KR101674457B1 - Pharmaceutical Composition for Preventing or Treating Vascular Permeability Disease Comprising Dasatinib or Pharmaceutically Acceptable Salts thereof as an Active Ingredient - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating vascular permeability related diseases, which comprises dasatinib or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition according to the present invention inhibits vascular permeability, It is possible to effectively prevent or treat a disease caused by vascular permeability.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for preventing or treating vascular permeability related diseases comprising, as an active ingredient, dasatinib or a pharmaceutically acceptable salt thereof, }

The present invention relates to a pharmaceutical composition for the prevention or treatment of vascular permeability related diseases comprising dasatinib or a pharmaceutically acceptable salt thereof as an active ingredient.

The blood vessels are essential for the survival and normal functioning of all the cells constituting the human body. In particular, the innermost vascular endothelial cells constitute a single layer, which regulates the leakage of proteins, fluids and electrolytes in the blood into surrounding tissues To form a cellular barrier. The gap between these endothelial cells is very narrow in the normal vessels and the permeability of the blood vessels is low. However, when inflammatory cells are infiltrated into the blood vessels or become hypoxic by vascular injury, various cytokines and vascular endothelial growth factors , VEGF), the gap between vascular endothelial cells is destabilized and vascular permeability is significantly increased. Increased vascular permeability leads to increased leaking of body fluids to surrounding tissue.

Increased vascular permeability is a cause of various diseases, especially excessive retinal permeability in the retina or choroid promotes hemorrhage and macular edema, which is the most common cause of fatal visual loss do. Typical diseases with this pathogenesis are diabetic retinopathy (DR), diabetic macular edema (DME), macular edema due to retinal vein occlusion, macular degeneration, Choroidal neovascularization, retinopathy of prematurity (ROP), and the like (Non-Patent Document 1 and Non-Patent Document 2). To date, most studies on the regulation of vascular permeability have been limited to VEGF or VEGF receptors, and most of them are concentrated on the development of inhibitors against these genes.

On the other hand, dasatinib has been used as an anticancer agent for chronic myelogenous leukemia (CML) or Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL). Dasatinib is a drug that can be used as a secondary drug if it fails to heal during treatment with Gleevec or if it can not be used due to side effects. It can be selected according to the type of Gleevec resistance and can be selected from the viewpoint of side effects according to the patient's condition. It is known. Thus, there has been no report on the progress of some studies regarding the anticancer use of dasatinib, but whether it can regulate vascular permeability with dasatinib.

Surv Ophthalmol. 2007 Jan; 52 Suppl 1: S3-19. Afzal et al., Microvasc Res., 74 (2-3): 131-144, 2007

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating vascular permeability related diseases comprising, as an active ingredient, dasatinib or a pharmaceutically acceptable salt thereof.

In order to solve the above problems, the present invention provides a pharmaceutical composition for preventing or treating vascular permeability-related diseases comprising as an active ingredient dasatinib or a pharmaceutically acceptable salt thereof.

The term pharmaceutically acceptable salts refers to salts which are within the scope of medical judgment and which are suitable for use in contact with the tissues of humans and / or animals without undue toxicity, irritation, allergic response and the like.

Such pharmaceutically acceptable salts are well known in the art. The pharmaceutically acceptable salts may be obtained during the final isolation and purification of the compounds of the present invention or may be obtained by separately reacting free base functional groups with an appropriate inorganic acid such as hydrochloric acid, phosphoric acid or sulfuric acid, or by reacting an organic acid such as ascorbic acid, , Lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulfonic acid and the like. The acid functional group may be reacted with an organic base or an inorganic base, for example sodium hydroxide, potassium hydroxide or lithium hydroxide.

In the present invention, the term " vascular permeability-related disease "refers to a disease caused by the collapse of the normal regulation of vascular permeability, and generally refers to a disease that causes bleeding by increasing blood permeability and increasing permeability.

The vascular permeability related diseases include diabetic retinopathy, diabetic macular edema, macular edema due to retinal vein occlusion, macular degeneration, choroidal neovascularization, glaucoma retinitis pigmentosa, retinopathy of prematurity (ROP) ), Glaucoma, corneal dystrophy, retinoschisis, Stargardt's disease, autosomal dominant druzen, Best's macular dystrophy, cystoid macular edema, Ischemic retinopathy, inflammation-induced retinal degenerative disease, X-linked juvenile retinoschisis, Malathia retinoschisis, Maltia Leventinese (ML) or Doyne honeycomb retinal dystrophy, but the present invention is not limited thereto.

For purposes of the present invention, the term "treatment" refers to any act that is clinically intervened to alter the natural course of an individual or cell to be treated, and may be performed during or during the course of a clinical pathology have. The desired therapeutic effect is to prevent the occurrence or recurrence of the disease, to alleviate the symptoms, to reduce all direct or indirect pathological consequences of the disease, to prevent metastasis, to reduce the rate of disease progression, Or temporarily alleviating, or improving the prognosis. For the purpose of the present invention, the above-mentioned treatment is to administer a pharmaceutical composition comprising, as an active ingredient, dasatinib or a pharmaceutically acceptable salt thereof, to a patient suffering from a vascular permeability-related disease to improve the course of the vascular permeability- But is not limited thereto.

In the present invention, the term "prophylactic" refers to administration of a pharmaceutical composition containing, as an active ingredient, dasatinib or a pharmaceutically acceptable salt thereof provided by the present invention to a subject in whom the occurrence of a vascular permeability related disease is expected Quot; means all actions that inhibit or delay the onset of the disease.

The composition of the present invention, optionally together with pharmaceutically acceptable additives, is formulated into a formulation suitable for administration. Examples of formulations suitable for oral administration include tablets, capsules, granules, fine granules and powders, and the like; Formulations suitable for parenteral administration include injections, eye drops, ointments, patches, gels, and intercalating agents. These formulations may be formulated using conventional techniques commonly used in the art. Furthermore, in addition to these preparations, the composition of the present invention can be formulated into a preparation made from a drug delivery system (DDS) such as a preparation for guinea pig implant and a microsphere.

For example, the tablet may contain excipients such as lactose, glucose, D-mannitol, dicalcium phosphate anhydrous, starch and sucrose; Disintegrating agents such as carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially alpha-starch and low-substituted hydroxypropylcellulose; Binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially-alpha-starch, polyvinylpyrrolidone and polyvinyl alcohol; Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, and hydrogenated oils; A tablet such as tablets, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, and polyvinylpyrrolidone; And flavorings such as citric acid, aspartame, ascorbic acid and menthol.

Injection agents include, for example, isotonic agents such as sodium chloride; Buffering agents such as sodium phosphate; Surfactants such as polyoxyethylene sorbitan monooleate; And thickeners such as methylcellulose, and the like can be optionally used.

Eye drops include isotonic agents such as, for example, sodium chloride, potassium chloride, glycerin, concentrated glycerin, mannitol, sorbitol, boric acid, glucose, and propylene glycol; Buffers such as phosphate buffers, acetate buffers, borate buffers, carbonate buffers, citrate buffers, Tris buffers, and glutamic acid; Surfactants such as polyoxyethylene sorbitan monooleate, stearic acid polyoxyl 40 and polyoxyethylene hardened castor oil; Stabilizers such as sodium citrate and sodium edetate; And a preservative such as benzalkonium chloride and paraben can be optionally used. The pH of the eye drops may be within the ophthalmically acceptable range, but it is usually in the range of 4 to 8. In addition, the ointment can be prepared using a general-purpose base such as white petrolatum and liquid paraffin. Formulations for ocular administration, such as eye drops, may be formulated as liquid solutions, gels, sprays, suspensions, microemulsions, or nanoparticles, including creams, foams, and emulsions.

Dosage and dosage of the eye drops of the present invention vary depending on the patient's symptoms and age. In the case of eye drops and suspensions, the dose is normally 2 to 4 times per day, 1 to 5 drops per one time, and in the case of ophthalmic solution, ~ 3 times, it is used by applying an appropriate amount in the conjunctival sac.

The intercalating agent is prepared, for example, by pulverizing and mixing a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid together with the compound of the present invention, followed by compression molding the powder . Optionally, excipients, binders, stabilizers and pH adjusting agents may be used. The preparations for guinea pig implantation can be produced using biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid-glycolic acid copolymer, and hydroxypropylcellulose. The intercalating agent may be formulated into a patch or a contact lens.

The pharmaceutical composition of the present invention may be manufactured into a preparation in the form of immediate-release, sustained-release, pulsatile, or time-release release type. Any method capable of causing each active ingredient to have the above-described preferable time difference range can be achieved by using methods known in the art without any particular limitation.

Dosages suitable for the prevention or treatment of the disease will depend upon the type of disease to be treated, the severity and course of the disease, whether the composition of the invention is administered for prophylactic or therapeutic use, The clinical history and response to dasatinib, and the judgment of the attending physician. Dasatinib is suitable for administration to a patient once or throughout a series of treatment periods.

When co-administered with a second therapeutic agent that decreases vascular permeability, the second therapeutic agent can be administered first and then the dasatinib can be administered. It is also contemplated that co-administration or first administration of the dasatinib is contemplated. A suitable dosage for the second therapeutic agent is the amount currently used and the amount may be reduced due to the combined action (synergistic action) of such agent with dasatinib.

Said second therapeutic agent is an inhibitor that reduces the expression or activity of VEGF or its receptor (hereinafter referred to as "VEGF inhibitor"), Angiopoietin or its receptor, dexamethasone dexamethasone), and triamcinolone (corticosteroid-related drugs such as triamcinolone).

The VEGF inhibitor is an agent that inhibits the promotion of angiogenesis by attenuating the action of VEGF, and may also exhibit pharmacological actions such as inhibition of vascular permeability and inhibition of vascular endothelial cell proliferation. VEGF inhibitors include anti-VEGF antibodies, VEGF ligand inhibitors, antagonists of VEGF receptors, and nucleic acid drugs related to VEGF.

Specific examples of the VEGF ligand inhibitor include VEGF-Trap, and VEGF-Trap EYE. Specific examples of the anti-VEGF antibody include bevacizumab sodium and ranibizumab. Specific examples of antagonists of VEGF receptors are sorapenib and sunitinib. Specific examples of the nucleic acid medicines related to VEGF include pecticum sodium, which is an aptamer medicine, and RTP801i-14, which is siRNA. In addition, bevacizumab sodium, ranibizumab, VEGF-Trap, and VEGF-Trap EYE inhibit the binding of VEGF to the receptor by binding broadly to all VEGFs non-selectively.

Depending on the type and severity of the disease, about 1 ug / kg to about 100 mg / kg, preferably 0.1 mg / kg to 10 mg / kg of dasatinib, whether single or multiple doses or continuous infusion, Lt; / RTI > A typical daily dose may range from about 1 [mu] g / kg to 100 mg / kg or more, depending on the factors mentioned above. In the case of repeated administration over several days, the treatment is continued until the desired disease symptom suppression appears depending on the disease. However, other dosages may be used. In a preferred embodiment, the dasatinib is administered at a dose ranging from about 0.1 mg / kg to about 15 mg / kg.

In one embodiment of the present invention, dasatinib was administered to an animal model in which diabetic retinopathy, a representative vascular permeability related disorder, was induced, and as a result, vascular permeability was remarkably reduced (see FIG. 3) Its pharmaceutically acceptable salts have therapeutic effects on vascular permeability related diseases.

The route of administration of the pharmaceutical composition according to the present invention may be one selected from the group consisting of oral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, intramuscular, intravenous, intraarterial and intraocular administration, Oral, intraperitoneal, and topical administration, and more preferably, it may be an intraocular administration. The intraocular administration may be one selected from the group consisting of intraocular conjunctival injection, intravaginal administration (intrarectal administration), subconjunctival administration and subtenon injection, preferably intravenous administration.

Since the pharmaceutical composition according to the present invention significantly reduces the vascular permeability of an animal model in which diabetic retinopathy is induced, dasatinib or a pharmaceutically acceptable salt thereof can be used for the prevention or treatment of vascular permeability related diseases have.

The pharmaceutical composition containing the dasatinib or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient inhibits vascular permeability and thus can treat ocular diseases caused by vascular permeability.

1 is a graph showing the effect of dasatinib on blood glucose in an animal model of diabetic retinopathy.
Figure 2 is a graph showing the effect of dasatinib on body weight in an animal model of diabetic retinopathy.
FIG. 3 is a photograph and a graph showing the results of confirming the preventive effect of dasatinib on the induction of diabetic retinopathy, which is a disease model of increasing vascular permeability, wherein FIG. 3A is a graph showing blood vessel permeability FIG. 3 (B) is a graph showing the effect of improving the vascular permeability according to the treatment concentration of dasatinib: DM (Diabetic Mellitus). FIG.

Hereinafter, the present invention will be described in detail with reference to Experimental Examples and Production Examples.

However, the following Experimental Examples and Preparation Examples are for illustrating the present invention, and the contents of the present invention are not limited by the following Experimental Examples and Production Examples.

< Experimental Example  1> diabetic Retinopathy  For animal models Dasatinib  effect

When STZ (streptozotocin, Sigma) was administered to the abdominal cavity of Sprague Dawley rats (SD rats) for 3 days at a dose of 50 mg / kg (intravitreous injection) per day, blood glucose level was 300 mg / dl or more Were used as animal models of diabetic retinopathy. In addition, the group not treated with STZ was used as a normal control group for an animal model of diabetic retinopathy (hereinafter referred to as "normal"). DMSO was treated as a negative control in diabetic rats 3 days after STZ administration and intravitreous injection of dasatinib (Selleckchem. Houston, TX, USA) was carried out at a dose of 50 or 100 μg as an experimental group.

<1-1> Diabetic Retinopathy  Animal model for blood sugar Dasatinib  effect

On the 8th and 15th day of the first administration of STZ, blood glucose levels of the animal models (normal, control and experimental groups) were measured.

As a result, in the STZ-induced diabetic retinopathy animal model, both the dasatinib-treated group and the control group (DMSO-treated group) were found to have higher blood glucose levels than the STZ-treated normal group. However, no difference in blood glucose was observed between the Dasatinib treated group and the control group (DMSO treated group). As a result, it was confirmed that dasatinib did not directly affect blood glucose (Fig. 1).

<1-2> Diabetic Retinopathy  Animal Model for Weight Dasatinib  effect

On the 8th day and 15th day of the first administration of STZ, the body weight of the animal model (normal, control and experimental groups) was measured.

As a result, in STZ-induced diabetic retinopathy animal model, no difference in body weight between the group administered with dasatinib and the control group was observed. As a result, it was confirmed that dasatinib did not directly affect body weight (FIG. 2).

<1-3> Diabetic Retinopathy  On the vascular permeability of animal models Dasatinib  effect

To observe the change of retinal vascular permeability, the animal model was anesthetized on the 12th day after the administration of the drug (15 days as of the first day of STZ administration), and the FITC-labeled dextran (Fluorescein isothiocyanate-dextran) Was injected to allow the fluorescent material to flow along the blood. After 30 minutes, the retina of the animal model was extracted, separated, flat mounted, and observed for fluorescence distribution in the retina by fluorescence microscopy.

As a result, as shown in FIG. 3, it was confirmed that the retina of the diabetic rat (control group) increased the permeability of the retinal vasculature and the fluorescent material leaks into the surrounding tissue to induce diabetic retinopathy. However, It was confirmed that the leakage of the fluorescent substance was remarkably reduced and the occurrence of diabetic retinopathy was prevented or mitigated (FIG. 3). From the above results, it was found that dasatinib can treat or prevent diabetic retinopathy with increased vascular permeability.

< Formulation example  1> Dasatinib  Or a pharmaceutically acceptable salt thereof.

Representative pharmaceutical examples using dasatinib or a pharmaceutically acceptable salt thereof are shown below.

<1-1> Injection

In 10 ml

10 mg of dasatinib

90 mg of sodium chloride

Polysorbate 80 qs

Sterile purified water volume

Dasatinib and sodium chloride are dissolved in sterile purified water to prepare an injection. By changing the addition amount of the dasatinib, injections of 0.1 mg, 10 mg and 50 mg in 10 ml can be prepared.

<1-2> Eye drops (One)

In 100 ml

10 mg of dasatinib

900 mg of sodium chloride

Sterile purified water volume

The concentration of 0.001% (w / v), 0.03% (w / v), 0.1% (w / v), 0.3% (w / v), 1.0% (w / v) Eye drops can be prepared.

<1-3> Eye drops (2)

In 100 ml

Dasatinib 100 mg

800 mg of sodium chloride

100 mg of disodium hydrogen phosphate

Sodium dihydrogenphosphate

Sterile purified water volume

An eye drop of 0.05% (w / v), 0.3% (w / v), 0.5% (w / v) and 1% (w / v) can be prepared by changing the addition amount of dasatinib.

<1-4> Osteoporosis

Of 100g

0.3 g of dasatinib

Liquid paraffin 10.0 g

White petrolatum

By varying the amount of dasatinib added, ointments at concentrations of 1% (w / w) and 3% (w / w) can be prepared.

<1-5> Purification

100 mg

1 mg of dasatinib

Lactose 66.4 mg

Corn starch 20 mg

Carboxymethylcellulose calcium 6 mg

6 mg of hydroxypropylcellulose

0.6 mg of magnesium stearate

Dasatinib and lactose were mixed in a mixer, carboxymethylcellulose calcium and hydroxypropylcellulose were added thereto, and the mixture was granulated. The resulting granules were dried and sieved, and magnesium stearate was added to the granules. And the mixture was compressed into tablets. Further, by changing the addition amount of the dasatinib, a tablet having a content of 0.1 mg, 10 mg and 50 mg in 100 mg can be prepared.

Claims (10)

A pharmaceutical composition for preventing or treating vascular permeability related diseases comprising, as an active ingredient, dasatinib or a pharmaceutically acceptable salt thereof,
The vascular permeability related diseases include diabetic retinopathy, diabetic macular edema, macular edema due to retinal vein occlusion, macular degeneration, choroidal angiogenesis, glaucoma retinitis pigmentosa, retinopathy of prematurity, glaucoma, corneal dystrophy, Ischemic retinopathy, inflammation-induced retinal degenerative disease, X chromosome-associated burner retinal detachment, Malathia lentinensis, and ischemic retinal dystrophy. Or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the prevention or treatment of vascular permeability related diseases. delete The method according to claim 1,
Wherein the administration route of the composition is one selected from the group consisting of oral, subcutaneous, intraperitoneal, intrapulmonary, intranasal, intramuscular, intravenous, intraarterial, and topical intravenous administration for the prevention or treatment of vascular permeability related diseases Gt; The method of claim 3,
Wherein the administration route is one selected from the group consisting of oral, intraperitoneal, and intraocular administration. The method of claim 4,
Wherein the intraocular injection is one selected from the group consisting of intraocular conjunctiva, intravaginal injection, subconjunctival injection, and intramuscular administration. The method of claim 5,
Wherein said intraocular administration is intravaginal administration. &Lt; RTI ID = 0.0 &gt; 11. &lt; / RTI &gt; The method according to claim 1,
The pharmaceutical composition for preventing or treating vascular permeability related diseases, wherein the polysaccharide or the pharmaceutically acceptable salt thereof is administered at a dose of 1 / / kg to 100 mg / kg. The method of claim 7,
The pharmaceutical composition for preventing or treating vascular permeability related diseases, wherein said polysaccharide is administered at a dose of 0.1 mg / kg to 15 mg / kg. The method according to claim 1,
A pharmaceutical composition for the prevention or treatment of vascular permeability related diseases, which further comprises a second therapeutic agent which decreases vascular permeability. The method of claim 9,
Wherein said second therapeutic agent is selected from the group consisting of a VEGF inhibitor, an angiopoietin or an inhibitor that reduces the expression or activity of its receptor, dexamethasone and triamcinolone.

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