Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1999-11-10
2002-04-23
Krass, Frederick (Department: 1615)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C514S538000, C514S614000, C514S654000, C514S657000, C514S960000
Reexamination Certificate
active
06376545
ABSTRACT:
Throughout this application, various references are identified by authors and full citations. Disclosure of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical composition of a highly purified, stable, non-hygroscopic, crystalline composition of L-DOPA ethyl ester (LDEE). The L-DOPA ethyl ester is a new active ingredient for the treatment of patients suffering from Parkinson's disease and related indications.
2. Description of Related Art
The present invention relates to a novel formulation of L-DOPA ethyl ester that provides a dispersible oral dosage formulation of L-DOPA ethyl ester to result in a fast onset of therapeutic activity in a patient.
L-DOPA, also referred to as levodopa (The Merck Index, Twelfth Edition (1996)), in combination with carbidopa or benserazide, remains one of the most effective therapies for Parkinson's disease (PD). Within five years after initiation of such a therapy, disabling motor fluctuations appear in about 50 percent of the treated patients (Wooten G F (1988). Ann Neurol. 24: 363-365). This disability appears as random periods of sudden and unexpected loss of efficacy of levodopa therapy aggravated with time, and has been termed the ‘on-off’ phenomenon.
Several studies suggest that the motor fluctuations are directly related to the levels of plasma levodopa (Wooten G F supra). Various observations lend support to this contention, for example, gastric emptying in the elderly, particularly in PD (plasma deficiency) patients, is erratic, often much too slow to compensate for the plasma deficiency in levodopa at the ‘end of dose’ (Bozeman T, et al., (1990), Am J Gastroenterol 85: 1264 and Kurlan R, et al (1988) Neurology 38: 419-421). This effect, when coupled to the low water solubility of levodopa itself and to the usual retention in the stomach of particulate matter is expected to further decrease the rate of transfer of the ingested dose of levodopa from the gastrointestinal (GI) tract to the plasma (Kelly K A (1981). “Motility of the stomach and gastroduodenal junction”, in Johnson L R, editor, Physiology of the Gastrointestinal Tract, Raven Press, New York, pp. 393-410). For almost any drug, the combined pharmacokinetics of a low absorption rate and a high elimination rate (as is the case of levodopa with a plasma half-life of about 1 hour) are conducive to plasma drug levels that are below the effective therapeutic range, hence treatment becomes ineffective.
Various procedures have been sought to remedy this situation. In some cases, direct instillation of a slurry of levodopa through a duodenal tube has given rapid relief from the ‘off’ state (Kurlan R, et al., (1986) Ann. Neurol. 20: 262-265 and Cedarbaum et al., (1990) Neurology 40: 887-995). In another approach, oral dosing with a dilute aqueous solution of levodopa appeared to be effective (Kurth M C, et al., (1993). Neurology 43: 1036-1039). Neither of these measures are practical enough to allow self-medication when urgently needed. When rapid relief is needed, the more common procedure is to recommend to the patient to crush the levodopa tablet before intake, so as to minimize the time required for its disintegration in the GI tract. The efficacy of this procedure has never been demonstrated.
In an effort to provide pharmaceutical compositions that permit uniform and continuous dissolution of active materials, U.S, Pat. No. 4,259,314 (Lowey, 1981) discloses a composition comprising an active agent in admixture with from 80-95% hydroxypropylmethyl cellulose (HPMC) and 5-206 hydroxypropyl cellulose (HPC) having a moisture content of less than 1%. The formulation described therein is stated to be of use especially with hygroscopic therapeutic agents.
U.S. Pat. No. 5,354,885 (Milman, 1994) discloses a composition containing a solution form of L-DOPA ethyl ester substantially free of L-DOPA suitable for pharmaceutical use. The L-DOPA ethyl ester described therein has been shown to function as a prodrug of levodopa whether delivered by the oral or parenteral route.
There is a need for a pharmaceutical composition that will increase the bioavailability of L-DOPA ethyl ester to a patient requiring such treatment, since the existing compositions do not provide sufficient sustained levels of L-DOPA ethyl ester to maintain a satisfactory level of treatment.
There is a further need to develop a stable solid formulation that will give rapid dissolution of L-DOPA ethyl ester in a dispersible tablet formulation because other methods of administration present a series of limitations and drawbacks. The use of capsules affects dosage, since only single dosage is possible. It is not possible to cut the capsules into halves.
On the other hand, administration in solution form raises a series of drawbacks which may be summarized as follows:
(1) Dosage of the active ingredient requires the use of measuring devices which are not normally precise;
(2) There is limited ease of handling and transport for Parkinson's disease patients due to the volume involved; consequently there is a certain risk that therapy will not be completed, with the consequent loss of efficacy of treatment;
(3) Refrigeration is required and the solution is not stable after more than one year; and
(4) It is difficult to produce a solution for human consumption that will contain carbidopa, due to solubility and stability issues.
The subject invention provides a prodrug of L-DOPA to overcome problems such as facilitating their administration by the patient, administering to diabetic patients without additional difficulties, and enhancing the efficacy of treatment.
The development of a tablet formulation presented some unexpected difficulties which arise from the peculiar nature of the active ingredients of the present oral dispersible formulation, namely, the L-DOPA ethyl ester and carbidopa.
First, L-DOPA ethyl ester is not stable at room temperature, and is kept under refrigeration (2-8° C.), whereas the final dispersible tablet formulation should be designed, for optimum convenience to patients, pharmacists and physicians, for storage at room temperature.
Secondly, carbidopa contains 7.5% water. Because L-DOPA ethyl ester is highly sensitive to moisture and undergoes hydrolysis rather easily, the formulation cannot be prepared according to standard methods which comprise direct mixing of all the active ingredients or direct granulation followed by compression into oral tablet formulations. An additional consideration with respect to the high sensitivity of L-DOPA ethyl ester to moisture, is the selection of excipients for mixing in the formulation. The excipients are required to be of low moisture content otherwise the L-DOPA ethyl ester will undergo hydrolysis.
Thirdly, the active ingredients L-DOPA ethyl ester and carbidopa are very reactive towards various excipients. Some excipients ordinarily fungible for many standard formulations could not be used in the present formulation and their selection required exhaustive preformulation screening of many excipients.
This invention provides a solution to the problems referred to above by providing new pharmaceutical formulations which minimize the time required for the tablet disintegration in the gastrointestinal tract. Thereby, the composition of this invention which comprises L-DOPA ethyl ester, carbidopa, microcrystalline cellulose, starch, and magnesium stearate has improved the release of L-DOPA ethyl ester, in turn improving the efficacy of intake.
SUMMARY OF THE INVENTION
The present invention relates to a dispersible pharmaceutical composition comprising a therapeutically effective amount of L-DOPA ethyl ester, a therapeutically effective amount of a decarboxylase inhibitor, a filler, a disintegrant, and a lubricant.
In addition, the present invention provides a method of preparing a dispersible composition, preferably a tablet compositio
Cooper & Dunham LLP
Jagoe Donna
Krass Frederick
Teva Pharmaceutical Industries Ltd.
White John P.
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