WO2007131687A1

WO2007131687A1 - Pharmaceutical composition comprising plantago ovata and its use in the treatment of parkinson's disease

Info

Publication number: WO2007131687A1
Application number: PCT/EP2007/004107
Authority: WO
Inventors: Matilde Sierra Vega; Juan Jose Garcia Vieitiz; Maria Nelida Fernandez Martinez; Cesar Molinero Egea; Anna Maria Anguera Vila
Original assignee: Madaus, S.A.
Priority date: 2006-05-12
Filing date: 2007-05-09
Publication date: 2007-11-22
Also published as: ES2292345B1; ES2292345A1

Abstract

New use of Plantago ovata (husk) in the preparation of a drug intended for the treatment of Parkinson's disease, specifically in the preparation of a coadjuvant drug of the action of the active principle L-dopa. The invention also relates to pharmaceutical compositions and preparations which comprise Plantago ovata and at least L-dopa (Levodopa).

Description

PHARMACEUTICAL COMPOSITION COMPRISING PLANTAGO OVATA AND ITS USE IN THE TREATMENT OF PARKINSON' S DISEASE

Technical field of the invention

This invention relates to a new use and pharmaceutical compositions and preparations of Plantago ovata.

Background of the invention

Parkinson's disease is a neurodegenerative disease, of unknown origin, with a chronic, progressive evolution. The symptoms of the disease are tremors, rigidity and akinesia, arising from an anatomical lesion of the substantia nigra and a concentration deficiency of the neurotransmitter dopamine. Parkinson's disease is a frequent neurological disorder, with a prevalence of 0.3% of the general population, which drastically increases amongst elderly populations, being between 2% and 3% in individuals over 65.

Parkinson's disease is very debilitating and causes disability, severely diminishing the patients' quality of life, which in turn decreases their life expectancy. The most important occurrence in Parkinson's disease is the progressive loss or death of the pigmented dopaminergic neurons of the substantia nigra. These neurons, as the name suggests, respond to stimuli from the neurotransmitter dopamine, which is an endogenous catecholamine, a precursor of noradrenaline. Dopamine is synthesised from L-tyrosine at the dopaminergic neuron terminals, where, by means of active transport, L-tyrosine crosses the hematoencephalic barrier. L-tyrosine is hydroxylated to L-hydroxyphenylalanine or L-dopa (levodopa) and, subsequently, is decarboxylated by aromatic L-amino acid decarboxylase (LAAD) in order to form dopamine. The dopamine thus formed is stored at the nerve endings, in presynaptic vesicles. When the cell is depolarised, the dopamine is released to the synaptic cleft. Subsequently, through the action of carrier proteins, the dopamine is once again recaptured in vesicles; or, alternatively, is degraded by the action of the monoamino oxidase enzyme (MAO).

In the symptomatic treatment of Parkinson's disease, agonist substances of the dopamine and levodopa receptors, amongst others, are used. Levodopa is a prodrug which, once administered orally, is capable of crossing the hematoencephalic barrier, where it is subsequently decarboxylated to dopamine, particularly in the basal ganglions. Therapy with levodopa (L-dopa) may be very effective in controlling the signs and symptoms of Parkinson's disease. In the early stages, it reduces bradykinesia and rigidity. Tremor responds more slowly, but eventually are significantly reduced. Gait, posture disorders, speech and changes in the patient's conditions also improve. However, therapy with L-dopa also causes adverse secondary effects, primarily arising from the quick transformation to dopamine following the oral administration thereof, prior to passage into the central nervous system. These include alterations in the cardiosvascular system, in the gastrointestinal tract, in the nervous system, in the blood, in the respiratory system and in the locomotive system, in addition to endocrine dysfunctions. Consequently, in order to mitigate the secondary effects, L-dopa is usually administered jointly with LAAD enzyme inhibitors, such as carbidopa or benserazide.

One of the gastrointestinal problems that Parkinson's patients tend to suffer is constipation. This is due to the lack of muscle tone which they suffer or the lack of fibre intake, amongst other causes. This discomfort or disorder, which habitually appears in other diseases, is reduced by the administration of water-soluble dietetic fibre, such as, for example, Plantago ovata husk. Plantago ovata husk, also known as ispaghula seed husk, are fibres made up of husk of Plantago ovata seeds. It is a water-soluble fibre which, in contact with water, forms viscous solutions, suitable to regulate intestinal transit. Consequently, Parkinson's patients commonly receive, in addition to the medication indicated for the neuron-level treatment, a fibre supplement that allows them to regulate the gastrointestinal tract transit and improve their sense of well-being.

In order to reduce the secondary effects of the administration of L-dopa in Parkinson's patients and, at the same time, improve the efficacy thereof, the inventors have determined that, surprisingly, Plantago ovata husk exert other effects when administered to those patients who must take prescribed levodopa doses, which makes it possible to mitigate the medication's intrinsic problems.

Explanation of the invention

The object of this invention is the use of Plantago ovata in the preparation of a drug intended for the treatment of Parkinson's disease, specifically the preparation of a coadjuvant drug of the action of the active principle L-dopa in the above- mentioned disease. Preferably, in the preparation of the coadjuvant drug, the cuticle of the

Plantago ovata seed is used. Another object of this invention is the use of Plantago ovata in the preparation of a coadjuvant drug of the action of the active principle L-dopa, administered jointly with an aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor. Preferably, the aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor comprises carbidopa.

The object of this invention is also the use of Plantago ovata in the preparation of a drug intended for oral administration.

Another object of this invention consists of a pharmaceutical composition comprising L-dopa and Plantago ovata extract.

The pharmaceutical composition is also characterised in that it comprises an aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor. Preferably, the aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor comprises carbidopa. In the most preferred embodiment, carbidopa is in a weight percentage of between 0.5% and 8% with respect to the total weight of the composition.

Another object of the invention is the use of the pharmaceutical composition in the preparation of a drug intended for oral administration.

According to another aspect, the object of the invention is a combined pharmaceutical preparation containing L-dopa and Plantago ovata intended for the simultaneous, separate or time-spread use of both products.

The combined pharmaceutical preparation according to the invention is also characterised in that it is in the form of single-dose sachets of Plantago ovata which comprise L-dopa.

Brief description of the drawings

The attached drawings illustrate the results of some trials performed with white-coloured New Zealand breed rabbits, whereto equal doses of levodopa per kilogram of animal were administered, by itself or jointly with LAAD enzyme inhibitor, with different doses of Plantago ovata cuticle also being administered. Fig. 1 shows the median plasma concentration of levodopa (in ng/ml) following the oral administration thereof as a function of time (in minutes), comparing the administration of levodopa by itself to the administration of levodopa and Plantago ovata (A). It also shows the plasma concentration of levodopa (in ng/ml) in a logarithmic scale (B). Fig. 2 shows the evolution of the mean plasma concentrations of levodopa

(ng/ml) as a function of time (in minutes), following the oral administration thereof jointly with carbidopa, comparing them to the joint administration of levodopa and carbidopa with doses of Plantago ovata (A). It also shows the plasma concentration of levodopa (in ng/ml) in a logarithmic scale (B).

Detailed description of the invention

The detailed description given below represents a complete, clear description of this invention for those skilled in the art, but should not be considered to be a limitation of the essential aspects of the objects thereof.

In-vivo trial:

In the first place, and in order to determine the effect of Plantago ovata on the administration of levodopa, 20 mg/kg of levodopa were orally administered to different batches of white New Zealand rabbits, classified according to:

Batch 1.1 (6 rabbits): Levodopa in aqueous solution (20 mg/kg).

Batch 1.2 (6 rabbits): Levodopa in aqueous solution (20 mg/kg) with Plantago ovata cuticle (100 mg/kg) (Pantaben®, 70% richness).

Batch 1.3 (6 rabbits): Levodopa in aqueous solution (20 mg/kg) with Plantago ovata cuticle (400 mg/kg) (Pantaben®).

Batch 11.1 (6 rabbits): Levodopa in solid form (20 mg/kg) with carbidopa (5 mg/kg) (Sinemet Plus®).

Batch II.2 (6 rabbits): Levodopa in solid form (20 mg/kg) with carbidopa (5 mg/kg) (Sinemet Plus®) and Plantago ovata cuticle (100 mg/kg) (Pantaben®, 70% richness).

Batch II.3 (6 rabbits): Levodopa in solid form (20 mg/kg) with carbidopa (5 mg/kg) (Sinemet Plus®) and Plantago ovata cuticle (400 mg/kg) (Pantaben®).

Administration of the drugs was performed in such a way that those batches which only received levodopa or levodopa and carbidopa received it in 5 ml of aqueous suspension through an esophagic cannula. Subsequently, 45 ml of water were administered in order to drag the drugs that remained adhered to the cannula.

Alternatively, the batches which, in addition to levodopa or levodopa and carbidopa, received Plantago ovata cuticle, first received the fibre dissolved in 20 ml of water and 20 ml of additional water in order to clean the cannula. Subsequently, 5 ml of the levodopa solution or the levodopa and carbidopa suspension were administered, followed by another 5 ml of water, to complete in all cases a total volume of liquid of 50 ml.

The purpose of this batch distribution was to determine the pharmacokinetic parameters of levodopa and check the variation thereof when it is administered jointly with a LAAD inhibitor (Batches 1.1 and 11.1 ); when it is administered with fibre (Batches I.2 and II.2), which would allow to observe the effect of the fibre on the presystemic metabolism and/or on the absorption; and when levodopa is administered with carbidopa and different quantities of fibre (Batches I.3 and II.3), which would allow to observe whether the fibre interacts with the LAAD enzyme inhibitors.

In order to analyse the plasma concentration of levodopa, a blood sample was extracted at time 0 and after administering the corresponding drugs; samples were taken at the following time intervals: 5, 10, 20, 30, 60, 90, 120, 150, 180, 210, 240, 270 and 300 minutes. The volume of the extracted samples was 3 ml and they were centrifuged for 20 minutes at 1 ,500 rpm, subsequently extracting the supernatant plasma. If they were not immediately analysed, they were kept at -2O⁰C. For the quantification of the samples' levodopa concentration, the reverse- phase high-performance liquid chromatography (HPLC) technique with electrochemical detection was used. The identification and quantification of levodopa by HPLC was performed following the method described by Cummings et al (1990). The mobile phase consisted of 50 mM monobase sodium phosphate buffer at pH 2.9, 1 mM disodium EDTA and 1 mM heptanesulfonic acid; and in methanol, the proportion by volume of phosphate buffer and methanol being 90:10 (v/v). For the quantification, the electrochemical detection system was set at a voltage of 500 mV and a column with Ciβ filler (5-μm ODS 2, Waters Spherisorb®) was used.

The results of these trials are shown in the graphs in Figs. 1 and 2. Likewise, Table 1 shows the maximum mean plasma concentrations detected for each batch and administered product or products, the variation coefficient thereof and the time required to attain the maximum plasma levels.

Table 1

As can be seen in Figs 1 and 2, which represent the data in Table 1, the administration of fibre leads to variations in the pharmacokinetics of the active principle levodopa. Specifically, the graphs and the Table make it possible to deduce that those animals which received Plantago ovata cuticle, after a certain time and depending on the quantity of administered fibre, exhibited higher plasma levels of available levodopa.

Thus, when levodopa was administered with 100 mg/kg of Plantago ovata (Fig. 1 -Batch I.2), the quantity of levodopa available in plasma after 60 minutes was twice the quantity available when only levodopa was administered (Fig. 1 -Batch 1.1). When 400mg/kg of Plantago ovata were administered (Fig. 1 -Batch 1.3), the quantity of available levodopa after 20 minutes increased by 67%.

Regarding the value of U_3x, or the time at which the highest plasma level of levodopa is achieved, it is greater when the active principle is applied with fibre. Specifically, when levodopa is administered with Plantago ovata, the value of U_3x is about 20 minutes from the time when levodopa is administered, compared to the time or t_max corresponding to the single administration of levodopa, which is 10 minutes from the time of administration. These results suggest that the absorption of levodopa is slower when it is jointly administered with several doses of Plantago ovata cuticle; the same effect is observed when levodopa (20mg/kg) and carbidopa (5 mg/kg) are jointly administered (Fig. 2-Batch 11.1 ). When levodopa is administered with the LAAD inhibitor carbidopa, one must highlight that the plasma concentration of levodopa is lower when, in addition, Plantago ovata is administered. As can be deduced from Fig. 2, when the dose of Plantago ovata is 100 mg/kg (Fig. 2-Batch II.2), the maximum plasma concentration observed is 28.1% lower than when only levodopa and carbidopa are administered (Fig. 2-Batch 11.1). However, when the dose of Plantago ovata is increased to 400 mg/kg (Fig. 2-Batch II.3), the value of the maximum plasma concentration is recovered, being, not significantly, 24.6% lower than when only levodopa and carbidopa are administered.

However, as in Fig. 1 , in Fig. 2 one can observe that when the drug is administered with Plantago ovata, the available quantity of levodopa is greater after a certain time; this time is a function of the Plantago ovata dose, being 210 minutes with 100 mg/kg doses and 150 minutes with 400 mg/kg doses.

These figures make it possible to deduce that the quantity of absorbed levodopa is greater upon increasing the Plantago ovata dose. These results suggest that pharmaceutical compositions with L-dopa and

Plantago ovata, as well as those pharmaceutical preparations that contain Plantago ovata and L-dopa, are very beneficial when administered to individuals suffering from Parkinson's disease, because, in addition to exerting the already known effects of mitigating or improving gastric discharge, they optimise the pharmacokinetics of the active principle L-dopa or levodopa, in the sense that the intestinal absorption thereof increases and the plasma levels remain at high concentrations for longer periods of time. This leads to a more uniform response, which prevents fluctuations in the concentrations of levodopa, which largely cause the fluctuations in the patients' locomotive capacities.

Consequently, the levodopa doses are indicated because they are lower than those currently being administered. By reducing the dose of the effective active principle, the secondary effects thereof, such as, for example, gastrointestinal and cardiovascular disorders mediated by dopamine or levodopa itself, are also prevented to a larger extent.

Examples of pharmaceutical preparations and compositions:

The attached example lists the concentrations of some of the pharmaceutical compositions or preparations according to the invention.

Example 1. Single-dose sachet of Plantago ovata and tablet of L-dopa and carbidopa.

Each single-dose sachet comprises (units in grams):

Plantago ovata seed husk 3.50 g Sodium saccharin 0.03 g

Excipients (sodium bicarbonate, tartaric acid, orange essence, Pal super orange colouring agent)., q.s 4.0 g

Said single-dose sachet includes a tablet of L-dopa composed of 100 mg of levodopa; 25 mg of carbidopa; and suitable excipients in a sufficient quantity for 1 tablet. Such excipients may be, for example, mannitol, microcrystalline cellulose, calcium phosphate, starch, ethylcellulose, etc.

Attached to the box containing the single-dose sachets, one may also include a "blister" or a strip with the L-dopa tablets. In any event, the patient must dissolve the content of the single-dose sachet in water and take the L-dopa tablet with each sachet. The example listed may comprise, in its formulation, excipients which are known to those skilled in the art, and which will depend on the type of formulation desired, whether liquid or solid, and adapted to the required administration, for example, oral, intravenous, intradermal or intramuscular. Evidently, although the example lists a pharmaceutical preparation consisting of a single-dose sachet of Plantago ovata and a tablet, all those preparations or compositions which make it possible for an individual to jointly take both the active principle and the coadjuvant Plantago ovata, such as solutions of both compounds, solutions of one of them combined with solid forms of the other, etc., are also objects of the invention

The object of the invention provides numerous advantages in the field of Parkinson's disease therapy. As has already been noted, the use of Plantago ovata and the compositions or preparations of the invention make it possible for a patient who must take L-dopa to receive lower doses of the above-mentioned active principle with the certainty that neither the pharmacokinetics nor the pharmacodynamics thereof will be reduced. Furthermore, the administration of lower L-dopa doses very significantly reduces the secondary effects thereof.

Example of a treatment pattern and of the use of Plantaαo ovata with L-dopa in the preparation of a drug intended for the treatment of Parkinson's disease.

Finally, in order to give an example of the dosage or administration pattern of Plantago ovata with L-dopa and, additionally, carbidopa, a possible pattern is listed below for the achievement of the beneficial effects of the new use of Plantago ovata described in the invention: Each patient shall take a sachet containing 3.5 g of Plantago ovata (for example, a sachet of Plantaben® from the MADAUS company, which corresponds to 5 g of product equivalent to 3.5 g of Plantago ovata) dissolved in a 200-ml glass of water. Subsequently, the patient shall take a tablet of levodopa/carbidopa with 50 ml of additional water. The composition of this tablet is 100 mg of levodopa/25 mg of carbidopa.

This treatment shall be performed 3 times a day, in the morning before breakfast, at noon before lunch and in the evening before dinner.

Administration patterns such as the one described or similar ones make it possible to minimise the fluctuations of the active principle (L-dopa or L-dopa and carbidopa) in the patient's bloodstream and, in addition, that they may be administered in lower doses than the usual ones.

Claims

C L A I M S

1.- Use of Plantago ovata in the preparation of a drug intended for the treatment of Parkinson's disease, specifically in the preparation of a coadjuvant drug of the action of the active principle L-dopa.

2.- Use of Plantago ovata, according to claim 1 , characterised in that the Plantago ovata seed cuticle is used.

3.- Use, according to any of the preceding claims, in the preparation of a coadjuvant drug of the action of the active principle L-dopa administered jointly with an aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor.

4.- Use, according to claim 3, characterised in that the aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor comprises carbidopa.

5.- Use of Plantago ovata, according to any of claims 1 to 4 above, in the preparation of a drug intended for oral administration.

6.- Pharmaceutical composition which comprises L-dopa and Plantago ovata extract.

7.- Pharmaceutical composition, according to claim 6, characterised in that it further comprises an aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor.

8.- Pharmaceutical composition, according to claim 7, characterised in that the aromatic L-amino acid decarboxylase (LAAD) enzyme inhibitor comprises carbidopa.

9.- Pharmaceutical composition, according to claim 8, characterised in that it comprises between 0.5% and 8% by weight of carbidopa.

10.- Use of the pharmaceutical composition, according to any of claims 6 to 9, in the preparation of a drug intended for oral administration.

11.- Combined pharmaceutical preparation containing L-dopa and Plantago ovata intended for a simultaneous, separate or time-spread use of both products.

12.- Combined pharmaceutical preparation, according to claim 11 , characterised in that it is in the form of single-dose sachets of Plantago ovata which comprise L-dopa.

13.- A method for the treatment of Parkinson's disease which comprises the administration, to those individuals requiring it, of a suitable quantity of Plantago ovata by itself or jointly with L-dopa, in order to obtain a coadjuvant effect of L- dopa's pharmacological action.