Ophthalmic drug compositions

Details Ophthalmic drug compositions Ophthalmic drug compositions

1999-07-15

2001-04-24

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S018700, C514S912000

Reexamination Certificate

active

06221846

ABSTRACT:

TECHNICAL FIELD
The present invention relates to an ophthalmic drug composition containing Phe-Gly-Leu-Met-NH
2
(hereinafter, referred to as FGLM), which is a tetrapeptide at the C-terminal of Substance P, or a pharmaceutically acceptable salt thereof as an active ingredient. More particularly, it relates to a therapeutic agent for corneal disorders having a promoting action on corneal epithelial wound healing, characterized in that an insulin-like growth factor I (hereinafter, referred to as IGF-I), which is one of the growth factors, is formulated as another active ingredient with FGLM in a preparation or these two are administered jointly.
BACKGROUND ART
The cornea is a transparent, avascular tissue having a diameter of about 1 cm and a thickness of about 1 mm. Transparency of the cornea affects visual functions greatly and various physiological and biochemical phenomena in the cornea function mainly with an object of maintenance of transparency of the cornea.
Corneal epithelial defects caused by various diseases such as corneal ulcer, corneal erosion, keratitis and dry eye heals spontaneously unless mixed infection intercurrently occurs. However, if the healing is delayed or does not occur due to some causes and the corneal defects become persistent, the normal construction of the epithelium is badly affected, and further even the structure and function of corneal stroma and endothelium are damaged. The principle of the conventional therapeutic methods is merely passive, i.e., the surface of the cornea is protected from outside stimulation whereby the epithelium is spontaneously extended to re-cover the defected area. Recent progress of cell biology has revealed factors participating in proliferation, migration, attachment, spreading of cells, etc. and it was reported that compounds which enhance the migration of corneal epithelium play an important role in healing the corneal epithelial defects (
Jpn. J. Clin. Ophthalmol.,
46, 738-743 (1992); and
Jpn. J. Ophthalm. Surg.,
5, 719-727 (1992)).
FGLM is a tetrapeptide at the C-terminal of Substance P which is disclosed in U.S. Pat. No. 3,862,114 and the patent describes that it has an hypotensive action. Substance P is a polypeptide consisting of eleven amino acids which show actions such as vasodilation, smooth muscle contraction, promotion of salivary gland secretion and diuresis. With regard to Substance P, various studies were conducted in an ophthalmic field. For example, improvement in aberrant conjunctival goblet cell secretion in ophthalmic diseases was disclosed (WO95/13087) and sequential charges of Substance P in inflammation such as keratitis was reported (
J. Jpn. Ophthalmol. Soc.,
91, 982-987 (1987); ibid., 92, 448-452 (1988)). However, there has been no report on FGLM, which is its partial peptide, in an ophthalmic field.
On the other hand, an insulin-like growth factor is one of the growth factors controlling the growth of normal human cells such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor and transforming growth factor, and there are IGF-I and an insulin-like growth factor II (hereinafter, referred to as IGF-II) therein. Recently, it was reported that IGF-I stimulates thyroid cell proliferation (
J. Biol. Chem.,
264, 18485-18488 (1989)), that IGF-II regulates muscle growth and differentiation (
Hum. Mol. Genet.,
3, 1117-1121 (1994)), etc. In an ophthalmic field, also, it was disclosed that IGF-I, IGF-II and functional derivatives thereof promote the survival of retinal neurons (cf. Japanese Laid-Open Patent Publication Hei-07/500,839), that IGF-II is effective for therapy of every wound of various areas including the wound upon corneal transplantation (Japanese Laid-Open Patent Publication Sho-63/233,925) and that ocular tissues such as cornea provided to transplantation can be preserved at low temperature in a fresh state of the tissues by using a solution containing the above-mentioned growth factor (Japanese Laid-Open Patent Publications Hei-05/025,001 and Hei-06/048,901). It was also disclosed that, in general, gel compositions containing the growth factor are effective for wound healing in anterior segments etc. (Japanese Laid-Open Patent Publication Hei-02/000,112). However, the growth factors which are specifically disclosed in those patent publications are epidermal growth factors only and there is no description on the effect of IGF-I.
IGF-II has been known to be useful for a therapy of wound upon corneal transplantation etc. as mentioned above. However, with regard to IGF-I, there is only a report that it does not affect corneal epithelial wound healing (
Connect. Tissue,
27, 65 (1995)).
It was reported that Substance P itself does not affect the corneal epithelial wound healing but it promotes the corneal epithelial wound healing when it coexists with epidermal growth factor out of growth factor (
Prog. Med.,
13, 2626-2627 (1993)) or IGF-I (
Connect. Tissue,
27, 65 (1995)). However, it has not been revealed that which site of Substance P is an activity-exhibiting site.
As mentioned above, it has been a very interesting subject to find a minimum activity-exhibiting site of Substance P and to study actions of the compound in such a minimum unit in an ophthalmic field, particularly to study the action on corneal disorders.
DISCLOSURE OF THE INVENTION
The present inventors have paid their attention to the partial peptide at the C terminal of Substance P and studied its action on corneal disorders. As a result, they have found that FGLM, which is a tetrapeptide at the C terminal of Substance P, promotes the corneal epithelial wound healing when it coexists with IGF-I and that FGLM is a minimum unit of the partial peptide of Substance P for exhibiting the above-mentioned action. Thus, the novel use of FGLM as an ophthalmic drug composition has been found. Further, it has been found that a combined use of FGLM or a pharmaceutically acceptable salt thereof together with IGF-I as another active ingredient is useful for therapy of corneal disorders such as corneal ulcer, corneal erosion, keratitis and dry eye, where the cornea is in a wounded state due to various causes.
FGLM is a tetrapeptide of the C terminal of Substance P and has a structure of Phe-Gly-Leu-Met-NH
2
. Phe, Leu and Met have L-, D- and DL-forms respectively and all of them belong to the present invention. The preferred embodiment is a compound where all of them are the L-form.
Examples of the pharmaceutically acceptable salt of FGLM are hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate and p-toluenesulfonate.
The term “corneal disorders” used in the present invention stands for corneal ulcer, corneal erosion, keratitis, dry eye and the like, where the cornea is in a wounded state due to various causes.
In order to study the usefulness of FGLM and IGF-I, their influence on corneal disorders has been investigated. Although the details will be mentioned later in the item of the “pharmacological tests”, it has been found that the coexistence of FGLM and IGF-I promotes the migration of corneal epithelium in a tissue culture system of cornea pieces and the wound healing after corneal erosion. From these findings, it has been revealed that FGLM and IGF-I are useful for the therapy of corneal disorders such as corneal ulcer, corneal erosion, keratitis and dry eye, where the cornea is in a wounded state due to various causes and that they are particularly useful for the therapy of corneal erosion and dry eye.
FGLM or a pharmaceutically acceptable salt thereof and IGF-I can be administered either orally or parenterally and these two active ingredients can be either formulated together in one preparation or formulated separately, followed by administering them together. Examples of the dosage form are tablets, capsules, granules, powder, injection and ophthalmic preparations and the ophthalmic preparations such as eye drops and an eye ointment is particularly preferable. They can be prepared by widely used techniques. In the case of oral preparations such as tabl

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