Levodopa infusion solution

Abstract

An aqueous pharmaceutical solution for the treatment of a central nervous system (CNS) disorder is provided, the solution comprising at least 5 mg / ml dissolved levodopa and a pH in the range of 3.0 to 8.5. The solution is provided by mixing: a) an aqueous stock solution comprising levodopa, the stock solution having a pH of less than 2.8 at 25°C, and b) an aqueous buffer solution for increasing the pH of the stock solution, the buffer solution having a pH of at least 4.0 at 25°C. The aqueous pharmaceutical solution is administered to a subject having a central nervous system (CNS) disorder shortly after mixing the aqueous stock solution and the aqueous buffer solution. Further, a kit for administering an aqueous pharmaceutical solution to a subject having a central nervous system (CNS) disorder is provided.

Description

Technical Field

[0001] This invention relates to a pharmaceutical product for treating central nervous system diseases, the pharmaceutical product comprising a levodopa solution suitable for continuous parenteral or enteral administration and a delivery system suitable for administering the solution. Background Technology

[0002] Dopamine [3,4-dihydroxyphenylethylamine] is an organic compound belonging to the catecholamine and phenylethylamine family, playing several important roles in the brain and body. In the brain, dopamine acts as a neurotransmitter released by neurons (nerve cells). The brain includes several different dopamine pathways, and dopamine is crucial for many functions of the central nervous system, such as movement, attention, mood, and motivation. Several neurological disorders (such as Parkinson's disease) are associated with dopamine system dysfunction, and some key medications used modulate dopamine levels in the brain.

[0003] Parkinson's disease (PD) is very common, affecting approximately 15 out of every 10,000 people in the Western world. The age of onset is typically between 55 and 60 years old. The disease is characterized by rigidity, tremor, and bradykinesia (poverty of movement) caused by significant loss of neurons in the substantia nigra and striatum, followed by a lack of dopamine. Cognitive and behavioral problems may subsequently occur during the course of the disease. Symptoms of Parkinson's disease appear when approximately 80% of dopamine neurons are lost.

[0004] In the late 1950s, Nobel laureate Arvid Carlsson discovered that the natural amino acid levodopa (L-dopa) is converted into dopamine upon reaching the brain. Since then, levodopa has been considered the "gold standard" for treating Parkinson's disease (PD). Levodopa treatment improves patients' ability to perform their duties in society and their quality of life, while reducing both personal and social costs. Levodopa is a precursor to the neurotransmitters dopamine, norepinephrine, and epinephrine. Although a large number of dopamine neurons are lost in the early stages of the disease, sufficient storage capacity is maintained, allowing dopamine to be evenly released into the synaptic cleft when levodopa tablets are taken orally.

[0005] Unfortunately, after several years of oral levodopa treatment, pharmacokinetic and pharmacodynamic problems (on-off symptoms) emerged. On-off symptoms, characterized by fluctuating motor function, appeared approximately five years after oral treatment, progressing from disabling motor dysfunction (involuntary movements) to akinesia (complete lack of mobility). The on-off symptoms worsened during the course of the disease. Researchers believe that the on-off symptoms are likely caused by the route of levodopa administration. More specifically, it is believed that the intermittent oral administration of levodopa, along with the degeneration of dopaminergic neurons, is the primary cause of the development of on-off symptoms. Intermittent oral treatment ultimately narrowed the therapeutic window of levodopa, making oral administration even more problematic. The consensus is that more continuous administration of levodopa would be beneficial for patients with Parkinson's disease (PD).

[0006] Shoulson et al. demonstrated in 1979 that continuous administration of levodopa had a beneficial effect on on-off symptoms. Parenteral administration is the preferred method for achieving continuous administration. The problem is that it is impossible to produce an infusion solution with a sufficiently high physiologically acceptable concentration of levodopa, and thus a sufficiently small volume suitable for continuous parenteral administration. In the experiments conducted by Shoulson et al., patients were given several liters daily. The heart could not handle such a large infusion volume over any extended period.

[0007] Numerous attempts have been made over a 30-year period to increase physiologically acceptable levodopa concentrations in infusion solutions, but without decisive success. A major problem has persisted: levodopa precipitates at concentrations greater than 0.5–1.0 mg / ml at acceptable or at least required pH levels during continuous parenteral administration. Levodopa concentrations in the 0.5–1.0 mg / ml range would result in a volume of 1–2 liters per day for patients with advanced PD, typically requiring approximately 1000 mg of oral levodopa daily. Such volumes are unsuitable for prolonged continuous parenteral administration.

[0008] Infusion solutions containing API (active pharmaceutical ingredient) precipitation are unacceptable in pharmaceutical products. Parenteral infusion solutions must be completely clean and free of particles.

[0009] Levodopa molecules are generally stable and readily soluble at both very low pH values ​​(typically pH < 3) and very high pH values ​​(typically pH > 9), with concentrations exceeding 5 mg / ml obtainable within these pH ranges. Therefore, stable levodopa solutions at low pH values ​​are known in the art (e.g., the stock solution proposed in patent SE 512 655), as are levodopa solutions at very high pH values, as proposed in JP54105221 and WO 2012 / 066538 A1, both of which propose levodopa solutions with pH > 9).

[0010] Infusion solutions with a pH < 3 are unsuitable for continuous parenteral administration, as they can lead to severe adverse systemic acidosis and adverse skin effects (nodules). Infusion solutions with a pH > 9 are also associated with adverse skin effects such as severe nodules. Furthermore, when administered parenterally, infusion solutions with a pH > 9 can cause adverse systemic effects such as arrhythmias (arrhythmias). In addition, infusion solutions with a pH > 9 (which is required for long-term stability at concentrations of 10 mg / ml or higher) intended for subcutaneous infusion distribute very poorly in subcutaneous tissues, which in turn hinders, for example, the effective treatment of PD.

[0011] Levodopa infusion solutions intended for continuous parenteral administration should preferably contain inhibitors that reduce the metabolism of levodopa in systemic circulation. Carbidopa is a commonly used inhibitor in oral levodopa therapy. Infusion solutions containing inhibitors such as carbidopa can reduce volume by 30-50% while still achieving the same clinical efficacy as the corresponding levodopa solutions without carbidopa.

[0012] Infusion solutions containing the API levodopa and inhibitors such as carbidopa must meet several stringent conditions to be registered as pharmaceutical products and thus available for use by patients with Parkinson's disease (PD). The degradation of the API (from the time the pharmaceutical product is manufactured to the time of administration to the patient) must be within given limits. Typically, the reduction in the concentration of each API must be less than 10% of its original value. Furthermore, the levels of any toxic metabolites must be within certain prescribed limits. Therefore, it is required to successfully formulate APIs that typically degrade in aqueous solution at physiological pH for infusion applications.

[0013] In consideration of the benefits to patients treated with the drug product of interest, no adverse effect should be contrary to what may be a reasonable effect.

[0014] Existing technologies do not provide a suitable solution containing levodopa and carbidopa for continuous subcutaneous infusion, in which adequate uptake in the plasma enables individualized treatment of PD patients to minimize on-off symptoms, thereby meeting the requirements for approval as a pharmaceutical product.

[0015] Therefore, there is a great need for a drug product containing levodopa and carbidopa suitable for continuous subcutaneous infusion, with sufficient subcutaneous absorption to treat PD patients on an individual basis, in order to minimize on-off symptoms while causing minimal adverse effects. Furthermore, this drug product needs to have a long shelf life, preferably up to one year or longer.

[0016] In the late 1970s, Japanese Patent JP 54105221 disclosed a method for preparing a physically stable levodopa solution intended for injection, wherein the levodopa concentration is up to 15 mg / ml. According to the description, the solution is stable at very high pH, ​​which is to be expected given the chemical properties of levodopa (see further below). The proposed highly alkaline (pH approximately 9) injection solution achieves levodopa concentrations up to 15 mg / ml. To achieve the 15 mg / ml concentration, the injection solution is mixed with a gel. The injection solution mixed in the gel is not intended for parenteral administration but can advantageously be used for oral or enteral injection. Solutions intended for parenteral administration must be free of particles and must not be suspensions (must not contain gel). The proposed injection solution is entirely highly alkaline. The disadvantages of highly alkaline infusion solutions have been previously described.

[0017] In the early 1990s, a levodopa solution for continuous enteral administration was proposed. A levodopa concentration of approximately 20 mg / ml was achieved by making the solution a suspension, but this did not allow for parenteral administration. This solution, Duodopa, also contains carbidopa, which is used to reduce the metabolism of levodopa during its journey from the intestine through the bloodstream to the brain. The use of inhibitors is well-known and is used in most clinical cases of levodopa use. The main drawback of Duodopa is the need for surgery at the start of treatment. Continuous administration via the duodenum means the application of a probe that penetrates the abdominal wall, and troublesome side effects are common. Inflammation often occurs in and around the stoma in the abdominal wall. The probe sometimes moves, and if it is misaligned, a new surgical intervention is required. The high viscosity of the gel-based suspension requires a powerful pump to press the gel through the probe, making the administration system heavy and cumbersome. Another drawback is limited durability. Unopened packaging cannot be stored on shelves for more than three months, which means logistical disadvantages and more expensive products.

[0018] A breakthrough was achieved in the early 21st century in the development of a levodopa infusion solution for parenteral administration (Patent SE 512 655). This patent discloses a levodopa solution for parenteral administration, wherein the levodopa concentration is approximately 5 mg / ml within a pH range of 4-6. The patent does not teach how to include any inhibitors such as carbidopa. The proposed infusion solution can be used for intravenous infusion, but the 5 mg / ml concentration without inhibitors results in an excessively high volume for clinical treatment of onset symptoms via continuous subcutaneous infusion. According to the patent, the infusion solution is physically stable for up to 3 days. This shelf-storage period of no more than 3 days limits the practical use of the infusion solution.

[0019] Patent application PCT / SE2005 / 001135 describes an infusion solution for continuous parenteral administration of levodopa at a concentration of 10 mg / ml or higher at a pH of 6 or lower. One objective of the invention according to PCT / SE2005 / 001135 is to avoid precipitation of levodopa. The described solution optionally also contains an inhibitor such as carbidopa. Inhibitors such as carbidopa reduce the metabolism of levodopa in systemic circulation, resulting in an increased amount of levodopa reaching the brain. Consequently, it reduces the volume of such an infusion solution by up to 50% compared to an infusion solution lacking an inhibitor. An example described in the application is a 10 mg / ml levodopa solution containing 1 mg / ml carbidopa that is physically stable for at least 3 days at a pH in the range of 3.5 to 4.0. It is unclear whether the solution is physically stable for more than three days. Infusion solutions with short physical stability inevitably present serious logistical problems, which can practically render the product impractical for use as a medical drug. No information was found regarding the chemical stability of the API or the amount of any toxic metabolites. Its description lacks sufficient information regarding the properties of the solution to allow for determination of whether the solution can be classified as a pharmaceutical product that meets regulatory requirements.

[0020] Patent application WO 2012 / 066538 A1 describes an infusion solution containing at least 4% by weight (at least about 40 mg / ml) levodopa, including the inhibitor carbidopa, and with a pH in the range of 9.1 to 9.8 at 25°C. The infusion product described in this patent has a pH value even higher than that of an earlier product described in Japanese Patent JP 54105221. Based on the chemical properties of levodopa and carbidopa, these components exhibit good chemical stability at very high (and very low) pH values, which also explains the results obtained in experiments with levodopa at high pH values ​​described in Japanese Patent JP 54105221. However, several problems exist associated with solutions having such high pH values, particularly when administered parenterally.

[0021] Infusion solutions and injectable solutions with high pH values ​​(above 8-9) showed reduced subcutaneous absorption. The latter was demonstrated in clinical studies of product ND062, based on patent application WO 2012 / 066538 A1, where a plasma levodopa concentration of approximately 1,200 ng / ml was first reached after approximately 6 hours of continuous subcutaneous infusion, and a maximum of approximately 1,300 ng / ml was not reached even after 8 hours of continuous infusion. It is unclear whether therapeutic levels are achieved in all patients with advanced PD. Therefore, when treating patients with advanced PD with the infusion solutions described in this patent application, oral administration of an inhibitor or levodopa in combination with an inhibitor is recommended as an adjunct. For comparison, the average plasma levodopa concentration required to achieve therapeutic effect in patients with advanced PD participating in clinical studies of dodustatin was 1,600 ng / ml. Other disadvantages of infusion solutions with very high pH values ​​have been previously described.

[0022] Prior to this invention, no product containing levodopa and at least one inhibitor, suitable for continuous parenteral or enteral administration (and particularly continuous subcutaneous infusion), having a pH in the range of 3.0-8.5 (producing minimal adverse skin effects and low (if present) systemic adverse effects such as arrhythmias and high subcutaneous absorption), and meeting the stringent requirements imposed by medical authorities (API degradation and levels of toxic byproducts within prescribed limits) for approval as a pharmaceutical product, had been previously proposed in the art. Therefore, previously proposed infusion solutions for parenteral administration have not yet been registered as pharmaceutical products. However, there is a great need for such products. Therefore, this invention is highly needed. Summary of the Invention

[0023] Accordingly, the present invention preferably attempts to mitigate, alleviate, or eliminate one or more of the aforementioned defects and disadvantages of the products described in the art, either alone or in any combination, and addresses the problems mentioned above by providing formulations that offer a stock solution and a buffer solution, allowing for real-time mixing of the solutions to provide a pharmaceutically acceptable infusion solution for administration shortly after mixing. In some embodiments, the formulation allows for an “on-line” mixing method according to the invention, wherein specific stock solutions and buffer solutions are continuously mixed and the resulting infusion solution is continuously transported from the mixing location to the infusion site, where the drug infusion solution is continuously administered to the patient via a parenteral or enteral route for up to 24 hours. This is particularly advantageous for administration via continuous subcutaneous infusion, where online mixing allows the drug infusion solution to have a pH in the range of 4.5-6.5, where the infusion solution has reduced stability but optimal subcutaneous distribution (API uptake in the blood). Furthermore, online mixing and the corresponding low degradation of the API result in very low levels of toxic byproducts such as hydrazine in the infusion solution, which is beneficial for its approval as a pharmaceutical product. Because the inherent properties of the solutions of this invention allow for online mixing followed by online administration, any degradation of the API will be entirely within the limits permitted by pharmaceutical regulations (e.g., degradation of less than 15% of the original API concentration). This also allows for the administration of solutions with a risk of precipitation, such as supersaturated or metastable solutions. Therefore, according to a first aspect of the invention, an aqueous pharmaceutical solution for treating a central nervous system (CNS) disease is provided, the solution comprising: at least 5 mg / ml of levodopa dissolved in water with a pH in the range of 3.0 to 8.5, wherein the solution is provided by mixing: a) an aqueous stock solution containing levodopa, the stock solution having a pH less than 2.8 at 25°C; and b) an aqueous buffer solution for raising the pH of the stock solution, the buffer solution comprising at least one buffer component and having a pH of at least 4.0 at 25°C, wherein the aqueous pharmaceutical solution is administered to a subject suffering from a central nervous system (CNS) disease within 24 hours after mixing the aqueous stock solution and the aqueous buffer solution, such as 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0024] In addition, an aqueous drug solution for treating central nervous system (CNS) diseases is provided, the solution containing at least 5 mg / ml of dissolved levodopa and having a pH in the range of 3.0 to 8.5, wherein the aqueous drug infusion or injection solution is supersaturated with levodopa.

[0025] The stability of levodopa decreases with increasing concentration. Therefore, more dilute formulations can remain physically stable for a longer period. In some embodiments, the drug solution contains up to 10 mg / ml of levodopa and is administered within 24 hours of mixing the stock solution and buffer solution. These embodiments can be prepared for injection or infusion.

[0026] In other embodiments, the levodopa concentration can be increased to the point of supersaturation. Levodopa precipitation is observed more rapidly at concentrations above 10 mg / mL, and at very high concentrations, precipitation can be observed within 20 minutes. Due to the lower physical stability of supersaturated solutions, online mixing can be used to rapidly administer the solution to the patient before precipitation or degradation. Online mixing allows for continuous mixing of aqueous stock solutions and aqueous buffer solutions, followed by continuous administration of the resulting aqueous drug solution, where the infusion solution is typically transported from the mixing point to the infusion site via plastic tubing, and administered to the patient, for example, within two hours. In cases where the timeframe for API degradation to reach acceptable limits is less than two hours (for certain formulations), the transport time from mixing to infusion can be shortened. In some embodiments, the aqueous drug solution is thus administered within 1.5 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute after mixing the aqueous stock solution and aqueous buffer solution.

[0027] Furthermore, according to one embodiment, the aqueous stock solution contains at least one physiologically acceptable acid. The aqueous stock solution may also contain at least one stabilizer. Similarly, according to one embodiment, the aqueous drug solution further contains at least one enzyme inhibitor. The aqueous buffer solution may also contain at least one stabilizer. The aqueous buffer solution may also contain at least one solubilizer.

[0028] According to a preferred embodiment of the present invention, an aqueous pharmaceutical solution is provided, wherein the solution is provided by mixing the following:

[0029] I) An aqueous stock solution with a pH less than 2.8 at 25°C, containing:

[0030] a) Sterile water,

[0031] b) Levodopa,

[0032] c) At least one enzyme inhibitor,

[0033] d) At least one physiologically acceptable acid,

[0034] e) At least one stabilizer,

[0035] The stock solution was bubbled with nitrogen gas after mixing, and

[0036] II) An aqueous buffer solution having a pH of at least 4.0 at 25°C, containing:

[0037] f) Sterile water,

[0038] g) At least one buffer component,

[0039] h) At least one stabilizer and / or solubilizer,

[0040] The aqueous drug solution may be supersaturated, and the drug is administered to a subject with a central nervous system (CNS) disease within 24 hours after the aqueous stock solution and the aqueous buffer solution are mixed, such as within 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes or 1 minute.

[0041] Furthermore, according to another aspect of the invention, a kit is provided for providing an aqueous drug solution for treating central nervous system (CNS) diseases, the solution containing at least 5 mg / ml of dissolved levodopa and having a pH in the range of 3.0 to 8.5, the kit comprising: a) an aqueous stock solution containing levodopa according to any of the preceding claims, the stock solution having a pH less than 2.8 at 25°C; b) an aqueous buffer solution according to any of the preceding claims for raising the pH of the stock solution, the buffer containing a buffer and having a pH of at least 4.0 at 25°C; c) a mixing member (1) for mixing solutions a) and b); and d) an output member (2) for the mixed solution of step c).

[0042] Similarly, a kit for providing an aqueous drug solution is provided, comprising: I) an aqueous stock solution having a pH less than 2.8 at 25°C, comprising: a) sterile water, b) levodopa, c) at least one enzyme inhibitor, d) at least one physiologically acceptable acid, and e) at least one stabilizer; and II) an aqueous buffer solution having a pH of at least 4.0 at 25°C, comprising: f) sterile water, g) at least one buffer component, and h) at least one stabilizer and / or solubilizer.

[0043] According to another aspect of the invention, a method for continuously preparing the previously described aqueous drug solution is provided. The method includes the step of continuously mixing the previously described stock solution stream and the previously described buffer solution stream. This may include using the previously described kit.

[0044] According to another aspect of the invention, a method for continuously preparing an aqueous drug solution for treating central nervous system (CNS) diseases is provided, the aqueous drug solution being suitable for continuous parenteral or enteral administration, wherein the method comprises the steps of: continuously mixing a stock solution stream containing levodopa and an aqueous buffer solution stream, the stock solution having a pH less than 2.8 at 25°C and the buffer solution having a pH of at least 4.0 at 25°C; and continuously obtaining a continuous stream of an aqueous drug solution from the mixing, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15 or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa.

[0045] According to another aspect of the invention, a method for treating a central nervous system (CNS) disease is provided, comprising the steps of: continuously mixing an aqueous stock solution stream containing levodopa and an aqueous buffer solution stream, the aqueous stock solution having a pH less than 2.8 at 25°C and the aqueous buffer solution having a pH of at least 4.0 at 25°C; continuously obtaining a continuous stream of an aqueous drug solution from the mixing, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15, or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa; and continuously administering the obtained aqueous drug solution to a subject suffering from a central nervous system (CNS) disease.

[0046] According to another aspect of the present invention, an aqueous pharmaceutical solution containing one or more active pharmaceutical ingredients (APIs) is provided for treating central nervous system (CNS) diseases, the aqueous pharmaceutical solution comprising:

[0047] a1. At least 5 mg / ml of levodopa API, or

[0048] a2. At least 5 mg / ml of the API levodopa and at least 0.25 mg / ml of at least one API belonging to the inhibitor group, such as carbidopa, with a pH in the range of 3.0 to 8.5, wherein the aqueous drug solution is provided by mixing the following:

[0049] a) An aqueous stock solution containing one or more APIs, wherein the stock solution has a pH less than 2.8 at 25°C; and

[0050] b) An aqueous buffer solution for adjusting the pH of the stock solution, comprising at least one buffering component, wherein the buffer solution has a pH of at least 4 at 25°C.

[0051] The aqueous drug solution is administered to subjects with CNS disease, and administration is initiated and carried out as long as the concentration of any API decreases by no more than 15% of its concentration before mixing.

[0052] Using this method, any of the previously mentioned CNS diseases can be treated via any of the previously mentioned routes of administration.

[0053] Other advantageous features of the invention are detailed in the embodiments disclosed herein. Furthermore, advantageous features of the invention are defined in the appended claims. Attached Figure Description

[0054] Referring to the accompanying drawings, these and other aspects, features, and advantages of the invention will become apparent and will be set forth from the following description of embodiments of the invention, in which:

[0055] Figure 1 The diagram shows the structure of levodopa, with the pKa values ​​indicated at the centers of the molecule.

[0056] Figure 2 The diagram shows the structure of levodopa, which is dominant at pH levels in the range of 4 to 7.

[0057] Figure 3 The diagram shows the structure of carbidopa, with the pKa values ​​indicated at the centers of the molecule.

[0058] Figure 4 The diagram shows the structure of carbidopa, which is dominant at a pH of approximately 5.

[0059] Figure 5 The calculated micro species distribution of levodopa relative to pH is shown, where the y-axis represents the molar percentage of each molecular form relative to the total amount, and the x-axis represents pH.

[0060] Figure 6 The calculated micro species distribution of carbidopa relative to pH is shown, where the y-axis represents the molar percentage of each molecular form relative to the total amount, and the x-axis represents pH.

[0061] Figure 7 The calculated distribution (D) between the organic and aqueous phases obtained for levodopa at different pH values ​​is shown (represented by the octanol-water distribution coefficient logD);

[0062] Figure 8The calculated solubility of levodopa at different pH values ​​is shown (in log S, the logarithm of solubility measured in mol / L to base 10).

[0063] Figure 9 The calculated distribution (D) between the organic and aqueous phases of carbidopa at different pH values ​​is shown (represented by the octanol-water distribution coefficient logD).

[0064] Figure 10 Displays the calculated solubility of carbidopa at different pH values ​​(represented by logS, the logarithm of solubility measured in mol / L to base 10);

[0065] Figure 11 shows a schematic diagram of the kit, wherein the kit is gravity-fed (11A), includes one pump (11B) or two pumps (11C), and an example of a suitable mixing component is shown in 11D;

[0066] Figure 12 shows an overview of the results of the interim study in the clinical trial, in which (a) blood levels of levodopa and (b) carbidopa were monitored in the blood of patients during the administration period and plotted relative to the treatment time;

[0067] Figure 13 The results of a clinical trial were presented, in which a levodopa-carbidopa solution designed for continuous subcutaneous infusion was used, and in which the pH of the infusion solution was above 9. Blood levels of levodopa were monitored in the patient's blood during administration and plotted against treatment time.

[0068] Figure 14 shows the results of an interim clinical trial involving three patients, where levodopa blood levels were measured in patient plasma during (a) subcutaneous and (b) intravenous infusions and plotted against treatment time; and

[0069] Figure 15 The diagram shows a bag in which the compartments for the reserve solution and the buffer solution are pressed together as two components within a single bag, separated by a perforated barrier. Detailed Implementation

[0070] The following description focuses on embodiments of the invention, applicable to products intended for the treatment of central nervous system (CNS) diseases, the products comprising a levodopa infusion or injection solution suitable for continuous parenteral administration and a delivery system suitable for administering the infusion or injection solution to a patient suffering from a CNS disease.

[0071] To date, no method has been described for producing a solution containing levodopa at a sufficiently high concentration for continuous parenteral administration, with a pH in the range of 3.0-8.5, that meets the product requirements for registration as a pharmaceutical product. Similarly, no injectable solution for enteral administration has been shown to have the advantages described in this invention over existing products.

[0072] Application PCT / SE2005 / 001135 describes how to obtain a physiologically acceptable infusion solution containing at least 10 mg / ml of levodopa, which is physically stable (no precipitation) for more than 3 days and has a pH of 6 or less. However, the examples in the application are limited to solutions with a pH below 4. However, as shown in that application, the chemical stability of this product is insufficient (both levodopa and carbidopa degrade too rapidly to be approved as pharmaceuticals). Chemical degradation also produces toxic degradation products, which hinder the classification of the product as a pharmaceutical product, i.e., the product cannot be approved as a pharmaceutical product. To address this previously unknown problem related to chemical instability, the present invention provides a pharmaceutically viable product with API degradation completely within prescribed limits, and a method for preparing and administering such a product. Furthermore, the content of any toxic byproducts of the present invention is within prescribed limits. Moreover, the aqueous stock solution and aqueous buffer solution mixed to prepare the aqueous pharmaceutical solution of the present invention have a shelf life of at least one year, which implies significant logistical advantages. The product and method of the present invention also enable continuous dosing. This type of continuous dosing offers the advantage of adjusting the dose of levodopa administered to each patient to achieve therapeutic levels and minimizing the on / off effect.

[0073] Developing solutions with sufficiently high levodopa concentrations suitable for continuous parenteral administration, with a pH range of 3.0 to 8.5, and meeting the product requirements of pharmaceuticals is of great significance. Levodopa exhibits very poor solubility within the preferred pH range (pH = 3.0 to 8.5), making it difficult to prepare drug formulations with sufficiently high levodopa concentrations suitable for continuous parenteral administration, as levodopa tends to precipitate. Figure 1 The structure of levodopa is shown, along with the calculated pKa values ​​indicated at each center of the molecule. Depending on the pH of the solution, these centers will be either protonated or deprotonated. The calculated micro-species distribution of levodopa is shown in [the diagram / image / image]. Figure 5 The diagram shows the distribution of micro-species, where the Y-axis represents the percentage of each molecular form (relative to the total amount) and the X-axis represents the pH value. The pKa value of each center causes the distribution of micro-species shown. Figure 2 The dominant structure of levodopa in water is shown in the pH range of 4 to 7. (Example) Figure 2 As shown, levodopa is primarily uncharged (neutral) in this pH range.

[0074] DOPA decarboxylase inhibitors, or aromatic L-amino acid decarboxylase inhibitors (DDCIs), are compounds that inhibit dopamine synthesis via aromatic L-amino acid decarboxylases. Peripheral DDCIs, which cannot cross the protective blood-brain barrier (BBB), are used in the treatment of Parkinson's disease (PD) to increase levodopa levels and reduce adverse side effects by blocking the peripheral conversion of levodopa to dopamine. Examples of such DOPA decarboxylase inhibitors include carbidopa, benzylhydrazine, and DFMD (α-difluoromethyl-DOPA). Figure 3 The structure of the DOPA decarboxylase inhibitor carbidopa can be seen, along with the calculated pKa values ​​indicated at each center of the molecule. The calculated micro-species distribution of carbidopa relative to pH is shown in the image. Figure 6 As shown in the figure, the Y-axis represents the percentage of each molecular form relative to the total amount, and the X-axis represents the pH value. Figure 4 The diagram shows the most dominant structure of carbidopa in water at a pH of approximately 5. At this pH, carbidopa will be primarily uncharged (neutral).

[0075] Based on the microdistribution described above (where uncharged compounds will have higher lipophilicity than charged compounds), and according to the lipophilicity of similar molecular structures, Figure 7 The calculated distribution (D) of levodopa between the organic and aqueous phases is shown (represented by the octanol-water distribution coefficient log D). Log D has its highest value in the pH range of 3 to 8. Therefore, the optimal distribution to lipids exists within this pH range. Similarly, Figure 9 The calculated distribution of carbidopa between the organic and aqueous phases is shown (represented by log D). The log D value has its highest value in the pH range of 4 to 6, with the maximum value at approximately pH 5. At this pH, the distribution to lipids will be optimal. Therefore, the pH ranges at which levodopa and carbidopa produce optimal lipid distribution overlap. Putting the two curves together, the preferred pH range should be in the pH range of 5 to 6.

[0076] The solubility of levodopa can be calculated based on the microdistribution described above (where uncharged compounds will have lower solubility than charged compounds) and the solubility (S) in an aqueous phase with similar molecular structures. Figure 8 The calculated solubility curve of levodopa is shown (expressed as logS, the logarithm to base 10 of solubility measured in mol / L). The log S value is minimum in the pH range of 3 to 8. Within this pH range, the solubility of levodopa in the aqueous phase will be lowest. Similarly, Figure 10The calculated solubility curve of carbidopa is shown in the figure (represented by log S). The log S value is minimum in the pH range of 4 to 6, with the minimum value at approximately pH 5. Therefore, at this pH, the solubility of carbidopa in the aqueous phase is lowest.

[0077] It is generally accepted that the higher the lipophilicity of a compound, the better its passive distribution into biological tissues and cells (Buxton and Benet, 2011). Therefore, it is likely that the optimal uptake of levodopa and carbidopa into skin tissue and capillaries will be achieved at pH values ​​of approximately 5 to 6 (levodopa) and 5 (carbidopa), respectively. This, in turn, improves the rate of absorption and clinical efficacy when administered to patients with CNS diseases.

[0078] On the other hand, it is evident that the calculated solubility of levodopa and carbidopa in water is lowest within essentially the same pH range. Therefore, it is desirable to maximize solubility within this pH range. This can be achieved by selecting appropriate components of the buffer system and by choosing additives that improve the stability and solubility of the API. To optimize overall performance, the pH value can be slightly altered near the optimal pH range.

[0079] Furthermore, and importantly, this invention teaches that by using a supersaturated solution (supersaturated with API) administered to the human body shortly after API mixing (e.g., within minutes) and before precipitation, the concentration of API can be significantly increased within a selected pH range (relative to the use of standard delivery systems). This principle is quite different from the prevailing view in the art.

[0080] The risk of metabolic alkalosis at high pH levels is another reason to keep parenteral drug solutions at a pH below 7. Metabolic alkalosis can cause hypocalcemia and subsequent headache, somnolence, neuromuscular excitability, sometimes accompanied by delirium, convulsions, and seizures. Furthermore, clinical studies have shown that high pH levels can induce alkalosis, which lowers the threshold for angina symptoms and arrhythmias (J Lewis, 2017).

[0081] The drug solutions disclosed herein, generated by mixing aqueous stock solutions and aqueous buffer solutions, can be administered via parenteral or enteral administration. Parenteral administration is a route of administration that does not involve drug absorption via the gastrointestinal tract. Parenteral administration routes include, but are not limited to, subcutaneous, intravenous, intrathecal, intradermal, intra-arterial, intraosseous, intramuscular, intracerebral, and intraventricular administration. In some embodiments, parenteral administration is subcutaneous. In some embodiments, parenteral administration is intravenous. Enteral administration involves administration via the gastrointestinal tract. Enteral administration routes include, but are not limited to, oral, sublingual, buccal, duodenal, and rectal administration. In some embodiments, enteral administration is duodenal administration.

[0082] Solutions suitable for parenteral administration must also meet several other conditions. Administering solutions that are too dilute or too concentrated may disrupt the patient's sodium, potassium, magnesium, and other electrolyte balance. Therefore, parenteral drug solutions should preferably have a weight molar osmolality in the range of 150 to 1500 milli-osmoles per kilogram, preferably 300 to 600 or 500 to 1000 milli-osmoles. The present invention meets the aforementioned requirements regarding weight molar osmolality, which facilitates its suitability as a pharmaceutical product.

[0083] The inventors have discovered that an aqueous drug infusion or injection solution with a desired pH (3.0-8.5) for treating central nervous system (CNS) diseases can be achieved using a system of two liquids, namely an aqueous stock solution containing levodopa and optionally an inhibitor such as carbidopa and a corresponding aqueous buffer dilution solution, which are mixed shortly before treatment.

[0084] By using an optimized aqueous stock solution along with an optimized aqueous buffer solution, it was found that the two solutions can be mixed rapidly without precipitation. This contrasts with previous teachings, such as those in WO 2006 / 006929, where solution preparation relies on the slow addition of the buffer solution to the stock solution in small batches during continuous stirring. Therefore, the aqueous stock solution and aqueous buffer solution of this invention can be simply mixed only before treatment, for example, using a medical bag or container with two compartments, one containing the aqueous stock solution and the other containing the aqueous buffer solution. This infusion or injection solution requires only a few hours to a few minutes to stabilize. This, in turn, opens up the use of levodopa and / or carbidopa concentrations exceeding 10 mg / ml at desired pH ranges.

[0085] According to one embodiment, an aqueous drug solution for treating central nervous system (CNS) disorders is provided, comprising at least 5 mg / ml of dissolved levodopa and having a pH in the range of 3.0 to 8.5. The solution is provided by mixing (a) an aqueous stock solution containing levodopa and (b) an aqueous buffer solution for raising the pH of the stock solution. The aqueous stock solution has a pH less than 2.8 at 25°C. The aqueous buffer solution comprises at least one buffer component and has a pH of at least 4.0 at 25°C. The aqueous drug solution is administered to a subject suffering from a CNS disorder within 24 hours after mixing the aqueous stock solution and the aqueous buffer solution, such as at 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0086] The stability of levodopa decreases with increasing concentration. Therefore, more dilute formulations will have a longer period of physical stability. In some embodiments, the drug solution contains up to 10 mg / ml of levodopa and is administered within 24 hours of mixing an aqueous stock solution and an aqueous buffer solution. These embodiments can be prepared for injection or infusion.

[0087] Surprisingly, the optimized properties of the stock and buffer solutions, along with their suitability for rapid mixing, allow for the formation of a supersaturated levodopa drug solution at a physiologically acceptable pH and molar osmotic concentration, optionally also containing carbidopa. Thus, in another embodiment, the aqueous drug solution is supersaturated with levodopa.

[0088] Supersaturation is a state in which a solution at a given temperature contains more dissolved substances than the solvent can normally dissolve. Such solutions often have relatively short long-term stability because, from a thermodynamic point of view, supersaturated solutions are not energy-favorable. However, precipitation of the solute takes time because molecules need to meet and form a precipitate without being knocked apart by water. Furthermore, nucleation events may be required to trigger precipitation. Due to the principles of Brownian motion, larger molecules will require a longer time.

[0089] In some embodiments, the concentration of levodopa may be increased to the supersaturation point. Levodopa precipitation has been observed at concentrations above 10 mg / mL. Due to the lower physical stability of supersaturated solutions, online mixing can be used to ensure the solution remains stable when administered to patients. Online mixing allows for continuous mixing of aqueous stock solutions and aqueous buffer solutions, followed by continuous administration of the resulting aqueous drug solution within 2 hours of mixing the stock solutions. In some embodiments, the aqueous drug solution is administered within 1.5 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute after mixing the aqueous stock solution and aqueous buffer solution.

[0090] According to one embodiment, an aqueous drug solution for treating central nervous system (CNS) diseases is provided, comprising at least 5 mg / ml of dissolved levodopa and having a pH in the range of 3.0 to 8.5, wherein the aqueous drug infusion or injection solution is supersaturated with levodopa.

[0091] In another embodiment, the aqueous drug solution is provided by mixing (a) an aqueous stock solution containing levodopa and (b) an aqueous buffer solution for raising the pH of the stock solution. The aqueous stock solution has a pH of less than 2.8 at 25°C. The aqueous buffer solution contains at least one buffer component and has a pH of at least 4.0 at 25°C.

[0092] In some embodiments, the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0, or 0.5; preferably, the pH of the aqueous stock solution is in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0, or 0.0 to 0.5. Optionally, the pH of the aqueous stock solution is in the range of 0.0 to 1.0. The aqueous stock solution may contain at least one physiologically acceptable acid. In some embodiments, the physiologically acceptable acid is an inorganic acid, such as hydrochloric acid, sulfuric acid, or nitric acid. Optionally, the inorganic acid is hydrochloric acid (HCl); preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl, or 150 mM HCl. In some embodiments, the physiologically acceptable acid is acetic acid. In one embodiment, the physiologically acceptable acid is acetic acid, lactic acid, tartaric acid, maleic acid, sodium bicarbonate, or sodium phosphate. The aqueous stock solution may contain more than one physiologically acceptable acid. Optionally, the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35 or 40 mg / ml levodopa.

[0093] In some embodiments, the aqueous buffer solution has a pH between 4 and 12 at 25°C. The pH of the aqueous buffer solution can be in the range of 4 to 12, such as 4 to 9, such as 4 to 7.5, such as 4 to 6. The aqueous buffer solution may contain at least one buffer component having at least one pKa value in the range of 3 to 9. Optionally, at least one buffer component has at least one pKa value in the range of 5 to 7.5. Optionally, at least one buffer component has at least one pKa value in the range of 4 to 6. In some embodiments, the buffer is selected from the group consisting of: adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate dihydrate, sodium dihydrogen phosphate, tris(hydroxymethyl)aminomethane, or combinations thereof. The buffer component may be citric acid. Optionally, the buffer components are citric acid and phosphate.

[0094] The following section provides a more detailed explanation of the aqueous drug solution containing at least 5 mg / ml of levodopa, provided by any of the mixing methods described above.

[0095] Patients with advanced PD require up to 1000 mg of levodopa daily via oral administration. Levodopa concentrations in the range of 0.5 to 1.0 mg / ml result in a daily dosing volume of 1 to 2 liters. Therefore, the stock solution should preferably contain at least 5 mg / ml of levodopa. However, a levodopa concentration of 5 mg / ml is low for infusion solutions intended for parenteral administration, especially when the solution does not contain an inhibitor. Infusion solutions intended for continuous subcutaneous infusion should contain an inhibitor and at least 10 mg / ml of levodopa. A series of mixing experiments using the methods of the present invention are summarized in Tables 8 to 20, highlighting the effects of using different formulations containing acids, buffers, stabilizers, and other additives. By mixing the specific stock solutions and buffer solutions of the present invention, and then immediately administering the resulting infusion solution, pharmaceutically acceptable infusion solutions with levodopa concentrations of 10 mg / ml or higher at the desired pH range can be obtained. This has never been achieved before. Nor has it been taught in the art prior to this invention.

[0096] Therefore, according to one embodiment, the aqueous drug solution contains at least 5 mg / ml of levodopa dissolved in water, such as at least 6, 7, 8, 9, 10, 15, or 20 mg / ml of levodopa dissolved in water. In one embodiment, the aqueous drug solution contains at least 5 mg / ml of levodopa dissolved in water, such as at least 6, 7, 8, 9, 10, or 15 mg / ml of levodopa dissolved in water. In another embodiment, the aqueous drug solution contains at least 5 mg / ml of levodopa dissolved in water, such as at least 6, 7, 8, 9, or 10 mg / ml of levodopa dissolved in water. Therefore, the aqueous drug solution may contain 5 to 20 mg / ml of levodopa dissolved in water, such as 5 to 15 mg / ml or 5 to 10 mg / ml of levodopa dissolved in water. In some embodiments, the aqueous drug solution contains at least 10 mg / ml of levodopa dissolved in water. Therefore, the aqueous drug solution may contain 10 to 20 mg / ml of levodopa dissolved in water, such as 10 to 15 mg / ml or 15 to 20 mg / ml of levodopa dissolved in water.

[0097] As mentioned above, the required pH range for aqueous drug solutions is 3.0 to 8.5. Figure 7 As shown, this range aligns with the higher lipophilicity of levodopa, which is more pronounced at pH values ​​of 3.5, 4, 4.5, or 5 to 5, 5.5, 6.0, 6.5, or 7.0, leading to better passive distribution into biological tissues and cells, which in turn increases the rate of absorption and clinical efficacy. In one embodiment, the aqueous drug solution has a pH between 3.5 and 8.0, such as between 4.0 and 7.5, 4.0 and 5.0, or 4.5 and 7.0. In another embodiment, the aqueous drug solution has a pH between 4.3 and 4.6. In some embodiments, the aqueous drug solution has a pH between 5.0 and 6.0.

[0098] Table 22 summarizes the interim data from the clinical trials, demonstrating that the solution of the present invention exhibits high bioavailability of both levodopa and carbidopa during continuous subcutaneous infusion. The high bioavailability of carbidopa during subcutaneous infusion supports the finding that the lipophilicity of an API is extremely important for the uptake of the API of interest in the bloodstream. The pH of the infusion solution of the present invention is close to 5, under which the lipophilicity of carbidopa is optimal. Therefore, the bioavailability (and corresponding plasma uptake of carbidopa) during subcutaneous infusion is approximately 100%, compared to the carbidopa bioavailability of intestinal gel dodurin (which is approximately 75%). The approximately 100% levodopa bioavailability of both dodurin and the infusion solution of the present invention can be achieved through... Figure 7 This is explained by the optimal lipophilicity of levodopa over a much wider pH range (3-8).

[0099] By administering the solution shortly after mixing, a pharmaceutically acceptable infusion solution with concentrations of levodopa and / or carbidopa, or even higher, can be obtained within the desired pH range.

[0100] The increased absorption rate of levodopa allows for personalized treatment for individual patients. The amount of levodopa required to achieve a therapeutic effect will vary depending on the stage of Parkinson's disease (PD). A therapeutic effect is achieved when the blood concentration of levodopa reaches the level required by the patient of interest (for patients with on / off symptoms associated with Parkinson's disease). The large variation in the required levodopa levels among different patients is due to… Figure 14A As shown in Figures B and C. One patient with severe PD (Patient 101) required a levodopa concentration of approximately 5,000–6,000 ng / mL in the blood, while another patient with moderate or mild PD (Patient 103) required only 1,600–1,700 ng / mL to achieve a therapeutic effect. The therapeutically effective dose required for patients with PD will depend on factors such as the subject's size, health, age, and stage of Parkinson's disease. Rapid absorption of levodopa and carbidopa in the blood allows for adjustment of the drug solution flow rate until the desired effect is achieved for each individual patient. Adjusting the drug solution flow rate (by adjusting the flow rate of the pump supplying the reserve and buffer solutions to the mixing device) enables control over both the response time (the time from the start of infusion in the morning during the off-stage until the first therapeutic effect is achieved) and the concentration of the API in the blood, minimizing on / off symptoms.

[0101] The fact that the formulation allows for real-time mixing of the stock solution and buffer solution enables the “online” administration method of the present invention, in which specific stock solutions and buffer solutions can be continuously mixed and the resulting infusion solution can be continuously administered. This is particularly advantageous for continuous subcutaneous infusion, where the infusion solution can be continuously mixed during a slow, continuous infusion process to provide a completely fresh infusion solution. This method cannot be used with known solutions or formulations in the prior art, but the inherent properties of the solutions of the present invention allow for rapid online mixing, and any degradation of the API will be entirely within the limits of pharmaceutical regulations due to the subsequent rapid online administration. Table 21 summarizes the results of online mixing experiments using the solutions and online mixing system of the present invention.

[0102] In one embodiment, the aqueous drug solution is administered to a subject with a central nervous system (CNS) disease within 2 hours after the aqueous stock solution and the aqueous buffer solution are mixed, such as within 90 minutes, 60 minutes, 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0103] In one embodiment, an aqueous buffer solution and an aqueous reserve solution are continuously mixed, and the resulting aqueous drug solution is continuously administered to a subject suffering from a central nervous system (CNS) disease.

[0104] In one embodiment, the aqueous drug solution is administered to a subject with a central nervous system (CNS) disorder within one hour, such as 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute, after mixing the aqueous stock solution and the aqueous buffer solution. According to one embodiment, the aqueous drug solution is administered to a subject with a CNS disorder within 10 minutes, 8 minutes, 6 minutes, 4 minutes, 2 minutes, or 1 minute, after mixing the aqueous stock solution and the aqueous buffer solution.

[0105] In one embodiment, the aqueous drug solution is administered before 15 wt% of levodopa is degraded in the aqueous drug solution, such as before 10 wt% of levodopa is degraded.

[0106] In one embodiment, the time from mixing the aqueous stock solution and the aqueous buffer solution to administering the aqueous drug solution to a subject with a central nervous system (CNS) disease is shorter than the time from mixing the aqueous stock solution and the aqueous buffer solution to the degradation of 15 wt%, such as 10 wt%, of levodopa in the aqueous drug solution.

[0107] Several factors can affect the stability of levodopa and carbidopa in aqueous drug solutions, such as concentration and the presence of other additives in the solution. In some embodiments, the aqueous drug solution is both physically and chemically stable for up to 24 hours. In other embodiments, the aqueous drug solution is physically stable for only 2 hours, and API degradation may violate acceptable limits within 30 minutes. The stability of the solution can be determined using methods well known in the art. For example, those skilled in the art will understand that toxic byproducts derived from API degradation can be detected using high-performance liquid chromatography (HPLC). Depending on the stability of the aqueous drug solution, different methods of mixing aqueous stock solutions and aqueous buffer solutions are feasible. For example, an aqueous drug solution with a higher degree of stability may be mixed for up to 24 hours before administration to a patient. Such a solution may be placed in two compartments separated by a perforated barrier in a single bag. Once the barrier is punctured, such as by squeezing the bag, the two solutions are mixed. Squeezing the bag will also allow for thorough mixing of the solutions, resulting in an aqueous drug solution sufficiently stable to be administered to a patient within 24 hours. Alternatively, for aqueous drug solutions with lower levels of stability, an online mixing method can be used to ensure that the level of API degradation and the concentration of toxic byproducts remain within acceptable limits. Online mixing would allow for the continuous mixing of aqueous stock solutions and aqueous buffer solutions while the resulting aqueous drug solution is continuously administered to the patient. This online mixing method would allow for the administration of the solution to the patient in ways that are otherwise impractical due to their limited stability window.

[0108] Although both the stock solution and the buffer solution must meet conditions for sufficient stability and solubility, the resulting aqueous drug solution must still meet the criteria discussed above (controllable precipitation risk, suitable pH range, limited API degradation, limited toxic byproduct content, acceptable osmotic concentration level, etc.) to be suitable for parenteral administration. This means that a stability-optimized stock solution containing levodopa may not only be unsuitable for mixing with a buffer solution, but may also not produce an aqueous drug infusion or injection solution suitable for treating central nervous system disorders. This is further explained below. Therefore, it is necessary to specifically design both the stock solution and the buffer solution to ensure that the solution meets the necessary parameters before, during, and after mixing.

[0109] It is well known that low pH values ​​increase solubility. However, low-pH stock solutions will need to be mixed with strongly alkaline buffer solutions to achieve a pH value preferred for clinical use. As shown, for example, in Table 20, when high concentrations or multiple additives are used in the stock and buffer solutions, the final solution's osmotic concentration becomes very high. The normal human reference range for osmotic concentration in plasma is 285-295 mOsm / kg, and excessively high osmotic concentrations will adversely affect local tolerance in the human body at the cellular level. Therefore, in one embodiment, the aqueous drug solution has an osmotic concentration of 50 to 1400 mOsm / kg, preferably 100 to 1000 or even 200 to 600 mOsm / kg.

[0110] The stability of the stock solutions was assessed during the experimental period outlined in Tables 1 to 7. It was found that levodopa stock solutions with a pH <3 exhibited excellent stability when frozen, with no significant degradation after 4 months. Solutions containing levodopa and carbidopa with a pH above 3 showed carbidopa degradation over time.

[0111] In one embodiment, the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35, or 40 mg / ml levodopa. In one embodiment, the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0, or 0.5. The pH of the aqueous stock solution may be in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0, or 0.0 to 0.5.

[0112] To provide a low pH, the aqueous stock solution may contain a physiologically acceptable acid, preferably an inorganic acid, such as hydrochloric acid, sulfuric acid, or nitric acid. In one embodiment, the physiologically acceptable acid is HCl. Preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl, or 150 mM HCl. In one embodiment, the physiologically acceptable acid is acetic acid, lactic acid, tartaric acid, maleic acid, sodium bicarbonate, or sodium phosphate. The aqueous stock solution may contain more than one physiologically acceptable acid.

[0113] In some embodiments, the aqueous stock solution disclosed herein may contain at least one stabilizer. The stabilizer may be sodium metabisulfite. Sodium metabisulfite is a preferred stabilizer because it has been found to have a positive effect on the long-term storage of the stock solution. Sodium metabisulfite (also known as sodium disulfite) is an inorganic compound with the chemical formula Na₂S₂O₅. Sodium metabisulfite is oxidized to sulfate in the liver and excreted in the urine, thus allowing for the intake of tens of milligrams as a daily dose without adverse effects.

[0114] As seen in the experiments outlined in Table 5, the removal of air from the solution (e.g., an aqueous stock solution) also has a positive effect on long-term stability and the reproducibility and consistency of certain experimental results. In one embodiment, the aqueous stock solution is de-aired; for example, by bubbling an inert gas, such as nitrogen, through the stock solution. According to one embodiment, the buffer solution is de-aired using an inert gas, such as nitrogen, by bubbling the inert gas through the solution.

[0115] Including DOPA decarboxylase inhibitors is advantageous because they prevent the metabolism of levodopa in plasma during systemic circulation. Examples of DOPA decarboxylase inhibitors include carbidopa, benzylhydrazine, methyldopa, and DFMD (α-difluoromethyl-DOPA). In some formulations, the DOPA decarboxylase inhibitor is carbidopa. COMT inhibitors are also frequently combined with other drugs used to treat Parkinson's disease. COMT inhibitors inhibit the action of catechol-O-methyltransferases, enzymes involved in the degradation of neurotransmitters. Examples of COMT inhibitors include entacapone, tolcapone, opicapone, and nitecapone. Monoamine oxidase inhibitors (MOAIs) inhibit the activity of the monoamine oxidase family (and thus affect dopaminergic neurons) already used in the treatment of Parkinson's disease. Examples of MOAIs include rasagiline, selegiline, and safinamide.

[0116] Therefore, the aqueous pharmaceutical solution according to one embodiment further comprises at least one enzyme inhibitor. In some embodiments, the stock solution comprises at least one dopa decarboxylase (DDC) inhibitor, or at least one catechol-o-methyltransferase (COMT) inhibitor, or at least one monoamine oxidase (MAO-B) inhibitor, or a combination thereof. The dopa decarboxylase (DDC) inhibitor may be selected from the group consisting of carbidopa such as carbidopa monohydrate, benserazide, methyldopa, and DFMD (α-difluoromethyl-DOPA). The catechol-o-methyltransferase (COMT) inhibitor may be selected from the group consisting of entacapone, tocapone, and niticapone. The monoamine oxidase (MAO-B) inhibitor may be selected from the group consisting of rasagiline, selegiline, and safinamide.

[0117] Aqueous buffer solutions are designed to match the properties of the stock solution in order to achieve, upon mixing / after mixing, an aqueous pharmaceutical solution with desired properties (such as desired pH, good buffering capacity, minimal API degradation), minimal toxic byproducts, and acceptable osmotic concentration levels over a specific period. An important property of buffer solutions is to raise the pH of the mixed solution while preventing precipitation of the stock solution components. In one embodiment, the pH of the aqueous buffer solution is at least 4.0. The pH of the aqueous buffer solution can be in the range of 4 to 12, such as 4 to 9, such as 4 to 7.5, such as 4 to 6. In one embodiment, the aqueous buffer solution contains at least one buffer component having at least one pKa value between 3 and 9, such as between 5 and 7.5.

[0118] The pH of a buffer in the acidic or alkaline range can be adjusted by adding a strong acid (such as hydrochloric acid) or a strong base (such as sodium hydroxide) to the buffer, respectively. Alternatively, buffers can be made from mixtures of acids and their conjugate bases. For example, an acetate buffer can be made from a mixture of acetic acid and sodium acetate. Similarly, alkaline buffers can be made from mixtures of bases and their conjugate acids. The buffering capacity of a buffer is at a local maximum when pH = pKa. It decreases to 33% of its maximum at pH = pKa ± 1 and to 10% of its maximum at pH = pKa ± 1.5. Therefore, the practical buffering range is approximately pKa ± 1. Buffers with a wide range of pKa values ​​can be obtained by combining buffer components with pKa values ​​differing by only two units or less and adjusting the pH. Buffering capacity is proportional to the concentration of the buffer, resulting in dilute solutions having smaller buffering capacities.

[0119] There are several suitable pharmaceutical buffer components that can be combined to obtain a suitable buffer solution. Examples of such suitable buffer components are:

[0120] Adipic acid - Acidity / Alkalinity pH = 2.7 (saturated solution at 25°C); pH = 3.2 (0.1% w / v aqueous solution at 25°C)

[0121] Boric acid - pH = 3.5-4.1 (5% w / v aqueous solution),

[0122] Calcium carbonate - pH = 9.0 (10% w / v aqueous dispersion)

[0123] Calcium lactate - pH = 6.0-8.5 (10% aqueous solution)

[0124] Tricalcium phosphate - pH = 6.8 (20% in water slurry),

[0125] Citric acid monohydrate - pH = 2.2 (1% w / v aqueous solution),

[0126] Diethanolamine - Acidity / Alkalinity pH = 11.0 (0.1 in aqueous solution),

[0127] Glycine - Acidity / Alkalinity pH = 4 (0.2 M aqueous solution),

[0128] Maleic acid - Acidity / Alkalinity pH 2 (at 25°C, 5% w / v aqueous solution),

[0129] Methionine - Acidity / Alkalinity pH = 5.6-6.1 (1% w / v aqueous solution),

[0130] Monosodium glutamate - pH = 7.0 (0.2% w / v aqueous solution),

[0131] Potassium citrate - pH = 8.5 (saturated aqueous solution)

[0132] Sodium acetate - pH = 7.5-9.0 (5% w / v aqueous solution)

[0133] Sodium bicarbonate - pH = 8.3 (freshly prepared 0.1 M aqueous solution at 25°C).

[0134] Sodium borate - pH = 9.0-9.6 (4% w / v aqueous solution)

[0135] Sodium carbonate - Strongly alkaline; pH = 11.4 (in a 1% w / v aqueous solution at 25°C).

[0136] Sodium citrate dihydrate - pH = 7.0-9.0 (5% w / v aqueous solution)

[0137] Sodium lactate - pH = 7 (aqueous solution)

[0138] Disodium hydrogen phosphate - pH = 9.1 (1% w / v aqueous solution of anhydrous substance at 25°C).

[0139] Sodium dihydrogen phosphate - pH = 4.1-4.5 (5% w / v aqueous solution of monohydrate at 25°C).

[0140] Meglumine - pH = 10.5 (1% w / v aqueous solution), and trometamol.

[0141] According to another embodiment, there are several pharmaceutically suitable buffer components that can be combined to obtain a suitable buffer solution. Examples of such suitable buffer components are:

[0142] Adipic acid - Acidity / Alkalinity pH = 2.7 (saturated solution at 25°C); pH = 3.2 (0.1% w / v aqueous solution at 25°C)

[0143] Boric acid - pH = 3.5-4.1 (5% w / v aqueous solution),

[0144] Citric acid monohydrate - pH = 2.2 (1% w / v aqueous solution),

[0145] Diethanolamine - Acidity / Alkalinity pH = 11.0 (0.1 in aqueous solution),

[0146] Glycine - Acidity / Alkalinity pH = 4 (0.2M aqueous solution),

[0147] Maleic acid - Acidity / Alkalinity pH 2 (at 25°C, 5% w / v aqueous solution),

[0148] Methionine - Acidity / Alkalinity pH = 5.6-6.1 (1% w / v aqueous solution),

[0149] Monosodium glutamate - pH = 7.0 (0.2% w / v aqueous solution),

[0150] Potassium citrate - pH = 8.5 (saturated aqueous solution)

[0151] Sodium acetate - pH = 7.5-9.0 (5% w / v aqueous solution)

[0152] Sodium bicarbonate - pH = 8.3 (freshly prepared 0.1 M aqueous solution at 25°C).

[0153] Sodium borate - pH = 9.0-9.6 (4% w / v aqueous solution)

[0154] Sodium carbonate - Strongly alkaline; pH = 11.4 (in a 1% w / v aqueous solution at 25°C).

[0155] Sodium citrate dihydrate - pH = 7.0-9.0 (5% w / v aqueous solution)

[0156] Sodium lactate - pH = 7 (aqueous solution)

[0157] Disodium hydrogen phosphate - pH = 9.1 (1% w / v aqueous solution of anhydrous substance at 25°C).

[0158] Sodium dihydrogen phosphate - pH = 4.1-4.5 (5% w / v aqueous solution of monohydrate at 25°C).

[0159] Meglumine - pH = 10.5 (1% w / v aqueous solution), and tromethamine.

[0160] The buffer component is preferably citric acid, which has a versatile function as both a buffer component and a stabilizer. Tests conducted by the inventors clearly demonstrate the stabilizing effect of citric acid on the API of this invention. US 8,815,950 B2 teaches that the stabilizing effect of citric acid is absent or at least very low at pH values ​​above 4. Nevertheless, as can be seen in Tables 14 and 15, the use of a two-solution system, along with a citrate / phosphate buffer system, unexpectedly provides very good stability even at pH values ​​above 4.

[0161] It has been reported that solutions containing citrate as a buffer are more likely to cause pain after subcutaneous injection compared to other solutions containing physiologically acceptable buffers, such as those using histidine as a buffer. Typically, pain is most intense immediately after subcutaneous administration, such as within minutes, and then subsides. Even so, pain caused by subcutaneous injection is an unpleasant condition that can limit patient compliance.

[0162] In this invention, it was found that by using a low-concentration (such as 30 to 70 mM, preferably 40 to 60 mM) citrate / phosphate buffer system, the positive effects of citrate can be preserved while avoiding or minimizing any pain following subcutaneous injection.

[0163] This invention enables buffer solutions to contain components that could adversely affect the stability of levodopa and / or carbidopa, since such components do not come into contact with levodopa and / or carbidopa until the stock solution and buffer solution are mixed. This is another advantage of the invention, which opens up the use of a variety of components that improve stability and reduce the formation of toxic metabolites.

[0164] Furthermore, adding another buffering component, such as a low concentration of phosphate, to an aqueous buffer solution already containing the buffering component citric acid (the term citrate may be used due to the high pH value) is highly advantageous while maintaining an acceptable weight molar osmotic concentration of the final infusion solution. This increases the range of buffering capacity covering the entire pH range of the invention. Moreover, and more importantly, it is possible to achieve higher pH values ​​for the buffer solution compared to the case containing only citrate. The maximum pH value of the buffer solution obtained using only citrate is 6.2 (pKa values ​​of citrate are 3.13, 4.76, and 6.40). Furthermore, the addition of phosphate brings the pH of the buffer solution to 7.6 (pKa value of phosphate is 7.20) while still maintaining good buffering capacity. Starting at a higher pH value allows the resulting infusion solution (after mixing) to achieve a pH range of 5.1–5.4. The foregoing is illustrated by the experiments described in the experimental section. This pH range is optimal considering the absorption of API in tissues during subcutaneous infusion (as previously mentioned in the description). Therefore, in one embodiment, both citric acid and phosphate are used as buffering components.

[0165] In some embodiments, the aqueous buffer solution further comprises a solubilizer. The solubilizer may be selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), collidone, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil (cremophor EL), DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzyl chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl beta-cyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, triolein, vitamin E polyethylene glycol succinate, or mixtures of two or more of these. In one embodiment, the solubilizer is HP-β-cyclodextrin. As can be seen in Tables 5, 6, and 16, a concentration of approximately 75 mg / ml of HP-β-cyclodextrin improves physical stability.

[0166] Both aqueous stock solutions and aqueous buffer solutions may preferably contain stabilizers such as stabilizers, antioxidants, and preservatives, or combinations thereof. Therefore, in one embodiment, the aqueous buffer solution further comprises at least one stabilizer. In another embodiment, the stabilizer is selected from the group consisting of stabilizers, antioxidants, and preservatives, or combinations thereof.

[0167] Stabilizers may be selected from the group consisting of: bentonite, calcium alginate, calcium stearate, carbidopa such as carbidopa monohydrate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, zinc acetate, and the like.

[0168] In one embodiment, the stabilizer is a physiologically acceptable sugar. A physiologically acceptable sugar may be glucose. In one embodiment, the glucose concentration is in the range of 5 to 100 mg / ml. Alternatively, a physiologically acceptable sugar may be fructose, dextran (e.g., dextran 70, dextran 60, or dextran 40), or mannitol.

[0169] In addition to its stabilizing effect on levodopa, as shown in Table 4, glucose can further enhance its analgesic effect during subcutaneous injection. Furthermore, there are indications that glucose can act as a mild procoagulant. These effects appear to already exist at lower glucose concentrations (such as 5 to 100 mg / ml), which are advantageous because the addition of glucose has been shown to increase carbidopa breakdown. These effects are particularly advantageous when glucose is used in conjunction with citrate or a citrate / phosphate buffer system, as the addition of glucose can help reduce or mitigate potential pain or bruising following subcutaneous injection of a solution containing citrate. Therefore, in one embodiment, the glucose concentration is 5 to 100 mg / ml. In one embodiment, the drug solution does not contain glucose.

[0170] As shown in Table 15, glucose can destabilize carbidopa. Accordingly, in some embodiments, the concentration of glucose is limited in the presence of carbidopa. Optionally, the aqueous drug solution does not contain glucose in the presence of carbidopa.

[0171] Antioxidants may be selected from the group consisting of: α-tocopherol, ascorbic acid, palmitic acid ascorbate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, pentetic acid, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, and analogues.

[0172] Preservatives may be selected from the group consisting of: anhydrous benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitol, butanediol, calcium acetate, calcium lactate pentahydrate, cetrimide, cetylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, dextran, edetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

[0173] Carbidopa can be used as a preferred stabilizer for levodopa in stock solutions, where it has a dual function due to its role as an inhibitor as well.

[0174] Sodium metabisulfite is another preferred stabilizer for use in stock solutions, where it improves solubility and reduces API degradation and the accumulation of toxic byproducts. Sodium metabisulfite (also known as sodium disulfite) is an inorganic compound with the chemical formula Na₂S₂O₅. Sodium metabisulfite is oxidized to sulfate in the liver and excreted in the urine, allowing for the intake of tens of milligrams as a daily dose without adverse effects.

[0175] By using online mixing, the infusion solution can meet the requirements of the drug product, provided that the time from the time of mixing to the time of infusion into the patient's tissue is less than 90 minutes, such as less than 50, 20, 10, or 1 minute, and the degradation of the API is within the specified limits. This stability window of supersaturation allows for the use of higher levodopa concentrations, thus reducing the infusion volume.

[0176] In a preferred embodiment, the aqueous drug solution is provided by mixing I) and II), wherein I) is an aqueous stock solution with a pH less than 2.8 at 25°C, comprising: a) sterile water, b) levodopa, c) at least one enzyme inhibitor, d) at least one physiologically acceptable acid, and e) at least one physiologically acceptable stabilizer, wherein the stock solution is bubbled with nitrogen after mixing. II) is an aqueous buffer solution with a pH of at least 4.0 at 25°C, comprising: f) sterile water, g) at least one physiologically acceptable buffer component, and h) at least one physiologically acceptable stabilizer and / or solubilizer. The aqueous drug solution may be supersaturated and is administered to a subject with a central nervous system (CNS) disorder within 24 hours after mixing the aqueous stock solution and the aqueous buffer solution, such as 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes, or 1 minute.

[0177] An example of this particular composition containing 10 mg / ml levodopa and 1.25 mg / ml (1:8) carbidopa is prepared by mixing I) and II), wherein I) is a 1000 ml aqueous stock solution containing: a) 963 g purified water, b) 43.3 g 5 M HCl, wherein the solution is purged with nitrogen, c) 20 g micronized levodopa, d) 2.71 g carbidopa monohydrate (equivalent to 2.5 g carbidopa), wherein the solution is again purged with nitrogen. II) is an aqueous buffer solution containing: e) 968 g purified water, f) 64.7 g trisodium citrate dihydrate, g) 3.56 g disodium hydrogen phosphate dihydrate, h) 3.67 g 1 M HCl.

[0178] More specifically, this composition was prepared using the following components, steps, and methods: A stock solution of 20 mg / ml levodopa and 2.5 mg / ml carbidopa was prepared in 1000 ml as follows: 963 g of water was poured into a Duran flask equipped with a magnetic stirrer, followed by the addition of 43.3 g of 5 M hydrochloric acid (HCl). The solution was then purged with nitrogen until the residual oxygen content was <0.1 ppm. 20 g of micronized levodopa was then added, followed by 2.71 g of carbidopa monohydrate (equivalent to 2.5 g of carbidopa). The resulting solution was stirred with a magnetic stirrer until all substances were dissolved. The pH was measured to be approximately 1. The solution was then purged again with nitrogen until the residual oxygen content was <0.1 ppm. Prepare the buffer solution as follows: Pour 968 g of water into a Duran flask equipped with a magnetic stirrer, then add 64.7 g of trisodium citrate dihydrate, followed by 3.56 g of disodium hydrogen phosphate dihydrate, and then 3.67 g of 1M hydrochloric acid (HCl). Stir the solution with the magnetic stirrer until all substances are dissolved. Measure the pH and adjust it to 7.6 using 1M HCl (if the solution is too alkaline) and 1M sodium hydroxide (NaOH) (if the solution is too acidic).

[0179] Pedro Chana et al. presented a study on the stability of carbidopa. The study confirmed that carbidopa in solution is an unstable compound and degrades spontaneously within a short period. No environmental factors studied reduced degradation and stability was maintained within 24 hours, with nearly 50% degradation observed in levodopa and carbidopa aqueous solutions within 24 hours. API degradation (from the time of drug product production to the time of patient administration) must be within given limits. Generally, the reduction in API concentration must be less than 10% of its original value, preferably substantially lower. Therefore, API degradation is not merely a shelf-life issue but may also represent a regulatory hurdle for registration as a drug product. In fact, several promising levodopa and carbidopa solutions in the art may practically be unable to be registered as drug products.

[0180] Carbidopa degrades into toxic byproducts such as hydrazine and 3,4-dihydroxyphenylacetone (DHPA). Table 7 shows the chemical degradation of levodopa and carbidopa over time. Other experiments, such as those outlined in Table 15, show short-term physical stability, degradation of levodopa and carbidopa, and accumulation of DHPA.

[0181] In one embodiment, less than 15% of levodopa is degraded in the aqueous drug solution after 1 minute, such as 5, 10, 15, 20, 30, 40, 50, 60, or 90 minutes, following mixing of the stock solution and the aqueous buffer solution.

[0182] In another embodiment, the aqueous drug solution contains carbidopa, wherein the degradation of carbidopa is less than 15% after 1 minute, such as 5, 10, 20, 30, 40, 50, 60 or 90 minutes, following the mixing of the stock solution and the aqueous buffer solution.

[0183] In some embodiments, the degradation of levodopa in the aqueous drug solution is less than 15% up to 24 hours from the time point from the time point of mixing the stock solution and the aqueous buffer solution, such as up to 16, 8, 6, 4, 3 or 2 hours.

[0184] In another embodiment, the aqueous drug solution contains carbidopa, wherein the degradation of carbidopa is less than 15% from the time point from the time point when the stock solution and the aqueous buffer solution are mixed up to 24 hours, such as up to 16, 8, 6, 4, 3 or 2 hours.

[0185] In one embodiment, the aqueous drug solution contains carbidopa, wherein the aqueous drug solution is administered before 15 wt% of the carbidopa is degraded in the aqueous drug solution, such as before 10 wt% of the carbidopa is degraded.

[0186] In one embodiment, the aqueous drug solution contains carbidopa, and the time from mixing the aqueous reserve solution and the aqueous buffer solution to administering the aqueous drug solution to a subject with a central nervous system (CNS) disease is shorter than the time from mixing until 15 wt% of, such as 10 wt% of, levodopa or carbidopa in the aqueous drug solution is degraded.

[0187] In another embodiment, at the time point after mixing the stock solution and the aqueous buffer solution, such as 5, 10, 20, 30, 40, 50 or 60 minutes later, the level of DHPA (3,4-dihydroxyphenylacetone) is less than 5 mg% of carbidopa (CD) and the level of hydrazine is less than 1 mg of carbidopa (CD).

[0188] Levodopa is primarily used to treat Parkinson's disease. However, it is also used to treat other dopamine-related conditions, such as restless legs syndrome. In one embodiment, the CNS disease is selected from the group consisting of: Parkinson's disease, atypical Parkinson's disease, Alzheimer's disease, restless legs syndrome (RLS), and neurotic psychosis; preferably, the CNS disease is Parkinson's disease.

[0189] In another implementation, the CNS disease is Parkinson's disease in the complication phase. The solution may also be beneficial for other conditions such as other movement disorders (dystonia, progressive supranuclear palsy; PSP), neuroleptic malignant syndrome (NMS), primary mental disorders (schizophrenia, mood disorders, personality disorders), endocrine disorders (diabetes, spontaneous obesity, hypopituitarism), liver diseases (alcoholic cirrhosis, steatohepatitis, hepatic encephalopathy), cardiovascular diseases, and asthma.

[0190] As mentioned above, the unique properties of aqueous drug solutions, such as a physiologically acceptable pH range and high levodopa concentrations, make them suitable for use as drug infusion or injection solutions. While it may be advantageous to inject large volumes of solution over a short time span to rapidly achieve high therapeutic levels of levodopa, optimal therapeutic effects are achieved using continuous dosing, as this has been shown to prevent various side effects associated with prolonged levodopa use.

[0191] Subcutaneous infusion is a suitable route of administration because it is a well-proven technique and is known to be highly effective for drugs that require administration via low infusion rates, such as insulin and morphine. Subcutaneous tissue has few blood vessels, resulting in a slow and prolonged absorption rate. Therefore, in one embodiment, the aqueous drug solution is a drug infusion or injection solution, and in another embodiment, the solution is used for continuous administration. In another embodiment, the solution is used for parenteral administration. In another embodiment, parenteral administration is administered subcutaneously, intravenously, intra-arterially, intraosseously, intramuscularly, intracerebrally, intravenously, or intrathecally, in a mode of administration such as injection or infusion. Parenteral administration may be subcutaneous. Optionally, parenteral administration is intravenous. In one embodiment, parenteral administration is continuous for up to 24 hours, such as 0.1 to 4 hours, such as 4 to 6 hours, such as 6 to 8 hours, such as 8 to 12 hours, such as 12 to 16 hours, and such as 16 to 20 hours. In one embodiment, the solution is intended for injection.

[0192] As mentioned above, the infusion solutions described in patent JP 54105221 and patent application WO 2012 / 066538 A1 all have pH values ​​in the range of 9 to 10. Therefore, they are not suitable for continuous parenteral administration. Clinical studies of the products described in WO 2012 / 066538 A1 showed that therapeutic levels of levodopa in plasma were not reached until 6 to 8 hours after the start of treatment (for patients with comorbid PD). In contrast, pharmacokinetic studies of patients with comorbid PD using the present invention showed that therapeutic levels of levodopa were reached in less than one hour after the start of administration. Several factors can contribute to this, but the pH range of the solutions of the present invention may improve the absorption rate of levodopa and clinical efficacy. In one embodiment of the invention, when treating on / off symptoms in patients with comorbid Parkinson's disease, therapeutic levels are reached within 3 hours after the start of administration, such as 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes, or 10 minutes.

[0193] Furthermore, the rapid response of this invention enables the adjustment of levodopa plasma concentrations (by varying the infusion rate) to meet short-term variations in the levodopa needs of different PD patients. In another embodiment of the invention, levodopa plasma levels can be adjusted by changing the infusion rate within a sufficiently short time period to minimize the on / off symptoms of individual patients with varying levodopa needs. (See Figure 12 and...) Figure 13 The figures show the average blood and plasma levels of levodopa and carbidopa in three patients. As can be seen, the solution of the present invention can rapidly reach and maintain the desired therapeutic level.

[0194] Other routes of administration are also possible, such as using the solution of the present invention for administration into the duodenum. However, as previously noted, administration via the duodenum typically requires a probe that passes through the abdominal wall. In one embodiment, the aqueous drug solution is intended for intravenous administration, preferably duodenal administration.

[0195] The formulation of the present invention allows for real-time mixing of the stock solution and buffer solution, enabling the use of an "online" drug delivery system. Table 21 summarizes the results of online mixing experiments using the solutions and online mixing system of the present invention. Even long after the stock solution and buffer solution have been mixed, the degradation of the API and the level of DHPA remain well within the prescribed limits.

[0196] In another embodiment, a kit is provided for providing an aqueous drug solution for treating central nervous system (CNS) disorders. As already outlined, the aqueous drug solution contains at least 5 mg / ml of levodopa dissolved in water and has a pH in the range of 3.0 to 8.5. In some embodiments, the kit comprises:

[0197] (a) An aqueous stock solution containing levodopa, wherein the aqueous stock solution has a pH of less than 2.8 at 25°C;

[0198] (b) An aqueous buffer solution for raising the pH of the aqueous reserve solution, comprising a buffer component and having a pH of at least 4.0 at 25°C.

[0199] In some implementations, the kit comprises:

[0200] (a) An aqueous stock solution containing levodopa, wherein the stock solution has a pH greater than or equal to 8.0 at 25°C; and

[0201] (b) An aqueous buffer solution used to lower the pH of the stock solution, comprising a buffer component and having a pH not greater than 6.0 at 25°C.

[0202] The aqueous stock solution of the kit may be any of the aqueous stock solutions disclosed herein. The aqueous buffer solution may be any of the aqueous buffer solutions disclosed herein.

[0203] In some implementations, any of the above-described reagent kits further comprises:

[0204] (c) Mixing component 1, which is used to mix solutions a) and b); and

[0205] (d) Output component 2, which is used to transport the mixed solution from step c).

[0206] The output component may be a connector, such as a coupler or connector. For drug administration, the output component may include or connect to the injection or infusion component 20, such as a syringe needle. The needle may be made of plastic to minimize chemical reactions between the needle material and the mixed aqueous drug solution and / or improve patient comfort during administration of the mixed aqueous drug solution.

[0207] Aqueous drug solutions can be infusion or injection solutions. Therefore, the injection or infusion component is selected based on the administration mode. Aqueous drug solutions can be used for continuous administration. They can be used for parenteral administration. In another embodiment, parenteral administration of aqueous drugs is subcutaneous, intravenous, intra-arterial, intraosseous, intramuscular, intracerebral, intraventricular, or intrathecal administration, via injection or infusion. In some embodiments, parenteral administration is subcutaneous. Parenteral administration can also be intravenous.

[0208] In one implementation, the kit is used to treat central nervous system (CNS) diseases.

[0209] The compartments for the reserve solution and the buffer solution can be compressed into two components in one bag (e.g.) Figure 11A (As seen in the image) or separately. The solution can be gravity-fed from mixing component 1 to output component 2 via a suspended bag. Using a sealed compartment provides sterility, ease of use, improved control, and lower total cost. Flow rate can also be controlled using flow regulators such as roller clamps.

[0210] According to an alternative simplified form of the implementation, the aqueous stock solution and the aqueous buffer solution can be pressed together as two components in a single bag, wherein the barrier between the two components is removable or temporary. For example, as can be seen in Figure 14, the two components can be separated by a perforated barrier 31, which can be removed by pressing the two components together, resulting in a bag containing only one component with the two miscible solutions and an output component 2. If so, mixing is facilitated by pushing the bag to move the solutions back and forth within the bag, thus mixing the stock solution and the buffer solution. This implementation is possible because the stock solution and the buffer solution allow for a simple mixing procedure. Administration can then be facilitated by a single pump (or possibly gravity delivery) to the patient within a time limit for that solution. The resulting solution can also be injected directly as a bolus injection. However, this simplified implementation may not be optimal for metastable solutions such as supersaturated solutions. Furthermore, it prolongs the time from mixing to administration. However, this simplified implementation may be acceptable in some clinical settings.

[0211] Using a pump allows for precise control of the delivered flow rate and total volume. According to one embodiment, pump 4 is used to transport the solution to and through a mixing component to an output component. Figure 11BA schematic diagram of this system is shown. In this kit, the mixing component includes two compartments 3A and 3B, a pump 4, and a mixing chamber 10, wherein the first compartment 3A contains an aqueous stock solution and the second compartment 3B contains an aqueous buffer solution. The pump 4 is configured to transport the solution from compartments 3A and 3B to the mixing chamber 10. The mixing chamber 10 is configured to provide mixing of the received aqueous stock solution and the received aqueous buffer solution, and wherein the pump 4 is further configured to transport the mixed aqueous drug solution from the mixing chamber to the output component 2.

[0212] The mixing component 1 may include two pumps 4, a first pump 4 connected to a first compartment 3A and a second pump 4 connected to a second compartment 3B. This allows for precise control of the flow rate and total volume delivered by each pump, enabling the use of stock solutions and buffer solutions with different mixing ratios. Because a buffer system is used, the pH of the mixed solution will change very slowly from the buffer equilibrium point, provided the buffer has buffering capacity. In one embodiment, the stock solution to buffer solution ratio is 10:1 to 1:10, such as 5:1 to 1:5, such as 2:1 to 1:2, such as 1:1.

[0213] Any pump suitable for controlled infusion can be used. This includes any system suitable for moving fluids, such as systems using vacuum or permeation power. In one embodiment, pump 4 is a syringe pump, positive displacement pump, peristaltic pump, or mobile pump.

[0214] In one embodiment, the kit further comprises conduits 5A, 5B, and 5C. Solution compartments 3A and 3B are connected to mixing chamber 10 via first conduit 5A and second conduit 5B, and the mixing chamber is connected to output component 2 via third conduit 5C. Experiments have demonstrated that opaque conduits and / or compartments can limit the degradation of levodopa and / or carbidopa. This indicates that the degradation reaction can be photoinitiated to some extent. Containers 3A and 3B and / or conduits 5A, 5B, and 5C can be opaque or UV-absorbing.

[0215] In some designs, such as when the entire mixing component 1 is located on a card or chip, the mixing chamber 10 can be directly connected to compartments 3A and 3B containing the aqueous reserve solution and the aqueous buffer solution without the use of conduits. Similarly, the mixing component 1 can be directly connected to the output component 2 without the use of conduits. This can also be a case where the mixing component is integrated into a bag, such as... Figure 11A As shown in the image.

[0216] Various types of mixing chambers 10 exist or can be developed, including Y-connectors 11 that combine two solutions into one solution at a contact point, to a channel having a shape that allows for active mixing of solutions. Therefore, in one embodiment, the mixing chamber 10 is a bidirectional Y-connector 11. In another embodiment, the bidirectional Y-connector 11 is a “bidirectional Y' connector assembly.” Examples of this connector that can be used in online systems include the bidirectional Y-connector 11 or similar devices from Becton, Dickinson and Company.

[0217] In some embodiments, the mixing of the stock solution and the buffer solution can be—under specific conditions—accompanied by a mixing assembly consisting of a Y-connector with a mixing chamber. The stock solution and buffer solution, fed by two pumps (or preferably a pump with two containers and two pistons operated by a motor) respectively, are guided to the mixing chamber via two plastic conduits. The resulting infusion solution is then guided from the mixing chamber to the infusion site via plastic conduits. The resulting solution may be unstable at levodopa concentrations close to or above 10 mg / ml, which could result in supersaturation of the mixture and API precipitation. Specific measures can be introduced, including optimization of the formulation, method, and apparatus.

[0218] Therefore, specific implementation plans may include:

[0219] 1. Stock solutions containing API are bubbled with nitrogen during production.

[0220] 2. Limit the flow rate of the infusion solution (typically 1.4-10.0 mL / h), where too low a flow rate may cause direct precipitation.

[0221] 3. Protect the plastic conduit from UV light.

[0222] 4. The Y-type connector has a mixing chamber, the size of which needs to be optimized taking into account the composition and flow rate of the reservoir solution and buffer solution.

[0223] 5. Optimize the total length of the plastic conduit by considering the following parameters:

[0224] The length (l) of the plastic catheter – from the output of the mixing component to the infusion needle – expressed in mm, should preferably not exceed:

[0225]

[0226] L = The maximum daily dose of levodopa required by a group of patients, expressed in mg.

[0227] t = The maximum allowable time, in seconds, for API degradation from mixing to infusion.

[0228] D = Diameter of the plastic conduit, expressed in mm.

[0229] c = concentration of levodopa in mg / mL

[0230] h = Daily treatment time for the patient group of interest

[0231] Mixing can also be actively promoted by directing fluid movement through certain channel shapes, such as helical channels, through which the aqueous drug solution is guided, thereby enhancing mixing due to the centrifugal force exerted on the solution as it is transported through the channel. In one embodiment, the mixing chamber 10 is formed by / contains a helical channel 12 for mixing two solutions. Other shapes may be Venturi mixers 13, i.e., channels that use constricted portions to induce a Venturi effect to promote mixing. Mixing can also be achieved using active mixing tools. In one embodiment, the mixing chamber 10 includes an electrically powered mixing tool 14, such as a piston, screw, propeller, or similar device. The mixing component is in Figure 11A -D provides a graphical overview.

[0232] To facilitate easy use of the kit, stock solutions and buffer solutions require suitable storage containers. Typically, medical solutions intended for infusion are stored in closed systems to prevent exposure to the atmosphere. Preferably, the solution containers must also be able to withstand autoclaving of the contained solutions. In one embodiment of the invention, the container is a syringe, bag, bottle, or box.

[0233] Solutions suitable for parenteral administration must be free of contaminants, such as particles from crystals or precipitates. Therefore, filtering the infusion solution prior to administration is advantageous. Various types of filters are known in the art, such as usable microbial filters or particle filters. In one embodiment, the kit also includes a filter 6, such as a microbial filter or particle filter, for filtering the solution prior to parenteral administration. Filter 6 is configured downstream of mixing chamber 1.

[0234] To facilitate increased mobility in patients using the kit, it is advantageous to provide a kit of an appropriate size. The kit may have solution compartments 3A and 3B with a volume allowing for continuous use throughout the day. Alternatively, solution compartments 3A and 3B may be relatively small and replaceable throughout the day. Thus, in one embodiment, the volume of the container is sufficient to allow a subject with central nervous system (CNS) disease to be continuously treated for at least 4 hours, such as 4 to 6 hours, such as 6 to 10 hours, such as 10 to 16 hours, such as 16 to 24 hours. In one embodiment, compartments 3A and 3B are replaceable or refillable, preferably replaceable. In another embodiment, compartments 3A and 3B can be refilled or replaced even during continuous administration. In one embodiment, the volume of the container is 10 to 1000 ml per container, such as 50 to 500 ml per container, such as 100 to 250 ml per container.

[0235] Using replaceable compartments 3A and 3B, treatment can be continuous as long as compartments 3A and 3B are replaced when emptied. In one implementation, compartments 3A and 3B can be replaced 2, 3, 4, 5, or 6 times during a 24-hour cycle, allowing the subject to receive continuous treatment for 24 hours. In one implementation, the time required to replace compartments 3A and 3B is less than 10 minutes, such as 8 minutes, 6 minutes, 3 minutes, or 1 minute.

[0236] For flexibility, the kit may include a control element 7. This can be simply for controlling the on / off state of pump 4, but it can also aid in controlling the infusion rate and, by varying the ratio of the stock solution to the buffer solution, control the composition of the mixed solution. Therefore, in one embodiment, the kit also includes a control element 7 to control the flow rate of pump 4. Thus, the infusion rate, infusion duration, and / or, in the case of using two pumps 4, the ratio of the stock solution to the buffer solution can be varied. In another embodiment, the kit also includes a battery to power active components such as pump 4, mixing chamber 10, and / or control element 7. Control element 7 may also include safety features to avoid hazards such as uncontrolled flow (causing overdosing), uncontrolled underdosing (causing underdosing), backflow (which can siphon blood from the patient), and air in the tubing (which can cause air embolism). Furthermore, pump 4 and / or control element 7 preferably do not have a single point of failure, i.e., a single cause of failure should not cause the pump to silently malfunction without triggering an (audible) error indication. Control element 7 may also store an internal electronic log of treatment events.

[0237] To enable easy use of the kit in any location, the kit may also include other components useful during use. In one embodiment, the kit also includes a pair of surgical gloves, cleaning wipes, and a disinfectant. In another embodiment, the kit includes a manual.

[0238] According to the present invention, a kit for providing an aqueous pharmaceutical solution is also provided. In some embodiments, the kit comprises: an aqueous stock solution having a pH less than 2.8 at 25°C. The stock solution comprises sterile water, levodopa, at least one enzyme inhibitor, at least one physiologically acceptable acid, and at least one stabilizer. The stock solution is preferably bubbled with nitrogen after preparation. The kit also comprises an aqueous buffer solution having a pH of at least 4.0 at 25°C. The aqueous buffer solution comprises: sterile water, at least one buffer component, and at least one stabilizer and / or solubilizer.

[0239] In other embodiments, the kit may comprise any of the previously described stock solutions and buffer solutions or features of these solutions. According to one embodiment, the present invention relates to a method for the continuous preparation of an aqueous drug solution for treating central nervous system (CNS) diseases, the aqueous drug solution being suitable for continuous parenteral or enteral administration. The method comprises the steps of continuously mixing a stock solution stream containing levodopa and an aqueous buffer solution stream, the stock solution having a pH less than 2.8 at 25°C and the buffer solution having a pH of at least 4.0 at 25°C, thereby continuously obtaining a continuous stream of the aqueous drug solution from the mixture. The aqueous drug solution contains at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15, or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa.

[0240] The fact that formulations are continuously prepared enables the "online" dosing method of this invention, in which specific stock solutions and buffer solutions can be continuously mixed and the resulting infusion solution can be continuously administered. This is particularly advantageous for continuous subcutaneous infusion, where the infusion solution can be continuously mixed during a slow, continuous infusion process, providing a completely fresh infusion solution. Because continuous preparation is followed by rapid online dosing, any degradation of the API will remain entirely within the limits of pharmaceutical regulations.

[0241] In other embodiments, the method for continuously preparing an aqueous drug solution for treating central nervous system (CNS) diseases may comprise any of the previously described aqueous drug solutions, stock solutions, and buffer solutions, or any characteristics of these solutions. Preferred aspects of the various solutions have been discussed above.

[0242] According to one embodiment, the present invention relates to a method for treating central nervous system (CNS) diseases. In some embodiments, the method includes the steps of: continuously mixing a stock solution stream containing levodopa and an aqueous buffer solution stream, the stock solution having a pH less than 2.8 at 25°C and the buffer solution having a pH of at least 4.0 at 25°C; continuously obtaining a continuous stream of an aqueous drug solution from the mixing, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15, or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa; and continuously administering the obtained aqueous drug solution to a subject suffering from a central nervous system (CNS) disease.

[0243] This document has described other features, aspects, and implementation methods for treating central nervous system (CNS) diseases with respect to other embodiments, such as the use of aqueous drug solutions in treating central nervous system (CNS) diseases, and such features, aspects, and implementation methods are equally applicable to methods for treating central nervous system (CNS) diseases.

[0244] Clearly, the compounds and pharmaceutical compositions disclosed herein can be used to manufacture medicaments for the treatment and prevention of such conditions as disclosed herein. One such embodiment relates to the use of the aqueous pharmaceutical solution according to the invention in the manufacture of a medicament for treating diseases of the central nervous system (CNS). The medicament is administered to a patient according to a prior embodiment.

[0245] Similarly, the compounds and compositions disclosed herein can obviously also be used in methods for treating or preventing diseases and conditions as disclosed herein. This method includes the step of administering an effective amount of the compound or pharmaceutical composition to a subject requiring this treatment.

[0246] Some further numbered embodiments of the present invention relate to:

[0247] 1. An aqueous drug solution for treating diseases of the central nervous system (CNS), the aqueous drug solution comprising:

[0248] Levodopa should be dissolved at a concentration of at least 5 mg / ml, with a pH ranging from 3.0 to 8.5, wherein the solution is provided by mixing the following:

[0249] a) An aqueous stock solution containing levodopa, wherein the stock solution has a pH less than 2.8 at 25°C; and

[0250] b) An aqueous buffer solution for raising the pH of the stock solution, comprising at least one buffering component, wherein the buffer solution has a pH of at least 4.0 at 25°C.

[0251] The aqueous drug solution is administered to a subject with a central nervous system (CNS) disease within 24 hours after the aqueous stock solution and the aqueous buffer solution are mixed, such as 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes or 1 minute.

[0252] 2. An aqueous drug solution for use according to implementation plan 1, wherein the aqueous drug solution is a drug infusion or injection solution.

[0253] 3. An aqueous drug solution for use according to embodiment 1 or 2, wherein the aqueous drug solution is administered intravenously or parenterally, such as parenterally.

[0254] 4. An aqueous drug solution for use according to implementation scheme 3, wherein the aqueous drug solution is for parenteral administration.

[0255] 5. The aqueous drug solution for use according to implementation plan 4, wherein the parenteral administration is performed subcutaneously, transdermally, intravenously, intra-arterially, intraosseously, intramuscularly, intracerebrally, intravenously, or intrathecally, and the administration mode is injection or infusion.

[0256] 6. The aqueous drug solution supplied according to Implementation Scheme 3, wherein...

[0257] This enteral administration is administered via the duodenum.

[0258] 7. An aqueous drug solution for use according to any one of embodiments 1 to 6, wherein the administration is continuous for up to 12 hours, such as 24 hours.

[0259] 8. An aqueous drug solution for use according to any one of embodiments 1 to 7, wherein the aqueous drug solution is administered before 15 wt% levodopa is degraded in the aqueous drug solution, such as before 10 wt% levodopa is degraded.

[0260] 9. An aqueous drug solution for use according to any one of embodiments 1 to 8, wherein the aqueous drug solution is administered to a subject with a central nervous system (CNS) disease within 1 hour, such as 50 minutes, 40 minutes, 30 minutes, 20 minutes, 10 minutes, 5 minutes or 1 minute after the aqueous stock solution and the aqueous buffer solution are mixed.

[0261] 10. An aqueous drug solution for use according to any one of embodiments 1 to 9, wherein an aqueous buffer solution and an aqueous reserve solution are continuously mixed, and the aqueous drug solution obtained therefrom is continuously administered to a subject suffering from a central nervous system (CNS) disease.

[0262] 11. An aqueous drug solution for use according to any one of embodiments 1 to 10, wherein the aqueous drug solution is supersaturated with levodopa.

[0263] 12. An aqueous pharmaceutical solution for treating diseases of the central nervous system (CNS), the aqueous pharmaceutical solution comprising:

[0264] Levodopa should be dissolved at a concentration of at least 5 mg / ml, and its pH should be between 3.0 and 8.5.

[0265] The aqueous drug solution is supersaturated with levodopa.

[0266] 13. An aqueous drug solution for use according to embodiment 12, wherein the aqueous drug solution is provided by mixing the following:

[0267] a) An aqueous stock solution containing levodopa, wherein the stock solution has a pH less than 2.8 at 25°C; and

[0268] b) An aqueous buffer solution for raising the pH of the stock solution, comprising at least one buffer component, wherein the buffer solution has a pH of at least 4.0 at 25°C.

[0269] 14. An aqueous drug solution for use according to any one of embodiments 1 to 13, wherein the aqueous drug solution contains at least 5 mg / ml of levodopa, such as at least 6, 7, 8, 9, 10, 15 or 20 mg / ml of levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of levodopa.

[0270] 15. An aqueous drug solution for use according to any one of embodiments 1 to 14, wherein the pH of the aqueous drug solution is 3.5 to 8.0, such as 4.0 to 7.5, 4.5 to 7.0 or 5.0 to 5.5.

[0271] 16. An aqueous drug solution for use according to any one of embodiments 1 to 10 or 12 to 15, wherein the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35 or 40 mg / ml levodopa.

[0272] 17. An aqueous drug solution for use according to any one of embodiments 1 to 10 or 12 to 16, wherein the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0 or 0.5; preferably, the pH of the aqueous stock solution is in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0 or 0.0 to 0.5.

[0273] 18. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 17, wherein the aqueous stock solution contains at least one physiologically acceptable acid.

[0274] 19. An aqueous drug solution for use according to embodiment 18, wherein the physiologically acceptable acid is an inorganic acid, such as hydrochloric acid, sulfuric acid or nitric acid.

[0275] 20. An aqueous drug solution for use according to embodiment 19, wherein the inorganic acid is hydrochloric acid (HCl); preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl or 150 mM HCl.

[0276] 21. An aqueous drug solution for use according to embodiment 20, wherein the physiologically acceptable acid is acetic acid.

[0277] 22. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 21, wherein the aqueous stock solution further comprises at least one stabilizer.

[0278] 23. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 22, wherein the aqueous stock solution has been de-aired; for example by bubbling an inert gas, such as nitrogen, through the aqueous stock solution before mixing with the aqueous buffer solution.

[0279] 24. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 23, further comprising at least one enzyme inhibitor.

[0280] 25. An aqueous drug solution for use according to embodiment 24, wherein the enzyme inhibitor is selected from the group consisting of: dopa decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO-B) inhibitors.

[0281] 26. The aqueous drug solution for use according to embodiment 25, wherein the enzyme inhibitor is:

[0282] a. Dopa decarboxylase (DDC) inhibitors selected from the group consisting of carbidopa such as carbidopa monohydrate, benserazide, methyldopa and DFMD (α-difluoromethyl-DOPA);

[0283] b. Inhibitors of catechol-o-methyltransferase (COMT), selected from the group consisting of entacapone, tocapone, and niticapone;

[0284] c. Monoamine oxidase (MAO-B) inhibitors, selected from the group consisting of rasagiline, selegiline, and safenamide; or

[0285] d. Their combination.

[0286] 27. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 26, wherein the pH of the aqueous buffer solution is at least 4.0; preferably, the pH of the aqueous buffer solution is between 4.0 and 12, such as between 4.0 and 9, 4.0 and 7.5 or 4.0 and 6.

[0287] 28. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 27, wherein the aqueous buffer solution comprises at least one buffer component having at least one pKa value in the range of 3 to 9, such as in the range of 5 to 7.5.

[0288] 29. An aqueous pharmaceutical solution for use according to embodiment 28, wherein the buffer component is citric acid.

[0289] 30. An aqueous drug solution for use according to embodiment 28, wherein the buffer components are citric acid and phosphate.

[0290] 31. An aqueous drug solution for use according to embodiment 28, wherein the buffer component is tromethamine (tris(hydroxymethyl)aminomethane).

[0291] 32. An aqueous drug solution for use according to embodiment 28, wherein the buffer component is adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a mixture of two or more thereof.

[0292] 33. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 11 to 32, wherein the aqueous buffer solution further comprises at least one solubilizer.

[0293] 34. An aqueous buffer solution for use according to embodiment 33, wherein the solubilizer is selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), clopidogrel, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil, DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzalkonium chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl beta-cyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, trioleic acid glyceride, vitamin E polyethylene glycol succinate, or a mixture of two or more of these.

[0294] 35. An aqueous pharmaceutical solution for use according to embodiment 34, wherein the solubilizer is HP-β-cyclodextrin, preferably, HP-β-cyclodextrin is present at a concentration of about 75 mg / ml.

[0295] 36. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 11 or 13 to 35, wherein the aqueous buffer solution further comprises at least one stabilizer.

[0296] 37. An aqueous pharmaceutical solution for use according to embodiment 36, wherein the stabilizer is selected from the group consisting of stabilizers, antioxidants and preservatives or combinations thereof.

[0297] 38. An aqueous pharmaceutical solution for use according to embodiment 37, wherein the stabilizer is a physiologically acceptable sugar.

[0298] 39. An aqueous pharmaceutical solution for use according to embodiment 38, wherein the physiologically acceptable sugar is glucose.

[0299] 40. An aqueous drug solution for use according to embodiment 39, wherein the glucose concentration is in the range of 5 to 100 mg / ml.

[0300] 41. An aqueous drug solution for use according to embodiment 37, wherein the aqueous drug solution does not contain glucose.

[0301] 42. An aqueous pharmaceutical solution for use according to embodiment 37, wherein the stabilizer is bentonite, calcium alginate, calcium stearate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, or zinc acetate.

[0302] 43. An aqueous pharmaceutical solution for use according to embodiment 37, wherein the antioxidant is selected from the group consisting of: α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, penteacin, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate.

[0303] 44. An aqueous pharmaceutical solution for use according to embodiment 37, wherein the preservative is selected from the group consisting of: benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitrile, butanediol, calcium acetate, calcium lactate pentahydrate, hexadecyltrimethylammonium bromide, hexadecylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, ethylenediaminetetraacetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

[0304] 45. An aqueous pharmaceutical solution for use according to any one of embodiments 36 to 44, wherein the solution is provided by mixing the following:

[0305] I) An aqueous stock solution with a pH less than 2.8 at 25°C, comprising:

[0306] a) Sterile water,

[0307] b) Levodopa,

[0308] c) At least one enzyme inhibitor,

[0309] d) At least one physiologically acceptable acid, and

[0310] e) At least one stabilizer,

[0311] The stock solution was bubbled with nitrogen gas after preparation, and

[0312] II) An aqueous buffer solution having a pH of at least 4.0 at 25°C, comprising:

[0313] f) Sterile water,

[0314] g) at least one buffer component, and

[0315] h) At least one stabilizer and / or solubilizer,

[0316] The aqueous drug solution is optionally supersaturated, and is administered to a subject with a central nervous system (CNS) disease within 24 hours after the aqueous stock solution and the aqueous buffer solution are mixed, such as 16 hours, 12 hours, 6 hours, 4 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, 10 minutes, 5 minutes or 1 minute.

[0317] 46. ​​An aqueous drug solution for use according to any one of embodiments 36 to 54, comprising 10 mg / ml levodopa and 1.25 mg / ml (1:8) carbidopa, the aqueous drug solution being prepared by mixing the following:

[0318] I) 1000 ml aqueous stock solution, comprising:

[0319] a) 963 g of water,

[0320] b) 43.3 g 5 M HCl

[0321] The solution was then purged with nitrogen gas.

[0322] c) 20 g micronized levodopa, and

[0323] d) 2.71 g carbidopa monohydrate (equivalent to 2.5 g carbidopa),

[0324] The solution was then purged again with nitrogen gas.

[0325] II) An aqueous buffer solution comprising:

[0326] e) 968 g of water,

[0327] f) 64.7 g of trisodium citrate dihydrate

[0328] 3.56 g of disodium hydrogen phosphate dihydrate, and

[0329] h) 3.67 g 1M HCl.

[0330] 47. An aqueous drug solution for use according to embodiment 46, wherein the 2.5 g of carbidopa is added as 2.71 g of carbidopa monohydrate.

[0331] 48. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 47, wherein after mixing the stock solution and the aqueous buffer solution, at least 85 wt.% of levodopa in the pharmaceutical composition remains undegraded for at least 1 minute, such as at least 5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutes.

[0332] 49. An aqueous drug solution for use according to any one of embodiments 1 to 10 or 12 to 47, wherein the aqueous drug solution contains carbidopa, and wherein after mixing the stock solution and the aqueous buffer solution, at least 85 wt.% carbidopa remains undegraded for at least 1 minute, such as at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110 or 120 minutes.

[0333] 50. An aqueous drug solution for use according to any one of embodiments 1 to 10 or 12 to 49, wherein the aqueous drug solution contains carbidopa, and wherein, after mixing the stock solution and the aqueous buffer solution, the level of DHPA (3,4-dihydroxyphenylacetone) is less than 5 mg% of carbidopa (CD) and the level of hydrazine is less than 1 mg% of carbidopa (CD) for at least 1 minute, such as for at least 5, 10, 20, 30, 40, 50 or 60 minutes.

[0334] 51. An aqueous pharmaceutical solution for use according to any one of embodiments 1 to 10 or 12 to 48, wherein the aqueous pharmaceutical solution contains carbidopa, and wherein the aqueous pharmaceutical solution is administered before 15 wt% of carbidopa in the aqueous pharmaceutical solution is degraded, such as before 10 wt% of carbidopa is degraded.

[0335] 52. An aqueous drug solution for use according to any one of embodiments 1 to 51, wherein the weight molar osmotic concentration of the aqueous drug solution is 50 to 1400 mOsm / kg, preferably 100 to 1000 mOsm / kg or 200 to 600 mOsm / kg.

[0336] 53. An aqueous drug solution for use according to any one of embodiments 1 to 52, wherein the CNS disease is selected from the group consisting of: Parkinson's disease, atypical Parkinson's disease, Alzheimer's disease, restless legs syndrome (RLS) and neurotic psychosis; preferably, the CNS disease is Parkinson's disease.

[0337] 54. An aqueous drug solution for use according to implementation plan 53, wherein the CNS disease is Parkinson's disease in the complication phase.

[0338] 55. An aqueous drug solution for use according to any one of embodiments 3 to 7, wherein the plasma level of levodopa reaches a therapeutic level within less than 3 hours after the start of administration, such as within 2 hours, 1 hour, 50 minutes, 40 minutes, 30 minutes, 20 minutes or 10 minutes.

[0339] 56. An aqueous drug solution for use according to any one of embodiments 3 to 7 and 55, wherein the plasma level of levodopa can be adjusted by adjusting the infusion rate over a sufficiently short time period to minimize the on / off symptoms associated with Parkinson's disease.

[0340] 57. An aqueous drug solution according to any one of embodiments 1 to 56, wherein the solution is for enteral administration, preferably via the duodenum.

[0341] 58. An aqueous drug solution according to any one of embodiments 1 to 54, wherein the solution is prepared for injection.

[0342] 59. A kit for providing an aqueous drug solution according to any one of the foregoing embodiments, the aqueous drug solution being used to treat central nervous system (CNS) diseases, the aqueous drug solution containing at least 5 mg / ml of levodopa dissolved in a pH range of 3.0 to 8.5, the kit comprising:

[0343] a) An aqueous stock solution containing levodopa according to any of the foregoing embodiments, wherein the aqueous stock solution has a pH of less than 2.8 at 25°C;

[0344] b) An aqueous buffer solution according to any of the foregoing embodiments, used to increase the pH of the aqueous reserve solution, comprising a buffer and having a pH of at least 4.0 at 25°C;

[0345] c) A mixing component (1) for mixing solutions a) and b); and

[0346] d) Output component (2), which is used for the mixed solution in step c).

[0347] 60. The kit according to embodiment 59, wherein the output component (2) includes or is connected to the injection or infusion component (20).

[0348] 61. The kit according to embodiment 60, wherein the injection or infusion component (20) is a needle.

[0349] 62. The kit according to embodiment 61, wherein the needle is made of plastic.

[0350] 63. A kit according to any one of embodiments 59 to 62, wherein the mixing component (1) comprises two compartments (3A, 3B), a pump (4) and a mixing chamber (10), wherein the first compartment (3A) comprises a component for receiving a container containing the aqueous stock solution and the second compartment (3B) comprises a component for receiving a container containing the aqueous buffer solution, the pump (4) is configured to transport the aqueous stock solution and the aqueous buffer solution from the compartments (3A, 3B) to the mixing chamber (10), the mixing chamber (10) is configured to provide mixing of the received aqueous stock solution and the received aqueous buffer solution, and wherein the pump (4) is further configured to transport the mixed aqueous drug solution from the mixing chamber to the output component (2).

[0351] 64. The kit according to embodiment 63, wherein the mixing component (1) includes two pumps (4), a first pump (4) connected to the first compartment (3A) and a second pump (4) connected to the second compartment (3B).

[0352] 65. The kit according to implementation scheme 63 or 64, wherein the pump (4) is an injection pump, volumetric pump, peristaltic pump or mobile pump.

[0353] 66. A kit according to any one of embodiments 63 to 65, wherein the first compartment (3A) is connected to the mixing chamber (10) via a first conduit (5A), and the second compartment (3B) is connected to the mixing chamber (10) via a second conduit (5B), and wherein the mixing chamber is connected to the output member (2) via a third conduit (5C).

[0354] 67. The kit according to embodiment 66, wherein the conduit (5A, 5B, 5C) and / or the compartment (3A, 3B) are opaque or UV-absorbing.

[0355] 68. A kit according to any one of embodiments 63 to 65, wherein the mixing chamber (10) is directly connected to the compartments (3A, 3B) containing the aqueous stock solution and the aqueous buffer solution, respectively, without the use of a conduit.

[0356] 69. A kit according to any one of embodiments 63 to 68, wherein the mixing chamber (10) is a bidirectional Y-type connector (11), preferably a bidirectional Y'-type connector assembly; or

[0357] The mixing chamber (10) includes a spiral channel (12) for mixing the two solutions; or

[0358] The mixing chamber (10) contains a Venturi mixer (13); or

[0359] The mixing chamber (10) contains an electric mixing tool (14), such as a piston, screw, propeller or similar device.

[0360] 70. A kit according to any one of embodiments 63 to 69, wherein the compartment (3A, 3B) contains a container such as a syringe, bag, bottle or box.

[0361] 71. A kit according to any one of embodiments 63 to 70, wherein the kit further comprises a filter (6), such as a microbial filter or a particle filter, configured downstream of the mixing chamber (10) for filtering the aqueous drug solution prior to injection or infusion.

[0362] 72. A kit according to any one of embodiments 63 to 71, wherein the kit further comprises a control component (7) for controlling the pump (4) to achieve control of the flow rate of the pump (4).

[0363] 73. A kit according to any one of embodiments 63 to 72, wherein the kit further comprises a battery for powering active components such as a pump (4), a mixing chamber (10), and / or a control component (7).

[0364] 74. A kit according to any one of embodiments 63 to 73, wherein the volume of the compartments (3A, 3B) is sufficient to allow a subject with a central nervous system (CNS) disease to be continuously treated for at least 4 hours, such as 4 to 6 hours, such as 6 to 10 hours, such as 10 to 16 hours, such as 16 to 24 hours; preferably, the volume of each of the compartments (3A, 3B) is 10 to 1000 ml, such as 50 to 500 ml, such as 100 to 250 ml.

[0365] 75. The reagent kit according to any one of embodiments 63 to 74, wherein the container contained in the compartment (3A, 3B) is replaceable or refillable.

[0366] 76. A kit according to any one of embodiments 63 to 75, wherein the container contained in the compartment (3A, 3B) can be replaced 2, 3, 4, 5 or 6 times during a 24-hour cycle, enabling the subject to be treated continuously for 24 hours.

[0367] 77. The kit according to embodiment 76, wherein the container has a rapid connector, enabling the container replacement cycle to be less than 10 minutes, such as 8 minutes, 6 minutes, 3 minutes and 1 minute.

[0368] 78. A kit according to any one of embodiments 59 to 77, wherein the kit further comprises a surgical glove, a cleaning wipe, and a disinfectant.

[0369] 79. A kit for providing an aqueous drug solution, comprising:

[0370] I) An aqueous stock solution with a pH less than 2.8 at 25°C.

[0371] It includes:

[0372] a) Sterile water,

[0373] b) Levodopa,

[0374] c) At least one enzyme inhibitor,

[0375] d) At least one physiologically acceptable acid, and

[0376] e) At least one stabilizer,

[0377] and

[0378] II) An aqueous buffer solution having a pH of at least 4.0 at 25°C, comprising:

[0379] f) Sterile water,

[0380] g) at least one buffer component, and

[0381] h) At least one stabilizer and / or solubilizer.

[0382] 80. The kit according to embodiment 79, wherein the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35 or 40 mg / ml levodopa.

[0383] 81. The kit according to embodiment 79 or 80, wherein the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0 or 0.5; preferably, the pH of the aqueous stock solution is in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0 or 0.0 to 0.5.

[0384] 82. A kit according to any one of embodiments 79 to 81, wherein the physiologically acceptable acid is an inorganic acid, such as hydrochloric acid, sulfuric acid, or nitric acid.

[0385] 83. The kit according to embodiment 82, wherein the inorganic acid is hydrochloric acid (HCl); preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl or 150 mM HCl.

[0386] 84. A kit according to any one of embodiments 79 to 83, wherein the physiologically acceptable acid is acetic acid.

[0387] 85. A kit according to any one of embodiments 79 to 84, wherein the enzyme inhibitor is selected from the group consisting of: dopa decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO-B) inhibitors.

[0388] 86. The kit according to embodiment 85, wherein the enzyme inhibitor is:

[0389] Dopa decarboxylase (DDC) inhibitors selected from the group consisting of carbidopa such as carbidopa monohydrate, benserazide, methyldopa and DFMD (α-difluoromethyl-DOPA);

[0390] Catechol-o-methyltransferase (COMT) inhibitors, selected from the group consisting of entacapone, tocapone, and niticapone;

[0391] Monoamine oxidase (MAO-B) inhibitors selected from the group consisting of rasagiline, selegiline, and safenamide; or

[0392] Its combination.

[0393] 87. A kit according to any one of embodiments 79 to 86, wherein the pH of the aqueous buffer solution is at least 4.0; preferably, the pH of the aqueous buffer solution is between 4.0 and 12, such as between 4.0 and 9, 4.0 and 7.5 or 4.0 and 6.

[0394] 88. A kit according to any one of embodiments 79 to 87, wherein the at least one buffer component has at least one pKa value in the range of 3 to 9, such as in the range of 5 to 7.5.

[0395] 89. A kit according to any one of embodiments 79 to 88, wherein the buffer component is citric acid.

[0396] 90. A kit according to any one of embodiments 79 to 88, wherein the buffer component is citric acid and phosphate.

[0397] 91. A kit according to any one of embodiments 79 to 88, wherein the buffer component is tromethamine (tris(hydroxymethyl)aminomethane).

[0398] 92. A kit according to any one of embodiments 79 to 88, wherein the buffer component is adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and the like or mixtures of two or more thereof.

[0399] 93. A kit according to any one of embodiments 79 to 92, wherein the solubilizer is selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), kolliphor, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil, DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzalkonium chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl betacyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, trioleic acid glyceride, vitamin E polyethylene glycol succinate, or a mixture of two or more of these.

[0400] 94. A kit according to any one of embodiments 79 to 92, wherein the solubilizer is HP-β-cyclodextrin, preferably, the HP-β-cyclodextrin is present at a concentration of 60 to 90 mg / ml, such as about 75 mg / ml.

[0401] 95. A kit according to any one of embodiments 79 to 94, wherein the stabilizer is selected from the group consisting of stabilizers, antioxidants and preservatives or combinations thereof.

[0402] 96. A kit according to any one of embodiments 79 to 94, wherein the stabilizer is a physiologically acceptable sugar.

[0403] 97. The kit according to implementation scheme 96, wherein the physiologically acceptable sugar is glucose.

[0404] 98. A kit according to any one of embodiments 79 to 96, wherein the drug solution does not contain glucose.

[0405] 99. A kit according to any one of embodiments 79 to 94, wherein the stabilizer is bentonite, calcium alginate, calcium stearate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, or zinc acetate.

[0406] 100. The kit according to embodiment 95, wherein the antioxidant is selected from the group consisting of: α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, penteacin, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate.

[0407] 101. The kit according to embodiment 95, wherein the preservative is selected from the group consisting of: benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitrol, butanediol, calcium acetate, calcium lactate pentahydrate, hexadecyltrimethylammonium bromide, hexadecylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, ethylenediaminetetraacetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

[0408] 102. A kit according to any one of embodiments 37 to 45, the kit being used to mix an aqueous drug solution containing 10 mg / ml levodopa and 1.25 mg / ml (1:8) carbidopa, the kit comprising:

[0409] I) 1000 ml aqueous stock solution, comprising:

[0410] a) 963 g of water,

[0411] b) 43.3 g 5 M HCl

[0412] The solution was then purged with nitrogen gas.

[0413] c) 20 g micronized levodopa, and

[0414] d) 2.71 g carbidopa monohydrate (equivalent to 2.5 g carbidopa),

[0415] The solution was then purged again with nitrogen gas.

[0416] II) An aqueous buffer solution comprising:

[0417] e) 968 g of water,

[0418] f) 64.7 g of trisodium citrate dihydrate

[0419] 3.56 g of disodium hydrogen phosphate dihydrate, and

[0420] h) 3.67 g 1M HCl.

[0421] 103. A method for continuously preparing an aqueous drug solution for treating diseases of the central nervous system (CNS), the aqueous drug solution being suitable for continuous parenteral or enteral administration, wherein the method comprises the following steps:

[0422] A continuous mixing of a stock solution stream containing levodopa and an aqueous buffer solution stream, wherein the stock solution has a pH less than 2.8 at 25°C and the buffer solution has a pH of at least 4.0 at 25°C; and

[0423] A continuous flow of an aqueous drug solution is obtained from the mixture, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15 or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa.

[0424] 104. The method according to embodiment 103, wherein the pH of the aqueous drug solution is 3.5 to 8.0, such as 4.0 to 7.5, 4.5 to 7.0 or 5.0 to 5.5.

[0425] 105. The method according to embodiment 103 or 104, wherein the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35 or 40 mg / ml levodopa.

[0426] 106. The method according to any one of embodiments 103 to 105, wherein the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0 or 0.5; preferably, the pH of the aqueous stock solution is in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0 or 0.0 to 0.5.

[0427] 107. The method according to any one of embodiments 103 to 106, wherein the aqueous stock solution contains at least one physiologically acceptable acid.

[0428] 108. The method according to embodiment 107, wherein the physiologically acceptable acid is an inorganic acid, such as hydrochloric acid, sulfuric acid, or nitric acid.

[0429] 109. The method according to embodiment 108, wherein the inorganic acid is hydrochloric acid (HCl); preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl or 150 mM HCl.

[0430] 110. The method according to embodiment 107, wherein the physiologically acceptable acid is acetic acid.

[0431] 111. The method according to any one of embodiments 103 to 110, wherein the aqueous stock solution further comprises at least one stabilizer.

[0432] 112. The method according to any one of embodiments 103 to 111, wherein the method further comprises the step of removing air from the stock solution; such as by bubbling an inert gas, such as nitrogen, through the stock solution before mixing with the aqueous buffer solution.

[0433] 113. The method according to any one of embodiments 103 to 112, wherein the aqueous drug solution further comprises at least one enzyme inhibitor.

[0434] 114. The method according to embodiment 113, wherein the enzyme inhibitor is selected from the group consisting of: dopa decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT) inhibitors and monoamine oxidase (MAO-B) inhibitors.

[0435] 115. The method according to embodiment 113 or 114, wherein the enzyme inhibitor is:

[0436] Dopa decarboxylase (DDC) inhibitors selected from the group consisting of carbidopa such as carbidopa monohydrate, benserazide, methyldopa and DFMD (α-difluoromethyl-DOPA);

[0437] Catechol-o-methyltransferase (COMT) inhibitors, selected from the group consisting of entacapone, tocapone, and niticapone;

[0438] Monoamine oxidase (MAO-B) inhibitors selected from the group consisting of rasagiline, selegiline, and safenamide; or

[0439] Its combination.

[0440] 116. The method according to any one of embodiments 103 to 115, wherein the pH of the aqueous buffer solution is at least 4.0; preferably, the pH of the aqueous buffer solution is between 4.0 and 12, such as between 4.0 and 9, 4.0 and 7.5 or 4.0 and 6.

[0441] 117. The method according to any one of embodiments 103 to 116, wherein the aqueous buffer solution comprises at least one buffer component having at least one pKa value in the range of 3 to 9, such as in the range of 5 to 7.5.

[0442] 118. The method according to embodiment 117, wherein the buffer component is citric acid.

[0443] 119. The method according to embodiment 117, wherein the buffer component is citric acid and phosphate.

[0444] 120. The method according to embodiment 117, wherein the buffer component is tromethamine (tris(hydroxymethyl)aminomethane).

[0445] 121. The method according to embodiment 117, wherein the buffer component comprises adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and similar substances or mixtures thereof.

[0446] 122. The method according to any one of embodiments 103 to 121, wherein the aqueous buffer solution further comprises at least one solubilizer.

[0447] 123. The method according to embodiment 122, wherein the solubilizer is selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), kolliphor, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil, DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzalkonium chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl betacyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, trioleic acid glyceride, vitamin E polyethylene glycol succinate, or a mixture of two or more of these.

[0448] 124. The method according to embodiment 122, wherein the solubilizer is HP-β-cyclodextrin, preferably, HP-β-cyclodextrin is present at a concentration of about 75 mg / ml.

[0449] 125. The method according to any one of embodiments 103 to 124, wherein the aqueous buffer solution further comprises at least one stabilizer.

[0450] 126. The method according to embodiment 125, wherein the stabilizer is selected from the group consisting of stabilizers, antioxidants and preservatives or combinations thereof.

[0451] 127. The method according to embodiment 125, wherein the stabilizer is a stabilizing agent, which is a physiologically acceptable sugar.

[0452] 128. The method according to implementation scheme 127, wherein the physiologically acceptable sugar is glucose.

[0453] 129. The method according to implementation plan 128, wherein the glucose concentration is in the range of 5 to 100 mg / ml.

[0454] 130. The method according to any one of embodiments 103 to 127, wherein the drug solution does not contain glucose.

[0455] 131. The method according to embodiment 126, wherein the stabilizer is bentonite, calcium alginate, calcium stearate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, or zinc acetate.

[0456] 132. The method according to embodiment 126, wherein the antioxidant is selected from the group consisting of: α-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, penteacin, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate.

[0457] 133. The method according to embodiment 126, wherein the preservative is selected from the group consisting of: benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitrol, butanediol, calcium acetate, calcium lactate pentahydrate, hexadecyltrimethylammonium bromide, hexadecylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, ethylenediaminetetraacetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

[0458] 134. The method according to any one of embodiments 103 to 133, wherein the aqueous drug solution is supersaturated with levodopa.

[0459] 135. A method for treating diseases of the central nervous system (CNS), comprising the following steps:

[0460] A continuous mixing of a stock solution stream containing levodopa and an aqueous buffer solution stream, wherein the stock solution has a pH of less than 2.8 at 25°C and the buffer solution has a pH of at least 4.0 at 25°C;

[0461] A continuous stream of aqueous drug solution is obtained from the mixture, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, such as at least 6, 7, 8, 9, 10, 15, or 20 mg / ml of dissolved levodopa; preferably, the concentration of levodopa is in the range of 5 to 20 mg / ml of dissolved levodopa, such as in the range of 5 to 15 mg / ml or 5 to 10 mg / ml of dissolved levodopa; and

[0462] An aqueous drug solution obtained by continuous administration to subjects with central nervous system (CNS) diseases.

[0463] 136. A method for treating central nervous system (CNS) diseases according to embodiment 135, wherein the solution is a drug infusion or injection solution.

[0464] 137. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 136, wherein the solution is administered parenterally.

[0465] 138. A method for treating central nervous system (CNS) diseases according to embodiment 137, wherein the parenteral administration is administered subcutaneously, percutaneously, intravenously, intra-arterially, intraosseously, intramuscularly, intracerebrally, intravenously, or intrathecally, and the administration mode is injection or infusion.

[0466] 139. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 138, wherein the CNS disease is selected from the group consisting of: Parkinson's disease, atypical Parkinson's disease, Alzheimer's disease, restless legs syndrome (RLS), and neurotic psychosis; preferably, the CNS disease is Parkinson's disease.

[0467] 140. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 139, wherein the aqueous drug solution is administered within 10 minutes, 5 minutes or 1 minute after mixing the aqueous stock solution and the aqueous buffer solution.

[0468] 141. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 140, wherein the pH of the aqueous drug solution is 3.5 to 8.0, such as 4.0 to 7.5, 4.5 to 7.0, or 5.0 to 5.5.

[0469] 142. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 141, wherein the aqueous stock solution contains at least 10 mg / ml levodopa, such as at least 15, 20, 25, 30, 35 or 40 mg / ml levodopa.

[0470] 143. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 142, wherein the pH of the aqueous stock solution is less than 2.0, such as less than 1.5, 1.0 or 0.5; preferably, the pH of the aqueous stock solution is in the range of 0.0 to 2.0, such as 0.0 to 1.5, 0.0 to 1.0 or 0.0 to 0.5.

[0471] 144. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 143, wherein the aqueous stock solution contains at least one physiologically acceptable acid.

[0472] 145. A method for treating a central nervous system (CNS) disease according to embodiment 144, wherein the physiologically acceptable acid is an inorganic acid, such as hydrochloric acid, sulfuric acid, or nitric acid.

[0473] 146. A method for treating a central nervous system (CNS) disease according to embodiment 145, wherein the inorganic acid is hydrochloric acid (HCl); preferably, the aqueous stock solution contains at least 30 mM HCl, such as at least 50 mM HCl, 100 mM HCl or 150 mM HCl.

[0474] 147. A method for treating central nervous system (CNS) diseases according to embodiment 144, wherein the physiologically acceptable acid is acetic acid.

[0475] 148. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 147, wherein the aqueous stock solution further comprises at least one stabilizer.

[0476] 149. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 148, wherein the method further comprises a step of de-airing the stock solution; such as by bubbling an inert gas, such as nitrogen, through the stock solution before mixing it with the aqueous buffer solution.

[0477] 150. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 149, wherein the aqueous drug solution further comprises at least one enzyme inhibitor.

[0478] 151. A method for treating a central nervous system (CNS) disease according to embodiment 150, wherein the enzyme inhibitor is selected from the group consisting of: dopa decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT) inhibitors, and monoamine oxidase (MAO-B) inhibitors.

[0479] 152. A method for treating central nervous system (CNS) diseases according to any one of embodiments 150 to 151, wherein the enzyme inhibitor is:

[0480] Dopa decarboxylase (DDC) inhibitors selected from the group consisting of carbidopa such as carbidopa monohydrate, benserazide, methyldopa and DFMD (α-difluoromethyl-DOPA);

[0481] Catechol-o-methyltransferase (COMT) inhibitors, selected from the group consisting of entacapone, tocapone, and niticapone;

[0482] Monoamine oxidase (MAO-B) inhibitors selected from the group consisting of rasagiline, selegiline, and safenamide; or

[0483] Its combination.

[0484] 153. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 152, wherein the pH of the aqueous buffer solution is at least 4.0; preferably, the pH of the aqueous buffer solution is between 4.0 and 12, such as between 4.0 and 9, 4.0 and 7.5 or 4.0 and 6.

[0485] 154. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 153, wherein the aqueous buffer solution comprises at least one buffer component having at least one pKa value in the range of 3 to 9, such as in the range of 5 to 7.5.

[0486] 155. A method for treating central nervous system (CNS) diseases according to embodiment 154, wherein the buffer component is citric acid.

[0487] 156. A method for treating central nervous system (CNS) diseases according to embodiment 154, wherein the buffer component comprises citric acid and phosphate.

[0488] 157. A method for treating central nervous system (CNS) diseases according to embodiment 154, wherein the buffer component is tromethamine (tris(hydroxymethyl)aminomethane).

[0489] 158. A method for treating central nervous system (CNS) diseases according to embodiment 154, wherein the buffer component comprises adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, and analogues thereof, or mixtures of two or more thereof.

[0490] 159. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 158, wherein the aqueous buffer solution further comprises at least one solubilizer.

[0491] 160. A method for treating central nervous system (CNS) diseases according to embodiment 159, wherein the solubilizer is selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), clopidogrel, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil, DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzalkonium chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl beta-cyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, trioleic acid glyceride, vitamin E polyethylene glycol succinate, or a mixture of two or more of these.

[0492] 161. A method for treating a central nervous system (CNS) disease according to embodiment 159, wherein the solubilizer is HP-β-cyclodextrin, preferably, HP-β-cyclodextrin is present at a concentration of 60 to 90 mg / ml, such as about 75 mg / ml.

[0493] 162. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 161, wherein the aqueous buffer solution further comprises at least one stabilizer.

[0494] 163. A method for treating central nervous system (CNS) diseases according to embodiment 162, wherein the stabilizer is selected from the group consisting of stabilizers, antioxidants and preservatives or combinations thereof.

[0495] 164. A method for treating central nervous system (CNS) diseases according to implementation plan 163, wherein the stabilizer is a stabilizing agent, which is a physiologically acceptable sugar.

[0496] 165. A method for treating central nervous system (CNS) diseases according to implementation scheme 164, wherein the physiologically acceptable sugar is glucose.

[0497] 166. A method for treating a central nervous system (CNS) disease according to embodiment 165, wherein the glucose concentration is in the range of 5 to 100 mg / ml.

[0498] 167. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 163, wherein the drug solution does not contain glucose.

[0499] 168. A method for treating central nervous system (CNS) diseases according to embodiment 163, wherein the stabilizer is bentonite, calcium alginate, calcium stearate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, or zinc acetate.

[0500] 169. A method for treating central nervous system (CNS) diseases according to embodiment 163, wherein the antioxidant is selected from the group consisting of: α-tocopherol, ascorbic acid, palmitic acid ascorbate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, pentiformin, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate.

[0501] 170. A method for treating central nervous system (CNS) diseases according to embodiment 163, wherein the preservative is selected from the group consisting of: benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitrile, butanediol, calcium acetate, calcium lactate pentahydrate, hexadecyltrimethylammonium bromide, hexadecylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, ethylenediaminetetraacetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

[0502] 171. A method for treating a central nervous system (CNS) disease according to any one of embodiments 135 to 170, wherein the aqueous drug solution is supersaturated with levodopa.

[0503] To further describe the present invention, reference will be made to the following experimental embodiments. These embodiments are included for the purpose of illustrating certain aspects and embodiments of the invention only and are not intended to limit the invention in any way.

[0504] Experimental Section

[0505] To provide a prospect for the range of components that can be part of the solutions of this invention and their functions, the results of several experiments are summarized below.

[0506] A preferred aqueous drug solution containing 10 mg / ml levodopa and 1.25 mg / ml (1:8) carbidopa was prepared using the following components, steps, and methods.

[0507] Prepare 1000 ml of stock solutions of 20 mg / ml levodopa and 2.5 mg / ml carbidopa as follows:

[0508] Pour 963 g of water into a Duran flask equipped with a magnetic stirrer, then...

[0509] Add 43.3 g of 5 M hydrochloric acid (HCl), then,

[0510] The solution was purged with nitrogen until the residual oxygen content was <0.1 ppm, then...

[0511] Add 20 g of micronized levodopa, then,

[0512] Add 2.71 g of carbidopa monohydrate (equivalent to 2.5 g of carbidopa).

[0513] Stir the resulting solution with a magnetic stirrer until all substances are dissolved.

[0514] The measured pH was approximately 1.

[0515] The solution was purged again with nitrogen until the residual oxygen content was <0.1 ppm.

[0516] Prepare the buffer solution as follows:

[0517] Pour 968 g of water into a Duran flask equipped with a magnetic stirrer, then...

[0518] Add 64.7 g of trisodium citrate dihydrate, then...

[0519] Add 3.56 g of disodium hydrogen phosphate dihydrate, then...

[0520] Add 3.67 g of 1M hydrochloric acid (HCl), then...

[0521] Use a magnetic stirrer to stir the solution until all substances are dissolved.

[0522] Measure the pH and adjust it to 7.6 using 1M HCl (if the solution is too alkaline) and 1M sodium hydroxide (NaOH) (if the solution is too acidic).

[0523] The stock solution is transferred to the syringe of the B Braun infusion pump (SPACE infusion pump system), and the buffer solution is transferred to the syringe of another infusion pump of the same type. The syringe outlet of the infusion pump is connected to a UV-protected line (light-protected B Braun Original Perfusor line) with a B Braun Safeflow valve and a back check valve, and each leads to a Y-connector (BD Carefusion Y' connector assembly, bidirectional; Becton, Dickinson and Company), in which the stock solution and buffer solution are mixed without the use of any active mixing components. The mixture is then guided from the single outlet of the Y-connector through the UV-protected line (B Braun) to a 0.2 μm particle filter (B Braun Sterifix) and finally to a steel needle designed for intravenous infusion (B Braun Venofix Safety).

[0524] Measurements were taken of the mixed solution after the needle was removed, showing a decrease in the concentrations of levodopa and carbidopa, as well as the DHPA content. After 22 hours of operation, the following results were recorded (hydrazine levels were calculated based on DHPA levels, assuming each degraded carbidopa molecule splits into one molecule of DHPA and one molecule of hydrazine): no levodopa degradation, 2.4% carbidopa degradation, and a DHPA content of 1.3 net mg%, corresponding to a hydrazine level of 0.25 mg% (relative to mg% of carbidopa).

[0525] To provide a prospect for the range of components that can be part of the solutions of this invention and their functions, the results of several experiments are summarized below.

[0526] Example 1

[0527] Prepare stock solutions (pH < 1) of levodopa and carbidopa, containing:

[0528] 50 mg / ml Levodopa

[0529] 5 mg / ml Carbidopa monohydrate

[0530] 5 mg / ml sodium metabisulfite

[0531] 0.303 M HCl

[0532] sterile water

[0533] As shown in the table below, three similar sample setups were used to prepare a mixture of test stock solutions and buffer solutions containing the buffer components tromethamine and glucose (approximately a 1:1 ratio of acidic stock solution to alkaline tromethamine and glucose solution). All batches were prepared by adding Addex-THAM (manufactured by B Braun or an in-house produced tromethamine solution; pH approximately 9) and glucose (or an in-house produced glucose solution). In 001C, glucose was first stirred into a solution, followed by tromethamine. In 001D and E, the two solutions were mixed and then stirred into a solution.

[0534]

[0535] In all tests conducted at both room temperature and refrigeration, physical stability was less than 3 days. No difference was observed when glucose and tromethorphan were stirred into a solution.

[0536] In addition, tests were conducted to determine whether reducing the concentrations of levodopa and carbidopa, respectively, would improve physical stability.

[0537]

[0538] The results showed that the formulation containing 5 mg / ml levodopa and 0.5 mg / ml carbidopa appeared to be soluble and physically stable at room temperature for up to 6 months, while 10 mg / ml levodopa together with 1 mg / ml carbidopa was unstable. Physical stability at room temperature appeared to be better than under refrigeration.

[0539] Three different types of solubility enhancers were tested in the formulation: Kolliphor HS 15 (a nonionic surfactant), polyethylene glycol 400 (a cosolvent), and HP-β-cyclodextrin (a complex forming agent). The pH ranged from 2.9 to 3.0.

[0540] Table 3. Enhanced physical stability at pH 2.9 to 3.0 via Kolliphor HS 15, polyethylene glycol 400, and HP-β-cyclodextrin.

[0541]

[0542] Therefore, at the tested concentrations, none of the three solubility enhancers could achieve an improvement in the physical stability of 10 mg / ml levodopa and 1 mg / ml carbidopa.

[0543] The test involved reducing the concentration of tromethamine and altering the glucose concentration.

[0544] Table 4. Physical stability of LD and CD at different concentrations of tromethamine and glucose.

[0545]

[0546] The results showed that increased glucose concentration may have prolonged the time before precipitation. Refrigeration reduced physical stability. Changing the pH from 3.1 to 6.6 did not improve physical stability at room temperature.

[0547] Two lower concentrations of polyethylene glycol 400 were tested, as well as a lower concentration of HP-β-cyclodextrin as an alternative.

[0548] Table 5 - Physical stability of LD and CD in the case of polyethylene glycol 400 or HP-β-cyclodextrin

[0549]

[0550] The results showed that increasing the concentration of polyethylene glycol 400 from 50 to 100 mg / ml improved the physical stability at room temperature. In this case, 100 mg / ml of polyethylene glycol 400 was the optimal concentration because, as previously shown, physical stability decreased with further increases in concentration. Further improvements in physical stability, particularly at room temperature, were achieved by reducing the concentration of HP-β-cyclodextrin to 75 mg / ml. However, chemical degradation of the API may occur later.

[0551] As shown in Table 5, the formulation containing 75 mg / ml HP-β-cyclodextrin, 10 mg / ml levodopa, and 1 mg / ml carbidopa is physically stable at room temperature. However, since sample 006A has a pH of 3.2, it was decided to investigate whether dissolution was also achieved at higher pH levels. The samples in the table below were prepared and bubbled with nitrogen before storage.

[0552] Table 6 - Physical stability of LD and CD at different pH values ​​for 75 mg / ml HP-β-cyclodextrin

[0553]

[0554] As shown in Table 6, 75 mg / ml HP-β-cyclodextrin is not physically stable at pH 3.5 or several units higher than 10 mg / ml levodopa and 1 mg / ml carbidopa. Replacing tromethamine with NaOH does not improve stability. Nitrogen bubbling may reduce physical stability, as HP-β-cyclodextrin is an effective stabilizer at pH 3.2, according to Table 6.

[0555] Long-term chemical stability of levodopa and carbidopa

[0556] In addition to the physical stability of the drug solutions, chemical stability was also determined. The degradation of levodopa and carbidopa was determined by measuring the concentrations or degradation products of levodopa and carbidopa. DHPA (3,4-dihydroxyphenylacetone), a degradation product of carbidopa, was formed in a molar ratio with hydrazine, and its concentration was analyzed using high-performance liquid chromatography (HPLC) in this experiment.

[0557] Some samples were stored for up to 4 months at both room temperature and in a refrigerator for chemical analysis of levodopa and carbidopa concentrations. The following results were obtained:

[0558]

[0559] The results showed that levodopa remained stable for up to 4 months after mixing at room temperature and pH 3.2. However, carbidopa exhibited poor chemical stability, decomposing by 18% after 5 days at room temperature. Refrigerating the mixture did not significantly slow down the decomposition. After 4 months, 52% of the carbidopa had decomposed.

[0560] Stock solutions of levodopa and carbidopa at pH < 1 exhibited excellent stability in a refrigerator, showing no significant decomposition after 4 months. After 4 months, the DHPA content in the stock solutions was below the detection limit, thus confirming the excellent stability of carbidopa in solution.

[0561] Dual-chamber mixing experiment and short-term stability

[0562] The following experiment employed the inventive concept of using a stock solution and a buffer solution. The solution was prepared by mixing equal volumes of the two solutions (by manually inverting the mixture approximately 15 times).

[0563] In the following text, the solutions are a) an acidic solution of levodopa and carbidopa (pH < 1) and b) an alkaline solution of HP-β-cyclodextrin, glucose, and tromethamine (pH approximately 9), which yield the following final solutions:

[0564]

[0565] pH changes were obtained by using different amounts of tromethamine.

[0566] Table 9 - Experimental results showing the protective and pH-dependent effects of some substances on the decomposition of LD and CD.

[0567]

[0568] *LD and CD are 5 and 1.25 mg / ml, respectively. Store in darkness at room temperature. The concentrations of levodopa and carbidopa differ from those in Table 8, but the remaining components and mixing procedure are the same.

[0569] As shown in Table 9, amino acids protect carbidopa from degradation better than some common stabilizers / antioxidants at pH values ​​of approximately 3 to 3.1. At pH 3.9, amino acids provide better protection against carbidopa degradation than at pH 3.1.

[0570] Table 10 - Experiments showing the protective and pH-dependent effects of some substances on the decomposition of LD and CD.

[0571]

[0572] *No light and room temperature

[0573] As can be read from Table 10, at a pH of around 3, the lower LD / CD ratio appears to protect CD from decomposition and precipitation to some extent.

[0574] Table 11 - Experiments showing the decomposition and pH dependence of LD and CD

[0575]

[0576] Table 11 shows that carbidopa rapidly degrades by 8-10% after 2 hours, while levodopa only degrades by 0-3%. The degradation of carbidopa is only slightly pH-dependent, with slightly higher degradation rates at higher pH levels.

[0577]

[0578] The results in Table 12 show that the decomposition of LD and CD was slightly higher at pH 5.6–7.2 than at pH 4.9.

[0579]

[0580] Table 13 illustrates how physical stability decreases as pH increases from 4.9 to 7. The physical stability of the combination with 15 mg / ml levodopa is significantly lower than that of the 10 mg / ml combination.

[0581] The Importance of Additives and pH - Citrate / Phosphate as Buffer Components

[0582] Citrate / phosphate was used instead of tromethamine as the buffer component in the tests. Furthermore, HP-β-cyclodextrin and glucose were excluded from the composition but were occasionally tested as additives. The principles for preparing the mixture were the same as those given in Table 8 above. The concentration of DHPA (a breakdown product of carbidopa) is given in mg% carbidopa. The following is the composition of the mixture:

[0583]

[0584]

[0585] The results summarized in Tables 14 and 15 show that the addition of glucose significantly increased carbidopa degradation and elevated DHPA levels. HP-β-cyclodextrin yielded the lowest DHPA values, but carbidopa degradation was minimally affected. The physical stability of all solutions was at least 4 h.

[0586]

[0587] The results summarized in Table 16 show that HP-β-cyclodextrin protects carbidopa from decomposition in a concentration-dependent manner; however, the physical stability of the product is adversely affected at the highest concentration.

[0588] Levodopa showed no degradation for up to 20 h in citrate buffer without other additives.

[0589] Solubility enhancer

[0590] Different tests were conducted to obtain enhanced solubility of levodopa in an environment with a pH of approximately 5 and based on previous tests using a citrate-phosphate buffer.

[0591] Table 17 - Experimental results showing the increased solubility of levodopa at pH 5, depending on the additives in the citrate buffer.

[0592]

[0593] Table 17 shows that NMP and DMA significantly enhance the solubility of levodopa. Because DMA exhibits good solubility enhancement and lower toxicity than NMP, it is worth testing whether DMA can be combined with other ingredients to optimize the solubility of levodopa.

[0594] Table 18 - Experimental results showing the increased solubility of levodopa at pH 5, depending on the additives and combinations in the citrate buffer.

[0595]

[0596] The results summarized in Table 18 show that the combination of glutathione and DMA, as well as the combination of cysteine ​​and DMA, provides the best solubility enhancement, followed by the combination of DMA and polyvinylpyrrolidone, and polyvinylpyrrolidone alone. Other combinations offer practical solubility enhancers.

[0597] Table 19 - Experimental results showing the protection of physical stability with 15% DMA.

[0598]

[0599] The results summarized in Table 19 show that 15% DMA can produce stable 10 mg / ml LD solutions for up to 7 h in both refrigerator and room temperature conditions. Improved physical stability is achieved when the LD concentration is reduced to 8 mg / ml and the pH is increased from 5.0 to 5.2.

[0600] Table 20 - Experimental results showing the permeability and effects on physical stability of 4% glutathione and 15% DMA.

[0601]

[0602] The results summarized in Table 20 show that when the concentrations of levodopa and carbidopa are increased, the combination of 4% glutathione and 8% DMA results in a further increase in high gravimetric osmotic concentration.

[0603] The solution is physically stable for less than 3 hours. Therefore, although glutathione and DMA will provide enhanced solubility and possible protection of physical stability for levodopa and carbidopa, the increase in osmotic concentration by weight moles is likely to have adverse effects on local tolerance.

[0604] Experiment using a dual infusion pump with online mixing

[0605] Two precision infusion pumps (each with a 50 ml syringe for either the stock solution or the buffer solution) for human clinical use have a short infusion lining leading to a mixing connector (Y-connector). Following the Y-connector is a single UV-protected infusion line terminating in a fine-pore filter, which in turn connects to the infusion needle. The discharge line following the needle is sampled. Both pumps are driven at the same speed and started at the same time, with both rapidly infusing 5 ml of the high-velocity solution at the start of the experiment; this 5 ml is then discarded. Conditions (pump speed, nitrogen treatment of the buffer, filter pore size) are varied to test system performance. The speed variation is given as the speed of the stock solution pump, so the syringe discharge rate is always twice this value. When no sampling is performed, the needle outlet is maintained in approximately 200 ml of pH 5 citrate buffer. At a rate of 4 ml / h, when the syringe is nearly empty, it is refilled after a 1–5 minute pause. The outlet buffer is then replaced. At lower rates, syringe replacement is not necessary.

[0606] The stock solution consisted of 20 mg / ml levodopa and carbidopa with an LD / CD ratio of 4 / 1 or 8 / 1 in 200 mM HCl at pH approximately 1, with metabisulfite as a preservative and air replaced by nitrogen. The buffer solution consisted of 200 mM citrate and 20 mM phosphate, with a pH of approximately 7.6. The pH obtained at the needle outlet was approximately 5.2. The buffer solutions were tested with and without nitrogen bubbling. The degradation of levodopa and carbidopa was determined by measuring their concentrations or degradation products. DHPA (3,4-dihydroxyphenylacetone), a degradation product of carbidopa, was formed in a molar ratio with hydrazine, and its concentration was analyzed by high-performance liquid chromatography (HPLC) in this experiment.

[0607] Table 21 shows the experiments that can be performed online for extended periods under various conditions with low decomposition of LD and CD.

[0608]

[0609] The results summarized in Table 21 show that when the pump's API rate is 4 ml / h and a 1.2 μM filter is used, the 4 / 1 and 8 / 1 concentrations of LD / CD are lower than those given by both methods for the degradation of levodopa and carbidopa. The levels of DHPA, the major degradation product of carbidopa, are also low. The pump can run for 16 h, the typical treatment duration for Parkinson's disease (or other levodopa-dependent diseases), or even longer, covering continuous daily treatment. Theoretically, nitrogen purging of the buffer solution should further prevent the degradation of levodopa and carbidopa and limit DHPA formation; however, the results show that it is not necessary to obtain pharmaceutically reasonable degradation values. Pump rates can be as low as 1.4 ml / h without any significant impact on performance. Filter pore sizes for both tests showed similar results, meaning the system can be used for both IV (intravenous; requiring high bacterial removal capacity) and SC (subcutaneous; requiring removal of very small particles) administration.

[0610] In summary, the results show that this system allows for therapeutic administration of levodopa and carbidopa at a ratio of 4 / 1 or 8 / 1 over a wide dose range for up to one day or even longer, suitable for both SC and IV administration, and the API breakdown is pharmaceutically acceptable.

[0611] Table 22 - Preliminary patient trials showing the extended time of levodopa bioavailability compared to transenteral administration.

[0612]

[0613] Preliminary patient trials were used to demonstrate the bioavailability of levodopa and carbidopa via continuous subcutaneous infusion (Table 22). Results were drawn from three randomly selected patients in a larger study, and for each patient, subcutaneous, intravenous, and enteral administration were compared.

[0614] When using the preferred aqueous drug solution according to the invention (containing 10 mg / ml levodopa and 1.25 mg / ml (1:8) carbidopa), the bioavailability of levodopa is equal to that of intravenous therapy administered subcutaneously. Furthermore, when compared in a manner similar to intravenous therapy with enteral administration of Dodonidin gel (containing 20 mg / ml levodopa and 5 mg / ml carbidopa monohydrate), the bioavailability of levodopa is 77.7%, as summarized in Table 22.

[0615] Detailed results are shown in Figure 12 and Figure 13 The figure shows the mean blood levels of (a) levodopa and (b) carbidopa monitored in the patient's blood during the treatment period, plotted relative to the treatment time.

[0616] This study was a prospective, randomized, 3-period crossover, open-label, multicenter trial conducted according to Good Clinical Practice (GCP) principles, comparing intravenous and subcutaneous infusions of a preferred aqueous drug solution with transenteral dodoxacin (LCIG). The trial included patients with Parkinson's disease receiving dodoxacin due to severe on-off symptoms while taking oral levodopa. During one treatment visit, patients received dodoxacin at the optimal dose for 16 hours. During another treatment visit, patients received an intravenous infusion of the preferred aqueous drug solution at a concentration estimated to produce corresponding serum levodopa levels for the same duration. At the third treatment visit, patients received the corresponding dose of levodopa, but via subcutaneous infusion. Blood samples were collected for up to 24 hours during treatment visits according to a pre-established schedule.

[0617] Intravenous infusion of a preferred aqueous drug solution is administered via an indwelling catheter placed in the arm. The preferred aqueous drug solution is delivered intravenously at 75% of the subject's pre-study doxorubicin dose, administered at a rapid morning intravenous constant rate followed by continuous intravenous infusion for up to 16 hours. A suitable infusion needle is positioned laterally on the abdomen for subcutaneous (SC) infusion of the preferred aqueous drug solution. The preferred aqueous drug solution is administered SC at the same dose as the subject's pre-study doxorubicin dose, also administered at a rapid morning SC constant rate followed by continuous SC infusion for up to 16 hours. Doxorubicin is supplied in a cartridge containing a gel with 20 mg / mL levodopa and 5 mg / mL carbidopa monohydrate, and administered directly into the proximal small intestine via a PEG-J tubing connected to a portable infusion pump. The optimized doxorubicin dose is administered at a rapid morning constant rate followed by continuous infusion for up to 16 hours.

[0618] In accordance with the principles of Good Clinical Practice (GCP), levodopa and carbidopa in patient plasma were analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS / MS).

[0619] Another advantage of this disclosure, demonstrated in preliminary patient trials, is its ability to provide personalized treatment for individual patients. Specifically, Figure 14A and 14B The levels of levodopa in the blood and plasma of three different patients throughout the entire process of continuous subcutaneous and intravenous infusions are detailed. The three patients were at different stages of PD severity, thus requiring different levels of levodopa to achieve therapeutic effects. Due to the rapid bioavailability of the levodopa disclosed herein, the infusion rate of the aqueous drug solution can be adjusted during treatment to ensure that patients receive an adequate amount of levodopa to benefit from the therapeutic effect. By avoiding excessive levodopa administration, treatment on / off symptoms can be minimized or even avoided.

[0620] Furthermore, preliminary patient trials have demonstrated improved carbidopa bioavailability compared to levels achieved during enteral administration of dodoxacin. Figure 13 Increased carbidopa absorption allows for the incorporation of lower carbidopa concentrations into aqueous drug solutions, thereby reducing the amount of the harmful byproduct hydrazine, which forms once the aqueous stock solution and aqueous buffer solution are mixed.

[0621] Although the invention has been described above with reference to specific embodiments, it is not intended to be limited to the specific forms set forth herein. Rather, the invention is limited only by the appended claims, and other embodiments besides the specific embodiments described above may also be within the scope of these appended claims, for example, those different from those described above.

[0622] In the claims, the term "comprises" does not exclude the presence of other elements or steps. Furthermore, although listed individually, a plurality of components, elements, or method steps may be implemented by, for example, a single unit or processor. Additionally, although individual features may be included in different claims, these features may be advantageously combined, and inclusion in different claims does not imply that such a combination of features is infeasible and / or disadvantageous. Furthermore, singular references do not exclude a plurality. Terms such as "a," "an," "first," "second," etc., do not exclude a plurality. Reference numerals in the claims are provided only as illustrative examples and should not be construed as limiting the scope of the claims in any way.

[0623] References

[0624] Buxton, LO. and Benet, LZ., “Pharmacokinetics: The dynamics of drugabsorption, distribution, metabolism, and elimination.” In Goodman and Gilman: The pharmacological basis of therapeutics, 2011, pp. 17-39. The McGraw-HillCompanies, Inc. ISBN 978-0-07-162442-8

[0625] Pedro Chana et al., “Gabapentin and Motor Fluctuations in Parkinson’s Disease”, Movement Disorders, Vol. 12, No. 4, 1997, pp. 608-623.

[0626] Lambers H, Piessens S, Bloem A, Pronk H, Finkel P. "Natural skin surface pH is on average below 5, which is beneficial for its resident flora.", Int JCosmet Sci. 2006 Oct;28(5):359-70.

[0627] Lewis, James L. III, “Metabolic Alkalosis.”, Attending Physician, Princeton Baptist Medical Center; Brookwood Medical Center, published on merckmanuals.com, May 8, 2017 (http: / / www.merckmanuals.com / professional / endocrine-and-metabolic-disorders / acid-base-regulation-and-disorders / metabolic-alkalosis).

[0628] Shoulson et al., “On-off response. Clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients.” Neurology 1975; 25: 1144.

Claims

1. A kit for providing an aqueous drug solution for use, said aqueous drug solution comprising at least 5 mg / ml of dissolved levodopa, dopa decarboxylase (DDC) inhibitor carbidopa, and a pH in the range of 3.0 to 8.5, said kit comprising: a) An aqueous stock solution containing levodopa, wherein the aqueous stock solution has a pH less than 2.8 at 25°C. b) An aqueous buffer solution for raising the pH of the aqueous reserve solution, comprising a buffer and having a pH of at least 4.0 at 25°C; c) A mixing component (1) for mixing solutions a) and b); and d) Output component (2), which is used for the mixed solution in step c). The mixing component (1) comprises two compartments (3A, 3B), a pump (4), and a mixing chamber (10), wherein the first compartment (3A) comprises a component for receiving a container containing the aqueous reserve solution and the second compartment (3B) comprises a component for receiving a container containing the aqueous buffer solution, the pump (4) is configured to transport the aqueous reserve solution and the aqueous buffer solution from the compartments (3A, 3B) to the mixing chamber (10), the mixing chamber (10) is configured to provide mixing of the received aqueous reserve solution and the received aqueous buffer solution, and wherein the pump (4) is further configured to transport the mixed aqueous drug solution from the mixing chamber to the output component (2).

2. The kit according to claim 1, wherein the output member (2) comprises or is connected to the injection or infusion member (20).

3. The kit according to claim 2, wherein the injection or infusion component (20) is a needle.

4. The kit according to claim 3, wherein the needle is made of plastic.

5. The kit according to claim 1, wherein the mixing component (1) comprises two pumps (4), a first pump (4) connected to the first compartment (3A) and a second pump (4) connected to the second compartment (3B).

6. The kit according to claim 1, wherein the pump (4) is an injection pump, a volumetric pump, a peristaltic pump or a mobile pump.

7. The kit according to claim 1, wherein the first compartment (3A) is connected to the mixing chamber (10) via a first conduit (5A), and the second compartment (3B) is connected to the mixing chamber (10) via a second conduit (5B), and wherein the mixing chamber is connected to the output member (2) via a third conduit (5C).

8. The kit according to claim 7, wherein the conduit (5A, 5B, 5C) and / or the compartment (3A, 3B) are opaque or UV-absorbing.

9. The kit according to claim 1, wherein the mixing chamber (10) is directly connected to the compartments (3A, 3B) that respectively contain the aqueous stock solution and the aqueous buffer solution without the use of a conduit.

10. The kit according to claim 1, wherein the mixing chamber (10) is a bidirectional Y-connector (11); or The mixing chamber (10) includes a spiral channel (12) for mixing the two solutions; or The mixing chamber (10) contains a Venturi mixer (13); or The mixing chamber (10) contains an electric mixing tool (14).

11. The kit according to claim 1, wherein the container contained in the compartment (3A, 3B) is a syringe, bag, bottle or box.

12. The kit according to claim 1, wherein the kit further comprises a filter (6) disposed downstream of the mixing chamber (10) for filtering the aqueous drug solution prior to injection or infusion of the aqueous drug solution.

13. The kit according to claim 1, wherein the kit further comprises a control component (7) for controlling the pump (4) to control the flow rate of the pump (4).

14. The kit according to claim 1, wherein the kit further comprises a battery for powering the active component pump (4), the mixing chamber (10) and / or the control component (7).

15. The kit according to claim 1, wherein the volume of the compartments (3A, 3B) is sufficient to allow a subject with a central nervous system (CNS) disease to be treated continuously for at least 4 hours.

16. The kit according to claim 1, wherein the container contained in the compartment (3A, 3B) is replaceable or refillable.

17. The kit according to claim 1, wherein the container contained in the compartment (3A, 3B) can be replaced 2, 3, 4, 5 or 6 times during a 24-hour cycle, enabling the subject to be treated continuously for 24 hours.

18. The kit according to claim 17, wherein the replacement container cycle is less than 10 minutes.

19. The kit according to claim 1, wherein the kit further comprises a surgical glove, a cleaning wipe, and a disinfectant.

20. A method for continuously preparing an aqueous drug solution suitable for continuous parenteral or enteral administration, wherein the method comprises: A continuous mixing of an aqueous stock solution stream and an aqueous buffer solution stream comprising levodopa and a dopa decarboxylase (DDC) inhibitor carbidopa, wherein the stock solution has a pH less than 2.8 at 25°C and the buffer solution has a pH of at least 4.0 at 25°C; and A continuous stream of an aqueous drug solution is obtained from the mixture, the aqueous drug solution containing at least 5 mg / ml of dissolved levodopa, dopa decarboxylase (DDC) inhibitor carbidopa, and having a pH in the range of 3.0 to 8.

5.

21. The method of claim 20, wherein the pH of the aqueous drug solution is from 3.5 to 8.

0.

22. The method of claim 20, wherein the pH of the aqueous drug solution is from 4.0 to 7.

5.

23. The method of claim 20, wherein the pH of the aqueous drug solution is from 4.5 to 7.

0.

24. The method of claim 20, wherein the pH of the aqueous drug solution is 5.0 to 5.

5.

25. The method of claim 20, wherein the aqueous stock solution comprises at least 10 mg / ml levodopa.

26. The method of claim 20, wherein the pH of the aqueous stock solution is less than 2.

0.

27. The method of claim 20, wherein the pH of the aqueous stock solution is less than 1.

5.

28. The method of claim 20, wherein the pH of the aqueous stock solution is less than 1.

0.

29. The method of claim 20, wherein the pH of the aqueous stock solution is less than 0.

5.

30. The method of claim 20, wherein the aqueous reserve solution comprises at least one physiologically acceptable acid.

31. The method of claim 30, wherein the physiologically acceptable acid is an inorganic acid.

32. The method according to claim 31, wherein the inorganic acid is hydrochloric acid (HCl).

33. The method of claim 30, wherein the physiologically acceptable acid is acetic acid.

34. The method of claim 20, wherein the aqueous reserve solution further comprises at least one stabilizer.

35. The method of claim 20, wherein the method further comprises the step of removing air from the stock solution before mixing it with the aqueous buffer solution.

36. The method of claim 20, wherein the pH of the aqueous buffer solution is between 4.0 and 12.

37. The method of claim 20, wherein the pH of the aqueous buffer solution is between 4.0 and 9.

38. The method of claim 20, wherein the pH of the aqueous buffer solution is between 4.0 and 7.

5.

39. The method of claim 20, wherein the pH of the aqueous buffer solution is between 4.0 and 6.

40. The method of claim 20, wherein the aqueous buffer solution comprises at least one buffer component having at least one pKa value in the range of 3 to 9.

41. The method of claim 40, wherein the buffer component is citric acid.

42. The method of claim 40, wherein the buffer component is citric acid and phosphate.

43. The method of claim 40, wherein the buffer component is tromethamine (tris(hydroxymethyl)aminomethane).

44. The method according to claim 40, wherein the buffer component is adipic acid, boric acid, calcium carbonate, calcium lactate, calcium phosphate, diethanolamine, glycine, maleic acid, meglumine, methionine, monosodium glutamate, potassium citrate, sodium acetate, sodium bicarbonate, sodium, sodium carbonate, sodium citrate dihydrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, or a mixture of two or more thereof.

45. The method of claim 20, wherein the aqueous buffer solution further comprises at least one solubilizer.

46. ​​The method of claim 45, wherein the solubilizer is selected from the group consisting of: glutathione, cysteine, HP-β-cyclodextrin, N-methylpyrrolidone (NMP), dimethylacetamide (DMA), clopidogrel, kolliphor HS 15, PEG 400, propylene glycol, polysorbate 80, glycerol, ethanol, polyoxyethylene castor oil, DMSO, methionine, EDTA, ascorbic acid, aspartic acid, benzalkonium chloride, benzyl benzoate, hexadecylpyridinium chloride, hydroxypropyl beta-cyclodextrin, lecithin, polyethylene glycol 15-hydroxystearate, meglumine, phospholipids, poloxamer, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, pyrrolidone, trioleic acid glyceride, vitamin E polyethylene glycol succinate, or a mixture of two or more thereof.

47. The method of claim 45, wherein the solubilizer is HP-β-cyclodextrin.

48. The method of claim 20, wherein the aqueous buffer solution further comprises at least one stabilizer.

49. The method of claim 48, wherein the stabilizer is selected from the group consisting of stabilizers, antioxidants and preservatives or combinations thereof.

50. The method of claim 48, wherein the stabilizer is a stabilizing agent, and the stabilizing agent is a physiologically acceptable sugar.

51. The method of claim 50, wherein the physiologically acceptable sugar is glucose.

52. The method of claim 51, wherein the glucose concentration is in the range of 5 to 100 mg / ml.

53. The method of claim 20, wherein the drug solution does not contain glucose.

54. The method according to claim 49, wherein the stabilizer is bentonite, calcium alginate, calcium stearate, calcium carboxymethyl cellulose, carob gum, cyclodextrin, dextran, diethanolamine, ethylene palmitate stearate, fructose, glyceryl monostearate, lecithin, polyethylene glycol 15-hydroxystearate, mannitol, monoethanolamine, propylene glycol, sodium acetate, sodium borate, sorbitol, sulfobutyl ether β-cyclodextrin, trehalose, or zinc acetate.

55. The method of claim 49, wherein the antioxidant is selected from the group consisting of: α-tocopherol, ascorbic acid, palmitic acid ascorbate, butylated hydroxyanisole, citric acid monohydrate, isoascorbic acid, malic acid, methionine, monothioglycerol, penteacin, potassium metabisulfite, propionic acid, sodium formaldehyde sulfoxylate, sodium metabisulfite, sodium sulfite, and sodium thiosulfate.

56. The method of claim 49, wherein the preservative is selected from the group consisting of: benzalkonium chloride, benzyl chloride, benzoic acid, boric acid, bromonitrol, butanediol, calcium acetate, calcium lactate pentahydrate, hexadecyltrimethylammonium bromide, hexadecylpyridinium chloride, chlorobutanol, chlorocresol, citric acid monohydrate, cresol, ethylenediaminetetraacetic acid, ethylparaben, glycerin, imidureus, methylparaben, thioglycerol, phenol, phenoxyethanol, and phenethyl alcohol.

57. The method of claim 20, wherein the aqueous drug solution is supersaturated with levodopa.

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