Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1999-03-02
2000-08-29
Jones, Dwayne C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544360, A01N 4360, A61K 31495
Patent
active
061109185
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The invention is directed to the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one (hereafter "ziprasidone mesylate trihydrate"), pharmaceutical compositions containing ziprasidone mesylate trihydrate, and methods of administering ziprasidone mesylate trihydrate to treat psychotic diseases. Ziprasidone is a potent psychotic agent and is therefore useful for treating various disorders including schizophrenia, migraine pain and anxiety. U.S. Pat. No. 5,312,925 refers to ziprasidone hydrochloride monohydrate, and states that ziprasidone hydrochloride monohydrate is substantially hygroscopically stable, which alleviates potential problems associated with weight changes of the active ingredient during the manufacture of capsules or tablets. U.S. Pat. No. 5,312,925 is herein incorporated by reference in its entirey. Ziprasidone hydrochloride monohydrate, however, has low aqueous solubility and, as a result, is more appropriate for capsule or tablet formulation than for injectable dosage forms.
Ziprasidone mesylate trihydrate also possesses hygroscopic stability. Ziprasidone mesylate trihydrate has the added advantage of having significantly greater aqueous solubility than the hydrochloride monohydrate, which makes the mesylate trihydrate more suitable for injectable dosage forms than the hydrochloride monohydrate. Further, of the four crystalline forms of ziprasidone mesylate, the mesylate trihydrate is the most thermodynamically stable in an aqueous medium at ambient conditions. This makes ziprasidone mesylate trihydrate advantageously suited for the preparation of consistent and precise dosage forms involving an aqueous medium.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one.
This invention also relates to a pharmaceutical composition for the treatment of a psychotic disorder, such as schizophrenia, migraine pain or anxiety, comprising an amount of the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one that is effective in treating said disorder, and a pharmaceutically acceptable carrier.
This invention also relates to a method of treating a psychotic disorder, such as schizophrenia, migraine pain or anxiety, in a mammal, including a human, comprising administering to said mammal an amount of the mesylate trihydrate salt of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)ethyl)-6-chloro-1,3-dihydr o-2H-indol-2-one that is effective in treating said disorder.
BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS
FIG. 1 depicts the X-ray powder diffraction spectrum of ziprasidone mesylate trihydrate expressed as intensity (Cps) versus diffraction angle (two-theta degrees).
FIG. 2 depicts the structure of ziprasidone mesylate trihydrate as determined by single crystal X-ray crystallographic analysis.
FIG. 3 shows a photomicrograph of ziprasidone mesylate trihydrate (prism crystals).
Table 1 below identifies selected peaks from the spectra of FIG. 1 by diffraction angle (two-theta), d-spacing, maximum intensity (max. int.), and relative intensity (rel. int.).
TABLE 1 ______________________________________
X-RAY POWDER DIFFRACTION DATA FOR
ZIPRASIDONE MESYLATE TRIHYDRATE
Two-Theta D-spacing Max. Int.
(degrees) (degrees) (counts/sec) Rel. Int.(%)
______________________________________
7.680 11.5025 84.00 8.54
9.657 9.1515 216.00 21.95
10.827 8.1650 48.00 4.88
12.205 7.2455 216.00 21.95
13.203 6.7002 803.00 81.61
13.564 6.5227 329.00 33.43
15.240 5.8089 191.00 19.41
15.507 5.7095 388.00 39.43
15.923 5.5612 836.00 84.96
16.680 5.3106 100.00 10.16
17.000 5.2112 103.00 10.47
17.946 4.9386 428.00 43.50
18.794 4.7178 383.00 38.92
19.881 4.4622 195.00 19.82
20.491 4.3306 93.00 9.45
21.585 4.1136 603.00 61.28
22.179 4.0047 984.00 100.00
23.472 3
REFERENCES:
patent: 5312925 (1994-05-01), Allen et al.
Howard et al., Journal of Medicinal Chemistry, vol. 39, No. 1, Jan. 5, 1996, pp. 143-148.
Howard H.R., et al., (1996) 3-Benzisothiazolylpiperazine Derivatives as Potential Atypical Antipsychotic Agents, Journal of Medicinal Chemistry, vol. 39, pp. 143-148.
Busch Frank R.
Rose Carol A.
Ginsburg Paul H.
Jones Dwayne C.
Konstas Kristina L.
Pfizer Inc
Richardson Peter C.
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