KR20150126021A - Compositions for use in treating eye disorders using dipyridamole - Google Patents

Abstract

The present invention discloses compositions for use in treating eye disorders, i. E. Compositions comprising an effective amount of topically-administered dipyridamole. Preferably, the topically-administered dipipidol is formulated as a solution. Preferably, the topically-administered dipiperidomoles are at least one agent selected from the group consisting of dipyridamole and pharmaceutically acceptable salts thereof. Preferably, an effective amount corresponds to a concentration of at least about 10 ^-5 molar concentration. Preferably, the effective amount is based on at least one treatment dose every two days.

Description

≪ Desc / Clms Page number 1 > COMPOSITIONS FOR USE IN TREATING EYE DISORDERS USING DIPYRIDAMOLE < RTI ID = 0.0 >

The present invention relates to compositions for use in treating eye disorders using dipyridamole.

As is known in the art, a medical condition referred to as a "dry eye " is a condition caused by tear deficiency or excessive tear evaporation that causes damage to the interpalpebral ocular surface associated with the symptoms of eye discomfort It is a disorder of the tear film. Currently, dry eye contains two main classes: (i) aqueous tear deficient dry eye (ADDE), and (ii) evaporative dry eye (EDE). ADDE mainly refers to the lack of sufficient tear secretion due to tear dysfunction. ADDE has two major subclasses: (i) Sjogren's Syndrome Syndrome (SSDE), and (ii) in non-SS dry eye (eg, Graft-versus-Host Disease (GvHD) ). EDE may be endogenous due to (i) a disease affecting the eyelid structure or epidemiology, or (ii) an ocular surface disease caused by some exogenous exposure such as topical drug preservatives, contact lens wear, pterygium or vitamin A deficiency It can be extrinsic.

The term "corneal ulcer" refers generally to a medical condition in which the corneal epithelium, substrate, or both are dissolved and dissolved and depleted by activation and secretion excess of the collagen soluble enzyme. Collagen-lytic enzymes that cause corneal ulcers, bacterial collagenases, and matrix metalloproteases (MMPs) are known to be involved in ulcerative processes.

Changes in the extracellular environment caused by degradation of matrix collagen promote ulceration. These conditions produce a vicious cycle of activation of the corneal stromal cells and degradation of the corneal matrix. When bacteria are killed by antibiotics, degradation of the bacterial collagenase is inhibited and direct corneal degradation due to bacteria is inhibited. However, since most antibiotics can not inhibit the activation of corneal stromal cells caused by biological signals once transmitted from bacteria to corneal stromal cells, the progression of ulcers is clinically observed occasionally.

Repeated erosion of the cornea and corneal / conjunctival disorders, including persistent corneal epithelial deficiency, are associated with these disorders. Repair of corneal / conjunctival epithelial defect causes subsequent reconstruction of normal cornea and conjunctiva with subsequent cell division and differentiation following the range of epithelial deficiency due to migration of corneal epithelium. Corneal paralysis and congenital keratopathy usually spread to neurotrophic keratopathy. Neurotrophic keratopathy is a degenerative corneal disease induced by damage of trigeminal nerve. Damage or loss of the corneal sensory nerve distribution results in corneal epithelium defects, ulceration and perforation.

Pterygium is a noncancerous growth that starts from the clean, thin tissue (conjunctiva) of the eye. This growth covers the white part of the eye (sclera) and extends to the cornea. It is often slightly elevated and contains visible blood vessels. Problems can occur in one or both eyes. Pterygium may cause irritation, burning sensation, irritation, or the presence of foreign objects in the eye. If growth is sufficiently prolonged on the cornea, vision may be affected. Apart from surgery, cure for pterygium is currently unknown.

The inspection panel is yellowish near the edge of the cornea, and is a slightly elevated thick part of the conjunctiva on the sclera. The inspector is typically on the part of the sclera between the eyelids and is thus exposed to sunlight. In some cases, the inspector is swollen and becomes a condition called inflammatory censor. Frequently, the inspection panel can cause the formation of pterygium. In addition to surgery, there is currently no cure for cure.

Uveitis is inflammation of the middle layer of the eye, called the uveal or ocular vasculature of the eye. The uveal consists of a pigmented vascular structure in the middle of the eye, including iris, ciliary body and choroid. In western countries, anterior uveitis accounts for 50% to 90% of cases of uveitis, while in Asian countries the rate drops to 28% to 50%. Uveitis is estimated to result in approximately 10 to 20% of blindness cases in the United States. The cause is usually infectious (bacterial or viral infection) or autoimmune. Genetic factors act as a scaffold for conditions that are difficult to treat.

In the prior art, a closely related substituted pyrimido-pyrimidine, dipyridamol {2,6-bis (diethanolamino) -4,8-dipiperidinopyrimido [5,4- And their manufacture are taught by Fischer in US Pat. No. 3,031,450 (hereafter referred to as Fischer's 450). Dipyridamol was introduced as a coronary vasodilator in the early 1960s and is well known to have platelet aggregation inhibitor properties due to inhibition of adenosine uptake. Subsequently, dipyridamole was shown to reduce thrombus formation in a study of cerebral arterial circulation in a rabbit model. These investigations have led to its use as anti-thrombin agents. Dipyridamole remains open to treatment prior to coronary angioplasty as well as coronary artery bypass and valve replacement, and is thus an option for this application as stroke prevention.

In European Patent Publication No. 0234854B1 (hereafter referred to as 854 of Zilbard) by Gilbard et al., Cyclic cAMP acts as a secondary messenger for the external action in the lacrimal gland and increases tear secretion Suggesting that it works. cAMP is degraded by phosphodiesterase. Therefore, it is believed that supporting phosphodiesterase leads to an increased level of intracellular cAMP, thus improving tear secretion. Dipyridamole is believed to act as a phosphodiesterase inhibitor and is believed to exert some of its cardiovascular benefits through this mechanism.

However, in page 19 of International Patent Application Publication No. WO 2007/140181 (hereafter referred to as Run 81 in the disclosure) by Leung, a negligible effect on cAMP after addition of dipyridamole compared to the control group Lt; / RTI > Only a combination of caffeine and dipyridamole is effective for the purpose of reducing cAMP in vitro, which is presumed to represent an increased cellular level of cAMP.

It is preferred to have a composition for use in treating eye disorders that utilize dipyridamole. Such compositions and therapeutic indications will overcome the above-mentioned problems, particularly in relation to such diseases.

It is an object of the present invention to provide compositions and therapeutic indications for use in the treatment of eye disorders using dipyridamole.

In a clear interest, the term "eye disorder" specifically refers to diseases such as scleritis, graft versus host disease (GvHD), keratitis, corneal ulcer, corneal abrasion, iris, Tigenson superficial punctate keratopathy, corneal neovascularization, , Keratoconus, dry keratoconjunctivitis (dry eye), iritis, keratopathy, neurotrophic keratopathy, congestion, red blood cell, corneal fungal disease, dry eye syndrome, retinoblastoma, uveitis, pterygium, keratopathy and screening , But are not limited to these.

Furthermore, the term "exemplary" is used herein to refer to embodiments and / or examples of implementations and is not necessarily meant to represent a more preferred use case. Similarly, the term "preferred " refers to examples other than the classifications of the embodiments and / or implementations set forth herein, and are not necessarily meant to represent more preferred use cases. It is therefore to be understood that the word "exemplary" and "advantageous" above may be applied to numerous embodiments and / or implementations herein.

Dipyridamol is easily absorbed from the gastrointestinal tract and reaches the maximum plasma level in 1-3 hours after oral administration in humans. The maximum plasma level is dose-dependent and ranges from about 0.5 g / ml after 25 mg dose to 1.6 g / ml after 75 mg dose. Blood levels are highly variable, possibly depending on feeding and gastrointestinal peristalsis. Ingestion on an empty stomach can result in higher blood levels. After intravenous (IV) administration, the distribution half-life in humans is about 25 minutes and about 3 hours after oral administration. When the plasma level of the drug is continued for 20 to 50 mg of IV or up to 60 hours after oral administration, the plasma level is tripled exponentially with trivalent half-lives of 5 minutes (IV only), 53 minutes and about 10 to 12 hours -exponentially. The distribution volume is about 140 L, and about 92 to 99% is bound mainly to the plasma protein which is an alpha-1-acid glycoprotein. Typical daily oral doses of dipyridamole are in the range of 100 to 400 mg.

The dipyridamole is substantially insoluble in water (water solubility is 8.17 mg / l (Meylan, WM ET AL. (1996)) and is highly soluble in methanol. This results in test infections in which an aqueous solution delivered via a single point will find a suitable method for desirable ocular application. Embodiments of the present invention provide compositions and therapeutic indications for use in treating eye disorders using dipyridamole. By adjusting the pH of the aqueous solution to ~ 6.6 (6.5 to 6.7), it was determined that the dipyridamole was completely dissolved in the aqueous solution. The natural pH of the tear fluid is 7.4; However, if the pH of the administered drug remains within the range of 6.6 to 7.8, the user will not feel discomfort (Sampath Kumar et al., &Quot; Recent Challenges and Advances in Ophthalmic Drug Delivery System ", The Pharma Innovation , Vol. 1, No. 4 (2012)).

Ultrasonic mixing or dissolution of dipyridamole in other carriers in which methanol, chloroform, acetic acid, DMSO or dipyridamole is dissolved, followed by adding to water or saline, and then removing all or part of the carrier Other methods for achieving water solubility such as the step can be used. Another method may involve pulverizing the mixture to nanoparticle size before mixing in water / saline. It should be noted that when making the more dilute exemplary Formulations C and D described below, less acidification is required. While aqueous solutions tend to be preferred for eye drop infusion, making dipiperidomoles out of water or cream bases is another way to overcome the aqueous solubility problem.

According to an embodiment of the present invention, dipypyrimol has been found to be effective in treating medical conditions of the eye when topically applied in a physiological saline formulation. Topical application of dipyridamole may be an action to treat dry eye caused by, for example, graft versus host disease (GvHD), diabetes, allergic conjunctivitis, contact lens-related dry eye, and Sjogren's syndrome.

In an exemplary embodiment of the invention, the topical dipyridamole is used to treat corneal ulcers resulting from, for example: viral infections, bacterial infections, fungal infections, injuries resulting from wearing contact lenses, traumatic injuries and parasitic infections Lt; / RTI > In addition, topical dipyridamol can also be used for the treatment of pterygium, corneal palsy and corneal neovascularization.

Thus, according to the present invention, there is provided a first composition for use in the treatment of an eye disorder, said composition comprising: (a) an effective amount of topically-administered dipyridamole. Preferably, the topically-administered dipipidol is formulated as a solution. Preferably, the topically-administered dipiperidomoles are at least one agent selected from the group consisting of dipyridamole and pharmaceutically acceptable salts thereof. Preferably, an effective amount corresponds to a concentration of at least about 10 ^-5 molar concentration. Preferably, the effective amount is based on at least one treatment dose every two days. These and further embodiments will be apparent from the following detailed description and examples.

The present invention relates to compositions for use in treating eye disorders using dipyridamole. Aspects, uses, and advantages of such compositions in accordance with the present invention may be better understood with reference to the following description. The description is not taken in a limiting sense, but merely for purposes of illustrating the general principles of the invention, since the scope of the invention is best defined by the appended claims. Exemplary embodiments of the invention are described below with the following exemplary formulations.

Exemplary Formulation A:

The dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in 100 ml of saline (0.9% w / v sodium chloride in sterilized water) to obtain a pH of 6.7. 8.5 mg of dipyridamole was weighed and then irradiated with UVB for sterilization for 30 minutes and diluted in 100 ml saline. The solution was then filtered through a 0.22 micron filter for sterilization resulting in a solution containing 85 mcg per ml of dipyridamole. One drop (approximately equal to 0.05 ml) was applied to the eye using a dropper.

Exemplary Formulation B:

The dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in 100 ml of saline (0.9% w / v sodium chloride in sterilized water) to obtain a pH of 6.7. 4.25 mg of dipyridamole was weighed and then irradiated with UVB for sterilization for 30 minutes and diluted in 100 ml saline. The solution was then filtered through a 0.22 micron filter for sterilization resulting in a solution containing 42.5 mcg of dipyridamole per ml. One drop (approximately equal to 0.05 ml) was applied to the eye using a dropper.

Exemplary Formulation C:

The dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in 100 ml of saline (0.9% w / v sodium chloride in sterilized water) to obtain a pH of 6.7. 2.125 mg of dipyridamole was weighed and then irradiated with UVB for sterilization for 30 minutes and diluted in 100 ml saline. The solution was then filtered through a 0.22 micron filter for sterilization resulting in a solution containing 21.25 mcg of dipyridamole per ml. One drop (approximately equal to 0.05 ml) was applied to the eye using a dropper.

Exemplary Formulation D:

The dipyridamole eye drops were prepared as follows. 1 g of citric acid was mixed in 100 ml of saline (0.9% w / v sodium chloride in sterilized water) to obtain a pH of 6.7. 1.0625 mg of dipyridamole was weighed and then irradiated with UVB for sterilization for 30 minutes and diluted in 100 ml saline. The solution was then filtered through a 0.22 micron filter for sterilization resulting in a solution containing 10.625 mcg of dipyridamole per ml. One drop (approximately equal to 0.05 ml) was applied to the eye using a dropper.

result:

Five human males suffering from GvHD-related dry eye were treated with one dose of Form A twice daily. Subjective relief of dry eye symptoms was achieved within 30 minutes. The patient required subsequent application twice a day. After 3 days of use, the redness (or red blood cell) of the eye disappeared.

Two human women suffering from diabetes - related dry eye syndrome were treated with one dose of Form C twice a day twice daily. Reduction of dry eye symptoms was achieved within 1 hour. The patient required subsequent application twice a day. After 5 days of use, the redness (or redness) of the eyes disappeared.

Human women suffering from diabetes - related dry eye were treated with one dose of Form B per day once every two days. Reduction of dry eye symptoms within 20 minutes was achieved. The patient needed follow-up once every two days. After 10 days of use, the redness (or redness) of the eyes disappeared. Maintenance was continued once every two days.

A human male suffering from a viral eye infection with a corneal ulcer was treated with one dose of Form B in the eye twice a day. Excretion was stopped within 8 hours. The patient required subsequent application twice a day. After 4 days of use, the redness (or redness) of the eyes disappeared, and the eyes were completely healed within 5 days.

A human male suffering from pterygium associated with dry eye and spongiform encephalopathy in one eye was treated with one dose of Form B twice a day. Reduction from dry eye symptoms was achieved within one day. The patient required subsequent application twice a day. After 10 days of use, the redness (or red blood cell) of the eye disappeared. After 6 weeks of use, the pterygium shrunk to almost half its size and continued to decrease in size by continuous use.

A human female suffering from pterygium associated with dry eye and inflammation in one eye was treated with one dose of Form C twice daily. Reduction from dry eye symptoms was achieved within 2 days. The patient required subsequent application twice a day. After 8 weeks of use, the pterygium shrinked to almost half its size and continued to decrease in size by continued use.

A human male suffering from a deep corneal ulcer involving temperament in one eye was treated with one dose of Form A three times a day. Pain and relief from irritation were achieved within 24 hours. The patient required subsequent application twice a day. After 7 days of use, the cornea was completely re-epithelialized.

Three women suffering from diabetic-related keratopathy (neurotrophic keratopathy) were treated with one dose of Form C daily. Corneal paralysis began to improve within 2 to 3 days. The patient required subsequent application twice a day. After approximately 3 weeks of use, the patient reported complete relief of symptoms.

One male suffering from diabetes-related neovascularization was treated with one dose of Form A twice a day. When tested after 4 weeks of use, abnormal blood vessels were no longer visible by slit lamp examination.

Two human males suffering from viral eye infections with corneal abrasions (ie, onset of corneal ulcers) were treated with one dose of Form A twice a day twice daily. Excretion was stopped within 5 hours. The patient required subsequent application twice a day. After 2 to 3 days of use, the redness (or red sea) of the eye disappeared and the eyes were fully healed within 5 to 6 days.

A human female suffering from corneal ulcers in one eye was treated with one dose of Form A twice a day. Pain and relief from irritation were achieved within one day. The patient required subsequent application twice a day. After 7 days of use, the ulcer was completely healed.

Four human males suffering from diabetes - related dry eye were treated with one dose of Form A twice daily. Mitigation from dry eye symptoms was achieved within an average of 30 minutes. The patient required subsequent application twice a day. After an average of one week of use, the redness (or redness) of the eyes completely disappeared.

Two women suffering from diabetic-related corneal paralysis were treated with one dose of Form A daily. Symptoms of corneal paralysis began to improve within two days. After approximately one week of use, the patient reported complete relief of symptoms.

A human male suffering from diabetes-related neovascularization was treated with one dose of Form C twice a day. The patient required subsequent application twice a day. After 16 days of testing, abnormal blood vessels were no longer visible by slit lamp examination.

Six human patients suffering from GvHD-related dry eye were treated with one dose of Form C twice a day in both eyes. Reduction from dry eye symptoms was achieved within 1 hour. The patient required subsequent application twice a day. After an average of one week of use, the redness (or redness) of the eye disappeared.

Men who suffered from both uveitis in both eyes were treated with one dose of Form C three times a day. Pain relief was achieved within 3 days. Visibility blur was resolved within 7 days. The inflammation was completely resolved within 14 days. The patient continued to follow-up twice daily to maintain remission.

A human male suffering from uveitis in both eyes was treated with one dose of Form B three times a day. Pain relief was achieved within two days. The field of view blur was resolved within 14 days. The inflammation was completely resolved within 18 days. Patients continued to follow-up twice daily to maintain remission.

Three human patients suffering from GvHD-related dry eye were treated with one dose of Form D in the eye twice a day. Reduction from dry eye symptoms was achieved within one hour. The patient required subsequent application twice a day. After an average of one week of use, the redness (or redness) of the eye disappeared.

Additional preferred embodiments and experiments

The dipyridamole eye drops were prepared by dissolving dipyridamole in sterile water. If necessary, the pH was adjusted to achieve solubility. Several concentrations ranging from 5 mcg / ml to 200 mcg / ml were prepared. The sterilization procedure was followed.

(8: 1: 1) to prepare a dipyridamole ophthalmic solution by mixing dipyramidol among liquid paraffin and base of wooly bark. Several concentrations ranging from 5 mcg / ml to 200 mcg / ml were prepared. The sterilization procedure was followed.

One of the dipyridamole drops (one to three times per day [approximately 0.05 ml] per day) or dipyridamol ointment (approximately 0.1 to 0.3 ml [one to two times a day]) was administered to a syringe-related dry eye, 0.0 > cornea < / RTI > or allergic conjunctivitis. The concentration used was gradually increased if allowed.

result

Sjogren-related dry eye: I experienced a slight temporal sensation when applying drops / ointment. Partial relief of dry eye symptoms began within one hour of application. After about 7 days of continuous use, relief is complete, continuing daily administration in some patients and period (every 3 to 4 days) in the remaining patients.

Nonspecific keratitis: I experienced a slight temporal sensation when applying drops / ointments. Experienced lower pain intensity within one to two hours of application. Pain relief was completed after 3 to 4 cycles (every few hours) of the drop solution / ointment. Complete resolution of keratitis was achieved within 2 to 7 days of continuous application.

Conical cornea: Daily administration for 3 months (1-2 times daily) resulted in improvement in astigmatism in which the cylinder could be reduced by 1/4 to 1/2 of the number in two subjects.

Conjunctivitis (nonspecific): I experienced a slight temporary tingling sensation when applying drops / ointments. Partial relief of conjunctivitis symptoms (itching, burning sensation or excessive tears) began within one hour of application. The application was continued once or twice a day. After 2 to 4 days of use, all symptoms including exudation were alleviated.

While the invention has been described with respect to a limited number of embodiments, it will be appreciated that many variations, modifications, and other applications of the invention may be made.

In the present description, for example, paragraphs [0002], [0003], [0004], [0006], [0007], [0008], [0014], [0019], [0020] [0028] In some embodiments of the present invention, the compounds of formula (I) are selected from the group consisting of [0029], [0029], [0030], [0031], [0032], [0033], [0034], [0035], [0036] All of the eye disorders listed in [0042], [0043], [0044], [0047], [0048], [0050] and [0051] ) And / or tear organs.

Industrial availability

Compositions employing dipyridamole are applied to the treatment of eye disorders and to innovations that overcome the problems associated with these diseases.

Claims (10)

A composition for use in treating an eye disorder,
Comprising an effective amount of topically-administered dipyridamole. 2. The composition of claim 1, wherein said topically-administered dipyridamole is formulated as a solution. 2. The composition of claim 1, wherein said topically-administered dipipidol is at least one agent selected from the group consisting of dipyridamole and pharmaceutically acceptable salts thereof. The composition of claim 1, wherein the effective amount corresponds to a concentration of at least about 10 ^-5 molar concentration. 2. The composition of claim 1, wherein said effective amount is based on at least one treatment dose every two days. A composition for use in treating tear organs and anterior segment eye disorders,
An effective amount of topically-administered dipiperidol for treating an eye disorder affecting the anterior segment of the eye, including the tear organs, and conjunctiva. 7. The composition of claim 6, wherein said topically-administered dipyridamole is formulated as a solution. 7. The composition of claim 6, wherein the topically-administered dipiperidomol is at least one agent selected from the group consisting of dipyridamole and pharmaceutically acceptable salts thereof. 7. The composition of claim 6, wherein the effective amount corresponds to a concentration of at least about 10 < ^-5 > molar concentration. 7. The composition of claim 6, wherein the effective amount is based on at least one treatment dose every two days.