Agent for preventing or treating diseases associated with excessive proliferation of the epithelial pigment cells of the retina

 

The invention relates to medicine, to the agent for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, such as proliferative vitreoretinopathy, and includes as the active ingredient N-(3,4-dimethoxycinnamoyl) Anthranilic acid of formula I or its pharmaceutically acceptable salt. The tool has a high efficiency. 4 C. and 1 C.p. f-crystals, 1 PL.

This invention relates to a pharmaceutical composition, which is used as a means for the prevention or treatment of diseases associated with increased epithelial proliferation of the pigment cells of the retina.

In particular, this invention relates to means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, which comprises as an active ingredient N-(3,4-dimethoxycinnamoyl)Anthranilic acid (common name Tranilast) represented by the formulaor its pharmaceutically acceptable salt.

In this invention as a disease associated with excessive PR

The existing level of technology In retinopexy performed surgically against addounia retina indicate a proliferative vitreoretinopathy, which is known as a disease associated with excessive proliferation of the epithelial pigment cells of the retina, as the cause of the deteriorating Outlook. Currently, the only treatment for this proliferative vitreoretinopathy is surgery of the vitreous body. In these circumstances, the forecast saving of vision even after surgery is not always favorable. It is well known that the proliferation of epithelial pigment cells of the retina plays an important role in the emergence and development of proliferative vitreoretinopathy. Many researchers studied the inhibitory effect of various drugs on the proliferation of epithelial pigment cells of the retina (Japanese Review of Clinical Ophthalmology, Vol. 9, pp. 1886-1890 (1993); Japanese Review of Clinical Ophthalmology, Vol. 9, pp. 2030-2034 (1993)).

On the other hand, technical progress in surgery of the vitreous body has resulted in a marked increase in the percentage cured rate in detachment of the retina. However, they say that the maximum percentage of cured rate is 92-94%. Believe that the reason for this javljaetsja to increase the percentage of cured rate when retinopexy in the case of retinal detachment and for the prevention or treatment of proliferative vitreoretinopathy need to create new drugs, possessing exceptional inhibitory effect on excessive proliferation of the epithelial pigment cells of the retina.

Tranilast widely used as a drug for the treatment of allergic diseases such as bronchial asthma, allergic rhinitis, atopic dermatitis and allergic conjunctivitis, and in the treatment of skin disorders such as keloid and hypertrophic scar. For example, it is known that Tranilast has inhibitory effect on the secretion of chemical mediators, resulting allergic reactions, and excessive accumulation of collagen fibroblastlike cells in skin tissues and excessive proliferation of smooth muscle cells of the coronary vessels of the heart.

However, there are no data that Tranilast inhibits proliferation of epithelial pigment cells of the retina and that it is used as a means for the prevention or treatment of proliferative vitreoretinopathy.

Description of the invention This invention relates to means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, which comprises as an active ingredient N-(3,4-is citiesi acceptable salt.

This invention relates to a method for prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, which includes the use of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of formula I or its pharmaceutically acceptable salt.

This invention relates to the use of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of formula I or its pharmaceutically acceptable salt for the manufacture of pharmaceutical compositions for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina.

In addition, this invention relates to the use of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of formula I or its pharmaceutically acceptable salt as a substance for preventing or treating diseases associated with increased epithelial proliferation of the pigment cells of the retina.

The authors of the present invention worked on the search for compounds with inhibitory effect on excessive proliferation of the epithelial pigment cells of the retina. The result found that Tranilast has a remarkable inhibitory effect on the proliferation of epithelial pigment glue is related to excessive proliferation of the epithelial pigment cells of the retina.

Accordingly, the authors present invention argue that Tranilast significantly inhibits proliferation of epithelial pigment cells of the retina in the test, investigating the inhibitory effect on the proliferation in the use of culture in vitro epithelial pigment cells of the retina of the rat.

As a consequence Tranilast has excellent inhibitory effect on the proliferation of epithelial pigment cells of the retina and therefore is a compound suitable as a means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina.

Therefore, the pharmaceutical composition that is suitable as a means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, can be obtained by including as an active ingredient Tranilast or its pharmaceutically acceptable salt.

There are various ways to obtain Tranilast and its pharmaceutically acceptable salts which are active ingredients, and they can be easily obtained by methods described in the literature, etc., (Publication of Japanese patent (kokoku) Sho. 56-40710; Sho. 57-36905; Sho. 58-17186; Sho. 58-48545; Sho. 5 is by salts with inorganic bases, such as sodium salt and potassium salt, salts formed with organic amines, such as morpholine, piperidine, piperazine and pyrrolidine, and salts formed with amino acids.

When the pharmaceutical compositions of this invention are used in practice, the treatment can be applied orally. Preferably topical application in the form of eye drops, eye ointments and injections.

For example, eye drops can be prepared by dissolving Tranilast or its pharmaceutically acceptable salt with a basic substance by heating the appropriate amount of sterile water in which is dissolved surface-active substance, adding polyvinylpyrrolidone, and optionally adding a suitable pharmaceutical additives such as a preservative, a stabilizing agent, a buffer substance, providing isotonicity, antioxidant and means of improving the viscosity for complete dissolution.

For example, eye ointments can be respectively prepared using bases that are typically used in eye ointments. Eye ointment can also be applied in the form thermally reversible glutinitwindowsize aqueous pharmaceutical compositions.

For example, the injection can be carried out directly in the affected tissue, such the intraocular perfusion solution.

The pharmaceutical compositions of the present invention can be applied in the form of the drug long-term selection. For example, the drug Tranilast make into a ball (granule) or a microcapsule polymer long-term allocation as of the preparation of long-term isolation and ball (granule) or a microcapsule implanted in the tissue, which need to be processed. As long polymers allocation can result in a copolymer of ethylene and vinyl acetate, polytraumatized, polyacrylamide, polyvinylpyrrolidone, methylcellulose, polylactic acid, copolymer of lactic acid and glycolic acid, etc., preferably as biodegradable polymers can result such as polylactic acid and a copolymer of lactic acid and glycolic acid.

When the pharmaceutical compositions of this invention are used in the practice of treatment, the dose Tranilast or its pharmaceutically acceptable salt as an active ingredient determined accordingly depending on age, degree of development of symptoms in this patient, therapeutic assessment, etc., the Dose should be assigned to the appropriate concentration that she had a therapeutic effect. For example, in the case of eye drops is concentratie, 0.001-2 wt.%.

The best variant implementation of the invention This invention more in detail explain the following examples.

The Test sample, confirming the inhibitory effect on the proliferation of epithelial pigment cells of the retina 1. Isolation and culturing of epithelial pigment cells of the retina.

Isolation and culturing of epithelial pigment cells of rats was carried out as described Sakagami et al. (Ophthalmic Res., Vol. 27, pp. 262-267 (1995)). The six-day rat Brown Norway was anestesiologi by intraperitoneally injection pentobarbital and then deleted the eyes. After immersion for sterilization in 70% ethanol eyes washed in balanced salt solution Hank (HBSS). Then they were incubated for 15 minutes at 37oWith a 0.1% solution of proteinase K. After incubation eyeballs were washed in HBSS and placed in a Cup containing a mixture (1:1) eagle medium, modified Dulbecco (DMEM) and environment F12 ham (HF12), supplemented with 10% fetal bovine serum (FBS). Every eye did annular incision below the ora serrata. Then was removed and was thrown out of the anterior segment, lens and vitreous body. Under a stereoscopic microscope was separated from the retinal pigment epithelial cells of the retina. Strips EPI is telilng pigment cells of the retina were incubated in 0.1% trypsin solution for 7 minutes at 37oC. Pasteur pipette was used to isolate cells. Isolated cells were cultured in a mixture (1:1) DMEM and HF12, supplemented with 10% FBS, and used in further experiments.

2. Preparation of investigational medicinal products
Investigational medicinal product was obtained by dissolving Tranilast in dimethyl sulfoxide (DMSO) and diluting the solution medium for culture of endothelial cells to the end of the prescribed concentration. The final concentration of DMSO was 0.5%.

3. Experimental method
Cell suspension (200 μl containing 4104cells were introduced into each well of the coated collagen tablet with 96 wells and cultured at 37oC in an atmosphere of 5% CO2in the air. After one day the medium was replaced and cultured in 200 μl of a mixture (1:1) environment DMEM and environment HF12, supplemented with 10% FBS containing various concentrations Tranilast. After 4 days in each well was added 20 μl of Alamar Blue reagent for analysis of cell proliferation. After 4 hours of incubation with the help of immunochemical measured the absorption at 620 nm and counted the number of cells.

4. Assessment actions
The number of cells in the untreated group took over 100% and calculated the percentage inhib the tats
The table also shows that Tranilast significantly inhibited the proliferation of epithelial pigment cells of the retina, depending on the applied concentration.

Industrial application
Pharmaceutical composition comprising as an active ingredient Tranilast or its pharmaceutically acceptable salt, has a remarkable inhibitory activity on the proliferation of epithelial pigment cells of the retina, and therefore very suitable as a substance for preventing or treating diseases associated with excessive proliferation of the epithelial pigment cells of the retina, such as proliferative vitreoretinopathy.


Claims

1. Means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, comprising as an active ingredient N-(3,4-dimethoxycinnamoyl) Anthranilic acid of the formula

or its pharmaceutically acceptable salt.

2. Means for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina, under item 1 in the form of eye drops or eye ointments.

3. Speak retina, including the introduction of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of the formula

or its pharmaceutically acceptable salt in the form of eye drops or eye ointments.

4. The use of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of the formula

or its pharmaceutically acceptable salt for the manufacture of pharmaceutical compositions for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina.

5. The use of N-(3,4-dimethoxycinnamoyl)Anthranilic acid of the formula

or its pharmaceutically acceptable salt as a vehicle for the prevention or treatment of diseases associated with excessive proliferation of the epithelial pigment cells of the retina.

 

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