Pharmaceutical Formulations of Nintedanib for Intraocular Use

Abstract

Formulations and intravitreal implants containing nintedanib can be used in methods for treating ocular fundus diseases.

Description

[Technical Field]

[0001] The present invention relates to pharmaceutical formulations of nintedanib suitable for intraocular use and for the treatment of retinal conditions, more particularly to long-term sustained-release pharmaceutical formulations of nintedanib, to intravitreal (IVT) implants formed from such formulations, to methods for preparing such formulations and IVT implants, and to the use of such formulations and IVT implants in methods for treating several ocular fundus diseases. [Background technology]

[0002] In the treatment of severe chronic ocular diseases, particularly in cases of degenerative retinal conditions such as wet age-related macular degeneration (wAMD), dry macular degeneration, geographic atrophy, diabetic macular edema (DME) or nonproliferative diabetic retinopathy (NPDR), cystoid macular edema (CME), choroidal neovascularization (CNV), and retinal vein occlusion, implantable sustained-release delivery devices or implantable sustained-release formulations that would continuously administer a therapeutic agent to the eye over an extended period of time are desirable alternatives to the burdensome regimen of intravitreal injections of therapeutic agents that must be repeated periodically, e.g., monthly, after relatively short intervals.

[0003] Age-related macular degeneration (AMD) is a common disease and the leading cause of severe vision loss in people over 50 years of age in the Western world. AMD leads to degeneration and irreversible damage to the macula, thereby impairing central vision. There are two common forms of AMD: dry AMD (also called non-exudative AMD) and wet AMD (also called wet or neovascular AMD, characterized by the abnormal growth of new blood vessels). Approximately 90 percent of AMD cases involve the dry form, which affects the central retina-macular area that allows us to see (especially fine details), read, and distinguish colors. In contrast, only about 10 percent of people with AMD have the wet form; however, wAMD can rapidly cause severe vision loss as new, abnormal choroidal and retinal blood vessels leak and bleed, destroying retinal architecture and leading to photoreceptor cell death. These rapidly growing abnormal blood vessels, known as choroidal neovascular membranes (CNVMs), and alterations in vascular permeability and exudation are treated with repeated intravitreal injections of anti-VEGF drugs.

[0004] Angiogenesis has been implicated in the pathogenesis of intraocular neovascular diseases such as proliferative retinopathies and AMD; therefore, the therapeutic use of inhibitors of vascular endothelial growth factor receptors (VEGFRs) to treat these diseases is an approach known in the art, as described in WO 2006 / 047325 and elsewhere. Nintedanib, a compound of formula A, (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone) [ka] Nintedanib is a highly potent, orally bioavailable intracellular tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs), and fibroblast growth factor receptors (FGFRs). It competitively binds to the adenosine triphosphate (ATP)-binding pockets of these receptors, blocking intracellular signaling. In addition, nintedanib inhibits Fms-like tyrosine-protein kinase 3 (Flt3), lymphocyte-specific tyrosine-protein kinase (Lck), tyrosine-protein kinase lyn (Lyn), and proto-oncogene tyrosine-protein kinase src (Src) (Hilberg et al., Cancer Res. 2008, 68, 4774-4782). Thus, its kinase specificity profile includes kinases involved in angiogenesis, fibrosis, inflammation, and proliferation. Nintedanib therefore has valuable pharmacological properties for treating, for example, immune disorders or conditions with an immune component, for tumor or fibrotic disorders.

[0005] Nintedanib is described in WO 01 / 27081. WO 2004 / 013099 discloses its monoethanesulfonate (esylate), which is particularly suitable for development as a pharmaceutical; further salt forms are provided in WO 2007 / 141283. Pharmaceutical dosage forms containing nintedanib are disclosed, for example, in WO 2009 / 147212 and WO 2009 / 147220. The use of nintedanib to treat immune diseases or conditions with an immune component is described in WO 2004 / 017948, its use to treat tumor diseases is described in WO 2004 / 096224, and its use to treat fibrotic diseases is described in WO 2006 / 067165.

[0006] Sustained-release formulations allow for the delivery of drugs over extended periods of time. Their mode of administration and their release kinetics can have a significant effect on therapeutic efficacy. The use of polymeric materials in this regard is well established and has led to numerous successful methods for both controlling drug release and providing sustained release over periods ranging from days to months. Polymeric drug delivery devices for in vivo implantation have demonstrated durability and biocompatibility. However, many of these drug delivery devices that provide sustained drug release are inactive under biological conditions, and surgical removal is required after drug release is complete, especially in the case of relatively large devices.

[0007] An additional challenge is the difficulty of manufacturing materials with therapeutic agents, especially maintaining uniformity among miniaturized devices with dimensions at or below the mm scale. There remains a need for biodegradable or bioerodible implantable drug delivery devices with controlled drug release that can be manufactured to consistent specifications at the mm or sub-mm scale.

[0008] Intravitreal implants have been developed that deliver sustained concentrations of drugs over a period of time. These implants are injected into the vitreous of the eye or surgically implanted to sustain the release of drugs into the fundus of the eye. Many matrix-based sustained-release drug delivery systems are known to be suitable for intraocular placement, particularly intravitreal placement, for the long-term treatment of ocular fundus indications. The field of sustained drug delivery is well documented, and many technologies exist. For sustained release from implants in which the drug is released by diffusion through the matrix, the release kinetics are typically defined by Fick's law of diffusion. Higuchi later described a solution to Fick's law for diffusion from ointments (Higuchi T, Physical chemical analysis of percutaneous absorption process from creams and ointments, J Soc Cosmet. Chem 1960; 1:85-97). These are directly applicable to drug release from solid systems, such as drugs in polymer matrices. Higuchi also described a situation in which the drug is not dissolved in the matrix material but is present as particles within the matrix (Higuchi T, Release of medicaments from ointment bases containing drugs in suspension, J Pharm Asci. 1961:50:874-875). In both cases, diffusion is a function of the square root of time, i.e., the amount of drug released over a period of time is a function of the square root of the period of time. While this is appropriate for some pharmaceutical dosage forms, in others, it is desirable for the drug to be released at a more constant rate, e.g., approximately according to zero-order kinetics over the majority of the release time.

[0009] In an attempt to achieve a more linear release, implants can be prepared from a matrix of the drug in a bioerodible polymer. "Bioerodible polymer" refers to a polymer that does not degrade in vivo. While bioerodible polymer matrices offer advantages over biodegradable polymer matrices, which are mechanically eroded by solubilization and excreted unchanged, biodegradable polymers are cleaved within the body into monomers that can cause toxicity problems. Many biodegradable implants have been prepared, often containing polylactic acid and polyglycolic acid or copolymers (PLGA). The basic principle is that the drug is released from these systems as the implant degrades, rather than by diffusion through the polymer matrix. In practice, this has been difficult to achieve. For implants of any shape, the surface area decreases as the implant erodes, so even in a perfect system, release will be nonlinear. Additionally, diffusion of the drug from the device still occurs, especially with water-soluble drugs or implants with high drug loads (greater than 10%). An example of this is the Ozurdex® implant (Allergan). This implant contains dexamethasone in a PLGA matrix and is purported to be a 6-month device. In practice, it releases more than 99% of its drug within the first month (Chang-Lin JE, Attar M, Acheapong AA et al. Pharmacokinetics and pharmacodynamics of a sustained-release dexamethasone intravitreal implant, Invest Ophth Vis Sci 2011;52:80-86). Another problem with these systems is that PLGA undergoes autocatalytic degradation, the net effect of which is slow initial degradation followed by rapid "bulk" erosion, resulting in so-called S kinetics, i.e., the initial release rate determined by diffusion through the matrix slows (square-root time kinetics), resulting in more rapid release as the device disintegrates.

[0010] One attempt to provide a more linear release has been to prepare implants with low drug loading (less than 5%) in the shape of wafers so that their surface area does not change significantly as they erode. This type of device was marketed as Gliadel®. In vitro, they provided a highly linear, long-term release, but in vivo data showed that release occurred by both diffusion and erosion, and that the wafers were completely removed by 5 days (Flemming AB, Saltzman WM, Pharmacokinetics of the carmustine implant, Clin Pharmacokinetics 41 (6) 403-419 (2002)). Non-erodible implants, such as Vitrasert®, Retisert®, and ILUVIEN®, provide a more constant release rate. In these systems, a central drug core (in a polymer matrix), such as a tablet or paste, is encased in an impermeable polymer. Drug release occurs through small pores (diffusion ports) in the impermeable layer and can be further controlled by coating a permeable polymer on the diffusion ports. When immersed in water (or placed in the eye), water diffuses into the central drug core, dissolving a portion of the drug, which then diffuses through the diffusion ports. The amount of water that enters the core is small because the amount of drug dissolved in this internal water is also small, and therefore the release rate is slow. Furthermore, as long as there is excess drug in the drug core, the drug solution within the core will become saturated, resulting in a constant concentration gradient through the diffusion ports and linear release. While these systems have the advantage of providing a relatively linear release, they are neither bioerodible nor biodegradable. Summary of the Invention

[0011] In the medical field, there is still a great need for alternative treatments for ocular fundus indications, such as sustained release delivery systems that release therapeutic concentrations of active agents from intravitreal implants directly to the fundus of the eye with a long-term safety and efficacy profile. Furthermore, any sustained release implant is highly dependent on the selection of polymers, copolymers, drug-polymer interactions, loading uniformity, porosity, size, surface area to volume ratio, and the like to achieve its drug release and degradation characteristics, and the manufacturing techniques used in prior art implants can introduce inherent shortcomings in each of these parameters. US 5,378,475 describes a sustained-release implant for insertion into the vitreous of the eye. The implant has a first impermeable coating, such as ethylene vinyl acetate, surrounding most, but not all, of a drug reservoir, and a second permeable coating, such as permeable cross-linked polyvinyl alcohol, disposed on the first coating, wherein the first coating includes an area where the first coating does not cover the drug reservoir, providing a location through which the drug can diffuse out of the implant. The implant also has tabs that can be used to suture the device into position within the eye. The implant device is prepared by applying a coating solution, for example, by dipping, spraying, or brushing various coating layers around the drug reservoir.

[0012] US 8,871,241 discloses an injectable sustained-release drug delivery device having a cylindrical cross-section, comprising a core containing one or more drugs and one or more polymers. The core may be surrounded by a polymer outer layer. The device is formed by extruding or otherwise preforming a polymer skin for the drug core, and the drug core may be co-extruded with the skin or inserted into the skin after the skin has been extruded and optionally cured. Polymers for forming the skin and core include poly(caprolactone), ethylene vinyl acetate polymer, poly(ethylene glycol) (PEG), polyvinyl alcohol (PVA), poly(lactic acid) (PLA), poly(glycolic acid) (PGA), poly(lactic-co-glycolic acid) (PLGA), polyalkyl cyanoacrylate, polyurethane, nylon, or copolymers thereof.

[0013] The device may have an outer diameter suitable for injection near a patient's eye as either an intraocular or periocular injection using a 30 gauge (0.3 mm outer diameter per EN ISO 9626) needle to about a 12 gauge (2.7 mm outer diameter per EN ISO 9626) needle, or using a needle ranging in inner diameter from about 0.0055 inches (0.1397 mm) to about 0.0850 inches (2.159 mm). The device may be formed by combining at least one polymer, at least one drug, and at least one liquid solvent to form a liquid suspension or solution; upon injection, such suspension or solution undergoes a phase change to form a gel. The configuration may result in controlled release of the drug over an extended period of time. The devices may be fabricated as elongated masses that are segmented into drug delivery devices, which may be left uncoated so that the drug core is exposed on the entire surface or at the end of each segment (if a skin is used), or they may be coated with a layer, such as a drug-permeable, drug-semipermeable, impermeable, or bioerodible layer.A wide range of drugs have been disclosed that can be incorporated into the devices, including, among others, angiogenesis inhibitors, antiproliferative compounds, and tyrosine kinase inhibitors.

[0014] WO 02 / 074196 discloses an ocular implant that delivers therapeutic drugs to the eye with dual-mode release kinetics, with an initial delivery of a "loading dose" at a high release rate immediately after placement of the implant in or near the eye as a first administration mode, followed by subsequent drug delivery at a lower continuous sustained release rate as a second maintenance dosing administration mode, all within the same treatment regimen using the same implant device. (a) (i) therapeutic drugs; and (ii) (1) a polymer that is permeable to the therapeutic agent and exists as a bioerodible solid matrix structure; and (2) Water-soluble polymers that are more water-soluble than permeable polymers a polymer matrix material having a therapeutic agent dispersed therein, comprising a composite matrix layer comprising: (b) a separate solid core containing an additional therapeutic agent, optionally surrounded by and coated with a composite matrix layer; Includes:

[0015] The permeable polymer may be non-crosslinked superhydrolyzed PVA, which allows the therapeutic agent to diffuse through it, forming a slowly bioerodible solid structure that releases the drug by surface erosion of the PVA and by diffusion, and the water-soluble polymer may be a pharmaceutical-grade cellulose ether. The erosion rate of the superhydrolyzed PVA is sufficiently slow that the polymeric material in the implant dissolves and the therapeutic agent disintegrates only after an extended period of time, resulting in slow, sustained delivery of the drug. The superhydrolyzed polyvinyl alcohol may be polyvinyl alcohol having a hydrolysis rate of at least 98.8% by weight and a weight-average molecular weight of about 85,000 to about 150,000. Heating the matrix implant at temperatures above 100°C promotes PVA crosslinking. This may be desirable when attempting to slow the drug release rate from a particular implant or to control the rate at which the implant erodes. Although embodiments of this implant can be incorporated into the vitreous humor to deliver 2-methoxyestradiol to treat CNVM, many other therapeutic agents and drugs have been disclosed that can be delivered by the implant, including angiogenic compounds such as VEGF antagonists, among others.

[0016] WO 2005 / 110362 discloses a drug delivery system for treating ocular conditions, comprising at least one bioerodible implant suitable for insertion into the ocular region, the implant comprising (i) an active agent and (ii) a bioerodible polymer, wherein the bioerodible implant should release therapeutic levels of the active agent into the ocular region over a period of between about 30 days and about 1 year. Preferably, the active agent is an anti-inflammatory drug, and the bioerodible polymer is a PLGA copolymer. The drug delivery system may comprise multiple bioerodible implants, each with a unique drug release profile, and preferably up to three implants that can be implanted in the posterior region of the eye. The implants may be prepared using an extrusion method.

[0017] WO 2006 / 039271 discloses a process for making multiple drug delivery devices for implantation into a patient's eye, made in part from polyvinyl alcohol, using a consistent curing process that results in less variation in drug release rates from device to device.

[0018] WO 2018 / 054077 discloses a method for treating ocular diseases, including anterior ocular and fundus indications, comprising administering to the eye of a subject in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition is a topical formulation, such as an eye drop, and comprises nintedanib or a salt thereof. The disclosure also relates to pharmaceutical compositions or formulations that can be used to treat ocular diseases.

[0019] WO 2020 / 219890 discloses a sustained-release biodegradable ocular hydrogel implant for treating ocular fundus indications, the sustained-release biodegradable ocular hydrogel implant comprising a tyrosine kinase inhibitor (TKI), such as nintedanib, a polymer network comprising a plurality of polyethylene glycol (PEG) units, and a clearance zone devoid of undissolved TKI particles prior to release of the TKI.

[0020] WO 2020 / 243608 discloses an implant comprising a tyrosine kinase inhibitor and a bioerodible polyester polymer that provides sustained release of a small molecule tyrosine kinase inhibitor, such as axitinib, from the bioerodible polyester polymer implant for treating ocular indications such as neovascular age-related macular degeneration and diabetic macular edema via intravitreal injection of the implant. The implant is preloaded into a small diameter needle and is designed to be injected via a self-sealing transscleral needle penetration at the pars plana.

[0021] WO 2017 / 083779 and WO 2020 / 102758 disclose solid aggregate microparticles, which may be biodegradable, having an average diameter of, for example, between 20 and 40 μm, for the long-term treatment of ocular disorders, comprising an effective amount of a therapeutic agent, such as the VEGFR inhibitor sunitinib, for injection into the fundus of the vitreous. The microparticles are composed of a polymer, such as PLGA, PLGA-PEG, or PLA, which aggregate in vivo to form at least one pellet of at least 500 μm, which provides sustained drug delivery in a manner such that the pellet remains substantially outside the visual axis so as not to significantly impair vision. [Brief explanation of the drawings]

[0022] [Figure 1] Mean release profile of nintedanib esylate in PBS at 37°C over 270 days for implant I-6 (n=6). [Figure 2] Release profile of nintedanib esylate in PBS at 37°C over 45 days for implants dried at 130°C for 3 hours. [Figure 3] Release profile of nintedanib esylate in PBS at 37°C over 45 days for implants dried at 150°C for 3 hours. [Figure 4] Release profile of nintedanib esylate in PBS at 37°C over 127 days for implants dried at 100°C for 1 hour (disintegrated before day 80). [Figure 5]Release profile of nintedanib esylate in PBS at 37°C over 135 days for implants dried at 130°C for 3 hours. [Figure 6] Daily release profile of nintedanib esylate in PBS at 37°C over 135 days for implants dried at 130°C for 3 hours. [Figure 7] E)2) Comparison of extrusions between nintedanib esylate (1), a nintedanib mixture of 20% esylate and 80% free base (2), and nintedanib free base (3) prepared from the above strand (I-6) containing 12% (w / v) PVA solution before oven heating. [Figure 8] E)2) Comparison of extrusions between nintedanib esylate (1), a nintedanib mixture of 20% esylate and 80% free base (2), and nintedanib free base (3) prepared from the above strand (I-6) containing 12% (w / v) PVA solution before oven heating. DETAILED DESCRIPTION OF THE INVENTION

[0023] In a first aspect, the present invention relates to a pharmaceutical formulation for long-term sustained release of an API, comprising 80-95% (w / w) of API and 5-20% (w / w) of PVA. In a second aspect, the present invention relates to a coated or uncoated IVT implant having a body consisting of a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the invention, said body optionally having a polymer coating.

[0024] In a third aspect, the present invention provides a method for preparing a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the invention, comprising the steps of: a) preparing an aqueous PVA solution; b) mixing the PVA solution with API powder; The present invention relates to a method comprising:

[0025] In a fourth aspect, the present invention provides a method for preparing an IVT implant according to the second aspect of the invention, comprising: a) preparing an aqueous PVA solution; b) mixing the PVA solution with API powder; c) loading the mixture into an extrusion device; d) extruding the mixture through an extruder head to form extruded strands; e) optionally drying the extruded strands; f) heating the extruded strand; g) cutting the extruded strand into implant pieces of equal length; h) sterilizing the implant piece thus obtained; Including, It further relates to a method which may include an optional step of coating said extruded strand after step d), e) or f) or said implant piece after step g) in a solution of a coating polymer.

[0026] In a fifth aspect, the present invention relates to a method for treating an ocular fundus disease in a patient in need thereof, characterized in that a pharmaceutical formulation according to the first aspect of the invention is administered to the eye of said patient, and in particular in that at least one IVT implant according to the second aspect of the invention is implanted into the vitreous of said patient's eye. The present invention also relates to a pharmaceutical formulation according to the first aspect of the invention, in particular an IVT implant according to the second aspect of the invention, for use in a method for treating an ocular fundus disease in a patient in need thereof. The present invention also relates to the use of the above API in the manufacture of a pharmaceutical formulation according to the first aspect of the invention, in particular an IVT implant according to the second aspect of the invention, for treating an ocular fundus disease in a patient in need thereof. Other aspects of the present invention will be immediately apparent to those skilled in the art from the foregoing and following descriptions.

[0027] General Terms and Definitions Terms not specifically defined herein are to be given the meaning that one of ordinary skill in the art would give them in light of this disclosure and the context. However, as used herein, unless specified to the contrary, the following terms have the meanings indicated and are subject to the following rules: The terms "treatment" and "treating" as used herein encompass both therapeutic, i.e., curative and / or palliative, and prophylactic, i.e., preventative, treatment. Therapeutic treatment refers to treatment of patients who already suffer from one or more of the above conditions in overt, acute, or chronic form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a specific indication, or causal treatment to reverse or partially reverse the indicated condition or to halt or slow the progression of the disease. Prophylactic treatment ("prevention") refers to treatment prior to the clinical onset of disease to reduce the risk of a patient at risk of developing one or more of the above conditions. The terms "treatment" and "treating" include the administration of one or more active compounds to prevent or delay the onset of the above symptoms or complications, and to prevent or delay the occurrence of the disease, condition, or disorder, and / or to eliminate and control the disease, condition, or disorder, as well as to alleviate the symptoms or complications associated with the above diseases, conditions, or disorders.

[0028] The term "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents a particular disease or condition, (ii) reduces, ameliorate, or eliminates one or more symptoms of a particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition described herein. The term "intraocular use" refers to use within the eye, including, inter alia, intravitreal, suprachoroidal, intracameral, and subconjunctival use. "Long-term sustained release" of a drug refers to release of the drug over an extended period of time, for example, over weeks or months, particularly over more than 3, 6, 9, or 12 months. The terms "API" and "nintedanib" as used herein with respect to any aspect of the invention or in the context of the present invention are intended to be interchangeable and to encompass the group consisting of nintedanib (free base), pharmaceutically acceptable salts of nintedanib, and blends of nintedanib (free base) and pharmaceutically acceptable salts of nintedanib. Amounts presented herein are generally expressed in terms of nintedanib esylate unless otherwise indicated.

[0029] The term "inactive ingredients" means any ingredient other than the active ingredient. The phrase "pharmaceutically acceptable" is used herein to refer to compounds, excipients, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and are compatible with a reasonable benefit / risk ratio. Suitable pharmaceutically acceptable excipients for preparing pharmaceutical formulations, e.g., IVT implants, are known to those skilled in the art. The terms "bioerodible" and "biodegradable" refer to the gradual breakdown, dissolution, or degradation of a polymer, formulation, or implant in a biological system over a period of time by one or more physical or chemical degradation processes, such as, for example, solubilization, enzymatic processes, or hydrolytic dissolution. Biodegradable polymers are typically capable of undergoing hydrolysis under physiological conditions due to the presence of hydrolytically and / or enzymatically cleavable functional groups (e.g., anhydride, ester, amide bonds). Biodegradation can result in scission of the polymer backbone or cleavage of water-soluble side chains. The cleavage products can then be metabolized and excreted, resulting in complete elimination. Bioerodible polymers are mechanically eroded by biological processes that solubilize the polymer and allow it to be absorbed into surrounding tissues.

[0030] Paste, as used herein, describes a thick, wet mixture of a solid, for example, an API, and a solution, for example, a PVA solution. Viscosity measurements are carried out using a rotational viscometer at 20° C. using a 4% solution in water according to the JPE Monographie of Polyvinylalcohol (Fully Hydrolyzed Polyvinyl Alcohol; Viscosity).

[0031] Detailed Description of the Invention There is a medical need to improve options for treating degenerative or persistent ocular fundus conditions by providing implantable sustained release delivery devices that continuously release a therapeutic agent to the eye at a release rate suitable for maintaining therapeutic agent levels in the desired ocular fundus region or site over an extended period of time, for example, over a treatment phase of at least 3 months, at least 6 months, at least 9 months, at least 12 months or more. To date, numerous matrix-based drug delivery systems have been developed; however, the implant according to the present invention offers the following unique combination of features: 1) Drug release is dependent on the surface area of the device, which decreases only slightly during the treatment phase as the drug is released; 2) the primary function of the polymer matrix (or coating, if used) is to substantially maintain the surface area of the implant, rather than to provide a diffusion barrier to drug release; 3) the release rate decreases very slowly throughout the release period, so that therapeutic concentrations of the drug are maintained in the vitreous of the eye throughout the prolonged treatment phase; 4) the matrix is bioerodible (not biodegradable); 5) The erosion rate can be adjusted by the thermal curing process so that the implant structure degrades after more than 90% of the drug has been released; 6) These implants can use relatively low concentrations of polymer in the matrix (>1:1, more typically >4:1 and ≥6:1 (w / w), e.g., up to 10:1 or 20:1 drug:polymer ratio (w / w)), while maintaining release and intravitreal drug concentrations within the drug's therapeutic window.

[0032] In addition, as shown by light stress and long-term stability studies, the implants according to the present invention are suitable for long-term storage in that they provide sufficient release, physical and chemical stability properties over several months. The formulation principle underlying this invention is to develop a delivery system with minimal pharmaceutical excipient addition and only a few steps in the manufacturing process. The pharmaceutical excipient of choice is polyvinyl alcohol (PVA). This material has a well-known safety profile and is used in several approved intraocular products. The low percentage of PVA in the formulation (20% (w / w) or less) allows for a high drug loading in the product. PVA dissolves in water at the desired concentration to form a viscous solution and can form a paste when mixed with the API.

[0033] The formulation process involves mixing the API with a PVA solution and extruding the paste, for example, through a needle tip. The extruded strands are then heat-treated, for example, in an oven. Depending on the temperature and time, this process alters the PVA crystallinity in the matrix, which subsequently alters the dissolution rate of the drug in a moist environment.

[0034] The nintedanib IVT implant of the present invention is bioerodible and provides a long-term, nearly constant sustained release of nintedanib in intraocular use. It has a very high drug:polymer ratio (drug loading rate of more than 80% by mass). These features are particularly attractive in ophthalmology, because the implant must be small enough to be injected into the eye through a small enough incision that does not need to be closed after injection. This requires injection through a needle with a diameter equal to or smaller than that of a 22-gauge needle. Therefore, a high drug loading rate is crucial.

[0035] Bioerodible IVT implants are particularly advantageous for treating diseases such as macular degeneration and diabetic macular edema, which are not considered curable but require treatment over the patient's lifetime. Non-erodible implants will accumulate in the eye unless removed (a nontrivial procedure). Erodible implants do not pose this problem. Biodegradable polymers have the potential problem of releasing monomers that may be inflammatory upon degradation (Evaluation of the toxicity of intravitreously injected PLGA microspheres and rods in monkeys and rabbits: effects of depot size on inflammatory response. Thackberry EA, Farman C, Zhong F et al., Invest Ophthalmol Vis Sci (2017) 58:4274-4285). Bioerodible polymers dissolve slowly and do not degrade themselves.

[0036] Because many ocular diseases need to be treated continuously, maintaining therapeutic concentrations of nintedanib as provided by an IVT implant according to the present invention is a considerable advantage, especially for drugs with a potentially small therapeutic window. In a first aspect, the present invention relates to a pharmaceutical formulation for long-term sustained release of an API comprising 80-95% (w / w) of the API and 5-20% (w / w) of PVA.

[0037] In one embodiment, the pharmaceutical formulation comprises 80-95% (w / w) API, 5-20% (w / w) PVA, optionally pharmaceutically acceptable inactive ingredients, and optionally trace amounts of water. Trace amounts of water may be present in the pharmaceutical formulation due to, for example, insufficient drying of the formulation. These amounts typically represent 1% (w / w) or less. Preferably, the pharmaceutical formulation comprises 80-95% (w / w) API and 5-20% (w / w) PVA.

[0038] In another embodiment, the pharmaceutical formulation comprises 85%-95% API and 5%-15% PVA (w / w), preferably 87%-91% API and 9%-13% PVA (w / w). Preferably, the pharmaceutical formulation consists of 85%-95% API and 5%-15% PVA (w / w), preferably 87%-91% API and 9%-13% PVA (w / w), and optionally trace amounts of water. For example, the API:PVA mass ratio may be 100:5, 100:7, 100:8, 100:10, 100:15, 100:16.5, or 100:18, particularly 100:10 and 100:15, most preferably 100:15. In particular, mass ratios of 100:15, 100:16.5, and 100:18 result in pastes that can still be easily extruded (see the fourth aspect of the invention) to form pharmaceutical formulations and implants with increased long-term integrity, i.e., slow degradation, and prolonged drug release in phosphate buffered saline (PBS).

[0039] To prepare pharmaceutical formulations and IVT implants that provide prolonged release of active pharmaceutical ingredients at therapeutic levels over several months, a low water-solubility active pharmaceutical ingredient would be preferred to reduce the risk of premature implant depletion due to rapid dissolution of the active pharmaceutical ingredient. Therefore, among the various available nintedanib species, the free base of nintedanib, which has very poor solubility in water, would be a reasonable choice for formulations and implants according to the present invention. However, it has been surprisingly found that the IVT implants according to the present invention containing nintedanib esylate, which has a very high water solubility of 2.8 mg / mL, also exhibit desirable long-release properties suitable for the intended clinical use. Therefore, the API in the pharmaceutical formulations according to the present invention is preferably nintedanib (free base); more preferably, it is a (pharmaceutically acceptable) nintedanib salt or a blend of a (pharmaceutically acceptable) nintedanib salt and nintedanib (free base), and most preferably, the salt is nintedanib esylate.Suitable pharmaceutically acceptable nintedanib salts for all aspects of the present invention include the mono-ethanesulfonate ("esylate") and nintedanib salts disclosed in WO 2007 / 141283, such as nintedanib chloride, bromide, phosphate, sulfate, methanesulfonate, ethanedisulfonate, benzenesulfonate, tosylate, camphorsulfonate, naphthalene-1,5-disulfonate, citrate, D-tartrate, L-tartrate, L-lactate, glycolate, glycinate, L-malate, D-malate, malonate, oxalate, benzoate, mandelate, saccharinate, salicylate, and ascorbate, or bis{3-Z-[1-(4-(N-((4-methyl-piperazine-1-yl)-2-methyl-4-(4 ... bis{3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone}-fumarate, bis{3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone}-maleate, and bis{3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone}-succinate.

[0040] Preferred nintedanib salts for all aspects of the present invention are nintedanib esilate, chloride, bromide, phosphate, sulfate, methanesulfonate, ethanedisulfonate, benzenesulfonate, tosylate, citrate, D-tartrate, L-tartrate, L-lactate, glycolate, glycinate, L-malate, D-malate, malonate, oxalate, benzoate, mandelate, salicylate, and ascorbate. Particularly preferred nintedanib salts for all aspects of the present invention are nintedanib esilate, chloride, bromide, phosphate, sulfate, methanesulfonate, and ethanedisulfonate. Most preferred is nintedanib esilate. According to one embodiment, with regard to particle size distribution, nintedanib esylate as used to prepare the aforementioned formulations should be characterized by a particle size distribution of D50≦20 μm and D90≦50 μm (e.g., as determined by the method described in Example A). Alternatively, nintedanib esylate may be characterized by D10≦5 μm, D50≦25 μm, D90≦50 μm, and / or D98≦60 μm; preferably, D10≦3 μm, D50≦20 μm, D90≦40 μm, and / or D98≦50 μm. More specifically, nintedanib esylate as used to prepare the aforementioned formulations can be characterized by 1.2 μm≦D10≦2.1 μm, 9.5 μm≦D50≦14.7 μm, 24.3 μm≦D90≦31.7 μm, and 34.3 μm≦D98≦42.1 μm, for example by 1.4 μm≦D10≦1.7 μm, 10.5 μm≦D50≦12.7 μm, 25.4 μm≦D90≦28.7 μm, and 35.2 μm≦D98≦39.2 μm.

[0041] PVA suitable for the pharmaceutical formulation should meet the requirements of pharmacopoeias (e.g., Ph.Eur., JPE). Various grades of PVA are available, which differ in their degree of polymerization and their degree of hydrolysis, which determine the physical properties of the various grades. They are characterized by their viscosity and ester value (which characterizes the degree of hydrolysis). It has been found that the use of PVA with a degree of hydrolysis of 88% to prepare pharmaceutical formulations according to the invention results in implants that disintegrate rapidly in PBS. PVA with a higher degree of hydrolysis, in particular about 99%, advantageously results in implants with improved long-term release properties. In one embodiment, the PVA has an average relative molecular mass between 20,000 and 150,000 and a viscosity of 3 mPa. * s~70mPa * s and the ester value does not exceed 280.

[0042] Preferably, the PVA grade is - 23.8~32.2mPa * s viscosity (4% PVA in aqueous solution) and - High degree of hydrolysis (≥97%) or ester value of 9-11 More preferably, the PVA grade is characterized by: - Approximately 28 mPa * s viscosity (4% PVA in aqueous solution) and - Approximately 99% degree of hydrolysis or an ester value of approximately 11 In another embodiment, only one grade of PVA is used in the pharmaceutical formulation. In a second aspect, the present invention relates to a coated or uncoated IVT implant having a body consisting of a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the invention, said body optionally having a polymer coating.

[0043] Said long-term sustained release pharmaceutical formulation of API may be according to any of the embodiments described above for the first aspect of the invention. For example, implants according to the present invention containing nintedanib esylate have been found to maintain their physical integrity for extended periods of time in humid conditions (such as in PBS) even without a coating. In contrast, implants with a coating may be at risk of rapid disintegration due to high osmotic pressure within the coating membrane. In a preferred embodiment, the IVT implant is uncoated. In another embodiment, the IVT implant is coated. The polymer coating of the IVT implant according to the present invention should be biocompatible, bioerodible, or biodegradable so as not to cause any inflammation, and may be selected from the group consisting of PVA, poly(D,L-lactide-co-glycolide) (PLGA), polycaprolactone (PCL), polylactic acid, polyglycolic acid, polyethylene adipate, and polyesteramide. In another embodiment, the IVT implant is coated, and the polymer coating is made of PVA. The PVA used in the coating may be of the same grade as the PVA used in pharmaceutical formulations.

[0044] The diameter of the IVT implant, whether coated or uncoated, should be small enough so that it can be inserted into the vitreous of the eye through an acceptably small incision. For many purposes, this is 22 gauge or smaller, or preferably 24 gauge or smaller, since a larger incision would require sutures to close the wound. Similarly, the overall length of the implant should be less than 10 mm, preferably 6 mm or less, to reduce the chance of the implant entering the visual axis.

[0045] In one embodiment, the IVT implant is shaped and sized to be administered through an inserter having a needle of 22 gauge or smaller, particularly 23, 24, 25, 26, or 27 gauge or smaller, e.g., through an inserter having a 22, 23, 24, 25, 26, or 27 gauge needle, preferably through an inserter having a 24 gauge or smaller needle, e.g., a 24 gauge ultra-thin-walled needle. In another embodiment, the IVT implant is cylindrical in shape. In another embodiment, the diameter of the IVT implant is in the range of 0.2-0.4 mm, e.g., 0.25-0.27 mm or 0.32-0.35 mm.

[0046] In one embodiment, the IVT implant is 10 mm or less in length; for safe clinical use, it should be 7 mm or less in length, preferably 6 mm or less in length. Preferably, it is 1 to 7 mm in length, more preferably 1.0 mm to 6.0 mm in length, for example, 1.0 mm, 2.5 mm, 3.5 mm, 4.0 mm, 4.5 mm, 5.0 mm, 5.5 mm, or 6.0 mm in length, and most preferably 2.5 mm, 3.5 mm, 5.0 mm, or 6.0 mm in length. In one embodiment, the IVT implant is characterized by a nintedanib esylate content of 100 μg to 250 μg, preferably 120 μg to 160 μg or 180 μg to 220 μg, for example, about 140 μg or about 200 μg.In another embodiment, the IVT implant is characterized by a nintedanib esylate content of 400 μg to 600 μg, preferably 420 μg to 500 μg or 520 μg to 570 μg, for example, about 440 μg, about 475 μg, or about 545 μg.

[0047] Surprisingly, IVT implants containing nintedanib esylate as the API have been found to exhibit desirable long-term release characteristics suitable for their intended clinical use, despite the good water solubility of nintedanib esylate. In one embodiment, the IVT implant is characterized by an in vitro daily release of nintedanib esylate in the range of 1 μg / day to 2 μg / day, preferably 1.1 μg / day to 1.8 μg / day, more preferably 1.2 μg / day to 1.6 μg / day, and most preferably about 1.3 μg / day (equivalent to about 1.1 μg / day of nintedanib base) from day 10 to day 30. In another embodiment, the IVT implant is characterized by an in vitro daily release of nintedanib esylate of about 1.1 μg / day or more over six months, preferably about 1.2 μg / day or more over six months, and more preferably about 1.3 μg / day or more over six months. In another embodiment, the IVT implant is characterized by an in vitro drug release of greater than nine months.

[0048] In a third aspect, the present invention provides a method for preparing a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the invention, comprising the steps of: a) preparing an aqueous PVA solution; b) mixing the PVA solution with API powder; The present invention relates to a method comprising: Said long-term sustained release pharmaceutical formulation of API may be according to any of the embodiments described herein above for the first aspect of the invention.

[0049] In step a), the aqueous PVA solution can be prepared by dissolving a desired amount of PVA in deionized water. Optionally, the mixture can be heated and / or stirred to facilitate the dissolution process. In one embodiment, the aqueous PVA solution prepared in step a) has a mass concentration of PVA between 2% and 20% (w / v), preferably between 8% and 15%, for example, about 10% or about 13.6%. In step b), the PVA solution can be mixed with the API powder by placing a weighed amount of nintedanib powder (esylate, base, or a blend of the two), which may be in micronized form, in a mortar and then slowly adding the paste to a specified volume of PVA solution while mixing with a pestle. On a larger scale, this can be done using a commercially available mixer (e.g., a Hobart mixer). A typical ratio of API to PVA solution is about 1:1 (w / v, e.g., g / mL). Step b) should be performed until a homogeneous paste of the ingredients is obtained.

[0050] The PVA and / or API powder used to prepare the pharmaceutical formulation preferably exhibits the characteristics described herein above for the first aspect of the invention. Accordingly, the API powder, e.g., nintedanib esylate, may be micronized prior to its use in step b) of the process to achieve a desired particle size distribution. In a fourth aspect, the present invention provides a method for preparing an IVT implant according to the second aspect of the invention, comprising: a) preparing an aqueous PVA solution; b) mixing the PVA solution with API powder; c) loading the mixture into an extrusion device; d) extruding the mixture through an extruder head to form extruded strands; e) optionally drying the extruded strands; f) heating the extruded strand; g) cutting the extruded strand into implant pieces of equal length; h) sterilizing the implant piece thus obtained; Including, The method may further comprise the optional step of coating the extruded strand after step d), e), or f), or the implant piece after step g), in a solution of a coating polymer.

[0051] The IVT implant may be according to any of the embodiments described herein above for the second aspect of the invention. Steps a) and b) of the process may be according to any of the embodiments described herein above for the third aspect of the present invention. Alternatively, the API powder, e.g., nintedanib esylate, may be micronized prior to its use in step b) of the process. Preferably, after mixing, the resulting mixture should not be kept in an open container for longer than 15 minutes, so as not to negatively affect the extrudability of the paste.

[0052] The extrusion device of step c) comprises an extrusion head (or extrusion tip) as described in step d). The extrusion device may be a syringe attached to a needle, a single-screw extruder, a twin-screw extruder, a piston pump, or a peristaltic pump. The extruder head may be any with an opening sized so that the resulting extruded strand is of a desired thickness, for example, a needle tip. The extrusion head may have a circular profile so that a cylindrical extruded strand is obtained. Instead of a cylindrical strand, a different strand shape, for example, a shaped Toblerone, can also be produced by using a different shaped extrusion head.

[0053] The extrusion tip may have various sizes, with the inner diameter of the tip defining the outer diameter of the implant. It has been found that extrusion using a 23-gauge or 22-gauge tip results in implants (0.25-0.27 mm and 0.32-0.35 mm diameter, respectively) that fit well into a 24-gauge ultra-thin-walled needle (approximately 0.37 mm inner diameter) and are particularly suitable for the intended clinical use. Therefore, the extrusion head should be 21-gauge or smaller, e.g., 22- or 23-gauge, preferably 22-gauge, so that the final implant can be injected into the eye via a 22-gauge or smaller, e.g., 23- or 24-gauge, preferably 24-gauge, inserter, particularly a 24-gauge ultra-thin-walled needle. Thus, after processing, the implant piece can be injected directly into the eye through an incision small enough that it does not need to be closed after injection. In one embodiment, the extrusion head has a circular profile. In one embodiment, the inner diameter of the extrusion head is about 0.5 mm or less, preferably about 0.4 mm or less, for example, about 0.33 mm or about 0.41 mm. In one embodiment, the extruded strand is obtained as a continuous cylindrical strand. In another embodiment, the extruded strand has a diameter of 0.2 to 0.4 mm, for example, 0.23 to 0.29 mm or 0.30 to 0.37 mm.

[0054] In step d), it has been surprisingly found that mixtures prepared according to steps a)-b) from nintedanib esylate or from a blend of nintedanib esylate and nintedanib free base (e.g., in a ratio of at least 1:9 (w / w), e.g., 1:9 or 2:8) can be extruded significantly more easily than mixtures prepared from nintedanib free base alone. An example of this is shown in Figure 8. Additionally, extruded strands formed from mixtures containing nintedanib esylate exhibit good physical properties: for example, such mixtures form continuous strands of favorable consistency and cohesion, i.e., do not easily separate during the extrusion process. Furthermore, after extrusion, even before any drying or heating steps, the extruded strands exhibit good dimensional stability, in particular, do not flatten under the influence of gravity and maintain their circular profile and cylindrical shape very well. An example of this is shown in Figure 7.

[0055] In optional step e), the extruded strands are air-dried for a suitable period of time. When step e) is performed at ambient temperature, 35°C, or 50°C, no significant deformation in the measured implant diameter was observed, and the in vitro release of the implants was comparable. In a preferred embodiment, step e) is performed without additional heating, for example, at ambient temperature. In another embodiment, step e) is performed at an elevated temperature, for example, at 35°C or 50°C. In another embodiment, the extruded strands are dried for about 30 minutes to about 24 hours, preferably for at least 2 hours, for example, for about 2 hours to about 14 hours, for example, 2, 4, 6, 10, or 12 hours. In a preferred embodiment, the extruded strands are dried at ambient temperature for at least 2 hours.

[0056] Step f) represents a heat curing step. This step aims to increase the crystallinity and hardness of the PVA, thereby decreasing the dissolution rate of the API from the implant and improving implant integrity. In one embodiment, heating is carried out for at least 2 hours, preferably at least 3 hours, e.g., about 3 hours, about 4 hours, about 5 hours, or about 8 hours. In another embodiment, the extruded strand is heated to a temperature between 100°C and 180°C, preferably between 120°C and 160°C, e.g., about 130°C, about 140°C, about 150°C, or about 160°C, more preferably between 130°C and 150°C. In a preferred embodiment, heating is carried out at a temperature between 120°C and 180°C for at least 2 hours, more preferably at about 130°C-150°C for at least 3 hours, and most preferably at about 130°C for about 3 hours.

[0057] In step g), the extruded strands are cut by suitable means into implants of equal length. Suitable implant lengths are described herein above for the second aspect of the invention. In one embodiment, the extruded strands are cut into implant pieces of equal length of 10 mm or less. In a preferred embodiment, 23G extruded strands are cut into implant pieces of equal length of 1 to 7 mm, e.g., 2.5, 4.0, 5.0, or 6.0 mm. In another preferred embodiment, 22G extruded strands are cut into implant pieces of equal length of 1 to 7 mm, e.g., 3.5, 4.5, 5.0, or 6.0 mm, preferably 5 or 6 mm. In the sequences of method steps described herein, step g) does not necessarily have to be performed after step f). As an alternative to the sequences described herein above, step g) can be performed before step f) or before any step e).

[0058] In step h), sterilization of the implant pieces can be achieved by gamma or e-beam irradiation. In one embodiment, sterilization is achieved by gamma irradiation. In one embodiment, gamma irradiation can be performed at a dose of up to 25 kGy, e.g., about 15 kGy, about 20 kGy, or about 25 kGy, e.g., 22.5-27.5 kGy. No significant difference has been observed in the release rate of the implant over a 10-week period before and after gamma irradiation. Alternatively, or in addition to step h), the method for preparing an IVT implant can be performed under aseptic conditions.

[0059] In a preferred embodiment, a fourth aspect of the invention relates to a method for preparing an IVT implant according to the second aspect of the invention, comprising the steps of: a) preparing an aqueous PVA solution having a mass concentration of PVA between 8% and 15% (w / v) by dissolving PVA in deionized water, optionally with heating and / or stirring; b) mixing the PVA solution with nintedanib esylate powder; c) loading the mixture into an extrusion device; d) extruding the mixture through a 22 or 23 gauge extruder head to form an extruded strand, preferably as a continuous strand of cylindrical shape and diameter between 0.2 and 0.4 mm; e) optionally drying the extruded strands at ambient temperature; f) heating the extruded strands at a temperature between 120°C and 180°C for at least 2 hours; g) cutting the extruded strand into implant pieces of equal length between 1 and 7 mm; h) sterilizing the implant piece thus obtained; wherein the extruded strand obtained after step d), e) or f) or the implant piece obtained after step g) may be coated in a solution of a coating polymer. The sequence of steps g) and f) is interchangeable, and step g) can be carried out before or after step f), or even before any step e).

[0060] In a fifth aspect, the present invention relates to a method for treating an ocular fundus disease in a patient in need thereof, characterized in that a pharmaceutical formulation according to the first aspect of the invention is administered to the eye of said patient. Similarly, the present invention relates to a method for treating an ocular fundus disease in a patient in need thereof, characterized by implanting at least one IVT implant according to the second aspect of the present invention into the vitreous of the patient's eye. The present invention also relates to a pharmaceutical formulation according to the first aspect of the present invention for use in a method for treating an ocular fundus disease in a patient in need thereof. Similarly, the present invention relates to an IVT implant according to the second aspect of the present invention for use in a method for treating an ocular fundus disease in a patient in need thereof. The present invention also relates to the use of an API in the manufacture of a pharmaceutical formulation according to the first aspect of the present invention for treating an ocular fundus disease in a patient in need thereof. Similarly, the present invention relates to the use of an API in the manufacture of an IVT implant according to the second aspect of the present invention for treating an ocular fundus disease in a patient in need thereof.

[0061] The ocular fundus disease may be selected from the group consisting of wet age-related macular degeneration (wAMD), dry macular degeneration, geographic atrophy, diabetic macular edema (DME), nonproliferative diabetic retinopathy (NPDR), cystoid macular edema (CME), choroidal neovascularization (CNV), retinal vein occlusion, and retinitis pigmentosa, preferably from the group consisting of wAMD, DME, or retinal vein occlusion; most preferably, the ocular fundus disease is wAMD. The treatment method may include single or repeated implantation of an IVT implant according to the second aspect of the present invention into the vitreous of the patient's eye. In one embodiment, the treatment method includes repeated implantation of an IVT implant according to the present invention into the vitreous of the patient's eye. In another embodiment, the implantation of the IVT implant is performed using a 24-gauge ultra-thin-walled needle. The time interval between repeated implantations should be at least 3 months or at least 6 months, preferably at least 9 months or at least 12 months, e.g., 9, 10, 11, 12, 13, 14, or 15 months, and most preferably the time interval between repeated implantations is 12 months. One or more IVT implants can be implanted into the vitreous of the patient's eye at each implantation. In a preferred embodiment, the method for treating ocular fundus diseases is characterized in that only one IVT implant is implanted into the vitreous of the patient's eye at a time. [Example]

[0062] Examples and Experimental Data The following examples are for illustrative purposes only and are not intended to limit the scope of the present invention in any way.

[0063] A) Methods for measuring particle size distribution The particle size distribution is determined by laser diffraction. A laser diffraction sensor (e.g., Helium-Neon Laser Optical System HELOS from Sympatec) equipped with a dry dispersion unit (e.g., RODOS from Sympatec) and a vibration feed unit (e.g., VIBRI from Sympatec) can be used with the following settings: - Semicircular multi-element photodetector with 31 channels - Focal length: 100mm (measures the range of 0.5 / 0.9~175μm) - Time unit: 100ms - Start: 0 seconds after optical density ≥ 2.0%, always applicable; Stop: 3 seconds after optical density ≤ 1.0% or 30 seconds in real time - Pressure: 2.0 bar; Vacuum: max. - Mode: HRLD (High Resolution Laser Diffraction Mode) - Optical density: 2~20% - Feeding speed: 80%; Feeding height: 1.3mm Results are reported as the average of three independent sample measurements.

[0064] B) Pharmaceutical preparations [Table 1] * Removed during the preparation process, leaving only trace amounts (i.e., approximately 1% (w / w) or less remaining in the formulation)

[0065] C) Bioerodible implants [Table 2]

[0066] D) General Process for Preparing Coated and Uncoated Bioerodible Nintedanib Implants The bioerodible nintedanib implant according to the present invention is prepared in a three-step process: 1) Preparation of PVA solution PVA is weighed and placed in a glass conical flask. Deionized water is then added, and the mixture is heated on a hot plate while stirring with a magnetic stirrer, with the top of the flask covered with a glass plate or foil to reduce evaporation. Once the PVA is completely dissolved, the heat is turned off, and the solution is allowed to cool to room temperature with constant stirring. Once cooled, the volume is adjusted with deionized water to compensate for any loss from evaporation. The typical mass concentration (w / v) of PVA in the final solution is between 2% and 20%, usually about 10% or about 13.6%. The PVA is dissolved at a pH of 23.8-32.2 mPa. * It is also preferred that the acrylic acid be a Ph.Eur. / JPE grade with a viscosity of 0.15 s (4% PVA in aqueous solution) and a high degree of hydrolysis (≧97%).

[0067] 2) Implant Preparation A weighed amount of micronized nintedanib powder (esylate, base, or a blend of the two), typically nintedanib esylate powder, is placed in a mortar and then slowly added to the PVA solution while mixing the paste with a pestle. On a larger scale, this can be done using a commercially available mixer (e.g., Hobart). A typical ratio of nintedanib to PVA solution is about 1:1, e.g., 100 g of nintedanib powder is mixed with 100 mL of PVA solution. The paste is then loaded into a syringe equipped with a needle. The paste is extruded through the needle tip onto a glass plate to form a continuous strand. The inner diameter of the needle determines the diameter of the strand. The strand is air-dried for more than 2 hours, and then heated in an oven at between 100°C and 180°C for up to 6 hours, preferably at 130°C and 135°C for 2 to 4 hours, e.g., 3 hours. After removal from the oven, the strand is cut to length. Alternatively, the strands can be coated in a solution of PVA, dried again, and then heated. Other options include heating the dried paste strands, then dip coating and then reheating, or cutting the implant to length before dip coating.

[0068] 3) Loading the applicator, packaging and sterilization The implant is loaded into the barrel of a custom-made applicator. The outer diameter of the barrel should be equal to or smaller than a 22-gauge needle, ideally even smaller. After sealing the end of the barrel to prevent the implant from falling out, the applicator is packaged to prevent accidental depression of the plunger or, if spring loaded, accidental activation of the spring. The assembly is then pouched for sterilization by gamma (e.g., up to 25 kGy) or e-beam. Pouching can be single or, ideally, double-pouched (so that the inner sterile pouch can be placed in the sterile field immediately before use).

[0069] E) Specific process for preparing uncoated bioerodible nintedanib implants according to C). A specific preparation process is described for I-6 in the following example, but can be applied analogously for I-3, I-4, I-5, and in a similar manner for further implants according to the invention, e.g., I-1 and I-2.

[0070] 1) Preparation of PVA solution 10% (w / v) and 13.6% (w / v) PVA solutions are prepared in glass flasks by adding 10 g and 13.6 g of PVA (Merck Germany, 99% hydrolysis), respectively, to 100 mL of water for injection. The flasks are placed on a heated stir plate and heated until the PVA is completely dissolved. After cooling, water is then added with stirring to increase the mass (to compensate for the evaporation of water during heating).

[0071] 2) Preparation of implant (I-6) In a mixing bowl, 5 g of nintedanib esylate was added to 5.5 mL of 13.6% (w / v) PVA solution and mixed with a stainless steel spatula to obtain a smooth, uniform paste. The paste was then transferred to a 1 mL syringe fitted with a 22-gauge blunt tip. The loaded syringe was then placed in a manual Arbor press with the distal end of the 22-gauge tip facing downward. The press arm was lowered to contact the syringe plunger, and then pressed down with a constant force not exceeding 40 N, extruding the API / PVA paste through the 22-gauge tip to form an approximately 20 cm strand. The syringe was then removed from the press, and the strand was laid flat on a flat surface and removed from the tip. This process can then be repeated depending on the required batch size. The extruded strand was air-dried for at least 2 hours and then placed in an oven heated to 130°C for 3 hours. After cooling, the strands are cut to lengths of 6.0 mm using a cutting tool and a razor blade. The implants are visually inspected for deformation and attached microparticulate matter.

[0072] 3) Loading the applicator, packaging and sterilization The implant is then loaded into an applicator, which consists of a 24-gauge XTW (ultra-thin-wall) needle on an inserter body (similar to a syringe, but with a pusher rod rather than a plunger, which is attached to the distal end of the needle). One (or optionally two) implants are loaded into the distal end of the needle, and an applicator cap is attached over the end to 1) cover the sharp end of the needle and 2) prevent the implant from slipping off the needle. A removable clip is placed on the pusher rod to prevent its accidental subsidence, and the assembly is then placed into a foil pouch and sealed with a bar heat sealer. The loaded foil pouch is then placed into a Tyvek (non-woven HDPE fiber material) pouch, which is heat-sealed with a bar heat sealer. The double-pouched sealed system is then gamma (25 kGy) sterilized.

[0073] F) Specific Process for Preparing Coated Bioerodible Nintedanib Implants Coated implants similar to the uncoated ones in E) can be prepared by taking the air-dried API / PVA strands of step 2) and immersing them in a 2% (w / v) or 5% (w / v) aqueous PVA solution. After air-drying for 12 hours, the coated strands are then heated in an oven at 130°C for 3 hours and then processed in the same manner as in E). This results in cylindrical implants whose walls are coated with a layer of PVA but whose ends are uncoated.

[0074] G) Method for determining drug release rates from implants in vitro Each implant is individually placed in a vial containing 20 mL of PBS in a water bath at 37 ° C. Samples are taken periodically, for example, once a day, and assayed by HPLC using a C-18 reverse-phase column with UV detection, and the buffer is replaced to ensure that sink conditions are maintained. The daily release rate is calculated from the HPLC results and is shown as μg of nintedanib esylate per day. An exemplary release profile is shown in Figure 1 for implant I-6 as described hereinabove.

[0075] H) Effect of formulation characteristics, implant characteristics, and process parameters on drug release rate The effect of various parameters on the release rate has been determined. 1) Effect of implant dimensions Uncoated nintedanib esylate implant prototypes of formulation F-4 (nintedanib esylate:PVA 100:10 (w / w)) were prepared by the process described herein. 22 and 23 gauge needles, respectively, were used for extrusion, and the strands were cut to lengths of 1.0 mm or 3.5 mm. Release rates were determined by the process described herein. For each implant, the cumulative amount of drug released was measured over several days and measured over a surface area of 1 mm. 2 The average release rate per 1000 μg / mL was calculated. The results show that at a given API:PVA ratio, the nintedanib release rate of implants according to the invention is proportional to their surface area. [Table 3]

[0076] 2) Effect of PVA content Uncoated nintedanib esylate implant prototypes of formulations F-4 and F-7 (nintedanib esylate:PVA mass ratios of 100:10 (w / w) and 100:18 (w / w), respectively) were prepared by the process described herein. They were extruded through a 23-gauge needle, heated at 130°C for 3 hours, and cut into 3.5 mm lengths. The release rate was determined by the process described herein. As can be seen, higher PVA content resulted in a slightly lower release rate. [Table 4]

[0077] 3) Effect of temperature during oven drying Uncoated nintedanib esilate implant prototypes of Formulations F-4 and F-7 (nintedanib esilate:PVA mass ratios of 100:10 (w / w) and 100:18 (w / w), respectively) were prepared by the process described herein. They were extruded through a 23-gauge needle, heated as shown below, and cut to 3.5 mm lengths. The release rate was determined by the process described herein. As can be seen from Figures 2 and 3, as well as the following tables (each showing data for Formulation F-7 implants), the release was relatively constant, and the curing temperature had no significant effect on the release rate. In addition, Figure 6 shows a surprisingly low initial burst release, i.e., less than 5% after the first two days, which favorably contributes to the relatively constant release.

[0078] [Table 5]

[0079] A similar graph was obtained for the implant (23G extrusion needle, 3.5 mm length) of formulation F-4 (nintedanib esylate:PVA 100:10 (w / w)). [Table 6]

[0080] Although the curing temperature did not affect the release rate, it did affect the disintegration rate of the implant. Implants heated at lower temperatures and for shorter periods of time often disintegrated during dissolution testing (the table above shows the release rates for devices that did not disintegrate). When the device disintegrates, there is a significant increase in drug release followed by a plateau in the measured release rate (see, e.g., Figures 4 and 5).

[0081] The disintegration of implants heated at 100°C for 1 hour appeared somewhat random, with all (n=6) implants disintegrating by day 120 (Figure 4 shows that only 3 implants disintegrated before day 80; the overall seemingly low release of one implant is an artifact of the early disintegration of this implant). Implants heated to 130°C for 3 hours are much less likely to disintegrate over the drug release time course (note: the total drug content of these implants is approximately 200 μg; therefore, a nearly linear release is maintained until the implant is largely depleted).

Claims

1. A pharmaceutical formulation for extended sustained release of an API comprising 80-95% (w / w) of API and 5-20% (w / w) of polypolyvinyl alcohol (PVA).

2. 2. The pharmaceutical formulation of claim 1, consisting of 80-95% (w / w) API, 5-20% (w / w) PVA (w / w) and optionally traces of water.

3. 3. The pharmaceutical formulation of any one of claims 1 to 2, wherein the API is a pharmaceutically acceptable nintedanib salt or a blend of a pharmaceutical nintedanib salt and nintedanib free base, preferably wherein the pharmaceutically acceptable nintedanib salt is nintedanib esylate, more preferably nintedanib esylate having a particle size distribution of D50≦20 μm and D90≦50 μm.

4. The PVA has a high degree of hydrolysis (≧97%) and, optionally, a viscosity of 23.8 to 32.2 mPa when determined in a 4% aqueous PVA solution. * 4. The pharmaceutical formulation according to claim 1, characterized by a viscosity of 0.15 s.

5. A coated or uncoated intravitreal (IVT) implant having a body consisting of the long-term sustained release pharmaceutical formulation according to any one of claims 1 to 4, wherein the body may have a polymer coating.

6. 6. The IVT implant of claim 5, which is cylindrical in shape, has a diameter of 0.2 to 0.4 mm, and a length of 7 mm or less.

7. 7. The IVT implant of any one of claims 5 to 6, characterized by a nintedanib esylate content in the range of 400-600 μg and / or an in vitro daily release of nintedanib esylate of about 1.1 μg / day or more over 6 months.

8. A method for preparing the pharmaceutical formulation according to any one of claims 1 to 4, comprising: a) preparing an aqueous PVA solution; b) mixing the PVA solution with the API powder; A method comprising:

9. 9. The method of claim 8, wherein in step a), the PVA solution has a mass concentration of PVA between 8% and 15% (w / v), and / or in step b), the ratio of PVA solution to API powder is about 1:1 (w / v).

10. A method for preparing an IVT implant according to any one of claims 5 to 7, comprising: Preparing a pharmaceutical formulation according to steps a) and b) according to any one of claims 8 to 9; c) loading the mixture into an extrusion device; d) extruding the mixture through an extruder head to form extruded strands; e) optionally drying the extruded strands; f) heating the extruded strand; g) cutting the extruded strand into implant pieces of equal length; h) sterilizing the implant piece thus obtained; Including, The method may further comprise the optional step of coating the extruded strand after step d), e), or f) or the implant piece after step g) in a solution of a coating polymer.

11. 11. The method of claim 10, wherein the extrusion head has a circular profile and an inner diameter of about 0.4 mm or less.

12. 12. The method of any one of claims 10 to 11, wherein in optional step e) the extruded strands are dried at ambient temperature for at least 2 hours, and / or in step f) the extruded strands are heated to a temperature between 120°C and 180°C for at least 2 hours.

13. A method for treating ocular fundus diseases in a patient in need thereof, characterized in that a pharmaceutical formulation according to any one of claims 1 to 4 is administered to the patient's eye, in particular by implanting at least one IVT implant according to any one of claims 5 to 7 into the vitreous of the patient's eye.

14. 14. The method of claim 13, wherein the ocular fundus disease is selected from the group consisting of wet age-related macular degeneration (wAMD), dry macular degeneration, geographic atrophy, diabetic macular edema (DME), nonproliferative diabetic retinopathy (NPDR), cystoid macular edema (CME), choroidal neovascularization (CNV), retinal vein occlusion, and retinitis pigmentosa.

15. 15. The method of any one of claims 13 to 14, comprising repeated implantation of one IVT implant, preferably using a 24 gauge ultra-thin walled needle, wherein the time interval between repeated implantations is at least 9 months.

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