KR20110062315A - Pharmaceutical composition comprising inosine or guanosine - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing inosine or guanosine is provided to increase the amount of tear drop and to prevent or treat ophthalmoxerosis. CONSTITUTION: A pharmaceutical composition for preventing or treating ophthalmoxerosis contains inosine or guanosine and pharmaceutically acceptable carrier. The pharmaceutical composition is manufactured in the form of parenteral formulation such as ophthalmic solution and ointment or oral formulation such as tablets, capsules, and granules. The pharmaceutical composition of ophthalmic solution additionally contains buffer, isotonic agent, antiseptic, dissolving agent(stabilizing agent), pH adjusting agent, thickening agent, or chelating agent.

Description

Pharmaceutical Composition Comprising Inosine or Guanosine {Pharmaceutical Composition Comprising Inosine or Guanosine}

The present invention relates to pharmaceutical compositions comprising inosine or guanosine. More specifically, the present invention relates to a pharmaceutical composition for treating or preventing dry eye syndrome comprising inosine or guanosine.

In general, when there is a lack of tears or fluctuations in the composition of the tear film (tear film) abnormalities cause a number of uncomfortable symptoms, such cases are referred to as dry eye syndrome. In 1994, the National Eye Institute / Industry Workshop on Clinical Trials in Dry Eyes showed that the cornea causes eye discomfort and irritation due to damage to the ocular surface of the eyelid crevices exposed by lack of tears and excessive evaporation of the tear film. It is defined as 'ocular surface disease'. Recently, a new form of dry eye syndrome due to a change in the composition of the tear film and neurogenic factors such as dry eye syndrome after LASIK has been developed, and its definition is being further interpreted (American Journal of Ophthalmology, 140). , 507, 2005).

Dry eye syndrome is found in more than 50% of all patients who visit ophthalmologists, and the elderly population, especially more than 70 to 80% of women who pass menopause, complain of eye discomfort due to dry eye syndrome. In the past, the cause of dry eye syndrome was thought to be due to lack of aqueous layer due to decreased tear production in tear glands, but recently, inflammatory response or endogenous inflammatory response due to external stimulation has been found to be the primary cause. Chronic ocular surface damage caused by disorder of epithelial cells and degradation of the interaction between corneal epithelial cells and corneal parenchymal cells has been a problem.

Dry eye may be caused by aging, hormonal changes, environmental factors (wind, heat, dust, tobacco smoke, hair dryers), reduction of eye blink frequency (VDT syndrome), contact lens wear, LASIK, cause of medication It can be caused by a variety of causes, including immune diseases (lupus, rheumatoid arthritis and Sjogren's syndrome) (American Journal of Ophthalmology, 137, 337-342, 2004).

In order to treat dry eye syndrome, artificial tears and ointments are used to improve lubrication and to hydrate the ocular surface. However, artificial tears do not show direct anti-inflammatory effects. dry eye syndrome, the therapeutic agent is, for example, i) tear supplements as an eye drop, such as artificial tears, ii) cyclosporine (cyclosporine) eye drops of reseutasiseu ^TM in conjunction with membrane proteins, cycloalkyl pilrin (cyclophillin) for inhibiting the activation of T cells (Restasis) , iii) Diquafosol ophthalmic solution, a P ₂ Y ₂ receptor stimulant, to promote tear loss and mucin secretion, and iv) to treat severe dry eye syndrome by increasing tear stability. Autologous serum eye drops, v) steroids.

However, most of these treatments are conservative healing methods, not fundamental healing methods, which are caused by various mechanisms and environmental factors such as chronic ocular surface damage and complicated complexes caused by the deterioration of corneal epithelial cells and corneal parenchymal cells. It does not provide a fundamental solution to dry eye syndrome, which is increasing the pain of patients and encouraging rising medical costs due to the continued abuse of eye drops. Moreover, the steroids are problematic because they increase intraocular pressure and can cause complications such as cataracts and glaucoma when used for a long time in chronic diseases.

Therefore, there is an urgent need for the development of a new type of dry eye treatment.

The present inventors conducted extensive studies to develop a new type of dry eye treatment, and found that inosine and guanosine can directly treat or prevent dry eye syndrome by increasing the amount of tears without side effects, thereby completing the present invention. .

It is therefore an object of the present invention to provide a pharmaceutical composition for the treatment or prevention of dry eye syndrome comprising inosine or guanosine.

The present invention relates to a pharmaceutical composition for treating or preventing dry eye syndrome comprising inosine or guanosine and a pharmaceutically acceptable carrier.

The pharmaceutical composition according to the present invention promotes the secretion of hyaluronic acid to directly induce an increase in tear amount, not the effect of preventing evaporation of tears through moisturizing.

The pharmaceutical compositions according to the invention may be prepared in parenteral preparations such as ophthalmic solutions, ophthalmic ointments and injections or oral preparations such as tablets, capsules and granules, with the preferred dosage form being ophthalmic solutions.

When the pharmaceutical composition of the present invention is used as an ophthalmic solution, any dosage form that can be used as an ophthalmic solution, for example, an aqueous ophthalmic solution, an aqueous suspension ophthalmic solution, a viscous ophthalmic solution and a dissolved ophthalmic solution Aqueous eye drops, such as solutions, or non-aqueous eye drops, such as non-aqueous ophthalmic solutions and non-aqueous suspension ophthalmic solutions.

When the pharmaceutical composition of the present invention is prepared as an ophthalmic solution, various additives commonly used in ophthalmic solutions may be optionally included in the composition so long as they do not adversely affect the object of the present invention. Examples of such additives include buffers, isotonic agents, preservatives, solubilizers (stabilizers), pH adjusters, thickeners and chelating agents.

The buffer may be selected from the group consisting of phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers (eg sodium acetate) and amino acids, but is not limited thereto.

Isotonic agents can be selected from the group consisting of sugars such as sorbitol, glucose and mannitol, polyhydric alcohols such as glycerin, polyethylene glycol and polypropylene glycol, and salts such as sodium chloride, but are not limited thereto.

Preservatives consist of benzalkonium chloride, benzetonium chloride, alkyl paraoxybenzoate such as methyl paraoxybenzoate and ethyl paraoxybenzoate, benzyl alcohol, phenethyl alcohol, sorbic acid and its salts, thimerosal and chlorobutanol It may be selected from the group, but is not limited thereto.

The solubilizer (stabilizer) may be selected from the group consisting of cyclodextrins and derivatives thereof, water soluble polymers such as poly (vinylpyrrolidone) and surfactants such as polysorbate 80 (trade name: Tween 80), but are not limited thereto. It is not.

The pH adjusting agent may be selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, sodium hydroxide, potassium hydroxide and ammonium hydroxide, but is not limited thereto.

The thickener may be selected from, but is not limited to, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose and carboxymethylcellulose and salts thereof.

The chelating agent may be selected from the group consisting of sodium edetate, sodium citrate and condensed sodium phosphate, but is not limited thereto.

If the pharmaceutical composition of the present invention is prepared with an ophthalmic ointment, a base compound must be present.

The base compound of ophthalmic ointment may be selected from the group consisting of purified lanolin, petrolatum, plastibase, liquid paraffin and polyethylene glycol, but is not limited thereto.

In addition to ophthalmic solutions and ophthalmic ointment preparations, the pharmaceutical compositions of the present invention may be formulated into parenteral preparations such as injection solutions and oral preparations such as tablets, capsules and granules.

The pharmaceutical compositions of the invention can be administered to mammals (humans, rabbits, dogs, cats, cattle, horses, monkeys, etc.). The dosage of the pharmaceutical composition of the present invention varies in a wide range depending on the route of administration, the extent of the disease, the age and weight of the patient, and the like. For example, when the pharmaceutical composition of the present invention is used as an ophthalmic solution in an adult dry eye patient, about 0.001 to 2.5 (w / v)%, preferably 0.05 to 1.0 (w / v)% of inosine or It may be desirable to administer one to eight drops per day of an aqueous solution eye drop containing guanosine as an active ingredient.

When using the pharmaceutical composition of the present invention as an ophthalmic ointment, an ophthalmology containing about 0.001 to 2.5 (w / w)%, preferably 0.05 to 1.0 (w / w)%, of inosine or guanosine as the active ingredient. It may be desirable to administer the ointment 1 to 4 times a day.

In addition, the pharmaceutical compositions of the present invention may further comprise one or more other agents for the treatment or prevention of dry eye syndrome, such as artificial tears containing viscoelastic substances such as methylcellulose, chondroitin sulfate and hyaluronic acid.

The pharmaceutical composition according to the present invention can be effectively used to treat or prevent dry eye syndrome by directly increasing the amount of tears, unlike a conventional dry eye treatment agent.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it is obvious to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1 Measurement of Tear Secretion

Tear secretion of inosine or guanosine in the dry eye model of CBA / J mice (8 weeks old; SLC Inc., Japan) using botulinum toxin B (BTX-B; Myobloc ^™ ; Elan Pharmaceuticals Inc., South San Francisco, CA) The impact was on.

Twenty CBA mice were tested for 30 minutes of phenol red threads (Zone-Quick; Oasis, Glendora, CA) before anesthesia, followed by anesthesia (Ketamine: 45 mg / kg and Xylazine: 4.5 mg / kg)) were then injected with 20 mU (0.05 ml / eye) of BTX-B into the bilateral tear glands. After confirming that the amount of tears decreased on the 7th day, inosine or guanosine (5%) eye drops were applied 4 times a day to both eyes (left and right eyes), and saline was applied 4 times as a control group.

On the 14th and 21st day, the tear amount was confirmed by performing a phenol red tread test in the anesthetic state, and the results are shown in Table 1 below.

[Table 1] Change in Tears

group/ Post-dose time (unit: week) Dose (%) Before administration One 2 3 Normal Average 7.27 7.33 7.28 7.41 0 Standard Deviation 1.12 1.42 1.81 1.33 N 27 17 11 11 Control group Average 7.28 4.74 ^# 5.45 ^# 5.8 ^# Standard Deviation 1.1 1.21 1.32 1.89 N 19 19 11 11 Inosine Average 7.72 4.81 8.48 * 8.78 * 5% Standard Deviation 1.08 1.24 2.19 1.02 N 5 5 5 5 Guanosine Average 7.08 4.82 5.88 7.48 * 5% Standard Deviation 1.48 1.33 1.12 1.72 N 5 5 5 5

#: p <0.05; *: p <0.05

From Table 1, it can be observed that the inosine and guanosine administration group increased the amount of tears from 2 to 3 weeks after administration compared to the control group.

Example 2 Measurement of Increase of Hyaluronic Acid

1.5 × 10 ⁵ HCE-T (human cornea epithelial cells) were placed in 6 well plates and incubated for 24 hours in a CO ₂ incubator at 37 ° C. Medium containing 1 ml of 10M inosine or guanosine (keratinocyte-SMF, Gibco, 17005-042) was added to the cultured cells and incubated for 72 hours in a CO ₂ incubator at 37 ° C. Transfer medium of cultured cells for 72 hours to a 1.5 ml tube and weigh it, and transfer the resulting medium by centrifugation at 4 ° C and 12,000 rpm for 10 minutes to a new 1.5 ml tube (hyaluronan-ELISA assay) kit; Echelon, K-1200) was used to measure the amount of hyaluronic acid in the medium. The results are shown in Table 2 below.

[Table 2] Increase in hyaluronic acid

Average Standard Deviation Control group 226 37.5 Inosine administration group 267 15.8 Guanosine group 263 16.2

From Table 2, it was confirmed that inosine and guanosine did not induce a statistically significant increase in hyaluronic acid.

Claims (4)

A pharmaceutical composition for treating or preventing dry eye, comprising inosine or guanosine and a pharmaceutically acceptable carrier. The pharmaceutical composition of claim 1, which directly induces an increase in tear amount. The pharmaceutical composition according to claim 1 or 2, which is in the form of an ophthalmic solution or an ophthalmic ointment. 4. A pharmaceutical composition according to claim 3, wherein the ophthalmic solution is an aqueous eye drop.