Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2001-07-09
2002-10-01
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S573000, C514S913000
Reexamination Certificate
active
06458836
ABSTRACT:
DESCRIPTION
BACKGROUND OF THE INVENTION
The present invention relates to the long-term treatment and prophylactic management of intraocular pressure in human patients. Further, the present invention relates to a composition useful for said treatment and management. Further more, the present invention relates to use of a specific compound for manufacturing said pharmaceutical composition. More specifically, the present invention relates to the long term management of hypertension or glaucoma in the eyes of human patients, without causing pigmentation or with causing comparatively minimal pigmentation of the iris, by periodic topical ocular application of a prostaglandin related compound.
Prostaglandins (hereinafter, referred to as PG(s)) are members of a class of organic carboxylic acids, which are contained in tissues or organs of human and most other animals, and exhibit a wide range of physiological activity. PGs found in nature (primary PGs) generally have a prostanoic acid skeleton as shown in the formula (A):
On the other hand, some of the synthetic analogues of primary PGs have a modified skeleton. The primary PGs are classified to PGAs, PGBs, PGCs, PGDs, PGEs, PGFs, PGGs, PGHs, PGIs and PGJs according to the structure of the five-membered ring moiety, and further classified into the following three types by the number and position of the unsaturated bond at the carbon chain moiety:
Subscript 1: 13,14-unsaturated-15-OH
Subscript 2: 5,6- and 13,14-diunsaturated-15-OH
Subscript 3: 5,6-, 13,14-, and 17,18-triunsaturated-15-OH.
Further, the PGFs are classified, according to the configuration of the hydroxyl group at the 9-position, into &agr; type (the hydroxyl group is of an &agr;-configuration) and &bgr; type (the hydroxyl group is of a &bgr;-configuration).
In addition, some 15-keto (i.e. having an oxo group at position 15 in place of the hydroxy group) prostaglandins and 13,14-dihydro-15-keto-prostaglandins are known as substances naturally produced by enzymatic reactions during in vivo metabolism of primary PGs. 15-keto PGs have been disclosed in, for example, EP-A-0281239, EP-A-0281480, EP-A-0289349, EP-A-0453127 and EP-A-0690049. These cited references are herein incorporated by reference.
At present, Latanoprost is available commercially in the United States for use as a topical ocular hypotensive and an anti-glaucoma agent. Chemically, Latanoprost is a 13,14-dihydro-17-phenyl-18,19,20-trinor PGF
2&agr;
isopropyl ester. One side effect of Latanoprost is a brown pigmentation of the iris found in about 10% or more of the human patients treated with Latanoprost for about three or more months for management of elevated intraocular pressure. Latanoprost possesses a substantial specific binding affinity for the FP receptor. Selen et al have reported that PGF
2
&agr;-IE, PGE
2
-IE and latanoprost induced increased iridial pigmentation in cynomolgus monkeys (Survey of Ophthalmology, 41, supplement 2, S125-S128 (1997)). (“IE” means isopropyl ester.)
Unoprostone isopropyl ophthalmic solution (Rescula®) has been commercially available outside Europe and the United States for topical application in the treatment of ocular hypertension and glaucoma. Unoprostone isopropyl is a docosanoid, namely 13,14-dihydro-15-keto-20-ethyl PGF
2&agr;
isopropyl ester. To the inventor's best knowledge, Resucla® has not been commercially used by Caucasians in the management of ocular hypertension or glaucoma by its periodic topical application to the eye at least once a day for a period of at least six months, more than one year prior to the filing date of this application. Preliminary results regarding no iridic pigmentation from a long-term monkey trial with Unoprostone isopropyl have been published. Resucla® exhibits substantial absence of FP receptor stimulatory activity.
15-keto-latanoprost (13,14-dihydro-15-keto-17-phenyl-18, 19, 20-trinor PGF
2&agr;
isopropyl ester) is a promising candidate for use as a topical ocular hypotensive drug. Short-term studies of its use have been reported in U.S. Pat. No. 5,321,128.
SUMMARY OF THE INVENTION
The present invention provides methods for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients without causing pigmentation or with causing less pigmentation than latanoprost of the patient's iris, by periodic topical administration of a prostaglandin related compound.
The present invention also provides a composition suitable for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients by periodic topical ocular administration, which comprises a prostaglandin related compound as an active ingredient.
The present invention also provides use of a prostaglandin related compound for producing a pharmaceutical composition suitable for the long-term treatment and prophylactic management of ocular hypertension and glaucoma in human patients by periodic topical ocular administration.
According to the present invention, the term “prostaglandin related compound” (hereinafter, referred as “PG related compound”) includes any of derivatives or analogs (including substituted derivatives) of a compound having the prostanoic acid basic structure irrespective of the configuration of the 5-membered ring, number of double bonds in the &agr; or &ohgr;-chain, presence or absence of hydroxy and oxo groups or any other substituent, or any other modification.
The nomenclature of the PG related compounds used herein is based on the numbering system of the prostanoic acid skeleton represented in the above formula (A).
The formula (A) shows a basic skeleton of 20 carbon atoms, but the PG related compounds in the present invention are not limited to those having a 20 carbon atom skeleton. In the formula (A), the numbering of the carbon atoms which constitute the basic skeleton of the PG compounds starts at the carboxylic acid (numbered 1), and carbon atoms in the &agr;-chain are numbered 2 to 7 towards the five-membered ring, those in the ring are 8 to 12, and those in the &ohgr;-chain are 13 to 20. When the number of carbon atoms is decreased in the &agr;-chain, the number is deleted in the order starting from position 2; and when the number of carbon atoms is increased in the &agr;-chain, compounds are named as substitution compounds having respective substituents at position 2 in place of carboxy group (C-1). Similarly, when the number of carbon atoms is decreased in the &ohgr;-chain, the number is deleted in the order starting from position 20; and when the number of carbon atoms is increased in the &ohgr;-chain, the carbon atoms beyond position 20 are named as substituents. Stereochemistry of the compounds is the same as that of the above formula (A) unless otherwise specified.
In general, each of the terms PGD, PGE and PGF represents PG compounds having hydroxy group (s) at positions 9 and/or 11, but in the present specification, these terms also include those PG related compounds having substituents other than the hydroxy group at positions 9 and/or 11 . Such compounds are referred to as 9-dehydroxy-9-substituted-PG compounds or 11-dehydroxy-11-substituted-PG compounds. A PG compound having hydrogen in place of the hydroxy group is simply named as 9- or 11-dehydroxy compound.
As stated above, the nomenclature of the PG related compounds is based on the prostanoic acid skeleton. However, in case the compound has a similar partial construction as a prostaglandin, the abbreviation of “PG” may be used. Thus, a PG compound of which &agr;-chain is extended by two carbon atoms; that is, having 9 carbon atoms in the &agr;-chain, is named as 2-decarboxy-2- (2-carboxyethyl)-PG compound. Similarly, a PG compound having 11 carbon atoms in the &agr;-chain is named as 2-decarboxy-2-(4-carboxybutyl)-PG compound, and a PG compound having 10 carbon atoms in the &ohgr;-chain is named as 20-ethyl-PG compound. These compounds, however, may also be named according to the IUPAC nomenclatures.
The PG related compounds used in the present invention may include any of PG derivatives or a
Fay Zohreh
Sucampo A.G.
Sughrue & Mion, PLLC
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