EA035966B1 - Use of a pharmaceutical composition for topical application in treating lacrimal system and anterior segment of the eye disorders - Google Patents

Abstract

The present invention provides the use of a pharmaceutical composition for topical application in treating lacrimal system and anterior segment of the eye disorders. Said pharmaceutical composition comprises dipyridamole or a pharmaceutically acceptable salt thereof at concentration of 5 to 200 g/ml. Said lacrimal system and anterior segment of the eye disorders include scleritis, dry eye syndrome (keratoconjunctivitis sicca) caused by Graft-versus-Host Disease (GvHD), keratitis, corneal ulcer, corneal abrasion, snow blindness, Thygeson's superficial punctuate keratopathy, corneal neovascularization, Fuch's dystrophy, keratoconus, iritis, corneal anesthesia, neurotrophic keratopathy, conjuctivitis, keratomycosis, xeropthalmia, retinoblastoma, uveitis, pterygium, keratopathy, pingueculae.

Description

Technology area

The present invention relates to the use of a topical pharmaceutical composition for the treatment of disorders of the lacrimal system and the anterior segment of the eye using dipyridamole.

State of the art

As is known in the art, a condition called dry eye is a disorder of tear film disruption due to lack of tears or excessive evaporation of tears, which leads to damage to the surface of the eyes between the eyelids and is associated with symptoms of eye discomfort. Currently, dry eye includes two main types: (i) dry eye caused by tear production deficiency (ADDE) and (ii) dry eye caused by evaporation of tears (EDE). ADDE refers primarily to impaired tear secretion due to dysfunction of the lacrimal system. ADDE includes two main subtypes: (i) Sjogren's syndrome (SSDE) and (ii) non-Shegren's dry eye syndrome (for example, in the case of graft versus host disease (GvHD) or diabetes mellitus). Dry eye syndrome, subtype EDE, can be (i) endogenous, due to diseases affecting the structure or movement of the eyelids, or (ii) exogenous, in which disease of the surface of the eyes occurs due to some external action, for example, under the action of preservatives in the composition of medicines for topical application, due to wearing contact lenses, pterygium or vitamin A deficiency.

The term corneal ulcer usually refers to a condition in which the epithelium of the cornea, stroma, or both of these structures is lysed and removed by activation and hypersecretion of a collagenolytic enzyme. It is known that a collagenolytic enzyme causing corneal ulcers, bacterial collagenase, and matrix metalloproteases (MMPs) are involved in the ulcerative process.

Changes in the extracellular environment caused by the degradation of stromal collagen contribute to the development of ulcers. Such conditions create a vicious circle of activation of corneal stromal cells and destruction of the corneal stroma. When bacteria are destroyed by antibiotics, the synthesis of bacterial collagenases is suppressed and, accordingly, the direct degradation of the corneal stroma under the action of bacteria is suppressed. However, since most antibiotics are unable to suppress the activation of corneal stromal cells caused by biological signals transmitted by bacteria to the corneal stromal cells, ulcer progression is clinically observed from time to time.

Corneal and conjunctival diseases are associated with these disorders, including re-erosion of the cornea and long-term corneal epithelial deficiency. The reparative process in disorders associated with the corneal / conjunct epithelium involves compensation of epithelial deficiency by migration of corneal epithelial cells, followed by cell division and differentiation, which leads to the restoration of the normal layer of the cornea and conjunctiva. Loss of sensation of the cornea or congenital loss of sensation of the cornea usually develops into neutrophic keratopathy. Neutrophic keratopathy is a degenerative disease of the cornea caused by damage to the trigeminal nerve. Damage or loss of sensory innervation of the cornea underlies the development of corneal epithelial defects, ulcers and perforations.

Pterygium is a benign overgrowth of cells that begins in the transparent thin tissue (conjunctiva) of the eye. This growth covers the white part of the eye (sclera) and spreads to the cornea. Often, the pterygium protrudes slightly from the palpebral fissure and contains visible blood vessels. This violation can occur in one or both eyes. The pterygium can become inflamed and cause a burning, irritation, or foreign body sensation in the eye. Increased overgrowth on the cornea can lead to visual impairment. Currently, there is no other treatment for pterygium other than surgical treatment.

Pinguecula is a yellowish, slightly raised above the sclera thickening of the conjunctiva, located closer to the edge of the cornea. Pinguecula usually occurs on the part of the sclera between the eyelids and is therefore exposed to the sun. In some cases, the pinguecula may become swollen and inflamed, and this condition is called pingueculitis. Often pinguecula can lead to the formation of a pterygium. Currently, there is no other treatment for pinguecula other than surgical treatment.

Uveitis is an inflammation of the middle lining of the eye called the choroid or uveal tract. The choroid of the eyeball consists of the medium, pigmented and vascular structures of the eye and includes the iris, ciliary body and the choroid itself. In Western countries, 50-90% of uveitis cases are due to anterior uveitis, while in Asian countries this proportion is lower and amounts to 28-50%. It is estimated that uveitis accounts for approximately 10-20% of blindness in the United States. It is usually caused by infectious (bacterial or viral infections) or autoimmune processes. Genetic factors are the contributing factors to this difficult to treat condition.

It is known from the prior art that dipyridamole [2,6-bis- (diethanolamino) -4,8-dipiperidinopyrimido [5.4 ^] pyrimidine], closely related to substituted pyrimidopyrimidines, and its preparation were described by Fischer in US Pat. 3031450 (hereinafter referred to as Fischer-450). Dipiri

- 1,035966 Damol was proposed as a coronary vasodilator in the early 1960s. and is well known to prevent platelet aggregation by blocking the uptake of adenosine. Subsequently, when studying the arterial circulation of the brain in rabbits, it was shown that dipyridamole reduces the formation of blood clots. This study led to the use of dipyridamole as an antithrombotic agent. Soon, dipyridamole was used, for example, for the prevention of stroke, maintaining patency of the coronary bypass graft and in the case of valve replacement, as well as before coronary angioplasty.

In patent publication EP 0234854 B1, Gilbard et al. (Hereinafter referred to as Gilbard-854) suggested that cyclic AMP functions as a secondary mediator for exocytosis in the lacrimal gland and promotes increased tear secretion. cAMP is destroyed by phosphodiesterase. Therefore, it is believed that suppression of phosphodiesterase can lead to an increase in intracellular cAMP levels and, as a consequence, increase lacrimal secretion. It is believed that dipyridamole acts as an inhibitor of phosphodiesterase, and this may be associated with some of its therapeutic effects on the cardiovascular system through this mechanism.

However, on page 19 of patent publication WO 2007/140181, Leung (hereinafter referred to as Leung-181) states that after the addition of dipyridamole, there was little effect on the cAMP level compared to the control. Only the combination of caffeine with dipyridamole led to the desired effect - a decrease in the level of cAMP in vitro, which, as was suggested, indicates an increase in intracellular levels of cAMP.

It would be desirable to develop compositions for use in the treatment of ocular disorders using dipyridamole. Such compositions and indications for treatment could, inter alia, eliminate the listed problems associated with these disease states.

Description of the invention

It is an object of the present invention to provide a composition and guidance for the treatment of eye diseases using dipyridamole.

Embodiments of the invention

For clarity, as used in the present invention, the term ocular disorder specifically includes, but is not limited to, any painful condition of scleritis, graft versus host reaction (GvHD), keratitis, corneal ulcer, corneal erosion, snow blindness, superficial Tygeson punctate keratopathy. , neovascularization of the cornea, Fuch's dystrophy, keratoconus, keratoconjunctivitis dry (dry eyes), irititis, loss of corneal sensitivity, neutrophic keratopathy, redness of the eyes, conjunctivitis, keratomycosis, xerophthalmia, retinoblastterioma, uveitis, pserathyroidism.

In addition, it should be noted that as used in the present invention, the term illustrative refers to the designation of examples of embodiments and / or implementation and does not mean an expression of necessity or a more desirable use case. Likewise, as used in the present invention, the term "preferred" refers to an example from a variety of contemplated implementations and / or implementations and does not mean an expression of necessity or a more desirable use case. Thus, from the foregoing, it should be understood that as used in the present invention, the terms illustrative and preferred may be applied to a variety of embodiments and / or implementations.

Dipyridamole is rapidly absorbed from the gastrointestinal tract, reaching its peak concentration in human plasma 1-3 hours after oral administration. Peak plasma concentrations of the drug depend on the administered dose and range from about 0.5 g / ml (in the case of a 25 mg dose) to 1.6 g / ml (in the case of a 75 mg dose). Blood concentration levels are quite variable, possibly due to the composition of food intake and gastrointestinal motility. Taking the drug on an empty stomach can lead to higher plasma levels of the drug. After intravenous administration (IV), the half-life in humans is approximately 25 minutes, and after oral administration - approximately 3 hours.In the study of plasma concentrations of the drug within the next 60 hours after IV or oral administration at a dose of 20-50 mg, it was found that they decrease three-exponential, with an elimination half-life of 5 minutes (only in the case of IV), 53 minutes and about 10-12 hours. The volume of distribution is approximately 140 liters. In this case, the drug is 92-99% bound to plasma proteins, mainly to alpha-1-acid glycoprotein. The usual daily dose of dipyridamole for oral administration is in the range of 100 to 400 mg.

Dipyridamole is practically insoluble in water (solubility in water is 8.17 mg / l (Meylan W.M. et al. (Meylan W.M. et al., 1996)) and very easily soluble in methanol. This poses a problem for finding a suitable method for ophthalmic applications, where the preferred route of administration to the eye is by administering aqueous solutions in the form of drops. According to embodiments of the present invention, compositions and indications for use in treating ocular disorders using dipyridamole have been found. After adjusting the pH of the aqueous solutions to about 6 , 6 (6.5-6.7) dipyridamole is completely soluble in aqueous solution.

- 2 035966 the pH level of the eye fluid is 7.4; however, the consumer will not feel discomfort as long as the pH of the administered drug is in the range of 6.6-7.8 (Sampath Kumar et al., Recent Challenges and Advances in Ophthalmic Drug Delivery System, in The Pharma Innovation, Vol. . 1, No. 4 (2012)).

To increase solubility in water, other methods can also be used, such as, for example, ultrasonic mixing or dissolution of dipyridamole in methanol, chloroform, acetic acid, DMSO or other solvents in which dipyridamole is soluble, followed by the addition of water or saline and removing all or parts of the solvent. Another method may be to grind the substance to nano-sized particles before mixing it with water / isotonic solution. It should be noted that in the case of making more dilute solutions than the illustrative formulations C and D described below, less acidification may be required. Although aqueous solutions are preferred for ocular instillation, the preparation of dipyridamole as an oil or cream base is another way of solving the problem of the low solubility of dipyridamole in water.

In accordance with aspects of the present invention, dipyridamole has been found to be effective for the treatment of ocular diseases when applied topically in the form of saline-based formulations. Topical application of dipyridamole may be suitable for the treatment of ocular disorders caused, for example, by graft versus host reaction (GvHD), diabetes, allergic conjunctivitis, dry eyes from contact lenses, and Sjogren's syndrome. In an illustrative embodiment of the present invention, topical dipyridamole may also be used to treat corneal ulcers resulting from, for example, viral infection, bacterial infection, fungal infection, wear due to contact, traumatic injury or parasitic infection. In addition, topical dipyridamole can also be used to treat pterygium, corneal numbness and corneal neovascularization.

Thus, in accordance with the present invention, in the first place, there is proposed the use of a pharmaceutical composition for topical use for the treatment of disorders of the lacrimal system and the anterior segment of the eye, containing dipyridamole or a pharmaceutically acceptable salt thereof at a concentration of 5 to 200 μg / ml, with said disorders the lacrimal system and the anterior segment of the eye are scleritis, dry eye syndrome (keratoconjunctivitis dry), graft versus host reaction (GvHD), keratitis, corneal ulcer, corneal erosion, snow blindness, Tigeson's superficial punctate keratopathy, neovascularization of the cornea keratoconjunctivitis dry, irititis, loss of corneal sensitivity, neutrophic keratopathy, conjunctivitis, keratomycosis, xerophthalmia, retinoblastoma, uveitis, pterygium, keratopathy, pinguecula. Preferably, said composition is a solution, preferably said solution is an aqueous solution. Preferably the pH of the solution is adjusted to <6.7, preferably the pH of the solution is 6.5 to 6.7. Preferably, the effective amount corresponds to a concentration of at least about 10 ^-5 mol / L. Preferably, the effective amount is calculated for administration of the drug at least once every two days. These and other embodiments of the present invention will be apparent from the following detailed description and examples.

Detailed description of embodiments of the invention

The present invention relates to the use of a topical pharmaceutical composition for the treatment of disorders of the lacrimal system and the anterior segment of the eye using dipyridamole. Aspects, uses and advantages of such compositions according to the present invention can be better understood in the context of the proposed description. The present description should not be construed as limiting, it is presented solely for the purpose of illustrating the general principles of the invention, since the scope of the invention is best defined in the appended claims. Illustrative embodiments of the present invention are described in detail below in the following illustrative formulations.

Illustrative composition of A.

Eye drops containing dipyridamole were prepared as follows. 1 g of citric acid was dissolved in 100 ml of physiological saline (0.9% w / v sodium chloride solution in sterile water), obtaining a solution with a pH of 6.7. A weighed portion of 8.5 mg of dipyridamole was prepared, irradiated with a UV lamp for 30 min for sterilization, and dissolved in 100 ml of saline. This solution was filtered through a 0.22 µm sterilizing filter to yield a solution containing 85 µg of dipyridamole in 1 ml. Using a pipette, apply 1 drop to the eye (equivalent to about 0.05 ml).

Illustrative composition of V.

Eye drops containing dipyridamole were prepared as follows. 1 g of citric acid was dissolved in 100 ml of physiological saline (0.9% w / v sodium chloride solution in sterile water), obtaining a solution with a pH of 6.7. A weighed portion of 4.25 mg of dipyridamole was prepared, irradiated with a UV lamp in those

- 3035966 30 min for sterilization and dissolved in 100 ml of physiological solution. This solution was filtered through a 0.22 µm sterilizing filter to yield a solution containing 42.5 µg of dipyridamole in 1 ml. Using a pipette, apply 1 drop to the eye (equivalent to about 0.05 ml).

Illustrative composition of S.

Eye drops containing dipyridamole were prepared as follows. 1 g of citric acid was dissolved in 100 ml of physiological saline (0.9% w / v sodium chloride solution in sterile water), obtaining a solution with a pH of 6.7. A sample of 2.125 mg of dipyridamole was prepared, irradiated with a UV lamp for 30 min for sterilization, and dissolved in 100 ml of saline. This solution was filtered through a 0.22 μm sterilizing filter to yield a solution containing 21.25 μg of dipyridamole in 1 ml. Using a pipette, apply 1 drop to the eye (equivalent to about 0.05 ml).

Illustrative composition D.

Eye drops containing dipyridamole were prepared as follows. 1 g of citric acid is dissolved in 100 ml of physiological solution (0.9% w / v sodium chloride solution in sterile water), obtaining a solution with a pH of 6.7. A weighed portion of 1.0625 mg of dipyridamole was prepared, irradiated with a UV lamp for 30 min for sterilization, and dissolved in 100 ml of saline. This solution was filtered through a 0.22 µm sterilizing filter to yield a solution containing 10.625 µg of dipyridamole in 1 ml. Using a pipette, 1 drop was applied to the eye (equivalent to about 0.05 ml).

Results.

Five male patients suffering from dry eye syndrome caused by GvHD reactions were administered 1 drop of Composition A in each eye twice a day. Subjective relief of the symptoms of dry eye syndrome was achieved after 1.5 hours from application. Patients required further administration of the drug on a twice daily schedule. After 3 days of application, the redness of the eyes (or conjunctivitis) disappeared.

Two patients suffering from diabetes-induced dry eye syndrome were administered 1 drop of Composition C in each eye twice daily. Relief of symptoms of dry eye syndrome was achieved after 1 hour. Patients required further administration of the drug on a scheme twice a day every day. After 5 days of application, the redness of the eyes (or conjunctivitis) disappeared.

A patient suffering from diabetic dry eye syndrome was administered 1 drop of Composition B in each eye once a day, every other day. The relief of dry eye symptoms was achieved after 20 minutes. The patient required further administration of the drug according to the scheme once a day every other day. After 10 days of application, the redness of the eyes (or conjunctivitis) disappeared. Further treatment was continued according to the scheme once a day every other day.

A male patient suffering from a viral infection of the eyes and corneal ulcers was administered 1 drop of Composition B in each eye twice a day daily. The cessation of exudation was achieved after 8 hours. After 4 days of application, the redness of the eyes (or conjunctivitis) disappeared, and the eyes were completely healed after 5 days.

A male patient suffering from pterygium in one eye with concomitant dry eyes and conjunctivitis was prescribed 1 drop of Composition B twice daily. Relief of dry eye symptoms was achieved after one day. The patient required further administration of the drug on a twice daily schedule. After 10 days of application, the redness of the eyes (or conjunctivitis) disappeared. After 6 weeks of use, the pterygium was reduced by about half and retained a tendency to decrease in size with subsequent use.

A patient suffering from pterygium in one eye with concomitant dry eyes and inflammation was prescribed 1 drop of Composition C twice a day daily. Relief of dry eye symptoms was achieved after two days. The patient required further administration of the drug according to the scheme twice a day every day. After 8 weeks of use, the pterygium was reduced by about half and retained a tendency to decrease in size with subsequent use.

A male patient suffering from a deep corneal ulcer involving the stroma was prescribed 1 drop of Composition A three times a day daily. Relief of symptoms of pain and irritation was achieved after 24 hours. The patient required further administration of the drug on a twice daily basis. After 7 days of application, the corneal ulcer was completely epithelized.

Three patients suffering from loss of corneal sensitivity caused by diabetes (neutrophic keratopathy) were prescribed 1 drop of Composition C daily. Symptoms of loss of corneal sensitivity began to subside after 2-3 days. The patients required further administration of the drug on a twice daily schedule. After 3 weeks of use, the patient reported complete relief of symptoms.

A male patient suffering from neovascularization associated with diabetes was administered 1 drop of Composition A twice daily daily. On repeated examination after 4 weeks using a slit lamp, no abnormal vessels were found.

- 4 035966

Two male patients suffering from viral eye infections and corneal erosion (ie, with an incipient corneal ulcer) were given 1 drop of Composition A in each eye twice daily. The cessation of exudation was achieved after 5 hours. After 2-3 days of application, the redness of the eyes (or conjunctivitis) disappeared, and the eyes were completely healed in 5-6 days.

A patient suffering from a corneal ulcer in one eye was prescribed 1 drop of Composition A twice a day daily. Pain and irritation relief was achieved after one day. The patient required further administration of the drug according to the scheme twice a day every day. After 7 days of application, the ulcer completely disappeared. Four male patients suffering from diabetes-related dry eyes were administered 1 drop of Composition A in each eye twice daily. Relief of symptoms associated with dry eye syndrome was achieved after 0.5 hours. Patients required further administration of the drug twice a day daily. After about a week of application, the redness of the eyes (or conjunctivitis) has completely disappeared.

Two patients suffering from loss of corneal sensitivity associated with diabetes (neutrophic keratopathy) were prescribed 1 drop of Composition A daily. Symptoms of loss of corneal sensitivity began to subside after 2 days. After about one week of use, the patient reported complete relief of symptoms.

A male patient suffering from diabetes-induced neovascularization was administered 1 drop of Composition C twice daily daily. The patient required further administration of the drug on a twice daily schedule. When re-examining using a slit lamp, carried out 16 days after the start of drug administration, no abnormal vessels were found.

Six male patients suffering from dry eye syndrome associated with GvHD reactions were administered 1 drop of Composition C in each eye twice daily. Relief of the symptoms of dry eye syndrome was achieved after 1 hour. Patients required further administration of the drug on a twice daily basis. After about one week of using the drug, the redness of the eyes (or conjunctivitis) disappeared.

A male patient suffering from anterior uveitis in both eyes was administered 1 drop of Composition C three times daily. Pain relief was achieved after three days. The problem with blurred vision was resolved after 7 days. The resulting inflammation was completely eliminated after 14 days. The patient continued further treatment according to the scheme twice a day daily until remission was achieved.

A male patient suffering from anterior uveitis in both eyes was administered 1 drop of Formulation B three times daily daily. Pain relief was achieved after two days. Blurred vision was resolved after 15 days. The resulting inflammation was completely eliminated after 18 days. The patient continued further treatment according to the scheme twice a day daily until remission was achieved.

Three male patients suffering from dry eye syndrome caused by GvHD reactions were administered 1 drop of Formulation D in each eye twice daily. Relief of the symptoms of dry eye syndrome was achieved after 1 hour. Patients required further administration of the drug on a twice daily basis. After about one week of using the drug, the redness of the eyes (or conjunctivitis) disappeared.

Additional preferred embodiments and experiments

Eye drops containing dipyridamole were prepared by dissolving dipyridamole in sterile water. If necessary, the pH was adjusted to obtain better solubility of dipyridamole. Various concentrations were prepared ranging from 5 to 200 μg / ml. The resulting formulations were sterilized.

An ophthalmic ointment containing dipyridamole was prepared by mixing dipyridamole with a base consisting of yellow soft paraffin, petroleum jelly and lanolin in a ratio of 8: 1: 1. Various concentrations were prepared ranging from 5 to 200 μg / ml. The resulting formulations were sterilized.

Subjects suffering from dry eye syndrome caused by Sjogren's syndrome, nonspecific keratitis, keratoconus or allergic conjunctivitis were injected into the eyes with either eye drops containing dipyridamole (1 drop [about 0.05 ml] one to three times a day), or containing dipyridamole ophthalmic ointment (approximately 0.1-0.3 ml [one to two times a day]). The concentrations used in the experiments were gradually increased depending on the tolerability of the drug.

Results.

Sjogren's Syndrome: There was a slight passing burning sensation when applying drops or ointment. Partial relief of the symptoms of dry eye syndrome occurred within 1 hour after drug administration. In some patients, complete relief of symptoms was achieved after about seven days of continuous use of the drug, while the effect persisted in some patients in the case of daily use, and in others - in the case of administration of the drug every 3-4 days.

Nonspecific keratitis: When using drops or ointment, a slight passing burning sensation was observed. A decrease in pain intensity was noted after 1-2 hours from application. Complete relief of pain was achieved after 3-4 periodic injections (with a break of several hours) drops or ointment. Complete relief from keratitis was achieved after 2-7 days of constant use.

Keratoconus: Daily administration (once or twice a day) to two subjects for three months resulted in a decrease in astigmatism, which manifested itself in a decrease in the cylinder of 0.25-0.5 units.

Conjunctivitis (nonspecific): A slight passing burning sensation was observed with the use of drops or ointment. Partial relief of the symptoms of conjunctivitis (itching, burning or lacrimation) occurred within 1 hour after drug administration. The introduction was continued according to the scheme once or twice a day daily. After 2-4 days of use, all symptoms, including exudation, were arrested.

While the present invention has been described with respect to a limited number of embodiments, it should be appreciated that numerous variations, modifications, and other uses of this invention are possible.

As is known, all of the ocular disorders listed herein affect the anterior segment of the eye (including the conjunctiva) and / or the lacrimal system.

Industrial applicability

Compositions using dipyridamole are useful in the treatment of ocular disorders and this innovation overcomes the problems associated with such disorders.

Claims (6)

CLAIM 1. The use of a pharmaceutical composition for topical use for the treatment of disorders of the lacrimal system and the anterior segment of the eye, containing dipyridamole or its pharmaceutically acceptable salt at a concentration of 5 to 200 μg / ml, wherein said disorders of the lacrimal system and the anterior segment of the eye are scleritis, dry eyes (keratoconjunctivitis dry) due to graft versus host reaction (GvHD), keratitis, corneal ulcer, corneal erosion, snow blindness, Tigeson superficial punctate keratopathy, corneal neovascularization, Fuch's dystrophy, keratoconus, keratoconjunctivitis, keratoconia , conjunctivitis, keratomycosis, xerophthalmia, retinoblastoma, uveitis, pterygium, keratopathy, pinguecula. 2. Use according to claim 1, characterized in that said composition is a solution. 3. Use according to claim 2, characterized in that said solution is an aqueous solution. 4. Use according to claim 3, characterized in that the pH of the solution is adjusted to <6.7. 5. Use according to claim 4, characterized in that the pH of the solution is 6.5-6.7. 6. Use according to claim 1, characterized in that the composition is administered at least once every two days.