HK40000005B - Compositions and methods of using nintedanib for improving glaucoma surgery success - Google Patents

Description

Compositions and methods for improving the success of glaucoma surgery using nintedanib

Priority claim

This application claims the benefit of U.S. Provisional Patent Application Serial No. 62/344,878, filed June 2, 2016, and U.S. Provisional Patent Application Serial No. 62/344,870, filed June 2, 2016, each of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates to ophthalmic compositions comprising nintedanib and methods of using the same to improve the success rate of glaucoma surgery.

Background Art

Glaucoma refers to a series of eye conditions that damage the optic nerve, usually caused by abnormally elevated intraocular pressure. One method of reducing intraocular pressure in glaucomatous eyes is to form a drainage opening in the eye through surgery. This type of surgery is called glaucoma filtering surgery (e.g., trabeculectomy). In glaucoma surgery, a piece of tissue in the drainage angle of the eye is removed to form an opening. This new opening forms a drainage opening, allowing liquid to drain from the eye. Because the fluid can now be discharged into the reservoir (bubble) below the conjunctiva relatively easily through the new opening, the intraocular pressure is reduced. The fluid is then absorbed by the body.

As a result of glaucoma filtration surgery, scarring and fibrosis may develop at the surgical site. Scarring and fibrosis often lead to a gradual decrease in filtration and loss of control of intraocular pressure. Excessive fibrosis is a key factor leading to scarring and failure of glaucoma filtration surgery. Current treatments to reduce failure remain inadequate and need improvement.

Summary of the Invention

In certain aspects, the present disclosure provides a method for improving the success rate of glaucoma surgery (e.g., glaucoma filtering surgery) by administering nintedanib to the eye of a subject in need of such treatment. One aspect is characterized in that a method for adjuvant therapy related to glaucoma filtering surgery performed in a subject is provided, the method comprising administering a therapeutically effective amount of a composition containing nintedanib or a pharmaceutically acceptable salt thereof to a subject in need thereof. The method improves the success rate of glaucoma surgery. Glaucoma surgery includes, for example, a classic trabeculectomy method or a method selected from the group consisting of trabecular ablation, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation. The glaucoma surgery performed may also be the implantation of an eye filtering device, wherein the eye filtering device is an eye stent. For example, the eye filtering device may be selected from the group consisting of iStent, Hydrus, and CyPass micro-stent.

In some aspects of the methods disclosed herein, the amount of nintedanib administered to the subject is effective to prolong the duration of lower IOP, increase the absolute success rate, or the qualified success rate for at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days after surgery; or the amount of nintedanib administered is effective to prolong bleb survival.

In some aspects, the nintedanib composition is administered in the form of a topical ophthalmic preparation (e.g., topical eye drops) or an implant. In some instances, nintedanib is a topical ophthalmic preparation applied topically to the affected eye. In some aspects, the concentration of nintedanib in the preparation is 0.001% to 10% of the total composition by weight or by volume. In some aspects, the topical ophthalmic preparation is a solution, suspension, or emulsion. In another aspect, nintedanib is an implant or semisolid sustained-release formulation injected into the affected eye. In some aspects, the amount of nintedanib in the implant is from 1 μg to 100 mg.

In certain aspects, the disclosed methods are implemented by combining nintedanib with an antimetabolite. Antimetabolites may be, but are not limited to, mitomycin C, 5-fluorouracil, floxuridine, cytarabine, 6-azauracil, azathioprine, methotrexate, mycophenolate mofetil, and thiothixene.

In another aspect, the disclosed method reduces scarring in glaucoma surgery by reducing abnormal vascular distribution and fibrosis of the surgical site. In some aspects, the disclosed method is performed before surgery, in combination with surgery, or after surgery to reduce the failure of glaucoma surgery. Therefore, in some aspects, the amount of nintedanib administered effectively reduces scarring at the surgical site; in some aspects, the amount of nintedanib administered effectively extends the duration of lower IOP for at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days after surgery. In some aspects, the amount of nintedanib administered effectively extends bubble survival.

As used in this application, the term "one or more" includes at least one, and more suitably 1, 2, 3, 4, 5, 10, 20, 50, 100, 500, etc., of the referred item.

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

Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those of ordinary skill in the art to which the invention pertains. This application describes methods and materials for use with the present invention; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and are not intended to be limiting. The entire contents of all publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference. In the event of a conflict, the present specification (including definitions) will prevail.

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

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a flow chart showing an exemplary mechanism for reducing excess scarring and improving the success rate of glaucoma surgery.

FIG2 is a graph showing bleb survival after glaucoma filtering surgery in a rabbit model.

FIG3 is a graph showing intraocular pressure (IOP) after glaucoma filtering surgery in a rabbit model.

4 is a graph showing the absolute success rate of glaucoma filtering surgery in a clinical study according to the methods disclosed herein.

DETAILED DESCRIPTION

Glaucoma is a series of diseases characterized by death of retinal ganglion cells ("RGCs"), loss of specific visual fields, and optic nerve atrophy. Glaucoma is a worldwide cause of blindness. Various treatment options that effectively reduce intraocular pressure ("IOP") can be used to control and possibly slow the progression of the disease. Treatment options include, for example, medications (i.e., IOP lowering drugs), laser eye surgery, and/or conventional surgical methods, such as glaucoma filtering surgery (alternatively also referred to as filtering surgery or trabeculectomy).

Despite the widespread use of topical IOP-lowering medications in developed countries, glaucoma surgery remains widely performed in other parts of the world (particularly for angle-closure glaucoma). Glaucoma surgery has the advantage of being less expensive over time and does not present the compliance issues associated with the need for multiple daily applications of topical eye drops. Traditional glaucoma filtration surgery and trabeculectomy have high failure rates (Schlunck et al., Exp Eye Res. 2016; 142: 76-82) and implantation of ocular filtration devices (e.g., glaucoma filtration devices) also presents a long-term failure problem (Amoozgar et al., Curr Opin Ophthalmol. 2016; 27(2): 164-9). Failure is attributed to excessive postoperative wound healing followed by fibrotic scarring that obstructs drainage. Surgical damage to tissue typically induces proinflammatory and profibrotic factors, which lead to abnormal extracellular matrix changes and fibrosis. Excessive proliferation of myofibroblasts induced by these factors subsequently causes excessive fibrosis and scarring.

The antimetabolite mitomycin C (MMC) has been administered as an anti-scarring agent during or after glaucoma surgery. Another antimetabolite, 5-fluorouracil (5-FU), is also used during follow-up, primarily by local injection (Schlunck et al., Exp Eye Res. 2016; 142: 76-82). These antimetabolites act by blocking the rapid proliferation of fibroblasts. Their activity is not selective and is known to cause side effects. For example, antimitotic activity sometimes leads to postoperative bleb leakage. Better postoperative management of glaucoma remains an unmet medical need.

Because there are many factors that contribute to scarring after glaucoma surgery, targeting any single pathway alone may not be sufficient to improve the success of surgery. The present disclosure improves the success of glaucoma surgery by administering to the eye a composition with the following key attributes: 1) the composition will simultaneously inhibit several important pathological pathways disclosed below; 2) the composition utilizes small molecule drugs rather than antibody drugs to achieve more efficient drug delivery to target tissues; 3) the composition is a topical formulation in the form of eye drops or implants for convenient and consistent drug delivery to the surgical site; and 4) the composition contains nintedanib, which can be used in combination with antimetabolites to achieve additive or synergistic effects in improving the success of glaucoma filtering surgery.

The present disclosure provides a method for using a topical formulation (e.g., topical eye drops, implants) containing nintedanib before, during, or after surgery. Nintedanib meets the requirements of inhibiting vascular endothelial growth factor ("VEGF") receptors ("VEGFR") 1-3, platelet-derived growth factor receptor (PDGFR)-α and -β, and fibroblast growth factor receptor 2 ("FGFR2") to achieve the desired therapeutic effect.

Without being bound by theory, it should be understood that it is important to inhibit all members of the VEGFR because it is necessary to block placental growth factor ("PIGF") in addition to VEGF. PIGF only acts on pathological angiogenesis and inflammation and is more related to problems associated with glaucoma surgery (Van Bergen et al., J Cell Mol Med. 2013; 17(12): 1632-43). For glaucoma filtering surgery, the disclosed method also inhibits FGFR2 because it plays a role in scar formation. The topical formulations disclosed in the present application can facilitate treatment before, during and after surgery. The mechanism of improving the success rate of glaucoma surgery disclosed in the present application is shown in Figure 1, which shows that nintedanib in a suitable ophthalmic formulation will simultaneously block the signaling pathways of key pathological factors (including PIGF, VEGF, PDGF, FGF) involved in excessive wound healing, and will increase the success of glaucoma surgery by reducing scarring.

As used in this application, the term "improving the success of glaucoma surgery" refers to extending the duration of reduced (i.e., lower) IOP over a period of at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days after surgery, increasing the percentage reduction in IOP over a given period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days) after surgery compared to a pre-operative baseline, increasing the absolute (also known as complete) success rate (defined as maintaining normal IOP) over a given period of time. 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days), an increase in qualified success rate (defined as the percentage of patients who remain within the normal IOP range and have a reduced IOP compared to a baseline on glaucoma medications) over a period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days), and an improvement in bleb grade and survival over a period of time (e.g., at least 10 days, at least 90 days, at least 365 days, at least 750 days, or at least 3650 days).

As used in this application, "normal IOP" or "normal IOP range" refers to an intraocular pressure in a human eye between about 5 mmHg and about 22 mmHg, or between about 10 mmHg and about 21 mmHg.

As used in this application, the terms "treatment", "treating", "treat" and the like generally refer to obtaining a desired pharmacological and/or physiological effect. The effect can be prophylactic in terms of preventing a disease or its symptoms in whole or in part and/or can be therapeutic in terms of partially or completely stabilizing or curing a disease and/or the adverse reactions due to the disease. The term "treatment" includes any treatment for a disease in a mammal (particularly a human being) and includes: (a) preventing the appearance of a disease and/or symptom in a subject that may be susceptible to the disease or symptom but has not yet been diagnosed as having the disease or symptom; (b) suppressing the disease and/or symptom, i.e., preventing its development; or (c) alleviating the symptoms of the disease, i.e., causing the disease and/or symptoms to subside. Those that need treatment include those that are already ill (e.g., those with high IOP, those with infection, etc.) and those that wish to be prevented (e.g., those with increased susceptibility to glaucoma, those suspected of having high IOP, etc.).

Nintedanib {(3Z)-3-{[(4-{methyl[(4-methylhexahydropyrazin-1-yl)acetyl]amino}phenyl)amino](phenyl)methylene}-2-oxo-2,3-dihydro-1H-indole-6-carboxylic acid methyl ester} is a kinase inhibitor as described herein. Nintedanib primarily inhibits receptor tyrosine kinases, including, for example, vascular endothelial growth factor receptors (VEGFR1-3), platelet-derived growth factor receptors (PDGFRα and β), and fibroblast growth factor receptors (FGFR 1-4).

Formulation and dosing regimen

The methods described herein encompass the production and use of pharmaceutical compositions comprising a compound identified as an active ingredient by the methods described herein, and also encompass the pharmaceutical compositions themselves.

Pharmaceutical compositions generally contain a pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with drug administration.

As used in this application, the phrase "pharmaceutically acceptable salt" refers to a salt of a target compound that is safe and effective and has the desired biological activity when administered to a mammal. Pharmaceutically acceptable acid salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, carbonate, bicarbonate, acetate, lactate, salicylate, citrate, tartrate, propionate, butyrate, pyruvate, oxalate, malonate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoic acid (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoic acid)) salts. Suitable basic salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, bismuth, and diethanolamine salts.

Methods for formulating suitable pharmaceutical compositions are well known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, solutions, suspensions, or emulsions for ophthalmic use may contain the following components: a sterile diluent, such as water for injection, saline solution, fixed oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antibacterial agent; an antioxidant; a chelating agent; a buffer, such as acetate, citrate, or phosphate, and a tonicity adjuster, such as sodium chloride or dextrose. The pH may be adjusted using an acid or base, such as hydrochloric acid or sodium hydroxide.

The pharmaceutical composition suitable for injection can include sterile aqueous solution (if soluble in water) or dispersion and sterile powder for preparing sterile injectable solution or dispersion immediately. It should be stable under the conditions of production and storage, and must prevent the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium, which contains, for example, water, ethanol, polyols (for example, glycerol, propylene glycol and liquid polyethylene glycol, etc.) and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by using a coating (such as lecithin), by maintaining the required particle size in the case of a dispersion, and by using a surfactant. The effects of microorganisms can be prevented by using various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferred to include isotonic agents in the composition, such as sugars, polyols (such as mannitol, sorbitol) and sodium chloride. Prolonged absorption of the injectable composition can be achieved by including an agent that delays absorption (such as aluminum monostearate and gelatin) in the composition.

Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound into an appropriate solvent having one of the ingredients listed above or a combination of these ingredients (as required), followed by sterile filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle containing a basic dispersion medium and the desired other ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze drying, which produce a powder of the active ingredient plus any other desired ingredients from a previously sterile-filtered solution thereof.

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

The pharmaceutical compositions can be placed in a container, pack, or dispenser together with instructions for administration.

It can be applied topically (e.g., in the form of a topical ophthalmic preparation) or in the form of an injection of a semisolid preparation or solid implant, or the compositions and preparations of nintedanib can be applied by any other suitable method known in the art. Although the medicament disclosed in the present application can be used as is, it is preferred to administer the medicament in the form of a pharmaceutical preparation, for example, mixed with a suitable pharmaceutical excipient, diluent or carrier selected according to the intended route of administration and standard pharmaceutical practice. The pharmaceutical preparation comprises at least one active compound combined with a pharmaceutically acceptable excipient, diluent and/or carrier.

The pharmaceutical compositions disclosed herein may comprise a "therapeutically effective amount" of an agent described herein. This effective amount can be determined based on the effect of the administered agent, or if more than one agent is used, based on the combined effects of the agents. The therapeutically effective amount of an agent may also vary based on factors such as the individual's disease state, age, sex, and weight, as well as the ability of the compound to stimulate the response in the individual (e.g., improvement in at least one parameter of the condition or improvement in at least one symptom of the condition). A therapeutically effective amount is also an amount in which the beneficial effects of the treatment outweigh any toxic or deleterious effects of the composition.

The effective dose of the disclosed compositions for treating a condition may vary depending on a variety of factors, including the method of administration, the target site, the physiological state of the subject, whether the subject is human or animal, other drugs administered, and whether the treatment is prophylactic or therapeutic. The therapeutic dose may be titrated to optimize safety and efficacy using conventional methods well known to those skilled in the art.

In some examples, the topical ophthalmic formulation is a solution, suspension, cream, ointment, gel, gel-forming liquid, suspension containing liposomes or micelles, spray formulation, or emulsion. In some examples, the topical ophthalmic formulation further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of stabilizers, surfactants, polymer-based carriers, gelling agents, organic cosolvents, pH active ingredients, osmotic active ingredients, and with or without preservatives. In some examples, the sustained-release semisolid formulation, sustained-release solid formulation, or ophthalmic implant is injected into the affected eye. In some embodiments, the sustained-release semisolid formulation, sustained-release solid formulation, or ophthalmic implant further comprises a pharmaceutically acceptable excipient. In some examples, the sustained-release semisolid formulation, sustained-release solid formulation, or ophthalmic implant comprises a multikinase inhibitor, an antimetabolite, or a combination thereof; and a biodegradable polymer selected from the group consisting of polylactic acid (PLA), polyglycolic acid (PLGA), and polylactic acid-polyglycolic acid copolymers.

The composition or formulation can be administered once a day, twice a day, three times a day, four times a day, or more frequently. The frequency can be reduced during the maintenance phase of treatment, for example, every two or three days instead of once a day or twice a day. The dosage and frequency of administration can be adjusted according to the judgment of the treating physician, for example, taking into account the clinical signs, pathological signs, and clinical and subclinical symptoms of the condition being treated using the methods of the present invention, as well as the patient's clinical history.

It should be appreciated that the amount of the medicament disclosed herein required for treatment will vary with the route of administration, the nature of the condition to be treated, and the patient's age, weight, and condition and will ultimately be determined by the attending physician. The composition will typically contain an effective amount of nintedanib. The initial dose can be determined based on animal studies, and the dose can be scaled for human administration based on practices generally recognized in the art.

The length of treatment (i.e., number of days) will be readily determined by the subject's physician; however, the number of days of treatment may vary within the range of about 1 day to about 365 days. As provided by the methods of the present invention, the efficacy of treatment can be monitored during treatment to determine whether the treatment is successful or whether additional (or modified) treatment is needed.

The dosage, toxicity and efficacy of therapeutic compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, such as procedures for determining LD50 (the dose lethal to 50% of the population) and ED50 (the dose therapeutically effective in 50% of the population). The dosage form of nintedanib can be easily determined by those of ordinary skill in the art and can be obtained, for example, in animal models that determine dosage, safety and efficacy according to standard methods known in the art and in clinical studies reported in the literature. The exact formulation, route of administration and dosage can be selected by individual physicians based on the patient's condition.

The composition used in the method of the present invention may comprise nintedanib at a concentration of 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% nintedanib.

As is familiar to those skilled in the art, aqueous solutions administered to the eye can be in the form of a "drop" or drops (e.g., nintedanib solution) of a dropper or pipette or other specialized sterile device. Such drops will typically be up to 50 microliters in volume, but may be less, for example, less than 10 microliters.

Example

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

Example 1: Rabbit glaucoma surgical model

A rabbit glaucoma surgery model was used to illustrate the use of the disclosed method to improve the success of glaucoma filtration surgery. Specifically, an established rabbit glaucoma filtration surgery model was used to study the effects of 0.2% nintedanib solution on postoperative wound healing events. The surgical procedure was as described by Wong et al. (Wong et al., Invest Ophthalmol Vis Sci. 2003; 44(3): 1097-1103). Briefly, a partially torn 8-0 silk corneal traction suture was placed above and the eye was pulled down. The conjunctival flap based on the fornix was raised, and then blunt dissection of the subconjunctival space was performed approximately 5 mm along the limbus and 8 mm posteriorly. A partially torn scleral incision was made 3 to 4 mm posterior to the limbus using a microretinal (MVR) knife, and a scleral tunnel was created to the corneal stroma. A 22-gauge, 25-mm intravenous cannula (Venflon 2; Beckton Dickinson, Oxford, UK) was advanced through the scleral tunnel until the trocar was visible in the clear cornea. The trocar was advanced into the anterior chamber and then withdrawn when the cannula advanced to the mid-pupil. The cannula was trimmed and tilted at the scleral end so that it protruded 1 mm from the insertion point, and a 10-0 nylon suture was placed to secure the tube to the scleral surface. The conjunctival incision was closed using two interrupted sutures and a central mattress 10-0 nylon suture, which was connected to a needle (B/V 100-4; Ethicon) to form a watertight seal. At the end of the operation, one drop of chloramphenicol and Betnesol-N (Glaxo Wellcome, Uxbridge, UK) ointment was instilled into the eye, respectively.

Prior to the start of the experiment, 20 female New Zealand White rabbits (2-2.4 kg, 12-14 weeks old; Charles River) were acclimated for 5 days. Glaucoma surgery, as described above, was performed on the left eye. Postoperatively, the rabbits were divided into two groups, one treated with vehicle and the other with 0.2% nintedanib solution. Treatment began immediately after surgery and continued three times daily for 2 weeks. The survival of the bleb formed after surgery and the intraocular pressure (IOP) were followed for 28 days. Histological analysis of scar tissue was performed at the end of the study.

result

Compared with the vehicle group, the nintedanib group significantly prolonged the successful outcome of the surgery. Figure 2 provides a graph showing the postoperative blister survival curve. As shown in Figure 2, the nintedanib group showed significantly prolonged blister survival compared with the vehicle group. At the end of the 28th day study, no blister survived in the vehicle group, while most blister survived in the nintedanib group. Figure 3 is a graph showing the IOP curve during the postoperative follow-up period. The IOP in the nintedanib group was still low (ie, below 20 mm Hg), while the IOP in the vehicle group gradually increased. The difference was statistically significant. In addition to blister survival and IOP changes, histological analysis of scar tissue at the surgical site showed that the nintedanib group had less scar tissue compared with the vehicle group.

The results of this experiment indicate that nintedanib 0.2% solution increases the success of glaucoma surgery (ie, prolongs bleb survival, prolongs the duration of lower IOP, and/or reduces fibrosis/scarring after surgery).

Example 2: Topical ophthalmic formulation of Nintedanib as an adjunct to glaucoma filtration surgery

In a clinical study, topical nintedanib 0.2% was used as adjunctive therapy to increase the success of trabeculectomy. The effect of topical nintedanib 0.2% on the success rate of trabeculectomy was investigated in a randomized, double-blind, placebo-controlled, 12-month trial. The study design was as described by Vandewalle et al. (Vandewalle et al., Br J Ophthalmol. 2014, Jan;98(1):73-8).

Patients with medically uncontrolled open-angle glaucoma who were scheduled for primary trabeculectomy were enrolled and randomized to receive either one drop of nintedanib or a placebo solution three times daily. Treatment began immediately after surgery and continued for one month. Approximately 150 patients were enrolled in this study.

Surgery will be performed by an experienced surgeon using a modified Moorfields technique under general or retrobulbar anesthesia. IOP will be measured using a Goldmann applanation tonometer. Two measurements will be performed by a blinded observer, and if the difference between the two results is within 2 mm Hg, the two results will be averaged to determine the mean IOP. If the difference between the first two results is >2 mm Hg, a third measurement will be performed.

Patients will be examined at 1 day after trabeculectomy; 1, 2, and 4 weeks; and 3, 6, and 12 months. All patients will undergo a comprehensive ophthalmologic examination, including measurement of best-corrected visual acuity, slit-lamp examination including the Seidel test, IOP measurement, and fundus biomicroscopy using a 90-diopter lens. The number of postoperative IOP-lowering medications used, preoperative and postoperative complications, and surgical interventions will also be recorded.

Absolute success was the primary endpoint, defined as intraocular pressure (IOP) ≤21 mm Hg and >5 mm Hg, a reduction of at least 20% from baseline, and no loss of light perception.

result

Compared to baseline, IOP was effectively reduced in both the nintedanib and placebo groups at the 12-month visit. As shown in Figure 4, the absolute success rate of glaucoma surgery (i.e., maintaining IOP below approximately 20 mm Hg for more than 12 months after surgery) was higher in the nintedanib group than in the placebo group. At the 6-month time point, the difference was statistically significant.

Example 3: Formulation

Nintedanib ophthalmic solution

The drug product is an isotonic ophthalmic solution prepared in 2-hydroxypropyl β-cyclodextrin or other similar cyclodextrins and a buffered solution (pH range 5.5 to 8.0). Other viscosity enhancers, lubricants, and preservatives may be added to enhance the formulation's functionality. The composition of the ophthalmic solution is shown in Table 1.

Table 1 Nintedanib ophthalmic solution

Nintedanib ophthalmic suspension

The drug product is an isotonic ophthalmic suspension prepared in sodium carboxymethylcellulose and a buffer solution (pH range 5.5 to 8.0). The drug particle size is reduced to less than 40 microns. Other viscosity enhancers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the suspension formulation. The composition is shown in Table 2.

Table 2 Nintedanib ophthalmic suspension

Nintedanib ophthalmic emulsion

The drug product is an isotonic ophthalmic emulsion. The drug is dissolved in a mixture of an oil phase and an emulsifier excipient, which is then emulsified and mixed with an aqueous phase (pH range from 5.5 to 8.0). Additional viscosity enhancers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the emulsion formulation. The composition is shown in Table 3.

Table 3 Nintedanib ophthalmic emulsion

Nintedanib sustained-release semisolid dosage form

The drug product is an isotonic sustained-release semisolid formulation. The drug is dissolved and/or suspended in a semisolid medium (pH range 5.5 to 8.0). Other viscosity enhancers, lubricants, solubilizers, and preservatives may be added to enhance the functionality of the sustained-release semisolid formulation. The composition is shown in Table 4.

Table 4 Sustained release semisolid dosage form

Nintedanib sustained-release implant

The drug product is a solid implant. The drug is mixed and blended with one or more polymers. The drug-polymer mixture is melted at a predetermined temperature and extruded into a filament having a predetermined diameter. The filament is then cut into segments of a predetermined size that can be implanted into ocular tissue. The composition is shown in Table 5.

Table 5 Sustained release implants

Without limitation, exemplary compositions for use in accordance with the methods of the present invention may be modified from existing ophthalmically acceptable compositions.

Other implementations

It should be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to be illustrative and not limiting of 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 (35)

1. Use of a therapeutically effective amount of nintedanib in the preparation of a medicament for improving the success rate of glaucoma filtration surgery, wherein the medicament is administered to the eye of a subject in need of it. 2. The use according to claim 1, wherein nintedanib is administered as a topical eye drop or implant. 3. The use according to claim 1, wherein the amount of nintedanib applied effectively reduces scar formation at the surgical site. 4. The use according to claim 1, wherein the amount of nintedanib applied effectively prolongs the duration of lower IOP compared to the preoperative baseline after surgery, improves the absolute success rate or qualified success rate by at least 10 days; or the amount of nintedanib applied effectively prolongs bleb survival. 5. The use according to claim 1, wherein nintedanib is administered in the form of a semi-solid sustained-release implant or a solid sustained-release implant injected into the affected eye. 6. The use according to claim 1, wherein the drug is a topical ophthalmic preparation. 7. The use according to claim 1, wherein the application is performed before, during, or after surgery. 8. The use according to claim 1, wherein the glaucoma filtering surgery is performed using classic trabeculectomy or a method selected from the group consisting of: trabeculotomy, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation. 9. The use according to claim 1, wherein the glaucoma filtration surgery is performed for the implantation of an ocular filtration device. 10. The use according to claim 9, wherein the eye filter is an eye support. 11. The use according to claim 1, wherein nintedanib is administered in combination with an antimetabolite that inhibits cell proliferation. 12. The use according to claim 11, wherein the antimetabolite is selected from the group consisting of mitomycin C, 5-fluorouracil, fluorouracil, cytarabine, 6-azouridine, azathioprine, methotrexate, mycophenolate mofetil, and thiothiophene. 13. The use according to claim 4, wherein the amount of nintedanib applied effectively prolongs the duration of lower IOP compared to the preoperative baseline after surgery, and improves the absolute success rate or qualified success rate by at least 90 days. 14. The use according to claim 13, wherein the amount of nintedanib applied effectively prolongs the duration of lower IOP compared to the preoperative baseline after surgery, and improves the absolute success rate or qualified success rate for at least 365 days. 15. The use according to claim 14, wherein the amount of nintedanib applied effectively prolongs the duration of lower IOP compared to the preoperative baseline after surgery, and improves the absolute success rate or qualified success rate by at least 750 days. 16. The use according to claim 15, wherein the amount of nintedanib applied effectively prolongs the duration of lower IOP compared to the preoperative baseline after surgery, and improves the absolute success rate or qualified success rate for at least 3650 days. 17. The use according to claim 6, wherein the topical ophthalmic preparation is a solution, suspension, cream, ointment, gel, spray, or emulsion. 18. The use according to claim 6, wherein the topical ophthalmic formulation is a suspension containing liposomes or micelles, or a gel-forming liquid. 19. Use of an effective amount of a composition containing nintedanib in the preparation of a medicament for adjunctive treatment in connection with glaucoma filtration surgery performed on a subject. 20. The use according to claim 19, wherein the composition is applied in the form of topical eye drops or an implant. 21. The use according to claim 19, wherein the composition contains a certain amount of nintedanib to effectively reduce scar formation at the surgical site. 22. The use according to claim 19, wherein the composition contains a certain amount of nintedanib to effectively prolong the duration of a lower IOP compared to the preoperative baseline or to improve the absolute success rate or qualified success rate by at least 10 days after surgery. 23. The use according to claim 20, wherein the amount of nintedanib applied effectively prolongs the survival of the vesicle. 24. The use according to claim 19, wherein nintedanib is administered before, during, or after glaucoma filtration surgery. 25. The use according to claim 19, wherein nintedanib is a semi-solid sustained-release implant or a solid sustained-release implant injected into the affected eye. 26. The use according to claim 19, wherein the drug is a topical ophthalmic preparation. 27. The use according to claim 19, wherein the glaucoma filtering surgery is performed using classic trabeculectomy or a method selected from the group consisting of: trabeculoablation, gonioscopy-assisted transluminal trabeculotomy, excimer laser trabeculostomy, and endoscopic cyclophotocoagulation. 28. The use according to claim 19, wherein the glaucoma filtration surgery is performed for the implantation of an eye filtration device. 29. The use according to claim 28, wherein the eye filter is an eye support. 30. The use according to claim 19, wherein nintedanib is administered in combination with an antimetabolite that inhibits cell proliferation. 31. The use according to claim 30, wherein the antimetabolite is selected from the group consisting of mitomycin C, 5-fluorouracil, fluorouracil, cytarabine, 6-azouridine, azathioprine, methotrexate, mycophenolate mofetil, and thiothiophene. 32. The use according to any one of claims 1 or 19, wherein the nintedanib is in the form of a pharmaceutically acceptable salt. 33. The use according to claim 22, wherein the composition contains a certain amount of nintedanib to effectively prolong the duration of a lower IOP compared to the preoperative baseline or to improve the absolute success rate or qualified success rate for at least 365 days after surgery. 34. The use according to claim 33, wherein the composition contains a certain amount of nintedanib to effectively prolong the duration of IOP lower than the preoperative baseline or improve the absolute success rate or qualified success rate for at least 3650 days after surgery. 35. The use according to claim 26, wherein the topical ophthalmic preparation is a solution, suspension or emulsion.