U.S. patent application number 09/957107 was filed with the patent office on 2002-06-27 for 3-heteroatom substituted and two carbon homologs of 15-hete and methods of use.
Invention is credited to Graff, Gustav, Hellberg, Mark R., Klimko, Peter G..
Application Number | 20020082286 09/957107 |
Document ID | / |
Family ID | 22594175 |
Filed Date | 2002-06-27 |
United States Patent
Application |
20020082286 |
Kind Code |
A1 |
Klimko, Peter G. ; et
al. |
June 27, 2002 |
3-heteroatom substituted and two carbon homologs of 15-HETE and
methods of use
Abstract
3-heteroatom substituted and two carbon homologs of 15-HETE, and
their derivatives, compositions and methods of their use for
treating dry eye are disclosed.
Inventors: |
Klimko, Peter G.; (Fort
Worth, TX) ; Hellberg, Mark R.; (Arlington, TX)
; Graff, Gustav; (Cleburne, TX) |
Correspondence
Address: |
ALCON RESEARCH, LTD.
R&D COUNSEL, Q-148
6201 SOUTH FREEWAY
FORT WORTH
TX
76134-2099
US
|
Family ID: |
22594175 |
Appl. No.: |
09/957107 |
Filed: |
September 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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09957107 |
Sep 20, 2001 |
|
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09694613 |
Oct 23, 2000 |
|
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60164368 |
Nov 9, 1999 |
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Current U.S.
Class: |
514/381 ;
514/513; 514/549; 514/625 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 27/04 20180101; C07C 59/60 20130101; C07C 59/42 20130101 |
Class at
Publication: |
514/381 ;
514/549; 514/625; 514/513 |
International
Class: |
A61K 031/41; A61K
031/21; A61K 031/22; A61K 031/16 |
Claims
What is claimed is:
1. A composition for the treatment of dry eye and other disorders
requiring the wetting of the eye comprising a pharmaceutically
acceptable carrier and a pharmaceutically effective amount of one
or more compounds of the following formula I: 10wherein: R.sup.1 is
(CH.sub.2).sub.nCO.sub.2R, (CH.sub.2).sub.nCONR.sup.2R.sup.3,
(CH.sub.2).sub.nCH.sub.2OR.sup.4,
(CH.sub.2).sub.nCH.sub.2NR.sup.5R.sup.6- ,
(CH.sub.2).sub.nCH.sub.2N.sub.3, (CH.sub.2).sub.nCH.sub.2Hal,
(CH.sub.2).sub.nCH.sub.2NO.sub.2,
(CH.sub.2).sub.nCH.sub.2SR.sup.20, (CH.sub.2).sub.nCOSR.sup.21 or
(CH.sub.2).sub.n-2,3,4,5-tetrazol-1-yl, wherein: R is H or
CO.sub.2R forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; is NR.sup.2R.sup.3 and
NR.sup.5R.sup.6 are the same or different and comprise a free or
functionally modified amino group; OR.sup.4 comprises a free or
functionally modified hydroxy group; Hal is F, Cl,Bror I; SR.sup.20
comprises a free or functionally modified thiol group; R.sup.21 is
H or COSR.sup.21 forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable thioester; n is 0 or 2; X is O,
S(O).sub.p, NR.sup.7 or CH.sub.2, with the proviso that X cannot be
CH.sub.2 when n is 0; p is 0, 1 or 2; NR.sup.7 comprises a free or
functionally modified amino group; A-B, D-E, G-T and J-K are the
same or different and are CH.sub.2CH.sub.2, CH.dbd.CH or C.ident.C,
with the proviso that at least one of A-B, D-E, G-T and J-K must be
CH.dbd.CH or C.ident.C; and Y is C(O) (i.e., a carbonyl), or Y is
11 wherein R.sup.9O constitutes a free or functionally modified
hydroxy group.
2. The composition of claim 1, wherein for the compound of formula
I: R.sup.i is (CH.sub.2).sub.nCO.sub.2R, wherein R is H or
CO.sub.2R forms an ophthalmically acceptable salt or an
ophthalmically acceptable ester; X is O or CH.sub.2, with the
proviso that X cannot be CH.sub.2 when n is 0; and Y is 12
3. The composition of claim 2, wherein the compound of formula (I)
is selected from the group consisting of: 13
4. The composition of claim 1, wherein the composition is a topical
ophthalmic formulation.
5. A method for the treatment of dry eye and other disorders
requiring the wetting of the eye which comprises administering to a
mammal a composition comprising a pharmaceutically acceptable
carrier and a pharmaceutically effective amount of one or more
compounds of the following formula I: 14wherein: R.sup.1 is
(CH.sub.2).sub.nCO.sub.2R, (CH.sub.2).sub.nCONR.sup.2R.sup.3,
(CH.sub.2).sub.nCH.sub.2OR.sup.4,
(CH.sub.2).sub.nCH.sub.2NR.sup.5R.sup.6,
(CH.sub.2).sub.nCH.sub.2N.sub.3, (CH.sub.2).sub.nCH.sub.2Hal,
(CH.sub.2).sub.nCH.sub.2NO.sub.2,
(CH.sub.2).sub.nCH.sub.2SR.sup.20, (CH.sub.2).sub.nCOSR.sup.21 or
(CH.sub.2).sub.n-2,3,4,5-tetrazol-1-yl, wherein: R is H or
CO.sub.2R forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; NR.sup.2R.sup.3 and
NR.sup.5R.sup.6 are the same or different and comprise a free or
functionally modified amino group; OR.sup.4 comprises a free or
functionally modified hydroxy group; Hal is F, Cl, Br or I;
SR.sup.20 comprises a free or functionally modified thiol group;
R.sup.21 is H or COSR.sup.21 forms a pharmaceutically acceptable
salt or a pharmaceutically acceptable thioester; n is 0 or2; X is
O, S(O).sub.p, NR.sup.7 or CH.sub.2, with the proviso that X cannot
be CH.sub.2 when n is 0; p is 0, 1 or 2; NR.sup.7 comprises a free
or functionally modified amino group; A-B, D-E, G-T and J-K are the
same or different and are CH.sub.2CH.sub.2, CH.dbd.CH or C.ident.C,
with the proviso that at least one of A-B, D-E, G-T and J-K must be
CH.dbd.CH or C.ident.C; and Y is C(O) (i.e., a carbonyl), or Y is
15 wherein R.sup.9O constitutes a free or functionally modified
hydroxy group.
6. The method of claim 5, wherein for the compound of formula I:
R.sup.1 is (CH.sub.2).sub.nCO.sub.2R, wherein R is H, or CO.sub.2R
forms an ophthalmically acceptable salt or an ophthalmically
acceptable ester; X is O or CH.sub.2, with the proviso that X
cannot be CH.sub.2 when n is 0; and Y is 16
7. The method of claim 5, wherein the compound of formula (I) is
selected from the group consisting of: 17
8. The method of claim 5, wherein the composition is a topical
ophthalmic formulation.
9. The method of claim 5 wherein the dry eye and other disorders
requiring the wetting of the eye is symptoms of dry eye associated
with refractive surgery.
10. A compound of formula I: 18wherein: R.sup.1 is
(CH.sub.2).sub.nCO.sub.2R, (CH.sub.2).sub.nCONR.sup.2R.sup.3,
(CH.sub.2).sub.nCH.sub.2OR.sup.4,
(CH.sub.2).sub.nCH.sub.2NR.sup.5R.sup.6- ,
(CH.sub.2).sub.nCH.sub.2N.sub.3, (CH.sub.2).sub.nCH.sub.2Hal,
(CH.sub.2).sub.nCH.sub.2NO.sub.2,
(CH.sub.2).sub.nCH.sub.2SR.sup.20, (CH.sub.2).sub.nCOSR.sup.21 or
(CH.sub.2).sub.n,-2,3,4,5-tetrazol-1-yl, wherein: R is H or
CO.sub.2R forms a pharmaceutically acceptable salt or a
pharmaceutically acceptable ester; NR.sup.2R.sup.3 and
NR.sup.5R.sup.6 are the same or different and comprise a free or
functionally modified amino group; OR.sup.4 comprises a free or
functionally modified hydroxy group; Hal is F, Cl, Br or I;
SR.sup.20 comprises a free or functionally modified thiol group;
R.sup.21 is H or COSR.sup.21 forms a pharmaceutically acceptable
salt or a pharmaceutically acceptable thioester; n is 0or 2; X is
O, S(O).sub.p, NR.sup.7 or CH.sub.2, with the proviso that X cannot
be CH.sub.2 when n is 0; p is 0, 1 or2; NR.sup.7 comprises a free
or functionally modified amino group; A-B, D-E, G-T and J-K are the
same or different and are CH.sub.2CH.sub.2, CH.dbd.CH or C.ident.C,
with the proviso that at least one of A-B, D-E, G-T and J-K must be
CH.dbd.CH or C.ident.C; and Y is C(O) (i.e., a carbonyl), or Y is
19 wherein R.sup.9O constitutes a free or functionally modified
hydroxy group; with the proviso that the compound of formula (I) is
excluded: 20
11. The compound of Claim 10, wherein for the compound of formula
I: R.sup.1 is (CH.sub.2).sub.nCO.sub.2R, wherein R is H or
CO.sub.2R forms an ophthalmically acceptable salt or an
ophthalmically acceptable ester; X is O or CH.sub.2, with the
proviso that X cannot be CH.sub.2 when n is 0; and Y is 21
12. The compound of claim 10, wherein the compound of formula (I)
is selected from the group consisting of: 22
Description
[0001] This application claims priority to co-pending U.S.
Provisional Application, U.S. Ser. No. 60/164,368, filed Nov. 9,
1999.
[0002] The present invention is directed to novel
hydroxyeicosatetraenoic acid related compounds, compositions and
methods of use. The compounds are particularly useful in treating
dry eye.
BACKGROUND OF THE INVENTION
[0003] Dry eye, also known generically as keratoconjunctivitis
sicca, is a common ophthalmological disorder affecting millions of
Americans each year. The condition is particularly widespread among
post-menopausal women due to hormonal changes following the
cessation of fertility. Dry eye may afflict an individual with
varying severity. In mild cases, a patient may experience burning,
a feeling of dryness, and persistent irritation such as is often
caused by small bodies lodging between the eye lid and the eye
surface. In severe cases, vision may be substantially impaired.
Other diseases, such as Sjogren's disease and cicatricial
pemphigoid manifest dry eye complications.
[0004] Although it appears that dry eye may result from a number of
unrelated pathogenic causes, all presentations of the complication
share a common effect, that is the breakdown of the pre-ocular tear
film, which results in dehydration of the exposed outer surface and
many of the symptoms outlined above (Lemp, Report of the National
Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The
CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
[0005] Practitioners have taken several approaches to the treatment
of dry eye. One common approach has been to supplement and
stabilize the ocular tear film using so-called artificial tears
instilled throughout the day. Other approaches include the use of
ocular inserts that provide a tear substitute or stimulation of
endogenous tear production.
[0006] Examples of the tear substitution approach include the use
of buffered, isotonic saline solutions, aqueous solutions
containing water soluble polymers that render the solutions more
viscous and thus less easily shed by the eye. Tear reconstitution
is also attempted by providing one or more components of the tear
film such as phospholipids and oils. Phospholipid compositions have
been shown to be usefull in treating dry eye; see, e.g., McCulley
and Shine, Tear film structure and dry eye, Contactologia, volume
20(4), pages 145-49 (1998); and Shine and McCulley,
Keratoconjunctivitis sicca associated with meibomian secretion
polar lipid abnormality, Archives of Ophthalmology, volume 116(7),
pages 849-52 (1998). Examples of phospholipid compositions for the
treatment of dry eye are disclosed in U.S. Pat. Nos. 4,131,651
(Shah et al.), 4,370,325 (Packman), 4,409,205 (Shively), 4,744,980
and 4,883,658 (Holly), 4,914,088 (Glonek), 5,075,104 (Gressel et
al.), 5,278,151 (Korb et al.), 5,294,607 (Glonek et al.), 5,371,108
(Korb et al.) and 5,578,586 (Glonek et al.). U.S. Pat. No.
5,174,988 (Mautone et al.) discloses phospholipid drug delivery
systems involving phospholipids, propellants and an active
substance.
[0007] U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of
ocular inserts in the treatment of dry eye. Other semi-solid
therapy has included the administration of carrageenans (U.S. Pat.
No. 5,403,841, Lang) which gel upon contact with naturally
occurring tear film.
[0008] Another approach involves the provision of lubricating
substances in lieu of artificial tears. For example, U.S. Pat. No.
4,818,537 (Guo) discloses the use of a lubricating, liposome-based
composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses
compositions containing glycerin and propylene glycol for treating
dry eye.
[0009] Aside from the above efforts, which are directed primarily
to the alleviation of symptoms associated with dry eye, methods and
compositions directed to treatment of the dry eye condition have
also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin)
discloses the use of sex steroids, such as conjugated estrogens, to
treat dry eye condition in post-menopausal women; U.S. Pat. No.
5,290,572 (MacKeen) discloses the use of finely divided calcium ion
compositions to stimulate pre-ocular tear film production; and U.S.
Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine
particles of one or more retinoids for ocular tissue
normalization.
[0010] Although these approaches have met with some success,
problems in the treatment of dry eye nevertheless remain. The use
of tear substitutes, while temporarily effective, generally
requires repeated application over the course of a patient's waking
hours. It is not uncommon for a patient to have to apply artificial
tear solution ten to twenty times over the course of the day. Such
an undertaking is not only cumbersome and time consuming, but is
also potentially very expensive. Transient symptoms of dry eye
associated with refractive surgery have been reported to last in
some cases from six weeks to six months or more following
surgery.
[0011] The use of ocular inserts is also problematic. Aside from
cost, they are often unwieldy and uncomfortable. Further, as
foreign bodies introduced in the eye, they can be a source of
contamination leading to infections. In situations where the insert
does not itself produce and deliver a tear film, artificial tears
must still be delivered on a regular and frequent basis.
[0012] Mucins are proteins which are heavily glycosylated with
glucosamine-based moieties. Mucins provide protective and
lubricating effects to epithelial cells, especially those of
mucosal membranes. Mucins have been shown to be secreted by
vesicles and discharged on the surface of the conjunctival
epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles
in Conjunctival Epithelial Cells of Wearers of Contact Lenses,
Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and
Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in
Man, with Special Reference to the Production of Mucous from a
Non-Goblet-Cell Source, British Journal of Ophthalmology, volume
65, pages 833-842 (1981)). A number of human-derived mucins which
reside in the apical and subapical corneal epithelium have been
discovered and cloned (Watanabe et al., Human Corneal and
Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the
Apical Surface, Investigative Ophthalmology and Visual Science,
volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe
discovered a new mucin which is secreted via the cornea apical and
subapical cells as well as the conjunctival epithelium of the human
eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344
(1995)). These mucins provide lubrication, and additionally attract
and hold moisture and sebaceous material for lubrication and the
corneal refraction of light.
[0013] Mucins are also produced and secreted in other parts of the
body including lung airway passages, and more specifically from
goblet cells interspersed among tracheal/bronchial epithelial
cells. Certain arachidonic acid metabolites have been shown to
stimulate mucin production in these cells. Yanni reported the
increased secretion of mucosal glycoproteins in rat lung by
hydroxyeicosatetraenoic acid ("HETE") derivatives (Yanni et al,
Effect of Intravenously Administered Lipoxygenase Metabolites on
Rat Trachael Mucous Gel Layer Thickness, International Archives of
Allergy And Applied Immunology, volume 90, pages 307-309 (1989)).
Similarly, Marom has reported the production of mucosal
glycoproteins in human lung by HETE derivatives (Marom et al.,
Human Airway Monohydroxy-eicosatetraenoic Acid Generation and
Mucous Release, Journal of Clinical Investigation, volume 72, pages
122-127 (1983)).
[0014] Agents claimed for increasing ocular mucin and/or tear
production include vasoactive intestinal polypeptide (Dartt et.
al., Vasoactive intestinal peptide-stimulated glycocongjugate
secretion from conjunctival goblet cells, Experimental Eye
Research, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et.
al., Gefarnate stimulates secretion of mucin-like glycoproteins by
corneal epithelium in vitro and protects corneal epithelium from
dessication in vivo, Experimental Eye Research, volume 65, pages
569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens
(U.S. Patent No. 5,620,921), melanocycte stimulating hormones (U.S.
Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No.
4,753,945), and retinoids (U.S. Pat. No. 5,455,265). However, many
of these compounds or treatments suffer from a lack of specificity,
efficacy and potency and none of these agents have been marketed so
far as therapeutically useful products to treat dry eye and related
ocular surface diseases.
[0015] U.S. Pat. No. 5,696,166 (Yanni et al.) discloses
compositions containing naturally occurring HETEs, or derivatives
thereof, and methods of use for treating dry eye. Yanni et al.
discovered that compositions comprising HETEs increase ocular mucin
secretion when administered to a patient and are thus useful in
treating dry eye.
[0016] 3-oxa prostaglandins have been prepared in order to prolong
duration of action for the dosed compound by prevention of the
.beta.-oxidation metabolism pathway (Buchmann et. al., Tetrahedron
Lett., volume 31, page 3425 (1990)). Similarly, attachment of a two
carbon extension of the .alpha. chain allows one cycle of the
.beta.-oxidation metabolism pathway to yield the active compound.
The compound of formula (II) has been reported in Haviv, F.; et.
al. J. Med. Chem., volume 30, page 254 (1987)). This compound,
however, has not been reported to be useful for the treatment of
dry eye. 1
[0017] In view of the foregoing, there is a need for an effective,
convenient treatment for dry eye that is capable of alleviating
symptoms, as well as treating the underlying physical and
physiological deficiencies of dry eye.
SUMMARY OF THE INVENTION
[0018] The present invention is directed to compounds, compositions
and methods of use. The present invention is particularly directed
to compositions and methods for the treatment of dry eye and other
disorders requiring the wetting of the eye, including symptoms of
dry eye associated with refractive surgery such as LASIK surgery.
More specifically, the present invention discloses ophthalmic
compositions containing 3-heteroatom substituted and two carbon
extended analogs of
(5Z,8Z,11Z,13E)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid
(15-HETE) and certain derivatives, compositions and methods of use.
The compositions are preferably administered topically to the
eye.
[0019] The compounds of the present invention are believed to be
more stable than the naturally occurring HETE-related
compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0020] The present invention is directed to novel 3-heteroatom
substituted and two carbon homolog congeners of 15-HETE and their
analogs derivatives, compositions and methods of use. It is
believed that, among other utilities, the compounds stimulate
ocular mucin production and/or secretion following topical ocular
application and are therefore believed to be useful in treating dry
eye. These 2
[0021] compounds are of formula I:
[0022] wherein:
[0023] R.sup.1 is (CH.sub.2).sub.nCO.sub.2R,
(CH.sub.2).sub.nCONR.sup.2R.s- up.3,
(CH.sub.2).sub.nCH.sub.2OR.sup.4,
(CH.sub.2).sub.nCH.sub.2NR.sup.5R.- sup.6,
(CH.sub.2).sub.nCH.sub.2N.sub.3, (CH.sub.2).sub.nCH.sub.2Hal,
(CH.sub.2).sub.nCH.sub.2NO.sub.2,
(CH.sub.2).sub.nCH.sub.2SR.sup.20, (CH.sub.2).sub.nCOSR.sup.21 or
(CH.sub.2).sub.n-2,3,4,5-tetrazol-1-yl, wherein:
[0024] R is H or CO.sub.2R forms a pharmaceutically acceptable salt
or a pharmaceutically acceptable ester;
[0025] NR.sup.2R.sup.3 and NR.sup.5R.sup.6 are the same or
different and comprise a free or functionally modified amino group,
e.g., R.sup.2, R.sup.3, R.sup.5 and R.sup.6 are the same or
different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or
alkoxy, with the proviso that at most only one of R.sup.2 and
R.sup.3 are OH or alkoxy and at most only one of R.sup.5 and
R.sup.6 are OH or alkoxy;
[0026] OR.sup.4 comprises a free or functionally modified hydroxy
group, e.g., R.sup.4 is H, acyl; alkyl, cycloalkyl, aralkyl, or
aryl;
[0027] Hal is F, Cl, Br or I;
[0028] SR.sup.20 comprises a free or functionally modified thiol
group;
[0029] R.sup.21 is H or COSR.sup.21 forms a pharmaceutically
acceptable salt or a pharmaceutically acceptable thioester;
[0030] n is 0 or 2;
[0031] X is O, S(O).sub.p, NR.sup.7 or CH.sub.2, with the proviso
that X cannot be CH.sub.2 when n is 0;
[0032] is 0, 1 or 2;
[0033] NR.sup.7 comprises a free or functionally modified amino
group, e.g., R.sup.7 is H, alkyl, cycloalkyl, aralkyl, aryl, OH or
alkoxy,
[0034] A-B, D-E, G-T and J-K are the same or different and are
CH.sub.2CH.sub.2, CH.dbd.CH or C.ident.C, with the proviso that at
least one of A-B, D-E, G-T and J-K must be CH.dbd.CH or C.ident.C;
and
[0035] Y is C(O) (i.e., a carbonyl), or Y is 3
[0036] wherein R.sup.9O constitutes a free or functionally modified
hydroxy group.
[0037] The compounds of formula (I) are novel with the exception of
the compound of formula (II): 4
[0038] The compounds of formula (I) may also be incorporated into
phospholipids as glyceryl esters or sphingomyelin amides.
Phospholipid sphingomyelin amides of the compounds of formula (I)
will typically comprise a formula (I) compound amidated via its
carbon 1 carboxylate to the amino group of the sphingomyelin
backbone. The phospholipid formula (I) esters will comprise various
phospholipids. Phospholipid esters of the compounds of formula (I)
will typically comprise a formula (I) compound esterified via its
carbon 1 carboxylate to the sn-1 or sn-2 position alcohol, or both,
of the glycerol backbone of the phospholipid. If the sn-1 or sn-2
position of the glyceryl ester class does not contain an ester of a
compound of formula (I), then such carbon positions of the glycerol
backbone will comprise a methylene, ether or ester moiety linked to
a substituted or unsubstituted C.sub.12-30 alkyl or alkenyl (the
alkenyl group containing one or more double bonds);
alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl);
alkyl(heteroaryl)alkyl; or alkyl-M-Q; wherein the substitution is
alkyl, halo, hydroxy, or functionally modified hydroxy; M is O or
S; and Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl),
alkyl(heteroaryl) or alkyl(heteroaryl)alkyl. However, at least one
of the sn-1 or sn-2 position alcohols of the glycerol backbone must
form an ester with a compound of formula (I) via the carbon 1
carboxylate of the latter. Preferred phospholipid-formula (I)
esters will be of the phosphatidylethanolamine,
phosphatidylcholine, phosphatidylserine, and phospatidylinositol
type. The most preferred phospholipid-formula (I) esters will
comprise a formula (I) compound esterified via its carbon 1
carboxylate to the alcohol at the sn-2 position of
phosphatidylcholine, phosphatidylethanolamine or
phosphatidylinositol. The phospholipid-formula (I) esters and
sphingomyelin amides may be synthesized using various phospholipid
synthetic methods known in the art; see for example, Tsai et al.,
Biochemistry, volume 27, page 4619 (1988); and Dennis et al.,
Biochemistry, volume 32, page 10185 (1993).
[0039] Included within the scope of the present invention are the
individual enantiomers of the compounds of the present invention,
as well as their racemic and non-racemic mixtures. The individual
enantiomers can be enantioselectively synthesized from the
appropriate enantiomerically pure or enriched starting material by
means such as those described below. Alternatively, they may be
enantioselectively synthesized from racemic/non-racemic or enriched
starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W.
Scott, Eds.; Academic Press Publishers: New York, 1983-1985,
volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and
J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also
be isolated from racemic and non-racemic mixtures by a number of
known methods, e.g. by purification of a sample by chiral HPLC (A
Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.;
VCH Publishers: New York, 1994; Chiral Separations by HPLC; A. M.
Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by
enantioselective hydrolysis of a carboxylic acid ester sample by an
enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1
(1989)). Those skilled in the art will appreciate that racemic and
non-racemic mixtures may be obtained by several means, including
without limitation, nonenantioselective synthesis, partial
resolution, or even mixing samples having different enantiomeric
ratios. Departures may be made from such details within the scope
of the accompanying claims without departing from the principles of
the invention and without sacrificing its advantages. Also included
within the scope of the present invention are the individual
isomers substantially free of their respective enantiomers.
[0040] As used herein, the terms "pharmaceutically acceptable
salt", "pharmaceutically acceptable ester" and pharmaceutically
acceptable thioester" means any salt, ester or thioester,
respectively, that would be suitable for therapeutic administration
to a patient by any conventional means without significant
deleterious health consequences; and "ophthalmically acceptable
salt", "ophthalmically acceptable ester" and "ophthalmically
acceptable thioester" means any pharmaceutically acceptable salt,
ester or thioester, respectively, that would be suitable for
ophthalmic application, i.e. non-toxic and non-irritating.
[0041] The term "free hydroxy group" means an OH. The term
"functionally modified hydroxy group" means an OH which has been
functionalized to form: an ether, in which an alkyl, aryl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for
the hydrogen; an ester, in which an acyl group is substituted for
the hydrogen; a carbamate, in which an aminocarbonyl group is
substituted for the hydrogen; or a carbonate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or
alkynyloxy-carbonyl group is substituted for the hydrogen.
Preferred moieties include OH,
OCH.sub.2C(O)CH.sub.3,OCH.sub.2C(O)C.sub.2H.sub.5, OCH.sub.3,
OCH.sub.2CH.sub.3, OC(O)CH.sub.3, and OC(O)C.sub.2H.sup.5.
[0042] The term "free amino group" means an NH.sub.2. The term
"functionally modified amino group" means an NH.sub.2 which has
been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-,
cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-,
heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the
appropriate group is substituted for one of the hydrogens; an
aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino
group, wherein the appropriate group is substituted for one or both
of the hydrogens; an amide, in which an acyl group is substituted
for one of the hydrogens; a carbamate, in which an aryloxy-,
heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-,
alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl
group is substituted for one of the hydrogens; or a urea, in which
an aminocarbonyl group is substituted for one of the hydrogens.
Combinations of these substitution patterns, for example an
NH.sub.2 in which one of the hydrogens is replaced by an alkyl
group and the other hydrogen is replaced by an alkoxycarbonyl
group, also fall under the definition of a functionally modified
amino group and are included within the scope of the present
invention. Preferred moieties include NH.sub.2, NHCH.sub.3,
NHC.sub.2H.sub.5, N(CH.sub.3).sub.2, NHC(O)CH.sub.3, NHOH, and
NH(OCH.sub.3).
[0043] The term "free thiol group" means an SH. The term
"functionally modified thiol group" means an SH which has been
functionalized to form: a thioether, where an alkyl, aryl,
cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl,
heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for
the hydrogen; or a thioester, in which an acyl group is substituted
for the hydrogen. Preferred moieties include SH, SC(O)CH.sub.3,
SCH.sub.3, SC.sub.2H.sub.5, SCH.sub.2C(O)C.sub.2H.sub.5, and
SCH.sub.2C(O)CH.sub.3.
[0044] The term "acyl" represents a group that is linked by a
carbon atom that has a double bond to an oxygen atom and a single
bond to another carbon atom.
[0045] The term "alkyl" includes straight or branched chain
aliphatic hydrocarbon groups that are saturated and have 1 to 15
carbon atoms. The alkyl groups may be interrupted by one or more
heteroatoms, such as oxygen, nitrogen, or sulfur, and may be
substituted with other groups, such as halogen, hydroxyl, aryl,
cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched
alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and
t-butyl.
[0046] The term "cycloalkyl" includes straight or branched chain,
saturated or unsaturated aliphatic hydrocarbon groups which connect
to form one or more rings, which can be fused or isolated. The
rings may be substituted with other groups, such as halogen,
hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred
cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0047] The term "heterocycloalkyl" refers to cycloalkyl rings that
contain at least one beteroatom such as O, S, or N in the ring, and
can be fused or isolated. The rings may be substituted with other
groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower
alkyl. Preferred heterocycloalkyl groups include pyrrolidinyl,
tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.
[0048] The term "alkenyl" includes straight or branched chain
hydrocarbon groups having 1 to 15 carbon atoms with at least one
carbon-carbon double bond, the chain being optionally interrupted
by one or more heteroatoms. The chain hydrogens may be substituted
with other groups, such as halogen. Preferred straight or branched
alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and
4-pentenyl.
[0049] The term "cycloalkenyl" includes straight or branched chain,
saturated or unsaturated aliphatic hydrocarbon groups which connect
to form one or more non-aromatic rings containing a carbon-carbon
double bond, which can be fused or isolated. The rings may be
substituted with other groups, such as halogen, hydroxyl, alkoxy,
or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl
and cyclohexenyl.
[0050] The term "heterocycloalkenyl" refers to cycloalkenyl rings
which contain one or more heteroatoms such as O, N, or S in the
ring, and can be fused or isolated. The rings may be substituted
with other groups, such as halogen, hydroxyl, aryl, aryloxy,
alkoxy, or lower alkyl. Preferred heterocycloalkenyl groups include
pyrrolidinyl, dihydropyranyl, and dihydrofuranyl.
[0051] The term "carbonyl group" represents a carbon atom double
bonded to an oxygen atom, wherein the carbon atom has two free
valencies.
[0052] The term "aminocarbonyl" represents a free or functionally
modified amino group bonded from its nitrogen atom to the carbon
atom of a carbonyl group, the carbonyl group itself being bonded to
another atom through its carbon atom.
[0053] The term "lower alkyl" represents alkyl groups containing
one to six carbons (C.sub.1-C.sub.6).
[0054] The term "halogen" represents fluoro, chloro, bromo, or
iodo.
[0055] The term "aryl" refers to carbon-based rings which are
aromatic. The rings may be isolated, such as phenyl, or fused, such
as naphthyl. The ring hydrogens may be substituted with other
groups, such as lower alkyl, halogen, free or functionalized
hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl,
3-(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
[0056] The term "heteroaryl" refers to aromatic hydrocarbon rings
which contain at least one heteroatom such as O, S, or N in the
ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or
fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or
heteroatoms with open valency may be substituted with other groups,
such as lower alkyl or halogen. Examples of heteroaryl groups
include imidazole, pyridine, indole, quinoline, furan, thiophene,
pyrrole, tetrahydroquinoline, dihydrobenzofliran, and
dihydrobenzindole.
[0057] The terms "aryloxy", "heteroaryloxy", "alkoxy",
"cycloalkoxy", "heterocycloalkoxy", "alkenyloxy",
"cycloalkenyloxy", "heterocycloalkenyloxy", and "alkynyloxy"
represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl,
alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group,
respectively, attached through an oxygen linkage.
[0058] The terms "alkoxycarbonyl", "aryloxycarbonyl",
"heteroaryloxycarbonyl", "cycloalkoxycarbonyl",
"heterocycloalkoxycarbony- l", "alkenyloxycarbonyl",
"cycloalkenyloxycarbonyl", "heterocycloalkenyloxycarbonyl", and
"alkynyloxycarbonyl" represent an alkoxy, aryloxy, heteroaryloxy,
cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy,
heterocycloalkenyloxy, or alkynyloxy group, respectively, bonded
from its oxygen atom to the carbon of a carbonyl group, the
carbonyl group itself being bonded to another atom through its
carbon atom.
[0059] Preferred compounds of the present invention include those
of formula I,
[0060] wherein:
[0061] R.sup.1 is (CH.sub.2).sub.nCO.sub.2R, wherein R is H, or
CO.sub.2R forms an ophthalmically acceptable salt or an
ophthalmically acceptable ester;
[0062] X is O or CH.sub.2, with the proviso that X cannot be
CH.sub.2 when n is 0; and 5
[0063] Particularly preferred compounds are the compound of formula
II and those depicted below, whose preparations are detailed in the
following examples 1-2. 6
Example 1
[0064] 7
(5Z,8Z,11Z,13E)-(15)-15-hydroxy-3-oxa-eicosa-5,8,11,13-tetraenoic
acid (1)
[0065] Treatment of a mixture of commercially available propargyl
alcohol (3) with t-butyl bromoacetate, sodium hydroxide, and
tetra-n-butylammonium chloride in toluene:water affords ether 4,
which is reduced to alcohol 5 with diisobutylaluminum hydride in
THF at 0.degree. C. Silylation of 5 with t-butyldimethylsilyl
chloride in CH.sub.2Cl.sub.2 in the presence of
4-(dimethylamino)pyridine and imidazole gives silyl ether 6, which
is treated sequentially with ethylmagnesium bromide, copper
bromide, and (2Z)-1,4-dichloro-2-butene to provide enyne 7.
Treatment of 7 with Nal in acetone affords iodide 8, which is
treated with Me.sub.3SiC.ident.CMgBr in the presence of catalytic
CuBr to yield enediyne 9. Lindlar hydrogenation of 9
(Pd/BaSO.sub.4, quinoline, hexane solvent) affords cis, cis-diene
10, which is treated sequentially with Jones reagent in acetone,
followed by treatment of the resultant acid with CH.sub.2N.sub.2,
to provide ester 11. Desilyation of 11 to 12 is accomplished using
KF in DMF. Coupling of 12 with (1E)-(3S)-1-bromo-3-(t--
butyldimethylsiloxy)-1-octene [for the preparation of this
compound, see: Nicoloau, K. C.; Webber, S. E. J. Am. Chem. Soc.
1984,106, 1503] in the presence of catalytic Pd(PPh.sub.3).sub.4
and Cul in HNEt.sub.2 affords triene 13, which is hydrogenated
under Lindlar conditions (Pd/BaSO.sub.4, quinoline, hexane solvent)
to give tetraene 14. Treatment of 14 with tetra-n-butylammonium
fluoride in THF, followed by saponification of the resulting
hydroxyester with KOH in THF/water, affords 1.
Example 2
[0066] 8
(5Z,11Z,13E)-(15s)-15-hydroxy-3-oxa-eicosa-5,11,13-trienoic acid
(2)
[0067] Treatment of 1,6-hexanediol (15) with t-butyldiphenylsilyl
chloride in DMF in the presence of 4-(dimethylamino)pyridine and
imidazole affords silyl ether 16, which is oxidized using
pyridinium chlorochromate in CH.sub.2C1.sub.2 to provide aldehyde
17. Corey-Fuchs condensation of 17 with CBr.sub.4 in the presence
of PPh.sub.3 and Zn affords dibromoolefin 18, which is coupled with
(3S)-3-hydroxy-1-octyne [for the preparation of this compound, see:
Midland et. al., Tetrahedron, 40:1371 (1984)] in the presence of
catalytic PdCl.sub.2(PPh.sub.3).sub.2 and CuI in HNEt.sub.2 to
afford enyne 19. Reduction of 19 to the cis, trans-diene alcohol 20
is accomplished using
Na[H.sub.2AI(CH.sub.2CH.sub.2OCH.sub.3).sub.2] in toluene.
Treatment of 20 with tetra-n-butylammonium fluoride in
tetrahydrofuran gives diol 21, which is oxidized to aldehyde 22
using catalytic 2,2,6,6-tetramethyl-N-piperidinoxyl free radical
(TEMPO) and stoichiometric N-chlorosuccinimide. Condensation of 22
with (CF.sub.3CH.sub.20).sub.2P(O)CH.sub.2CO.sub.2CH.sub.3 at
-78.degree. C. in THF in the presence of potassium
bis(trimethylsilyl)amide and 18-crown-6 gives enoate 23, which is
reduced to allylic alcohol 24 with diisobutylaluminum hydride.
Alkylation of 24 with t-butyl bromoacetate in the presence of
Bu4NCl and KOH in water/toluene affords ester 25, which is
saponified with lithium hydroxde in THF/water to provide 2.
[0068] Salt forms of the formula (I) compounds are preferred as it
is believed that the neat salts are more stable than the
corresponding neat acids. Preferred salts of the present invention
are those wherein a terminal carboxylate of formula (I) (i.e.,
wherein R.sup.1 is CO.sub.2R) forms a salt with cations selected
from: Na.sup.+, K.sup.+, NH.sub.4.sup.+, benzyltrimethylammonium
ion, tetrabutylammonium ion, and phenyltrimethyl ammonium ion.
[0069] As used hereinafter, the term "compounds of formula (I),"
refers to compounds of formula (I), and/or the phospholipid-formula
(I) esters or amides described above. The compositions of the
present invention comprise one or more compounds of formula (I) and
a pharmaceutically acceptable carrier. The compositions are
formulated in accordance with methods known in the art for the
particular route of administration desired for the prevention,
treatment or amelioration of the particular disease or disorder
targeted. The level of peroxy compounds in the HETE derivative raw
materials that are used to prepare the pharmaceutical formulations
of the present invention may have an impact on the HETE
derivative's biological activity. Although the precise relationship
has not been defined, it is preferable to use HETE derivative raw
material supplies containing peroxy compounds at levels no greater
than about 0.3 ppm. Methods for determining peroxy levels are known
in the art (e.g., European Pharmacopoeia 1997 3.sup.rd Ed., Method
2.5.5-Peroxide Value).
[0070] As used herein, the term "pharmaceutically acceptable
carrier" refers to any formulation which is safe, and provides the
appropriate delivery of an effective amount of one or more
compounds of formula (I) for the prevention, treatment or
amelioration of the disease or disorder targeted.
[0071] As used herein, the term "pharmaceutically effective amount"
refers to an amount of one or more compounds of formula (I) that,
when administered to a patient, prevents, treats or ameliorates a
disease or disorder, or conditions associated thereof. As used
herein, "an ophthalmically effective amount" refers to an amount of
one or more compounds of formula (I) that, when administered to a
patient, prevents, treats or ameliorates an ophthalmic disease or
disorder, or conditions associated thereof. For the treatment of
dry eye, such an effective amount will stimulate secretion of mucin
in the eye and thus eliminate or improve dry eye conditions when
administered to the eye. As used herein, "an effective amount to
treat dry eye" refers to an amount of one or more compounds of
formula (I) that, when administered to a patient, prevents, treats
or ameliorates a dry eye disease or disorder, or conditions
associated thereof. Generally, the compounds of formula (I) will be
contained in a composition of the present invention in a
concentration range of about 0.00001 to 10 per cent weight/volume
("% w/v"). Preferred ophthalmic, including dry eye-treatment,
compositions will contain one or more compounds of formula (I) in a
concentration of from about 0.00001-0.01% w/v.
[0072] The present invention is particularly directed to
compositions useful in treating dry eye. Preferably, such
compositions will be formulated as solutions, suspensions and other
dosage forms for topical administration. Aqueous solutions are
generally preferred, based on ease of formulation, biological
compatibility (especially in view of the malady to be treated,
e.g., dry eye-type diseases and disorders), as well as a patient's
ability to easily administer such compositions by means of
instilling one to two drops of the solutions in the affected eyes.
However, the compositions may also be suspensions, viscous or
semi-viscous gels, or other types of solid or semi-solid
compositions. Suspensions may be preferred for compounds of formula
(I) which are less soluble in water.
[0073] Preferably, the ophthalmic compositions of the present
invention will also contain ethanol. As used herein, "an effective
concentration of ethanol" refers to a concentration that enhances
the biological efficacy of the formula (I) compositions in vivo. In
general, the concentration of ethanol necessary for the enhancement
of the compounds of formula (I) is believed to be somewhat
proportional to the concentration of the formula (I) compound(s)
administered. If a relatively high concentration of formula (I)
compound(s), e.g., above 0.01% w/v, is administered, the
concentration of ethanol in such compositions may be proportionally
less than analogous compositions containing lower concentrations of
formula (I) compounds. In general, however, the ethanol
concentration contained in the ophthalmic compositions of the
present invention will range from about 0.001-2% w/v. Compositions
containing formula (I) concentrations of about 0.00001-0.02% w/v
preferably will contain ethanol in a concentration of about
0.005-0.2% w/v, and most preferably, about 0.02-0.10% w/v.
[0074] Preferably, the compositions of the present invention will
also contain a surfactant. Various surfactants useful in topical
ophthalmic formulations may be employed. The surfactant(s) may
provide additional chemical stabilization of the formula (I)
compounds and may further provide for the physical stability of the
compounds. In other words, the surfactants may aid in preventing
chemical degradation of the compounds of formula (I) and also
prevent the compounds from binding to the containers in which their
compositions are packaged. As used herein, "an effective
concentration of surfactant(s)" refers to a concentration that
enhances the chemical and physical stability of formula (I)
compound(s). Examples of surfactants include, but are not limited
to: Cremophor.RTM. EL, polyoxyl 20 ceto stearyl ether, polyoxyl 40
hydrogenated castor oil, polyoxyl 23 lauryl ether and poloxamer 407
may be used in the compositions. A preferred surfactant is polyoxyl
40 stearate. The concentration of surfactant will vary, depending
on the concentration of formula (I) compound(s) and optional
ethanol present in the formulation. In general, however, the
surfactant(s) concentration will be about 0.001 to 2.0% w/v.
Preferred compositions of the present invention will contain about
0.1% w/v of polyoxyl 40 stearate.
[0075] The compositions of the present invention may also include
various other ingredients, such as tonicity agents, buffers,
preservatives, co-solvents and viscosity building agents.
[0076] Various tonicity agents may be employed to adjust the
tonicity of the composition, preferably to that of natural tears
for ophthalmic compositions. For example, sodium chloride,
potassium chloride, magnesium chloride, calcium chloride, dextrose
and/or mannitol may be added to the composition to approximate
physiological tonicity. Such an amount of tonicity agent will vary,
depending on the particular agent to be added. In general, however,
the compositions will have a tonicity agent concentration of about
0.1-1-5% w/v. Sodium chloride in the amount of 0.75% w/v is
preferred.
[0077] An appropriate buffer system (e.g., sodium phosphate, sodium
acetate, sodium citrate, sodium borate or boric acid) may be added
to the compositions to prevent pH drift under storage conditions.
The particular concentration will vary, depending on the agent
employed. In general, however, such a concentration will range from
about 0.02 to 2.0% w/v. Preferred compositions will contain about
0.25% w/v of boric acid.
[0078] Antioxidants may be added to compositions of the present
invention to protect the formula (I) compounds from oxidation
during storage. Examples of such antioxidants include, but are not
limited to, vitamin E and analogs thereof, ascorbic acid and
derivatives, and butylated hydroxyanisole (BHA).
[0079] Compositions formulated for the treatment of dry eye-type
diseases and disorders may also comprise aqueous carriers designed
to provide immediate, short-term relief of dry eye-type conditions.
Such carriers can be formulated as a phospholipid carrier or an
artificial tears carrier, or mixtures of both. As used in this
paragraph and the immediately succeeding paragraph, the term
"phospholipid" refers only to the phospholipids of the phospholipid
carrier, does not refer to a compound of formula (I) and, as such,
does not contain a formula (I) compound. As used herein,
"phospholipid carrier" and "artificial tears carrier" refer to
aqueous compositions which: (i) comprise one or more phospholipids
(in the case of phospholipid carriers) or other compounds, which
lubricate, "wet," approximate the consistency of endogenous tears,
aid in natural tear build-up, or otherwise provide temporary relief
of dry eye symptoms and conditions upon ocular administration; (ii)
are safe; and (iii) provide the appropriate delivery vehicle for
the topical administration of an effective amount of one or more
compounds of formula (I). Examples or artificial tears compositions
useful as artificial tears carriers include, but are not limited
to, commercial products, such as Tears Naturale.RTM., Tears
Naturale II.RTM., Tears Naturale Free.RTM., and Bion Tears.RTM.
(Alcon Laboratories, Inc., Fort Worth, Tex.). Examples of
phospholipid carrier formulations include those disclosed in U.S.
Pat. Nos. 4,804,539 (Guo et al.), 4,883,658 (Holly), 4,914,088
(Glonek), 5,075,104 (Gressel et al.), 5,278,151 (Korb et al.),
5,294,607 (Glonek et al.), 5,371,108 (Korb et al.), 5,578,586
(Glonek et al.); the foregoing patents are incorporated herein by
reference to the extent they disclose phospholipid compositions
useful as phospholipid carriers of the present invention.
[0080] The phospholipids useful in the phospholipid carriers are
any natural or synthetic phospholipid compound comprising a
glycerol-phosphoric acid ester or sphingomyelin backbone. Examples
of phospholipids useful in the present invention include those of
formula (III): 9
[0081] wherein, X.sup.21 and X.sup.22 are the same or different and
are O, NH(C.dbd.O), O(C.dbd.O), or a direct bond;
[0082] R.sup.22 is H or CH.dbd.CH(CH.sub.2).sub.12CH.sub.3;
[0083] X.sup.21-R.sup.1 is OH, or R.sup.1 is C.sub.12-26
substituted or unsubstituted alkyl or alkenyl;
[0084] R.sup.2 is C.sub.12-26 substituted or unsubstituted alkyl or
alkenyl; and
[0085] R.sup.3 is H, OH, OCH.sub.2CH(NH.sub.3.sub.+)COO.sup.31 ,
OCH.sub.2CH.sub.2NH.sub.3.sup.+,
OCH.sub.2CH.sub.2N.sup.+(CH.sub.3).sub.3- ,
OCH.sub.2CH(OH)CH.sub.2OH and O-inositol.
[0086] The phospholipids may be present as racemic or non-racemic
compounds. Preferred phospholipids are those wherein
X.sup.21-R.sup.1 and/or X.sup.22-R.sup.2 comprise fatty acid esters
or amides. Natural fatty acids are saturated, monounsaturated or
polyunsaturated. Examples of fatty acid residues include, but are
not limited to, laurate, myristate, palmitate, palmitoleate,
stearate, oleate, linoleate, linolenate, eicosanoate, docosanoate
and lignocerate. Preferred phospholipid types are the
phosphatidylethanolamines, phosphatidylcholines,
phosphatidylserines, phospatidylinositols and sphingomyelins.
Examples of specific phospholipids include: 1,2-dipalmitoyl
phosphatidyl choline ("DPPC") 1,2-dipalmityl phosphatidyl glycerol
("CDPPG"), N-stearyl sphingomyelin, N-palmityl sphingomyelin,
N-oleyl sphingomyelin, 1,2-distearoyl phosphatidyl ethanolamine
("DSPE"), 1,2-distearoyl phosphatidyl inositol ("DSPI"),
1-stearoyl-2-palmitoyl phosphatidyl ethanolamine ("SPPE"),
1-stearoyl-2-palmitoyl phosphatidyl choline ("SPPC"),
1,2-dipalmitoyl phosphatidyl ethanolamine ("DPPE"), 1,2-dioleoyl
phophatidyl ethanolamine ("DOPE"), 1,2-dioleoyl phophatidyl serine
("DOPS"), and 1,2-dipalmitoyl phosphatidyl serine ("DPPS"). The
most preferred phospholipid carriers are the
phosphatidylethanolamines and sphingomyelins. Phospholipids are
available from a variety of natural sources and may be synthesized
by methods known in the art; see, for example, Tsai et al.,
Biochemistry, volume 27, page 4619 (1988); and Dennis et. al.,
Biochemistry, volume 32, page 10185 (1993).
[0087] Other compounds designed to lubricate, "wet," approximate
the consistency of endogenous tears, aid in natural tear build-up,
or otherwise provide temporary relief of dry eye symptoms and
conditions upon ocular administration the eye are known in the art.
Such compounds may enhance the viscosity of the composition, and
include, but are not limited to: monomeric polyols, such as,
glycerol, propylene glycol, ethylene glycol; polymeric polyols,
such as, polyethylene glycol, hydroxypropylmethyl cellulose
("HPMC"), carboxy methylcellulose sodium, hydroxy propylcellulose
("HPC"), dextrans, such as, dextran 70; water soluble proteins,
such as gelatin; and vinyl polymers, such as, polyvinyl alcohol,
polyvinylpyrrolidone, povidone and carbomers, such as, carbomer
934P, carbomer 941, carbomer 940, carbomer 974P.
[0088] Other compounds may also be added to the ophthalmic
compositions of the present invention to increase the viscosity of
the carrier. Examples of viscosity enhancing agents include, but
are not limited to: polysaccharides, such as hyaluronic acid and
its salts, chondroitin sulfate and its salts, dextrans, various
polymers of the cellulose family; vinyl polymers; and acrylic acid
polymers. In general, the phospholipid carrier or artificial tears
carrier compositions will exhibit a viscosity of 1 to 400
centipoises ("cps"). Preferred compositions containing artificial
tears or phospholipid carriers will exhibit a viscosity of about 25
cps.
[0089] Topical ophthalmic products are typically packaged in
multidose form. Preservatives are thus required to prevent
microbial contamination during use. Suitable preservatives include:
benzalkonium chloride, chlorobutanol, benzododecinium bromide,
methyl paraben, propyl paraben, phenylethyl alcohol, edetate
disodium, sorbic acid, polyquatemium-1, or other agents known to
those skilled in the art. Such preservatives are typically employed
at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the
present invention will be sterile, but typically unpreserved. Such
compositions, therefore, generally will not contain
preservatives.
[0090] The preferred compositions of the present invention are
intended for administration to a human patient suffering from dry
eye or symptoms of dry eye. Preferably, such compositions will be
administered topically. In general, the doses used for the above
described purposes will vary, but will be in an effective amount to
increase mucin production in the eye and thus eliminate or improve
dry eye conditions. Generally, 1-2 drops of such compositions will
be administered 1-10 times per day for the treatment of dry eye or
other ocular disease or disorder. Preferably, 1-2 drops of the
compositions will be administered 1-4 times per day.
[0091] The present invention is also directed to stable, stock
compositions comprising one or more compounds of formula (I) and
ethanol. The inventors believe that storing the compounds of
formula (I) in an ethanolic solution provides greater stability of
the compounds of formula (I) over analogous aqueous compositions,
or neat compounds of formula (I) compositions. Such compositions
comprise one or more compounds of formula (I) and an amount of
ethanol to solubilize the compounds of formula (I) in solution.
Preferably, the ethanolic stock solutions will contain anhydrous
ethanol, but aqueous ethanolic solutions are also contemplated by
the present invention. Generally, the stock solutions will contain
ethanol in a concentration of about 25 to 100% volume/volume
("v/v"). Typically, such stock solutions will contain compounds of
formula (I) in high concentration relative to the pharmaceutical
compositions of the present invention.
[0092] The following Examples 1-5 describe preferred compositions
of the present invention. The actual pH of the compositions may
vary (e.g., between 6-8), and the concentrations of the various
ingredients included in the exemplified compositions may vary, but
are included in the compositions in the approximate amounts
shown.
Example 1
[0093]
1 Ingredient Amount (% w/v) Compound 1 0.00001-0.01 Ethanol 0.0505
Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium Chloride 0.75
Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl q.s., pH =
7.5 Purified Water q.s. 100%
[0094] The above composition is prepared by the following method.
The batch quantities of polyoxyl 40 stearate, boric acid, sodium
chloride, disodium edetate, and polyquatemium-1 are weighed and
dissolved by stirring in 90% of the batch quantity of purified
water. The pH is adjusted to 7.5.+-.0.1 with NaOH and/or HCl. Under
yellow light or reduced lighting, the batch quantity of Compound 1
as a stock solution in ethanol and the additional quantity of
ethanol necessary for the batch are measured and added. Purified
water is added to q.s. to 100%. The mixture is stirred for five
minutes to homogenize and then filtered through a sterilizing
filter membrane into a sterile recipient.
[0095] Preferably, the above process is performed using glass,
plastic or other non-metallic containers or containers lined with
such materials.
Example 2
[0096]
2 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01
Ethanol 0.005-0.2 Polyoxyl 40 Stearate 0.1 Boric Acid 0.25 Sodium
Chloride 0.75 Disodium Edetate 0.01 Polyquaternium-1 0.001 NaOH/HCl
q.s., pH = 7.5 Purified Water q.s. 100%
[0097] The above formulation may be made by a method similar to the
method described in Example 1.
Example 3
[0098]
3 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01
Polyoxyl 40 Stearate 0.1 Ethanol 0.005-0.2 Boric Acid 0.25 Sodium
Chloride 0.75 NaOH/HCl q.s., pH = 7.5 Purified Water q.s. 100%
[0099] The above formulation may be made by a method similar to the
method described in Example 1.
Example 4
[0100] The following is an example of an artificial tears
carrier-composition of the present invention:
4 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01
HPMC 0.3 Dextran 70 0.1 Sodium Chloride 0.8 Potassium Chloride 0.12
Dibasic Sodium Phosphate 0.025 Disodium EDTA 0.01 Polyquaternium-1
0.001 + 10% excess Purified Water Qs NaOH/HCl qs to pH 6-8
[0101] The above formulation may be made by a method similar to the
method described in Example 1.
Example 5
[0102] The following is an example of a phospholipid
carrier-composition of the present invention:
5 Ingredient Amount (% w/v) Compound of formula (I) 0.00001-0.01
Ethanol 0.005-0.2 Polyoxyl 40 Stearate 0.1 DPPC 0.05 DPPE 0.05
Sodium Chloride 0.8 Potassium Chloride 0.12 Dibasic Sodium
Phosphate 0.025 Disodium EDTA 0.01 Polyquaternium-1 0.001 + 10%
excess Purified Water Qs NaOH/HCl qs to pH 6-8
[0103] The above formulation may be made by a method similar to the
method described in Example 1.
[0104] The invention in its broader aspects is not limited to the
specific details shown and described above. Departures may be made
from such details within the scope of the accompanying claims
without departing from the principles of the invention and without
sacrificing its advantages.
* * * * *