the prior art, the addition of antioxidants slows the oxidation of LD and CD, but when the concentrations of LD and CD increase to a certain level, the effectiveness of the antioxidants is greatly compromised. The applicant has repeated the formulation in the prior patent, and when the contents of LD and CD are increased, on one hand, the complete dissolution is difficult, and on the other hand, the medicinal liquid is rapidly changed from light yellow to brown and black at room temperature, and the stability is poor. The applicant detects the larger impurity RRT 2.70\ RRT 4.01 in the liquid medicine by LC-MS, determines the molecular weight of the impurity and can basically determine the impurity in the above documents.

Chain reaction mechanism of CD oxidative degradation

Disclosure of Invention

Aiming at the technical problems that in the prior art, levodopa preparations have unevenness, inconvenience, poor compliance and the like, and high-concentration solution preparations cannot be prepared and combined with patch type infusion pumps due to poor solubility and stability of levodopa, the invention aims to provide an ultrahigh-concentration and stable-quality levodopa preparation which can be combined with a small-volume patch infusion pump for use, is convenient for patients to carry and use, and can effectively improve the medication compliance. The preparation is administrated by a patch infusion pump, is suitable for patients with advanced Parkinson, can reduce metabolism of levodopa in peripheral systems, enables more levodopa to enter a central system to exert drug effect, maintains stable blood concentration, and solves the problems of 'switching on and off' and dyskinesia of patients with severe Parkinson.

The levodopa preparation of the invention comprises the following components: 13-36 wt% of levodopa, a dopa decarboxylase inhibitor with a levodopa weight ratio of 1: 4-10 (i.e. the weight ratio of the dopa decarboxylase inhibitor to levodopa is 1: 4-10, and the other similar descriptions in the application are similar to the above description), arginine with a ratio of the sum of the moles of levodopa and dopa decarboxylase inhibitor being 0.3-1.0: 1, meglumine with a ratio of the sum of the moles of levodopa and dopa decarboxylase inhibitor being 0.05-0.8: 1, a pH regulator for regulating the pH of the solution to 9.6-10, 0.05-1 wt% of an antioxidant, 0.01-0.5 wt% of EDTA, and the balance of water; the antioxidant is selected from sodium metabisulfite or a combination of sodium metabisulfite and a radical trapping antioxidant.

The levodopa preparation is an injection for patch type infusion pumps with the specification of 2-4 mL, preferably 3-4 mL, and is a high-concentration liquid compound preparation, compared with a 6mL injection preparation of the patent CN 103442693A, the volume of the levodopa preparation is greatly reduced, a patient can use the levodopa preparation for 24 hours comfortably and conveniently, the volume per unit time in the continuous administration process is very small, and the medication compliance can be greatly improved.

The solution type preparation usually has the solubility reaching the preparation requirement at normal temperature, but for the levodopa preparation, a large amount of arginine and meglumine are added in the prescription of the prior patent to assist the dissolution, and the solution type preparation is prepared only by adjusting the pH to be proper, however, the stable high-concentration solution type preparation cannot be prepared by adopting the prescription of the prior patent, and the problems of turbidity and precipitation appear in a very short time after the preparation is cooled. Therefore, the problems of insufficient solubility and instability of levodopa and dopa decarboxylase inhibitors are solved by adjusting the dosage of the cosolvent arginine and meglumine and optimizing the antioxidant and the metal ion complexing agent in the formula of the compound preparation, and a foundation is laid for preparing the high-concentration compound preparation.

The levodopa preparation has the levodopa content of 13-36 wt% which is far higher than that of the existing preparation used in clinic, and is used as a basis for being used with a patch infusion pump. Further, the levodopa content may be preferably 15 to 30 wt%, more preferably 15 to 28 wt%, and still more preferably 15 to 24 wt%. If the levodopa content is lower than 13 wt%, the high-concentration preparation and portability of the invention can not be achieved; if the levodopa content is higher than 36 wt%, the levodopa is difficult to dissolve, and turbidity and precipitation are easy to occur, so that the problem of non-uniform solution is caused.

Preferably, the dopa decarboxylase inhibitor is selected from carbidopa, entacapone, tolcapone, and serine hydrazine, or a mixture of two or more thereof.

In the existing compound levodopa carbidopa preparation on the market, the content ratio of LD to CD is 4: 1-10: 1, and a small amount of CD can reduce the degradation of LD in the peripheral system and promote more LD to enter the central nervous system to exert the drug effect.

Furthermore, the carbidopa is selected as the dopa decarboxylase inhibitor, and the levodopa and carbidopa compound preparations with different proportions are subjected to parallel comparison, so that the dosage of the drug can be minimized under the same drug effect when the carbidopa is about one eighth of the levodopa, and the toxic and side effects of the drug are minimized.

Furthermore, the optional weight ratio of carbidopa to levodopa is 1: 7.5-8.5, preferably 1: 7.6-8.4, preferably 1: 7.7-8.3, preferably 1: 7.8-8.2, more preferably 1: 7.9-8.1, and most preferably 1: 8.0.

According to the characteristics of carboxyl, amino and hydroxyl in LD and CD molecular structures, the invention tries to improve the solubility of the drug by using the cosolvent which can generate intermolecular hydrogen bonds with the LD and CD molecular structures. Compounds such as glycine, arginine, methionine, histidine, lysine, leucine, isoleucine, threonine, meglumine, and cysteine were examined. Experiments have found that only arginine, meglumine and cysteine among the arginine, the meglumine and the cysteine can form a solution with higher concentration. Through scientific combination, the solubility of the drug in some embodiments of the invention is significantly improved, with LD and CD respectively as high as 268.7mg/mL and CD as high as 41.3mg/mL, which are much higher than the formulations of the published patent CN 103442693A and much higher than the target solubility (to ensure that the drug does not precipitate during use or storage).

In the levodopa preparation, arginine and meglumine are used as cosolvents, so that the solubility of levodopa can be effectively improved. In the formula of the application publication patent CN 103442693A, the dosage of arginine (Arg) and meglumine (Meg) is larger, and for a low-concentration preparation, the solubility of an active substance can be effectively improved and the stability of the preparation can be improved due to the increase of a cosolvent. However, in the case of a high concentration preparation, since the amount of the solvent itself is small, the presence of an excessive amount of the cosolvent is disadvantageous to the stability of the whole preparation system, the drug is liable to be precipitated, and the irritation of the preparation may be increased. In the present invention, the molar amounts of arginine and meglumine, even if not higher than the active ingredient, still give a stable clear liquid formulation.

In some preferred embodiments of the invention, the ratio of the number of moles of meglumine to the sum of the number of moles of levodopa and dopa decarboxylase inhibitor is 0.05-0.3: 1, preferably 0.15-0.3: 1, more preferably 0.2 to 0.3: 1.

in some preferred embodiments of the invention, the ratio of the number of moles of arginine to the sum of the number of moles of levodopa and dopa decarboxylase inhibitor is 0.45 to 1: 1, preferably 0.5 to 1.0: 1, preferably 0.6 to 1.0: 1, more preferably 0.7 to 1.0: 1, most preferably 0.85 to 1.0: 1.

In some preferred embodiments of the invention, the weight ratio of meglumine to arginine is 0.15-0.40: 1, preferably 0.25-0.40: 1, more preferably 0.3-0.35: 1, and most preferably 0.32: 1.

In some preferred embodiments of the invention, the dopa decarboxylase inhibitor is selected from carbidopa, entacapone, tolcapone, and serine hydrazine, or a mixture of two or more thereof.

In some preferred embodiments of the present invention, the pH adjusting agent is selected from citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, trisodium citrate, or a mixture of two or more thereof.

In some preferred embodiments of the present invention, the antioxidant is preferably present in an amount of 0.01 to 0.5 wt%, more preferably 0.05 to 0.2 wt%.

In some preferred embodiments of the present invention, the free radical trapping antioxidant is one or two or more selected from the group consisting of ubiquinones of cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methyl phenol, tert-butyl methoxy phenol, polyphenols, tocopherols and caffeic acid, or pharmaceutically acceptable salts thereof.

In some preferred embodiments of the present invention, the mass ratio of sodium metabisulfite to the radical trapping antioxidant is 0.5-5: 1, preferably 1.1-2: 1, and more preferably 1.3: 1.

In the levodopa preparation, the antioxidant can prevent the levodopa and the carbidopa from being oxidized, and can effectively improve the stability of the liquid preparation. The antioxidant can be divided into a reduction type antioxidant and a free radical capture type antioxidant according to an antioxidant mechanism, wherein the reduction type antioxidant realizes an antioxidant effect by reducing oxygen content through redox reaction, and a representative antioxidant is a sulfite compound; the free radical trapping antioxidant is a chain reaction for trapping free radicals and stopping oxidative degradation of LD/CD free radicals, and representative compounds are vitamin C compounds. The research of the invention finds that the combined reduction type antioxidant and the free radical capture type antioxidant can play a synergistic role, have obvious advantages in stability compared with a single antioxidant sample, have better stability compared with the prior patent prescription, and simultaneously can not reduce the solubility and clarity of the preparation.

According to the invention, various reduction type antioxidants and the using amounts thereof are firstly considered, wherein the effect of combining sodium metabisulfite with other free radical capture type antioxidants is particularly good, and the stability of the preparation can be further improved.

The present inventors studied the inhibitory effect of a bisantioxidant (redox mechanism and chain reaction mechanism) on the oxidation of a drug under accelerated conditions (accelerated 2d at 37 ℃). Researches show that the combined use of the reduction type antioxidant, the free radical capture type antioxidant and the metal ion complexing agent in a specific dosage range has the best antioxidant effect and does not influence the solubility of the liquid medicine. Wherein the content of the metal ion complexing agent EDTA is 0.01-0.5 wt%, preferably 0.01-0.1 wt%, more preferably 0.01-0.05 wt%, and more preferably 0.02-0.03 wt%.

In some preferred embodiments of the invention, the dopa decarboxylase inhibitor is carbidopa or entacapone; the pH regulator is selected from the group consisting of citric acid, disodium citrate, trisodium citrate and sodium hydroxide, or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the free radical trapping antioxidant is selected from cysteine, leucine, methionine, vitamin E, or a combination of two or more of the above.

In some preferred embodiments of the invention, the levodopa formulation comprises the following components: 15-30 wt% of levodopa, carbidopa with a weight ratio of 1: 7.5-8.5 to levodopa, arginine with a molar sum of levodopa and carbidopa of 0.6-1: 1, meglumine with a molar sum of levodopa and carbidopa of 0.15-0.3: 1, a pH regulator for regulating the pH of the solution to 9.6-9.8, 0.05-1 wt% of an antioxidant, 0.01-0.1 wt% of EDTA and the balance of water.

In some preferred embodiments of the invention, the levodopa formulation comprises the following components: 15-24 wt% of levodopa, carbidopa with a weight ratio of 1: 7.5-8.5 to levodopa, arginine with a molar sum of levodopa and carbidopa of 0.6-1: 1, meglumine with a molar sum of levodopa and carbidopa of 0.2-0.3: 1, a pH regulator for regulating the pH of the solution to 9.6-9.8, 0.01-1 wt% of an antioxidant, 0.01-0.1 wt% of EDTA and the balance of water.

In some preferred embodiments of the invention, the levodopa formulation comprises the following components: 15-24 wt% of levodopa, carbidopa with a weight ratio of 1: 7.8-8.2 to levodopa, arginine with a molar sum of levodopa and carbidopa of 0.6-1: 1, meglumine with a weight ratio of arginine of 0.25-0.40: 1, a pH regulator for regulating the pH of the solution to 9.6-9.8, 0.01-0.5 wt% of an antioxidant, 0.01-0.05 wt% of EDTA and the balance of water.

In some preferred embodiments of the invention, the levodopa formulation comprises the following components: 15-24 wt% of levodopa, carbidopa with a weight ratio of 1: 8 to levodopa, arginine with a total molar number sum of levodopa and carbidopa of 0.6-1: 1, meglumine with a weight ratio of arginine of 0.32: 1, a pH regulator for regulating the pH of the solution to 9.6-9.8, 0.1-0.3 wt% of an antioxidant, 0.02-0.03 wt% of EDTA and the balance of water.

In some preferred embodiments of the present invention, the kit further comprises 0-50 mg/mL of a lyoprotectant.

Preferably, the lyoprotectant is selected from maltose, trehalose, sucrose, mannitol, lactose, glucose, sorbitol, xylitol, erythritol, threonine, or a mixture of two or more thereof. Preferably maltose, trehalose, sucrose, mannitol, or a mixture of two or more thereof, more preferably mannitol, lactose, or a mixture of both.

Furthermore, the levodopa preparation can be lyophilized or spray-dried to remove water and then made into a powder preparation, and a certain amount of water for injection is injected before use for re-dissolution.

Another object of the present invention is to provide a method for preparing the levodopa preparation, which comprises the following steps:

1) weighing the solid component powder according to the formula ratio, and mixing and dissolving the solid component powder with a proper amount of water at 40-90 ℃ under the protection of inert gas;

2) and (3) adding water to the solution at room temperature to a full volume, and then sterilizing by using a filter membrane to obtain the levodopa preparation.

Preferably, the water used in the steps 1) and 2) is deoxygenated water or water for injection, so that the oxidation of oxygen in the water can be effectively avoided.

The preparation process, especially the dissolution in step 1, has an important influence on the physical and chemical stability of the obtained levodopa preparation, and preferably, the components in step 1) can be dissolved according to any one of the following procedures:

procedure 1: weighing the powder components of the formula, mixing with a proper amount of water, heating the suspension for 10-30 min, preferably 20min, at 75-80 ℃ while stirring until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min;

procedure 2: weighing the inactive ingredient powder with the formula ratio, mixing with a proper amount of water, and heating the suspension for 3-10 min, preferably 5min, at 30-50 ℃, preferably 40 ℃ while stirring until the inactive ingredient powder is completely dissolved; weighing all active ingredients (API, i.e. levodopa and dopa decarboxylase inhibitor) and adding to the above non-active ingredient aqueous solution; heating the suspension at 60-80 ℃, preferably 70 ℃, for 10-30 min, preferably 20min while stirring until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min;

Procedure 3: weighing solid component powder except the antioxidant in the formula, adding the solid component powder into a preheated antioxidant solution, stirring the suspension at 70-80 ℃ for 10-30 min, preferably 20min until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min;

procedure 4: weighing solid component powder except the reduction type antioxidant in the formula, adding the solid component powder into preheated reduction type antioxidant solution for dissolving, stirring the suspension for 10-30 min, preferably 20min at 70-80 ℃ until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min.

After the mixing and dissolving in the step 1), if the pH value of the solution is not in the formula range, a proper amount of pH regulator can be added for regulation.

The invention also aims to provide application of the levodopa preparation in preparing a medicament for treating Parkinson's disease.

The levodopa preparation can be directly combined with a patch pump for administration, and other pharmaceutically acceptable synergistic drugs or additives can also be added.

Preferably, the dosage form of the drug is a dosage form for transdermal, intradermal, subcutaneous, intravenous, intrathecal, epidural, intracranial, or intraduodenal administration.

The fourth object of the present invention is to provide a patch-type infusion pump for treating parkinson's disease, which is characterized in that it contains the levodopa preparation or a drug prepared therefrom.

Preferably, the volume of the patch pump is 2-4 mL, preferably 3-4 mL, the patch pump can accurately, micro, uniformly and continuously pump a small amount of liquid medicine into the body, the operation is convenient, timed and quantitative, the speed of the medicine can be adjusted at any time according to the disease condition, and the medicine can keep effective blood concentration in the body. For example, the formulations or medicaments of the present application can be administered during the day or during patient activity at a rate of at least about 0.04mL/h to about 0.125mL/h, or for example about 0.08 mL/h; and from about 0 to about 0.04mL/h at rest or sleep. Those skilled in the art will readily understand that the dosage and timing of administration of the levodopa + carbidopa compound formulation can be flexibly adjusted depending on the pharmaceutical dosage form, the constitution of the individual to be administered, the body weight, the age, the progress of the condition, the timing of administration, and other therapeutic factors.

The invention has the advantages that:

1. according to the levodopa preparation, the proportion of the cosolvent arginine to the meglumine is adjusted, so that high-concentration levodopa and a dopa decarboxylase inhibitor can be completely dissolved, a stable clear liquid preparation is obtained, the stability is kept for a long time, and the precipitation of a medicament can be avoided.

2. The levodopa preparation has the best antioxidant effect by combined use of the reduction type antioxidant, the free radical capture type antioxidant and the metal ion complexing agent in a specific dosage range, does not influence the solubility of liquid medicine, can keep long-time liquid stability, and can further avoid medicine precipitation.

3. The levodopa preparation provided by the invention has the advantages that the ratio of the levodopa to the carbidopa is selected, the dose of the levodopa can be minimized, and toxic and side effects caused by metabolism of the levodopa in a peripheral system can be reduced.

4. The levodopa preparation does not contain any organic solvent, and fundamentally avoids irritation and toxicity caused by the organic solvent.

5. The levodopa preparation is a solution type homogeneous preparation, and avoids the irritation and toxicity of overhigh local drug concentration caused by the solid of a suspension.

6. The levodopa preparation is a 2-4 mL solution preparation, is greatly reduced in volume compared with the existing 6mL injection preparation, is continuously used for 24 hours in combination with a patch infusion pump with small volume and small volume, is free from the trouble of an infusion pipeline of a traditional infusion pump, and greatly improves medication compliance.

7. The levodopa preparation provided by the invention overcomes the problem of insufficient solubility of levodopa carbidopa in a real sense through a matched prescription process, and lays a foundation for preparing a high-concentration compound preparation.

8. The levodopa preparation has the local irritation equivalent to that of a conventional injection and is high in safety.

Drawings

FIG. 1 is a graph of pathological section results of a levodopa formulation of the invention following subcutaneous administration in rabbits;

fig. 2 is a schematic diagram showing the change of blood concentration of the levodopa preparation of the present invention after subcutaneous administration in rabbits.

Detailed Description

The present invention will be further described with reference to the following examples and the accompanying drawings. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

In the examples of the present invention and the comparative examples, if no specific description is made on the experimental operating temperature, the temperature is usually room temperature (10 to 30 ℃).

The examples and comparative examples of the present invention were prepared with reference to the following procedure:

1) weighing the solid component powder according to the formula ratio, and mixing and dissolving the solid component powder with a proper amount of water for injection at 40-90 ℃ under the protection of inert gas;

2) the solution is subjected to constant volume to full volume by using water for injection at room temperature; then sterilizing by using a 0.22 micron PES membrane to obtain the levodopa preparation.

The preparation process, especially the dissolution in step 1), has an important influence on the physical and chemical stability of the obtained levodopa preparation, and preferably, the components in step 1) can be dissolved according to any one of the following procedures:

Procedure 1: weighing powder components of the formula, mixing with a proper amount of water, stirring at 75-80 ℃, heating the suspension for 10-30 min, preferably 20min until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min;

procedure 2: weighing the inactive ingredient powder with the formula ratio, mixing with a proper amount of water, and heating the suspension for 3-10 min, preferably 5min, at 30-50 ℃, preferably 40 ℃ while stirring until the inactive ingredient powder is completely dissolved; weighing all active ingredients (API, i.e. levodopa and carbidopa), and adding into the above water solution of inactive ingredients; heating the suspension at 60-80 ℃, preferably 70 ℃, for 10-30 min, preferably 20min while stirring until the suspension is completely dissolved, and cooling at room temperature for 15-25 min, preferably 20 min;

The examples and comparative examples of the present application are preferably formulated according to the above-described procedure 3 or 4.

The amounts of carbidopa used in the examples and comparative examples of the present application are shown as net amounts, but the raw material actually used is carbidopa monohydrate, and therefore, the amount of carbidopa monohydrate should be converted to the weight of carbidopa monohydrate for weighing and preparation.

First, promoting solvent screening and solubility evaluation

Examples 1 to 12 and comparative examples 1 to 6

Examples 1-12 are levodopa formulations of preferred formulations of the invention;

comparative example 1 was formulated with reference to the formulation in example 3 of published application CN 103442693A (comparative example 1 formulation: LD 10%, CD 1.5%, arginine 14.6%, meglumine 9.9%; comparative example 2 formulation: LD 10%, CD 1.5%, arginine 19.2%, meglumine 4%); comparative examples 3 to 6 are formulations in which the amount of water used is reduced on the basis of comparative examples 1 to 2;

the specific formulation and dissolution results are shown in tables 2-1, 2-2, 3 and 4 below. Experiments show that under the necessary condition of high concentration of the preparation for the second generation patch pump, the ratio of meglumine to arginine in the formula of the application can be dissolved within 0.15-0.4: 1, and the dissolution can not be completed beyond the range, wherein 0.32 is the optimal ratio. The prescription of the patent application CN 103442693A can not complete the dissolution under low volume, and can not prepare the preparation for the second generation patch pump with high concentration.

TABLE 2-1 formulations and dissolution results of levodopa preparations of examples 1-6

TABLE 2-2 formulations and dissolution results for levodopa preparations of examples 7-12

TABLE 3 comparative formulations of the preferred Meg/Arg ratios and dissolution results

TABLE 4 formulation and results for comparative examples 1-6 levodopa formulations

The formulations of examples 1-7 and 11 were all completely dissolved to give a stable clear high concentration liquid formulation. The embodiment 1-7 and 11 of the invention can prepare a larger drug concentration when the volume of the injection liquid is smaller, the solubility of levodopa and carbidopa is respectively as high as 180-240 mg/mL and 22.5-30 mg/mL, and the drug can be used together with a second-generation patch type infusion pump, so that the drug is very convenient to carry and use.

The comparative examples 1 to 6 are prepared according to the formula of the existing patent, and the formula of the existing patent is characterized in that the proportion of the auxiliary solvent arginine and the meglumine relative to the active ingredient is much higher than that of the formula of the invention in order to improve the solubility of the active ingredient, wherein the comparative examples 1 to 2 also prepare a clear liquid preparation, but the solubility of the levodopa and the carbidopa only reaches 120mg/mL and 15mg/mL and is much lower than that of the examples 1 to 7 and 11, the volume is larger (6mL) under the same dosage, and the requirement of the second generation patch type infusion pump cannot be met. When the volume of the liquid medicine is reduced in comparative examples 3-6, the pH value of the system is increased, the medicine cannot be completely dissolved, and a clear liquid preparation cannot be prepared.

The stable and clear liquid preparation can be prepared in the above embodiments 1-7 and 11, and the key points include the precise proportion of levodopa and carbidopa, the dissolution-assisting combination of arginine, meglumine and EDTA, and the precise proportion of arginine and meglumine.

Further investigation As shown in examples 13-20 of Table 3, higher concentrations of small volumes (about 2mL) of the formulation were prepared, 720mg of LD was not completely dissolved, and the LD concentrations reported above were measured after filtration. In examples 13 to 14 and 19, the solubility of LD was higher than 180mg/mL, and the best one was found in example 13.

Second, the dosage of levodopa and carbidopa is selected

In the existing compound levodopa carbidopa preparation on the market, the content ratio of LD to CD is 4: 1-10: 1, and a small amount of CD can reduce the degradation of LD in the peripheral system and promote more LD to enter the central nervous system to exert the drug effect. According to the oral bioavailability of LD and CD, LD and CD can meet the requirement of 4: 1-10: 1, and the preferred ratio of the invention is 7.5-8.5: 1, and the most preferred ratio is 8: 1. According to the compound formula in the proportion range, the compound formula can be completely dissolved by the preparation procedure, and the results are shown in table 5.

TABLE 5 prescription and dissolution of levodopa and carbidopa in different ratio ranges

Thirdly, screening stabilizer and evaluating stability

1. Research on improvement effect of antioxidant on preparation stability

According to the invention, single 4 kinds of reduction type antioxidants (sodium bisulfite, sodium sulfite, sodium metabisulfite and sodium ascorbate) are firstly considered, the screening results of different antioxidants are shown in the following table 6, and the properties, pH, content and total impurity change of a sample containing sodium metabisulfite are minimum; the properties and the total impurity of the samples of the rest antioxidants are greatly changed. Further, specifically, the dosage of sodium metabisulfite in the formula of the invention is screened, referring to example 1, the difference is that the antioxidant is only added with sodium metabisulfite, the experimental result is shown in table 7, and it is shown that the more the sodium metabisulfite is used in a certain range, the less the total impurities are, and no obvious difference is found in other indexes such as pH and content. Therefore, sodium metabisulfite is a preferred reducing antioxidant of the present invention.

TABLE 6 reduced antioxidant screening results

Note: the screening prescription 1-4 only contains levodopa (1.4-1.5 wt%), carbidopa (0.17-0.2 wt%), antioxidant (0.2 wt%), pH regulator and water.

TABLE 7 sodium metabisulfite dosage screening results

In view of the fact that the single reduced antioxidant sample still has obvious increase of impurities, the invention scientifically combines the reduced antioxidant and the free radical capture antioxidant on the basis of the existing CD oxidation theory, finds that the invention can play a synergistic effect, has obvious advantage in stability compared with the single antioxidant sample and better stability compared with the original patent prescription, and simultaneously can not reduce the solubility and the clarity of the preparation. The stability is better when EDTA is contained.

In the invention, sodium metabisulfite is used as a reduction type antioxidant, the antioxidant effect of different free radical capture type antioxidants combined with the reduction type antioxidant is investigated, different antioxidants are adopted, the preparation procedures are adopted, samples are prepared, and the stability acceleration test is carried out, and the results are shown in table 8.

TABLE 8 stabilizing effect of bis-antioxidants

The examples in the table above are parallel runs of example 5, except that the percent antioxidant and EDTA are as shown in the table above.

From the results of the above examples 21 to 41, it can be seen that the scheme of the present application combines the reduction type antioxidant and the radical trapping type antioxidant for use, and simultaneously, the stability of the preparation can be effectively improved when EDTA is added, the preparation properties after an acceleration test do not obviously change, the stability is good, and the effect is optimal particularly when the combination of sodium metabisulfite and cysteine hydrochloride is adopted; when a single antioxidant is adopted or EDTA is not added, the effect is greatly reduced, the properties of the preparation are changed after an accelerated test, and the stability is reduced.

In addition, the proportion of the antioxidant and EDTA can also influence the stability of the preparation, and the proportion of the consumption of the reduced antioxidant (sodium metabisulfite) and the free radical capture antioxidant is preferably 0.5-5: 1, more preferably 1.1-2: 1, and most preferably 1.3: 1.

2. Effect of Co-solvent on physical stability of medicinal solution

The physical stability results of the samples of examples 1-7 and example 11 when left at room temperature. The samples of examples 1 to 7 and example 11 were able to maintain the solution state for at least 2 days at room temperature without precipitation, and satisfied the clinical requirements, and the results are shown in Table 9.

TABLE 9 Effect of Co-solvent on physical stability of drug solutions

3. Effect of stabilizers on chemical stability of drug solutions

1) Comparison of Single and Dual antioxidant samples

Samples of levodopa preparations of example 5 (bis-antioxidant), example 41 (bis-antioxidant), example 21 (sodium metabisulfite mono-reduced antioxidant) and example 40 (sodium sulfite mono-reduced antioxidant) were stored for 3 months (3M), and then sampled for assay and related substances, and the test results are shown in Table 10.

Table 10 long term stability test results for example 5, example 21 and example 41

The investigation result shows that the stability of the single oxygen reagent sample containing sodium metabisulfite is better, and the LD impurities of the single oxygen reagent sample containing sodium metabisulfite are obviously increased; the comparative bis-antioxidant sample has a higher CD impurity than the bis-antioxidant sample of example 5, and therefore, a mono-antioxidant sample containing sodium metabisulfite and a radical trapping bis-antioxidant are preferred.

The levodopa preparation sample solutions of example 5 (bis-antioxidant) and example 21 (mono-antioxidant) were placed at 37 ℃ and 5 ℃ to measure the content and related substances, and the test results are shown in table 11.

Table 11 example 5 and example 21 stability test results

The examination result shows that the CD total impurity of the sample of the single antioxidant in the example 21 is obviously increased at 37 ℃, while the CD total impurity of the sample of the double antioxidant is not obviously changed for 48 hours under the accelerated condition. The same results were obtained with 3M acceleration at 5 ℃. However, all the single antioxidant and double antioxidant samples meet the quality standard, which shows that the two samples are stable even under the acceleration condition, so that the requirement that the patient carries and uses the oxygen-enriched composition for a short time without using other professional refrigeration equipment is met, the use of the patient is facilitated, and the accessibility of the medicine is greatly improved; and the storage condition can be improved to refrigeration, and the transportation and storage cost of the sample is greatly reduced.

2) Accelerated stability of the preferred formulation

The aim of this experiment was to investigate the accelerated stability profile of the levodopa formulations of the invention. Samples of the levodopa preparations of examples 1, 4 and 5 were placed in an oven at 37 ℃, sampled for detection of content and related substances at 0h, 24h and 48h, respectively, and the accelerated stability of the samples was examined, and the results are shown in table 12.

Table 12 accelerated stability test results for examples 1, 4, 5

The research result shows that the sample is accelerated for 2 days at 37 ℃, and the content and related substances have no obvious change. The sample solution is stable, and can be carried and used for a short time without using other professional refrigeration equipment. The use of the patient is facilitated, and the accessibility of the medicine is greatly improved.

3) Compatibility test of infusion set with better formula

The purpose of this experiment was to investigate the stability of the levodopa formulations of the invention at 37 ℃. The levodopa preparation sample solution in the example 5 is placed in a stability experiment box, and the samples are respectively sampled and detected for content and related substances for 0h, 24h and 48h, and the stability of the sample at 37 ℃ is examined. The results are shown in Table 13.

TABLE 13 infusion set compatibility test results of example 5

The result shows that the content of the sample solution and related substances do not obviously change after 24 hours of infusion when the sample is at a temperature higher than the body surface temperature; the content of the sample solution is not obviously changed after the sample solution is infused for 48 hours, the total impurity of related substances is slightly increased, and the requirement of 24-hour continuous infusion of a patient is basically met.

Fourth, animal experiment

1. Eye irritation test in rabbits

The experiment aims to research the irritation of the levodopa preparation on the eyes of rabbits. Selecting rabbits with the weight of 2.5-3.0 kg in common grade. The levodopa preparation of example 5 was injected into the left eye of a rabbit and the right eye of a rabbit as reference eyes, and the injection was dripped into the left eye of a rabbit and the right eye of a rabbit with physiological saline as control solutions, and observed at 0h, 3h, and 24h, respectively.

The results are shown in Table 14. Research results show that when the liquid medicine is just dripped into eyes of rabbits, the rabbits blink or close the eyes, but the rabbits are normal after 1h observation, and severe irritation symptoms such as erythema, edema and the like do not appear in the whole observation process. Indicating that the sample was slightly irritating, but still within acceptable limits.

TABLE 14 Rabbit eye irritation test results

2. Subcutaneous irritation test in rabbits

The experiment aims to research the irritation of the levodopa preparation on rabbit skin. The infusion apparatus and the constant-speed infusion pump used in the embodiment are purchased from Shanghai minimally invasive surgery; 3 rabbits (

numbers

1, 2 and 3) are selected, and the weight of the common-grade male rabbit is 2.5-3.0 kg. The rabbits were bred adaptively for one week, depilated with shaving and depilatory cream on the backs one day before the test, wiped with warm water, and returned to the rabbit cages. The next day, after the backs of the rabbits are observed to confirm that no obvious stimulus response exists, the rabbits are fixed on a rabbit frame; injecting subcutaneously through an indwelling needle at the skin preparation part, and fixing with adhesive plaster; the test preparation of example 5 was injected subcutaneously into rabbits at a constant rate by connecting a syringe pump to a liquid line and injecting the solution continuously at a predetermined flow rate for 8 hours. The skin condition of the injection site and the nearby skin of the rabbit is observed, and the tissue of the injection site is fixed by neutral formalin to be made into pathological sections. The results of the subcutaneous irritancy and pathological section are shown in table 15, table 16 and fig. 1.

The results show that the skin surface administration site of 3 rabbits has no typical erythema and edema. Pathological section results show that the injection has slight inflammatory response, is equivalent to the irritation of the conventional injection and is within an acceptable range.

TABLE 15 observations of skin surface at the end of subcutaneous infusion of rabbits

Rabbit number	Erythema	Edema (edema)
			1	Is free of	Is free of
2	Is free of	Is free of
			3	Is free of	Is free of

TABLE 16 pathological section results of local tissue after completion of subcutaneous infusion of rabbits

Rabbit number	Inflammatory cells	Congestion and edema	Necrosis of muscle fiber
				1	0	1	0
2	0	1	0
				3	0	0	0

3. Rabbit subcutaneous administration experiment for investigating blood concentration stability

The infusion apparatus and the constant-speed infusion pump used in the embodiment are purchased from Shanghai minimally invasive surgery; selecting rabbits with common grade and male body weight of 2.5-3.0 kg. The rabbits were bred adaptively for one week, depilated with shaving and depilatory cream on the backs one day before the test, wiped with warm water, and returned to the rabbit cages. The next day, after the backs of the rabbits are observed to confirm that no obvious stimulus response exists, the rabbits are fixed on a rabbit frame; injecting subcutaneously through an indwelling needle at the skin preparation part, and fixing with adhesive plaster; the test preparation of example 5 was injected subcutaneously into rabbits at a constant rate by connecting a syringe pump to a liquid line and injecting the solution continuously at a predetermined flow rate for 8 hours. Blood was collected from the central artery of rabbit ears at a prescribed time after injection, heparin was anticoagulated, plasma was separated at 3000r/min, and blood concentrations of Levodopa (LD) and Carbidopa (CD) were measured.

Fig. 2 is a graph of blood concentration versus time showing that the levodopa formulation of the present invention peaks at about 2 hours during an 8 hour constant rate infusion, the LD and CD blood concentrations plateau between 2 hours and 8 hours, and the blood concentrations of both drugs are nearly completely eliminated at 24 hours. The stable blood concentration of the levodopa has important significance for treating patients with intermediate and advanced Parkinson.

While the preferred embodiments of the present invention have been illustrated and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A levodopa formulation comprising the following components: 13-36 wt% of levodopa, a dopa decarboxylase inhibitor with a weight ratio of levodopa to levodopa of 1: 4-10, arginine with a molar sum of levodopa and dopa decarboxylase inhibitor of 0.3-1.0: 1, meglumine with a molar sum of levodopa and dopa decarboxylase inhibitor of 0.05-0.8: 1, a pH regulator for regulating the pH of the solution to 9.6-10, 0.01-1 wt% of an antioxidant, 0.01-0.5 wt% of EDTA, and the balance of water; the antioxidant is selected from sodium metabisulfite or a combination of sodium metabisulfite and a radical trapping antioxidant.

2. The levodopa preparation according to claim 1, which is an injection for a patch-type infusion pump of 2 to 4 mL.

3. The levodopa formulation according to claim 1, wherein the ratio of the number of moles of meglumine to the sum of the number of moles of levodopa and dopa decarboxylase inhibitor is 0.05-0.3: 1.

4. The levodopa formulation according to claim 1 wherein the ratio of the number of moles of arginine to the sum of the number of moles of levodopa and dopa decarboxylase inhibitors is 0.45-1.0: 1.

5. The levodopa preparation according to any one of claims 1 to 4, wherein the weight ratio of meglumine to arginine is 0.15 to 0.40: 1.

6. The levodopa formulation according to claim 1, wherein said dopa decarboxylase inhibitor is selected from carbidopa, entacapone, tolcapone, and, serine, or a mixture of two or more thereof.

7. The levodopa formulation according to claim 1, wherein said dopa decarboxylase inhibitor and levodopa are present in a weight ratio of 1: 7.5-8.5.

8. The levodopa formulation according to claim 1 wherein said pH adjusting agent is selected from the group consisting of citric acid, hydrochloric acid, sodium hydroxide, phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium citrate, trisodium citrate, and mixtures of two or more thereof.

9. The levodopa preparation according to claim 1, wherein said free radical-capturing antioxidant is one or two or more selected from the group consisting of ubiquinones of cysteine, leucine, methionine, sodium ascorbate, vitamin E, di-tert-butyl methyl phenol, tert-butyl methoxy phenol, polyphenols, tocopherols and caffeic acid, or pharmaceutically acceptable salts thereof.

10. The levodopa preparation according to claim 1, wherein the weight ratio of sodium metabisulfite to said radical trapping antioxidant is 0.5-5: 1.

11. The levodopa formulation according to claim 1, wherein the dopa decarboxylase inhibitor is carbidopa or entacapone; the pH regulator is selected from the group consisting of citric acid, disodium citrate, trisodium citrate and sodium hydroxide, or a combination of phosphoric acid, disodium hydrogen phosphate, sodium dihydrogen phosphate and sodium hydroxide; the free radical trapping antioxidant is selected from cysteine, leucine, methionine, vitamin E or pharmaceutically acceptable salt thereof, or combination of two or more of the above.

12. The levodopa formulation according to claim 1, comprising the following components: 15-30 wt% of levodopa, carbidopa with a weight ratio of 1: 7.5-8.5 to levodopa, arginine with a molar sum of levodopa and carbidopa of 0.6-1: 1, meglumine with a molar sum of levodopa and carbidopa of 0.15-0.3: 1, a pH regulator for regulating the pH of the solution to 9.6-9.8, 0.05-1 wt% of an antioxidant, 0.01-0.1 wt% of EDTA and the balance of water.

13. The levodopa formulation according to claim 1, further comprising 0-50 mg/mL of a lyoprotectant.

14. The levodopa preparation according to claim 12, which is a powder preparation after removal of water by lyophilization or spray drying.

15. A method of preparing a levodopa formulation according to any one of claims 1 to 14, comprising the steps of:

2) and (3) adding water to a constant volume to a full volume, and then sterilizing by using a filter membrane to obtain the levodopa preparation.

16. Use of a levodopa formulation according to any one of claims 1 to 14 in the manufacture of a medicament for the treatment of parkinson's disease.

17. A patch-type infusion pump for the treatment of parkinson's disease, comprising the levodopa preparation according to any one of claims 1 to 14.