Phospholipid derivatives of valproic acid and mixtures thereof

Details Phospholipid derivatives of valproic acid and mixtures thereof Phospholipid derivatives of valproic acid and mixtures thereof

2000-07-12

2001-11-06

Carr, Deborah D. (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S076000, C514S114000, C514S117000, C514S143000, C514S144000, C514S526000, C554S078000, C554S079000, C554S080000

Reexamination Certificate

active

06313106

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds, which are phospholipid derivatives of valproic acid, to compositions comprising said compounds and their use for treating epilepsy, migraine, bipolar disorders and pain.
BACKGROUND OF THE INVENTION
Epilepsy is a neurological disease that is characterized by paroxysmal transient disturbances of the electrical activity of the brain. Epileptic seizures may be partial or focal seizures that are restricted to a particular locus within the brain, or generalized seizures which can result in abnormal activity throughout the brain. The disturbances of brain function during an epileptic attack may be manifested as psychic or sensory incidents such as amnesia, hallucinations, deja vu states etc., as abnormal motor phenomenon such as spasms or whole body convulsions or as loss of consciousness. In extreme cases, epilepsy can degenerate into status epilepticus which may be fatal (DeLorenzo et al.—J. Clin. Neurophysiol. (1995) 12: 316-325).
Valproic acid (VPA) and its sodium salt (sodium valproate, NaVPA) are among the most prescribed anti-epileptic drugs. These drugs are also effective in the treatment of bipolar disorders and in prophylaxis of migraines.
Although the clinical usefulness of valproic acid is well established, this compound suffers major drawbacks. Treatment with VPA is associated with adverse side effects such as gastro-intestinal irritation, bone marrow suppression (especially manifested as aplastic anemia and thrombocytopenia), and hepatic dysfunction. VPA has also been reported to have teratogenic effects and patients treated with VPA may experience nausea, vomiting, dizziness, confusion or sedation.
Another drawback of valproic acid is its short half-life due to rapid clearance of the drug. As a result plasma levels of VPA fluctuate during chronic treatment and the drug has to be administered several times a day even as a sustained release formulation. In addition, valproic acid, which is a liquid, is less desirable for use as an oral dosage form. The sodium valproate, on the other hand, is solid, but being hygroscopic is characterized by poor stability.
Efforts have been made in order to overcome the VPA-induced side effects and the disadvantageous physical and pharmacokinetic properties of the drug. Most approaches that have been taken involve modification of the VPA molecule. However, although some of the modified drugs were devoid of adverse side effects, in many cases they also lost the therapeutic effect or were much less potent.
Mergen et al (J. Pharm. Pharmacol. (1991), 43: 815-816) describe conjugates of valproic acid with 1,3-dipalmitoylglycerol, 1,2-dipalmitoylglycerol or 1,3-diaminopalmitoyl-propan-2-ol. According to the Mergen et al.'s publication, only the latter compound was found to have antiepileptic activity, while both conjugates of VPA with the diglycerides were inactive.
Hadad et al. (Biopharmaceutics & Drug Disposition (1993), 14: 51-59) investigated the anticonvulsant activity of 1,4-butanediol divalproate, glyceryl trivalproate and valpromide in comparison to valproic acid. Their study demonstrated that only 1,4-butanediol divalproate, in one of the model systems tested, had a better protective index value than VPA.
U.S. Pat. No. 4,654,370 to Marriott and Paris discloses glycerides esterified with one or two moles of valproic acid. These compounds have been found to have the same useful therapeutic effect as valproic acid alone but without causing gastric irritation.
U.S. Pat. Nos. 4,988,731 and 5,212,326 both to Meade, disclose oligomers having 1:1 molar ratio of sodium valproate and valproic acid which have physiological properties similar to those of valproic acid or sodium valproate but show superior stability characteristics.
U.S. Pat. No. 4,558,070 to Bauer and Shada discloses a stable complex between valproic acid and potassium, cesium or rubidium which may be formed by combining four moles of valproic acid with one mole of the alkali metal ion. The alkali metal salts of valproic acid were reported to have improved stability.
Despite continuous efforts in the field, it is still an unmet need to provide an anti-epileptic medication with improved pharmacokinetic properties and overall superior therapeutic index.
SUMMARY OF THE INVENTION
The present invention provides pharmaceutical compositions comprising, as an active ingredient, a compound comprising valproic acid or a pharmaceutically acceptable derivative thereof which is covalently bonded to a phospholipid moiety. In preferred embodiments of the invention, the phospholipid moiety is selected from plasmalogens, phosphatidic acids and phosphoglycerides. More preferred are compounds, wherein said phospholipid moiety is lysophosphatidyl-ethanolamine, N-mono-(C
1-4
)-alkyl, N,N-di-(C
1-4
)-alkyl and quaternary derivatives of the amines thereof.
Most preferred embodiments, in accordance with the invention, are compositions comprising phospholipid derivatives of valproic acid (hereinafter referred to as DP-VPA) wherein valproic acid is covalently linked as an ester at the sn-2 position of a phospholipid moiety.
Currently the most preferred DP-VPA compounds are 1-Palmitoyl-2-valproyl-sn-glycero-3-phosphatidylcholine, also referred to as 1-hexadecanoyl-sn-glycero-3-phosphorylcholine (hereinafter denoted as C
16
-DP-VPA) and 1-Stearoyl-2-valproyl-sn-glycero-3-phosphatidylcholine, also referred to as 1-octadecanoyl-sn-glycero-3-phosphorylcholine (hereinafter denoted as C
18
-DP-VPA).
According to preferred embodiments of the present invention, the pharmaceutical compositions comprise a mixture of DP-VPA compounds, more preferably a mixture of C
16
-DP-VPA and C
18
-DP-VPA (hereinafter denoted as C
16
/C
18
-DP-VPA).
In one preferred embodiment the ratio of C
16
-DP-VPA to C
18
-DP-VPA in the C
16
/C
18
-DP-VPA mixture is from around 1:20 to around 1:2 by weight. Most preferred are mixtures wherein the ratio of C
16
-DP-VPA to C
18
-DP-VPA is from around 1:5 to around 1:7 w/w (equivalent to 15±5% C
16
-DP-VPA: 85±5% C
18
-DP-VPA (w/w)).
The compounds and compositions of the invention are useful for the treatment of central nervous system disorders including, but not limited to, epilepsy, migraines, chronic pain and bipolar disorders.
Thus, according to yet another embodiment of the present invention, there is provided a method for the treatment of a central nervous system disorder in a subject, comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutical composition in accordance with the invention.
Further objects of the present invention will become apparent to those skilled in the art upon further review of the following disclosure, including the detailed descriptions of specific embodiments of the invention.


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