Levodopa infusion solution

Abstract

The invention provides an aqueous pharmaceutical solution for use in the treatment of diseases of the central nervous system (CNS), the solution comprising at least 5 mg / ml dissolved levodopa, and having a pH in the range of 3.0 to 8.5. Said solution is provided by mixing a) au aqueous stock solution comprising levodopa, said stock solution having a of less than 2.8 at 25° C. and b) an aqueous buffering solution, for increasing the pH of said stock solution, said buffering solution having a pH of at least 4.0 at 25° C. The aqueous pharmaceutical solution is administered to a subject suffering from a disease of the central nervous system (CNS) shortly after mixing of the aqueous stock solution and the aqueous buffering solution. Furthermore, the invention provides a kit for administration of aqueous pharmaceutical solutions to subjects suffering from diseases of the central nervous system (CNS).

Description

FIELD OF THE INVENTION[0001]The present invention relates to a pharmaceutical product for treatment of diseases of the central nervous system consisting of a levodopa solution suitable for continuous parenteral or enteral administration and an administration system suitable for administering the Said solution.BACKGROUND OF THE INVENTION[0002]Dopamine [3,4-dihydroxyphenylethylamine] is an organic substance of the catecholamine and phenethylamine families that plays several important roles in the brain and body. In the brain, dopamine functions as a neurotransmitter released by neurons (nerve cells). The brain includes several distinct dopamine pathways and dopamine is vital to several of the functions of the central nervous system such as movement, attention, mood and motivation. Several diseases of the nervous system, e.g. Parkinson's disease, are associated with dysfunctions of the dopamine system and some of the key medications used are modulating the levels of dopamine in the bra...

AI Technical Summary

Benefits of technology

The invention allows for the inclusion of components that may affect the stability of levodopa and carbidopa in the buffering solution. These components are not in contact with levodopa and carbidopa until the stock and buffering solutions are mixed. This is an advantage because it opens up the use of a variety of components that improve stability, reduce toxic metabolites, and improve the buffering capacity. Adding low concentration phosphate to the buffering solution increases the range of buffering capacity covering the entire pH-range of the invention. The resulting infusion solution has a pH range of 5.1-5.4, which is optimal for absorption of the APIs in the tissue at subcutaneous infusion. The buffer components used may include citric acid, phosphate, solubilizers, stabilizers, antioxidants, and preservatives. The use of a physiologically acceptable sugar, such as glucose or fructose, as a stabilizing agent is also contemplated.

Problems solved by technology

Later, during the course of the disease, cognitive and behavioural problems may arise.

Unfortunately, pharmacokinetic and pharmacodynamic problems (on-off symptoms) develop after several years, of oral treatment with levodopa.

More specifically, it is believed that the intermittent administration of levodopa through oral treatment, together with the degeneration of dopaminergic neurons, are the main causes of the development of on-off symptoms.

Intermittent oral treatment eventually leads to a narrower therapeutic window for levodopa making oral administration even more problematic.

The problem is that it has not been possible to produce a physiologically acceptable infusion solution of a high enough levodopa concentration—which in turn provides a sufficiently small volume—making it suitable for continuous parenteral administration.

The heart cannot handle such large infusion volumes for any extended period of time.

Numerous attempts have been made over a 30-year period to increase the levodopa concentration in a physiologically acceptable infusion solution, but without decisive success.

The researchers, have been facing a major problem in that levodopa precipitates at concentrations greater than in the range of 0.5-1.6 mg / ml at pH values acceptable or at least desirable at continuous parenteral administration.

Such volumes cannot be continuously administered parenterally for long periods.

An infusion solution having a pH of <3 is not suitable for continuous parenteral administration but would result in severe adverse systemic acidosis and adverse skin effects (noduli).

In addition, an infusion solution with a pH>9, when infused parenterally, may cause adverse systemic effects such as Cardiac Arrhythmia (irregular heartbeats).

It is thus demanding to successfully formulate an API typically being degraded in aqueous solution at physiological pH for infusion applications.

The prior art has failed to provide a solution containing levodopa and carbidopa suitable for continuous subcutaneous infusion, with sufficient uptake in the plasma enabling the treatment of PD-patients on an individual basis for maximal reduction of on-off symptoms, which fulfils the requirements' for being approved as a pharmaceutical product.

The disadvantages of very basic infusion solutions have been stated previously in the description.

A levodopa concentration of about 20 mg / ml was achieved by allowing the solution to take the form of a suspension, which however does not allow the solution to be used for parenteral administration.

Duodopa have major disadvantages in that the use requires a surgical procedure at the start of treatment.

Continuous administration via the duodenum means that a probe must be applied, which enters through the abdominal wall, and troublesome side effects are common.

The high viscosity of the gel-based suspension requires a powerful pump for the gel to be pressed through the probe, and the administration system thus becomes heavy and unwieldy.

The limited durability constitutes a further disadvantage.

The shelf life of unopened packages does not exceed three months, which means logistical disadvantages and a more expensive product.

The patent does not teach how to include any inhibitor such as carbidopa.

The presented infusion solution may be useful for intravenous infusion but a concentration of 5 mg / ml without inhibitors results in volumes which are too high for clinical treatment of on-off symptoms by continuous subcutaneous infusion.

A shelf life not exceeding 3 days limits the practical use of the infusion solution.

An infusion solution with, short physical stability entails serious logistical problems, which in reality may result in a product, which is not practical for use as a medical drug.

However, there are several problems associated with solutions having such high pH-values, in particular at parenteral administration.

Other disadvantages of infusion solutions having very high pH-values have been stated previously in the description.

Consequently, no infusion solution for parenteral administration previously presented in the art has managed to obtain a registration as a pharmaceutical product.

Images