Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-11-12
2004-02-24
Rotman, Alan L. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S042000, C514S538000, C514S567000, C514S649000
Reexamination Certificate
active
06696600
ABSTRACT:
Throughout this application, various references are cited, using arabic numbers within parentheses. Full citations for these references can be found at the end of the specification, immediately preceding the claims. These publications, in their entireties, are hereby incorporated by reference into the application to more fully describe the state of the art to which the invention pertains.
FIELD OF THE INVENTION
The present invention concerns the use of levodopa ethyl ester (LDEE) salts to treat Parkinson's disease, senile dementia, dementia of the Alzheimer's type, a memory disorder, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, withdrawal symptoms, epilepsy, convulsions or seizures.
BACKGROUND OF THE INVENTION
Typically, Parkinsonian patients are routinely treated with a combination of levodopa (L-DOPA) and an L-DOPA decarboxylase inhibitor such as carbidopa or benserazide. Unfortunately, after an initial period of satisfactory, smooth and stable clinical benefit from L-DOPA therapy lasting on the average 2-5 years, the condition of many patients deteriorates and they develop complex dose-related as well as unpredictable response fluctuations. The causes of the response fluctuations are probably multiple and complex, but pharmacokinetics problems (primarily faulty absorption of L-DOPA) may play a critical role. There is a correlation between the clinical fluctuations and the oscillations of L-DOPA plasma levels. Many of the problems are a result of the unfavorable pharmacokinetics properties of L-DOPA, i.e. very poor solubility, poor bio-availability and short half-life in vivo.
A typical problem commonly seen with these patients is the “on-off” oscillations in which daily motor activity is dominated by remarkable swings between off hours, when they are severely incapacitated, rigid, unable to move, and sometimes to speak or swallow, to on periods where they are responsive to L-DOPA and can, more or less, perform. The current treatments (apomorphine, lisuride) used to treat patients in the off period are unsatisfactory.
L-DOPA ethyl ester free base (LDEE) [10], a drug substance in phase III clinical trials for the treatment of Parkinson's disease, is a white, flowable, non-hygroscopic, crystalline powder with melting point of 87.1-87.5° C. It is stable at low temperature and low humidity, soluble in water (52 mg/ml), and its aqueous solution pH is 8.2. LDEE is more soluble than L-DOPA.
The properties of LDEE free base may, however, cause difficulties in pharmaceutical production such as the need for special conditions of storage. Processing of the pharmaceutical raw material has to be fast and performed at low temperature and low air humidity.
Thus, there is a need for a form of LDEE in addition to the free base, such as salts of LDEE. An advantage of a salt of LDEE over LDEE free base is that a salt has higher solubility and therefore usually provides better bioavailability of drug. High solubility is also important for preparation of injection dosage form; injection of LDEE as a salt may be an effective rescue therapy for patients with Parkinson's disease. Salts of LDEE may also provide a better stability profile than the free base.
However, salts are sometimes hygroscopic, therefore pharmaceutical solid form preparation may be very difficult. For instance, absorption of atmospheric humidity usually causes physical and chemical transformation of the drug product. L-DOPA ethyl ester itself is unstable in the presence of water due to hydrolysis to L-DOPA and ethanol. In the pharmaceutical industry, materials with hygroscopic point below 80% (j<80% RH) tend to be problematic and need special storage and processing techniques such as dry rooms and microencapsulation of the drug substance.
The only known salt of LDEE is the hydrochloride salt. The hydrochloride salt of LDEE is extremely hygroscopic [1,2]. The possibility of pharmaceutically acceptable acid salts of LDEE as candidates for pharmaceutical use (for a rectally absorbable form [3] and in the treatment of Alopecia [4]), have also been mentioned, but no example of practical preparation of such salts has ever been disclosed.
In addition, no quantitative data on LDEE salts, hygroscopicity, nor hygroscopic points have ever been measured. Conclusions about hygroscopicity have only been based on qualitative observations of solid materials exposed to atmosphere.
SUMMARY OF THE INVENTION
The subject invention provides a non-hygroscopic, crystalline salt of levodopa ethyl ester (LDEE), wherein the salt is the octanoate salt, the myristate salt, the succinate salt, the succinate dihydrate salt, the fumarate salt or the fumarate dihydrate salt of levodopa ethyl ester.
In addition, the subject invention encompasses a process for producing a salt of levodopa ethyl ester, which comprises:
(a) reacting levodopa ethyl ester with an acid, wherein the acid is octanoic acid, myristic acid, succinic acid or fumaric acid, so as to form a solution; and
(b) recovering the salt so formed
to produce a salt of levodopa ethyl ester.
DETAILED DESCRIPTION OF THE INVENTION
The subject invention provides a non-hygroscopic, crystalline salt of levodopa ethyl ester (LDEE), wherein the salt is the octanoate salt, the myristate salt, the succinate salt, the succinate dihydrate salt, the fumarate salt or the fumarate dihydrate salt of levodopa ethyl ester.
In one embodiment, the salt is the octanoate salt of levodopa ethyl ester.
In another embodiment, the salt is the myristate salt of levodopa ethyl ester.
In an additional embodiment, the salt is the succinate salt of levodopa ethyl ester.
In a further embodiment, the salt is the succinate dihydrate salt of levodopa ethyl ester.
In yet another embodiment, the salt is the fumarate salt of levodopa ethyl ester.
In an added embodiment, the salt is the fumarate dihydrate salt of levodopa ethyl ester.
The subject invention further provides a composition comprising the salt of levodopa ethyl ester and a carrier.
The subject invention also provides a pharmaceutical composition comprising the salt of levodopa ethyl ester (LDEE) in an amount sufficient to produce a therapeutically effective amount of levodopa (L-DOPA) and a pharmaceutically acceptable carrier.
Additionally, the subject invention provides a method for treating a subject suffering from a disease, wherein the disease is Parkinson's disease, senile dementia, dementia of the Alzheimer's type, a memory disorder, depression, hyperactive syndrome, an affective illness, a neurodegenerative disease, a neurotoxic injury, brain ischemia, a head trauma injury, a spinal trauma injury, schizophrenia, an attention deficit disorder, multiple sclerosis, withdrawal symptoms, epilepsy, convulsions or seizures comprising administering to the subject the non-hygroscopic, crystalline salt of levodopa ethyl ester (LDEE) in an amount sufficient to produce an amount of levodopa (L-DOPA) effective to treat the disease.
In one embodiment, the disease is Parkinson's disease.
In another embodiment, the amount of the salt of levodopa ethyl ester (LDEE) sufficient to produce a an amount of levodopa (L-DOPA) effective to treat the disease is an amount from 100 mg to 600 mg.
In a further embodiment, the amount of the salt of levodopa ethyl ester sufficient to produce a an amount of levodopa effective to treat the disease is an amount from 150 mg to 550 mg.
In an added embodiment, the amount of the salt of levodopa ethyl ester sufficient to produce a an amount of levodopa effective to treat the disease is an amount from 200 mg to 500 mg.
In still another embodiment, the amount of the salt of levodopa ethyl ester sufficient to produce a an amount of levodopa effective to treat the disease is an amount from 250 mg to 450 mg.
In one embodiment, the amount of the salt of levodopa ethyl ester sufficient to produce a an amo
Frenkel Anton
Lidor-Hadas Ramy
Cooper & Dunham LLP
Reyes Hector M.
Rotman Alan L.
Teva Pharmaceutical Industries Ltd.
White John P.
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