PHARMACEUTICAL COMPOSITIONS CONTAINING LEVODOPA METHYL ESTER, PREPARATION AND THERAPEUTIC APPLICATIONS THEREOF

Abstract: Pharmaceutical compositions for the treatment of Parkinson's disease and neurologic syndromes connected with it, containing as the active principle levodopa methyl ester optionally combined with other active princi­ ples selected from dopaminergic, anticholinergic, antide­ pressive drugs, carboxylase and monoaminoxidase inhibi­ tors.

Description: The present invention refers to pharmaceutical compositions for the treatment of Parkinson's disease, containing levodopa methyl ester alone or combined with other active principles. Parkinson's disease is characterized by a progressive degeneration of the dopaminergic nigrostriatal pathways in the brain. Biochemical studies carried out in the sixties lead to the discovery of the fundamental role played in the pathogenesis of this disease by the deficit of neurotransmitters, and particularly of dopamine. This important advance in the comprehension of the neurochemical bases of the pathology brought about a drastic change in the pharmacological approach to the disease, and lead to the introduction in the therapy of an immediate biologic precursor of dopamine, (-)-3-(3,4-dihydroxyphenyl)-L-alanine, more commonly known as levodopa. The use of levodopa lead to a dramatic improvement in the treatment of Parkinsonism, and it is still the treatment of choice of this disease. Chronic treatment per os, however, often leads to a progressive decrease of the therapeutic effectiveness and to the onset of serious unwanted effects, including abnormal involuntary movements, "end-of-dose deterioration" when efficacy is limited to 3-4 hours, and the "on-off" phenomenon - marked, very abrupt, almost instantaneous, changes in the level of disability. Pharmacokinetic factors, such as variability in the plasma concentration and interference with intestinal absorption of levodopa due to competition with proteins and amino acids, appear to play a primary role in the origin of the late complications from levodopa therapy, particularly in the "on-off'' fluctuations. Alternative therapies with dopaminergic drugs, such as bromocriptine, do not give actual advantages in prevention or reduction of response fluctuations. The importance of the pharmacokinetics of levodopa for the fluctuating clinical response has been emphasized by studies in which levodopa plasma levels are stabilized by administering the drug via constant intravenous infusion. Under these conditions, a stable clinical response can be maintained for hours. Levodopa itself, however, is not suitable for long-term systemic use, since it is slightly soluble and can therefore only be administered in large volumes of solvents. In spite of having been known for a long time, levodopa methyl ester has never been used in human therapy, even though, since 1965, Hanson L.C.F. and Utley J.D. showed, in reserpine-treated cats, by measuring brain catecholamine levels and assessing the behavior evaluation in the conditioned avoidance response, that levodopa methyl ester causes the same effects as levodopa (Psychopharmacologia 8 ; 140-144, 1965). Recently other experimental patterns have confirmed that levodopa methyl ester is as active as the starting compound, so that it has been suggested as a suitable candidate for the chronic infusion in Parkinsonian patients (Cooper D.R. et al, Clin. Neuropharmacol. 7 (1), 89-98, 1984). NEUROLOGY, no. 34, September 1984, p. 1131-1136, Niall Qinn et al discloses the treatment of patients with Parkinsons disease with levodopa administered by continous intravenous infusion. FR-A-2 290 912 discloses gastroresistant tablets or capsules containing LDME, whereas FR-A-2 085 735 discloses combination of L-dopa or derivatives with L-tyrosine or derivatives. Rectal formulations comprising LDME have been disclosed in US-A-4 663 349. It has now been found that levodopa methyl ester, hereinafter referred to LDME, can be used as active principle of particular pharmaceutical compositions with surprising therapeutic effects. A main object of the present invention refers therefore to pharmaceutical compositions containing LDME for the treatment of all kind of Parkinsonism and in the neurorologic syndromes related to it. Such compositions can be administered by the oral, or sublingual routes. Pharmaceutical compositions for oral administration are in liquid form. LDME, infact, thanks to its high solubility, can be successfully used for the preparation of aqueous pharmaceutical compositions, at the desired concentrations and in small administration volumes. The unit dose may range from 100 to 1.000 mg of active principle. Liquid pharmaceutical compositions for oral administration can be prepared by dissolving LDME in a suitable aqueous medium. The solution may also contain a preserving agent with antioxidant chelant or antibacterial action, examples of such additives being ascorbic acid, sodium metabisulfite, citrates and p-hydroxybenzoates. Other additives, such as buffers, viscosity regulators, sugars, cosolvents and flavouring agents, can be added to the formulations. Alternatively, the compositions can be prepared from powdered or granulated mixtures to be reconstituted with water at the moment of use. These compositions in form of mono-dose or multi-dose may contain the active ingredient in concentration up to 400 mg/ml. Liquid compositions as described above can be administered by oral or sublingual routes. The sublingual route of LDME administration proved to be rational and effective and grants remarkable advantages: more rapid and reliable absorption than from the gastrointestinal tract; bypass of the hepatic circulation; possibility of being employed in gastroresected subjects or, in general, in patients with impaired absorption. Another very suitable system of LDME administration is the buccal delivery by small tablets which adhere to the surface of the oral mucosa releasing drug amounts constant in time, assuring steady plasmatic levels and consequently avoiding fluctuating clinical responses. In order to improve the therapeutic action, LDME may also be advantageously used in combination with other active principles, selected from peripheral decarboxylase inhibitors, such as carbidopa or benserazide, or selective MAO-B inhibitors, such as deprenyl. The combined regimens: a) LDME + decarboxylase inhibitors; b) LDME + MAO-B inhibitor; c) LDME + decarboxylase inhibitor + MAO inhibitor, allow a remarkable reduction in the dose of LDME necessary to control the disease, consequently decreasing side effects, with a prolongation and an increase of effectiveness and with a more rapid pharmacological response. To allow the application of the therapeutic and posological scheme more suited to a particular pathological condition, LDME and the above mentioned active principles may be administered separately. Alternatively, the patient may be administered with therapeutic compositions containing as active principles both LDME and a peripheral decarboxylase inhibitor and/or a MAO-B inhibitor or optionally with both of them. Solid compositions for sublingual administration may contain as the active principle LDME in an unit dose ranging from 100 to 300 mg in combination with benserazide, in a ratio between 2:1 and 5:1, or in combination with carbidopa, in a ratio ranging from 4:1 to 10:1, and they may be extemporaneously administered in combination with oral pharmaceutical compositions, containing as the active principle deprenyl, in a quantity of 5 mg per unit dose. Liquid compositions may contain LDME in a concentration ranging from 50 to 400 mg/ml in combination with benserazide, in a ratio ranging from 2:1 to 10:1, or with carbidopa in a ratio ranging from 4:1 to 20:1, or with deprenyl, in a ratio ranging from 20:1 to 100:1, or, again, in association with benserazide and deprenyl, in ratios respectively ranging from 2:1:0.1 and 10:1:0.1 with carbidopa and deprenyl in ratios respectively ranging from 4:1:0.2 to 20:1:0.2. Said pharmaceutical compositions may ensure an immediate release of active principles, or may be formulated to allow a planned and sequential release of components. The following examples illustrate the invention in more details. Compositions containing LDME as the active ingredient. EXAMPLE 1 Ready solution administrable by drops. Levodopa methyl ester mg 250 Methyl p-hydroxybenzoate mg 1.35 Propyl p-hydroxybenzoate mg 0.15 Saccharin sodium mg 10 Orange flavour ml 0.002 Citric acid H₂O mg 20 Trisodium citrate dihydrate mg 31.5 Purified water q.s. to ml 1 The solution in example 1 may optionally contain an antioxidant such as sodium metabisulfite in quantity of mg 1.5; a sugar such as sucrose in quantity of mg 100; a co-solvent such as glycerol in quantity of mg 20. EXAMPLE 2 Powder composition to be reconstituted when used. Levodopa methyl ester HCl mg 2.500 Trisodium citrate dihydrate mg 50 Saccharin sodium mg 100 Saccharose mg 1.000 Flavouring powder q.s. To be reconstituted with water ml 10 EXAMPLE 3 Tablets for sublingual administration Levodopa methyl ester mg 200 Gum arabic mg 10 Lactose mg 90 Ammonium glycyrrhizinate mg 20 Saccharin sodium mg 10 Flavour mg 13 Magnesium stearate mg 7 Compositions containing LDME in combination with other active ingredients. EXAMPLE 4 Ready solution to be administered by drops Levodopa methyl ester HCl mg 250 Levodeprenyl (HCl) mg 2.5 Methyl p-hydroxybenzoate mg 1.35 Propyl p-hydroxybenzoate mg 0.15 Saccharin sodium mg 10 Orange flavour ml 0.002 Citric acid H₂O mg 20 Trisodium citrate dihydrate mg 31.5 Purified water q.s. to ml 1 As per Example 4 above, by using similar adjuvants in the specified quantities, compositions containing as active ingredients LDME in combination with peripheral decarboxylase inhibitors and/or MAO inhibitors in the quantities listed herebelow, may be prepared. EXAMPLE 5 Ready solution to be administered by drops Levodopa methyl ester HCl mg 100 Benserazide HCl mg 19 EXAMPLE 6 Ready solution to be administered by drops Levodopa methyl ester HCl mg 100 Carbidopa HCl mg 9.5 EXAMPLE 7 Ready solution to be administered by drops Levodopa methyl ester mg 100 Levodeprenyl HCl mg 1 Benserazide HCl mg 11.4 EXAMPLE 8 Ready solution to be administered by drops Levodopa methyl ester HCl mg 100 Levodeprenyl HCl mg 1 Carbidopa HCl mg 5.74 The pharmaceutical composition as per Example 1 above has been orally administered to Parkinsonian patients manifesting the on-off phenomenon, in order to evaluate the bioavailability and the clinical effect of LDME in this fomulation in comparison with levodopa. As previously illustrated, patients manifesting the on-off phenomenon alternate between periods when parkinsonian signs are relatively severe and intervals when parkinsonism is largely, if not completely, replaced by unvoluntary movements. The results have been very surprising. The absorption of LDME was in fact very rapid, reaching the maximum concentration peak at 40-45 minutes from the administration. Table 1 shows the single data of the levodopa plasmatic levels at the different times after administration respectively of LDME and levodopa in two patients. The rapid attainment of high concentrations of levodopa in the systemic circulations after LDME admistration produces a very early onset of the therapeutic effect, which appears at 20-30 minutes about from the administration of the composition as per Example 1 of the invention. Moreover, the duration of action noticed as "on" period duration, was superior with LDME in respect to the levodopa. A further advantage linked with the therapeutic action of LDME which came out from these preliminary trials, consists in that the drug in this composition and by this route of administration does not seem to induce dyskinesias at the moment of the appearance of the mobility ("on" phase) in the subjects presenting the "long-term syndrome", the phenomenon which occurs in about half of Parkinsonian patients treated for 3-5 or more years. Much more surprising have been the results obtained by administering the composition as per Example 1 by sublingual route. By this way, in fact, the absorption of the active principle is much more rapid and, the onset of the therapeutic effect is much more early and persistent (table 2). TABLE 2 Therapeutic effects in idiopathic Parkinsonian patients presenting "on-off" phenomenon determined as time of turn "on" and as duration of the "on" period. Comparison between two treatment regimens: I. LDME mg 200 sublingual administration + mg 25 of carbidopa oral administration. II. Sinemet® mg 275 oral administration (mg 250 of levodopa + mg 25 of carbidopa). LDME, particularly in certain administration forms and routes such as oral in liquid form, or sublingual, has demonstrated to be a valid therapeutic alternative for Parkinson's disease treatment, thanks to the particular advantages in comparison to levodopa. The sublingual route of administration, by passing the gastrointestinal system, may become the preferred approach for the treatment of patients with gastrointestinal problems.

Claims: Pharmaceutical compositions containing levodopa methyl ester (LDME) as active ingredient in solution in a liquid carrier or diluent for oral administration or in form of tablets for sublingual administration. Compositions according to claim 1, containing the active principle in concentration from 50 to 400 mg/ml. Pharmaceutical compositions containing LDME in combination with other active principles selected from dopamine agonists, anticholinergics, antidepressives, peripheral decarboxylase inhibitors, MAO-B inhibitors or their association. Compositions according to claim 3, containing levodopa methyl ester in an unit dose ranging from 100 to 300 mg in combination with benserazide or carbidopa or deprenyl, in a ratio from respectively 2:1 to 5:1; 4:1 to 10:1; 20:1 to 100:1 or their combination. Compositions according to claims 3 in solution in a liquid carrier or diluent for oral administration, containing levodopa methyl ester in a concentration ranging from 50 to 400 mg/ml in combination with benserazide or carbidopa or deprenyl in a ratio between respectively 2:1 and 10:1; 4:1 and 20:1; 20:1 to 100:1 or their combination.

Inventors: CHIESI, PAOLO
Applicants: CHIESI FARMACEUTICI S.P.A.
Application year: 1987
Main classification: A61K31
IPC codes: A61K31, A61K9, A61P25