HK40000009A - Compositions and methods of using nintedanib for treating ocular diseases with abnormal neovascularization - Google Patents

Description

Compositions and methods for treating ocular diseases with aberrant neovascularization using nintedanib

Priority requirement

The present application claims the benefit of U.S. provisional patent application serial No. 62/344,878 filed on day 6/2 of 2016 and U.S. provisional patent application serial No. 62/344,870 filed on day 6/2 of 2016, which are hereby incorporated by reference in their entirety.

Technical Field

The present disclosure relates to ocular compositions and methods for using nintedanib to treat and prevent graft rejection in high risk corneal transplant patients, as well as to treat ocular diseases involving abnormal neovascularization in the anterior portion of the eye.

Background

Abnormal neovascularization is implicated in many diseases in the anterior segment of the eye. Abnormal neovascularization is implicated in graft rejection in high risk corneal transplant patients. Current treatments for many of these indications require improvement. The methods disclosed herein address the problems in current treatments and provide improved treatments for these diseases.

Summary of The Invention

In certain aspects, the present disclosure provides methods of treating an ocular disease involving aberrant neovascularization in the anterior portion of the eye, the method comprising administering to the eye of a subject in need of such treatment an effective amount of nintedanib or a pharmaceutically acceptable salt thereof. In certain aspects, the disclosed methods treat, prevent, or delay the onset of graft rejection in a corneal transplant patient. For example, the disclosed methods treat, prevent, or delay the onset of graft rejection in a corneal transplant patient at high risk of graft rejection. In certain aspects, the disclosed methods are performed preoperatively, in combination with or post-operatively, to prevent graft rejection in high corneal graft risk.

In certain aspects, the nintedanib is administered in the form of a topical ocular formulation that is topically administered to the affected eye. In certain aspects, the concentration of nintedanib in the formulation is 0.001% to 10% by weight or volume of the total composition. For example, the aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% of nintedanib. In certain aspects, the topical ophthalmic formulation is a solution, suspension, gel, or emulsion. In another aspect, the nintedanib is administered in the form of an implant or a semi-solid sustained release formulation that is injected into the affected eye. In certain aspects, the amount of nintedanib in the implant is 1 μ g to 100 mg.

The term "subject" refers to an animal or human, or one or more cells derived from an animal or human. Preferably, the subject is a human. The subject may also include a non-human primate. A human subject may be referred to as a patient.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims.

Brief Description of Drawings

Fig. 1 is a schematic diagram illustrating an exemplary mechanism for preventing graft rejection in a high risk corneal transplant patient according to the present disclosure.

Figures 2A and 2B are graphs showing reduced corneal neovascularization in the presence of nintedanib in a rabbit corneal suture model. Figure 2A provides the results for day 12 and figure 2B provides the results for day 14. The area of corneal neovascularization for each treatment group is shown (CBT-1 ═ nintedanib eye formulation: 0.2% CBT-1BID, 0.2% CBT-1 TID; 0.05% CBT-1BID, 0.0.5% CBT-1 TID; vehicle control TID the level of T-test significance for each group compared to vehicle is shown by an asterisk.

Detailed Description

Corneal transplantation is a common surgical procedure. While the overall success rate of corneal transplantation is good, graft failure remains a problem for some high risk patients. These patients have high inflammation and neovascularization in the host bed, which confers enhanced immune response and allograft rejection (Yu et al.World J Transplant.2016; 6(1): 10-27). Oral immunosuppressive drugs are sometimes used to reduce the risk of graft failure, but they have systemic side effects. The disclosed methods will inhibit excessive neovascularization mediated by vascular endothelial growth factor ("VEGF") and platelet derived growth factor ("PDGFR") and attenuate VEGF and fibroblast growth factor ("FGF") related immune responses to prevent graft rejection in high risk patients. The mechanism is shown in fig. 1.

In addition to corneal graft rejection, the disclosed methods may be used to treat any ocular indication involving aberrant neovascularization in the anterior segment of the eye. These indications include graft versus host disease, atopic conjunctivitis, ocular rosacea, ocular pemphigoid, leigh's syndrome, neovascularization induced by viral, bacterial, fungal or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burn, stem cell deficiency, palpebral fissure, neovascular glaucoma, dry eye disease, Sjogren's syndrome, meibomian gland dysfunction, Sjogren's syndrome, tumors in the eye.

The terms "treatment" and the like are used herein generally to refer to obtaining a desired pharmacological and/or physiological effect. The effect may be prophylactic in terms of complete or partial prevention of the disease or symptoms thereof and/or may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or adverse effects attributable to the disease. The term "treatment" includes any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and/or symptom from occurring in a subject that may be predisposed to the disease or symptom but has not yet been diagnosed as having the disease or symptom; (b) inhibiting the disease and/or symptoms, i.e., arresting their development; or (c) relieving the symptoms of the disease, i.e., causing regression of the disease and/or symptoms. Those in need of treatment include those already with disease (e.g., those with increased corneal neovascularization, etc.) as well as those in whom prevention is desired.

Nintedanib { (3Z) -3- { [ (4- { Methyl [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl) amino ] (phenyl) methylene } -2-oxo-2, 3-dihydro-1H-indole-6-carboxylic acid Methyl ester } (Methyl (3Z) -3- { [ (4- { Methyl [ (4-methylpiperazin-1-yl) acetyl ] amino } phenyl) amino ] (phenyl) methylidene } -2-oxo-2, 3-dihydo-1H-index-6-carboxylate) is a kinase inhibitor as described herein nintedanib mainly inhibits receptor tyrosine kinases including, for example, vascular endothelial growth factor receptor (VEGFR 1-3), platelet derived growth factor receptor (PDGFR α and β), fibroblast growth factor receptor (FGFR 1-4).

Formulations and dosing regimens

The methods described herein include the preparation and use of pharmaceutical compositions comprising compounds identified as active ingredients by the methods described herein. Also included are the pharmaceutical compositions themselves.

Pharmaceutical compositions typically include a pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.

The phrase "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of interest that is safe and effective for administration to a mammal and that has a desired biological activity. Pharmaceutically acceptable acid salts include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, I0 isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartrate (bitartte), ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., I' ethylene-bis- (2-hydroxy-3-naphthoic acid)) salts. Suitable base salts include, but are not limited to, 15 aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.

Methods of formulating suitable pharmaceutical compositions are known in the art, see, e.g., Remington, the science and Practice of Pharmacy,21st ed., 2005; and books in the Drugs and pharmaceutical Sciences a Series of Textbooks and monggrams (Dekker, NY) Series. For example, a solution, suspension, cream, ointment, gel-forming liquid, liposome or micelle containing suspension, spray formulation or emulsion for ophthalmic use may comprise the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; an antibacterial agent; an antioxidant; a chelating agent; buffers such as acetates, citrates or phosphates and tonicity agents such as sodium chloride or dextrose. The pH can be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide.

The pharmaceutical compositions disclosed herein may comprise a "therapeutically effective amount" of an agent described herein. If more than one agent is used, such effective amount can be determined based on the effect of the administered agents or the combined effects of the agents. The therapeutically effective amount of the agent may also vary with factors such as the disease state, the age, sex, and weight of the individual, and the ability of the compound to elicit a desired response in the individual, e.g., an improvement in at least one parameter of the condition or an improvement in at least one symptom of the condition. A therapeutically effective amount is also one in which the therapeutically beneficial effect outweighs any toxic or detrimental effects of the composition.

Effective dosages of the compositions of the present disclosure for treating a condition vary with a number of different factors, including the mode of administration, the target site, the physiological state of the subject, whether the subject is a human or an animal, the other drug administered, and whether the treatment is prophylactic or therapeutic. Therapeutic doses can be titrated to optimize safety and efficacy using conventional methods known to those skilled in the art.

Pharmaceutical compositions suitable for injectable use may include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. It should be stable under the conditions of manufacture and storage and must provide protection against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. For example, proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants. The action of microorganisms can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it is preferred to include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, and sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and freeze-drying which yield a powder of the active ingredient plus any other desired ingredient from a previously sterile-filtered solution thereof.

In one embodiment, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound from rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers may be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Such formulations may be prepared using standard techniques, or are commercially available.

The pharmaceutical composition may be contained in a container, package or dispenser together with instructions for administration.

Compositions and formulations of nintedanib may be administered topically or as a semi-solid formulation or injection of a solid implant, or by any other suitable method known in the art. Although the agents disclosed herein may be used per se for therapy, it is preferred that the agents be administered as a pharmaceutical formulation, e.g., mixed with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical formulations include at least one active compound, together with pharmaceutically acceptable excipients, diluents and/or carriers.

The administration of the composition or formulation may be once a day, twice a day, three times a day, four times a day, or more frequently. The frequency may be reduced during the treatment maintenance phase of treatment, for example, once every two days or once every three days, rather than once a day or twice a day. The dosage and frequency of administration can be adjusted at the discretion of the treating physician, for example, to take into account the clinical signs, pathological signs and clinical and subclinical symptoms of the disease for the condition being treated by the method, as well as the clinical history of the patient.

It will be understood that the amount of reagent disclosed herein for use in treatment need will vary with the route of administration, the nature of the condition to be treated, and the age, weight and condition of the patient, and will ultimately be at the discretion of the attendant physician. The compositions generally contain an effective amount of nintedanib. Preliminary doses may be determined from animal testing, and scaling of human administered doses may be performed according to art-recognized practice.

The time of treatment (i.e., number of days) will be readily determined by the physician treating the subject; however, the number of treatment days can range from about 1 day to about 365 days. As provided by the present method, treatment efficacy can be monitored during the course of treatment to determine whether treatment was successful or whether additional (or modified) treatment is required.

The dose, toxicity and therapeutic efficacy of a therapeutic compound can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). Dosage forms of nintedanib can be readily determined by one of ordinary skill and can be obtained, for example, in animal models and clinical studies reported in the literature for determining dosage, safety and efficacy according to standard methods known in the art. The exact formulation, route of administration and dosage may be selected by the individual physician according to the patient's condition.

The composition used in the present method may comprise nintedanib in a concentration of 0.001% to 10% by weight or volume of the total amount of the composition. For example, the aqueous composition comprises 0.001%, 0.01%, 0.1%, 0.5%, 1.0%, 1.5%, 2.0%, 5.0% or up to 10% of nintedanib.

As is well known to those skilled in the art, administration of an aqueous solution to the eye may be in the form of a "drop" or a plurality of "drops" (e.g., a nintedanib solution) from a dropper or pipette or other special sterile device. The volume of such droplets is typically up to 50 microliters, but may be smaller, e.g., less than 10 microliters.

Examples

The invention is further described in the following examples, which do not limit the scope of the invention described in the claims.

Example 1: rabbit cornea suture model

The rabbit corneal suture model of neovascularization demonstrates the ability of this method to reduce abnormal corneal neovascularization.

Topical ophthalmic formulations

Topical compositions were prepared comprising 0.2% or 0.05% nintedanib in 10% 2-hydroxypropyl β cyclodextrin in phosphate buffered solution (ph 7.4).

Animals and treatment procedures

The study was carried out using 30 female Zealand White rabbits (Zealand White rabbit). Briefly, 5 sutures were placed in the upper cornea of the right eye of each animal on day 1 to induce neovascularization. Animals were treated with drug, vehicle or saline in both eyes as described in table 1.

TABLE 1

BID: twice daily (about 10 to 12 hours apart). TID: three times daily (about 6 to 8 hours apart). OD ═ right eye. OS is left eye.

For both eyes, the dose volume was about 40 μ L/eye.

Note that: the first dose of saline on day 1 was completed 4 hours after suture placement.

During the study, the animals were closely observed for various ocular indications as well as general physical conditions including body weight. Eye images were taken for analysis of hyperemia on days 7, 10, 12, 14, 21, and 28.

Data analysis

Software is used to analyze the eye images. Each image is atOpen, calibrate the scale using the ruler in the photograph, and select the newly vascularized area on the cornea near the suture by the selection tool. In mm²The area of the meter was calculated by the measurement tool in the software, recorded in excel, and the image captured and saved. Two-factor t-TEST to determine if pairs of groups differ significantly. The results were plotted as a histogram of mean and standard deviation for ease of comparison.

Results and discussion

As shown in fig. 2A and 2B, nintedanib had significant inhibitory effects on suture-induced neovascularization in rabbit cornea at 12 and 14 days post-suture induction. Higher doses of 0.2% nintedanib showed better efficacy than 0.05% nintedanib, while more frequent dosing regimens with TID showed higher efficacy compared to BID dosing.

In summary, nintedanib strongly inhibits suture-induced corneal neovascularization. The strong activity may be due to a special target profile of nintedanib with potent activity against VEGFR1-3 and FGFR 1-2. These results support the methods disclosed herein.

Example 2: mouse cornea transplant rejection model

In this example, the corneas of C57BL/6 mice were transplanted onto BALB/C mouse corneas as described (Sonoda et al Invest Ophthalmol Vis Sci.1995Feb; 36(2): 427-34; Invest Ophthalmol Vis Sci.2000Mar; 41(3): 790-8.; Yamagami et al Invest Ophthalmol Vis Sci.2001May; 42(6): 1293-8). Sutures will be cut on day 7 post-implantation. Mice were divided into two groups. Group 1 was treated with a nintedanib 0.2% solution and group 2 with a vehicle solution. Immediately after transplantation TID treatment was started for 8 weeks. Corneal haze and graft rejection will be assessed weekly for 8 weeks as described above.

The nintedanib treated group showed a significant increase in survival of the grafts (lower rejection rate) within 8 weeks of the experiment. The results indicate that a 0.2% solution of nintedanib can prevent corneal graft rejection.

Example 3: formulation

Nintedanib eye solution

The drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl β cyclodextrin or other similar cyclodextrins and buffer solutions, pH ranging from 5.5 to 8.0 other viscosities, lubricants, preservatives may be added to enhance the functionality of the formulation the composition of the ophthalmic solution is disclosed in table 2.

TABLE 2 Nintedanib ophthalmic solutions

Nintedanib eye suspension

The drug product is an isotonic eye suspension prepared in sodium carboxymethylcellulose and a buffer solution, with a pH in the range of 5.5 to 8.0. The drug particle size is reduced to below 40 microns. Other viscosities, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the formulation suspension. The composition is disclosed in table 3.

TABLE 3 Nintedanib eye suspensions

Nintedanib eye lotion

The pharmaceutical product is an isotonic eye emulsion. The drug is dissolved in the mixture oil phase and emulsifier vehicle, which is then emulsified and mixed with the water phase at a pH in the range of 5.5-8.0. Other viscosity, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the emulsion formulation. The composition is disclosed in table 4.

TABLE 4 Nintedanib eye emulsions

Nintedanib sustained release semisolid formulation

The pharmaceutical product is an isotonic sustained release semisolid formulation. The drug is dissolved and/or suspended in a semi-solid medium at a pH range of 5.5 to 8.0. Other viscosities, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the sustained release semisolid formulation. The composition is disclosed in table 5.

TABLE 5 sustained Release semisolid formulations

Nintedanib sustained release implant

The pharmaceutical product is a solid implant. The drug is mixed and admixed with one or more polymers. The mixture of drug and polymer is melted at a predetermined temperature and extruded into filaments having a predetermined diameter size. The formulation filaments are cut into segments of a predetermined size that can be implanted into ocular tissue. The composition is disclosed in table 6.

TABLE 6 sustained Release implants

Without limitation, exemplary compositions for use in the method according to the present invention may be modified from existing ophthalmically acceptable compositions.

Other embodiments

It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (25)

1. A method for treating an ocular indication involving aberrant neovascularization, comprising administering to the eye of a subject an effective amount of nintedanib or a pharmaceutically acceptable salt thereof in the form of topical eye drops or implants.

2. The method of claim 1, wherein the indication involving aberrant neovascularization is corneal graft rejection after receiving a corneal implant in a high risk patient.

3. The method of claim 1, wherein nintedanib is administered in an amount effective to prevent graft rejection by inhibiting abnormal neovascularization and inflammation in the eye of the subject.

4. The method of claim 1, wherein the indication involving aberrant neovascularization is graft versus host disease.

5. The method of claim 1, wherein the indication involving aberrant neovascularization is atopic conjunctivitis.

6. The method of claim 1, wherein the indication involving aberrant neovascularization is ocular rosacea.

7. The method of claim 1, wherein the indication involving aberrant neovascularization is ocular pemphigoid.

8. The method of claim 1, wherein the indication that involves aberrant neovascularization is Lele's syndrome.

9. The method of claim 1, wherein the indication involving aberrant neovascularization is neovascularization induced by viral, bacterial, fungal, or parasitic infection.

10. The method of claim 1, wherein the indication involving aberrant neovascularization is contact lens-induced neovascularization.

11. The method of claim 1, wherein the indication involving aberrant neovascularization is ulcer formation.

12. The method of claim 1, wherein the indication involving aberrant neovascularization is an alkaline burn.

13. The method of claim 1, wherein the indication involving aberrant neovascularization is a stem cell deficiency.

14. The method of claim 1, wherein the indication involving aberrant neovascularization is palpebral fissure.

15. The method of claim 1, wherein the indication involving aberrant neovascularization is neovascular glaucoma.

16. The method of claim 1, wherein the indication involving aberrant neovascularization is dry eye.

17. The method of claim 1, wherein the indication involving aberrant neovascularization is Sjogren's syndrome.

18. The method of claim 1, wherein the indication involving aberrant neovascularization is Meibomian gland dysfunction (Meibomian gland dysfunction).

19. The method of claim 1, wherein the indication involving aberrant neovascularization is Steven Johnson syndrome.

20. The method of claim 1, wherein the indication involving aberrant neovascularization is a tumor in the eye.

21. The method of claim 1, wherein the nintedanib is administered in the form of a topical ocular formulation or ocular implant.

22. The method of claim 21, wherein the ocular implant is in the form of a semi-solid or solid sustained release implant.

23. The method of claim 22, wherein the implant is injected into the eye of the subject.

24. The method of claim 21, wherein the topical ocular formulation is a topical eye drop.

25. The method of claim 21, wherein the topical ocular formulation is a solution, suspension, cream, ointment, gel-forming liquid, liposome or micelle containing suspension, spray formulation, or emulsion.