Pharmaceutical formulations of intraocular nintedanib

Abstract

Formulations and intravitreal implants containing nintedanib can be used in methods of treating diseases of the posterior portion of the eye.

Description

Technical Field

[0001] The present invention relates to pharmaceutical formulations of nintedanib suitable for intraocular use and for treating retinal disorders, and more particularly to long-term sustained-release pharmaceutical formulations of nintedanib, intravitreal (IVT) implants formed from these formulations, methods for preparing these formulations and IVT implants, and the use of these formulations and IVT implants in methods for treating certain posterior ocular diseases. Background Art

[0002] In the treatment of serious chronic ocular diseases, particularly in the case of degenerative retinal disorders such as wet age-related macular degeneration (wAMD), dry macular degeneration, geographic atrophy, diabetic macular edema (DME) or non-proliferative diabetic retinopathy (NPDR), cystoid macular edema (CME), choroidal neovascularization (CNV), and retinal vein occlusion, implantable sustained release delivery devices or implantable sustained release formulations capable of continuously administering therapeutic agents to the eye over long periods of time are desirable alternatives to the cumbersome regimen of intravitreal injections of therapeutic agents, which must be repeated regularly after relatively short intervals, for example once a month.

[0003] Age-related macular degeneration (AMD) is a common disease and the leading cause of severe vision loss in people over 50 years old in the Western world. Because AMD causes macular degeneration and irreversible damage, it impairs central vision. There are two main common forms of AMD: dry AMD (also known as non-exudative AMD) and wet AMD (also known as exudative or neovascular form, characterized by abnormal growth of new blood vessels). About 90% of AMD cases are associated with the dry form, which affects the central retina-macula area that allows us to see (especially details) to read and distinguish colors. In contrast, only about 10% of AMD patients suffer from the wet form; however, because the new abnormal choroid and retinal blood vessels leak and bleed and destroy the structure of the retina, resulting in the death of photoreceptor cells, wAMD can quickly lead to severe vision loss. Those rapidly growing abnormal blood vessels (called choroidal neovascular membrane (CNVM)) and changes in vascular permeability and exudation have been treated by repeated intravitreal injections of anti-VEGF agents.

[0004] Angiogenesis is implicated in the pathogenesis of intraocular neovascular diseases such as proliferative retinopathy and AMD; therefore, the therapeutic use of inhibitors of vascular endothelial growth factor receptor (VEGFR) for the treatment of these diseases is a method known in the art, as described in WO 2006 / 047325 and elsewhere.

[0005] Nintedanib (3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone), i.e. a compound of formula A,

[0006]

[0007] It is an efficient, orally bioavailable intracellular tyrosine kinase inhibitor. It inhibits vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). It competitively binds to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks intracellular signal transduction. In addition, nintedanib inhibits Fms-like tyrosine protein kinase 3 (Flt 3), 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). Therefore, its kinase specificity profile includes kinases related to angiogenesis, fibrosis, inflammation and proliferation. Therefore, nintedanib has valuable pharmacological properties, for example, for the treatment of immune diseases or pathological conditions involving immune components for tumorous or fibrotic diseases.

[0008] Nintedanib is described in WO 01 / 27081. WO 2004 / 013099 discloses its monoethane sulfonate (ethane sulfonate) salt which is particularly suitable for development as a medicament; further salt forms are presented in WO 2007 / 141283. Pharmaceutical dosage forms comprising nintedanib are disclosed in, for example, WO 2009 / 147212 and WO 2009 / 147220. The use of nintedanib for the treatment of immune diseases or pathological conditions involving an immune component is described in WO 2004 / 017948, for the treatment of neoplastic diseases in WO 2004 / 096224 and for the treatment of fibrotic diseases in WO 2006 / 067165.

[0009] Sustained release formulations allow the delivery of drugs over long periods of time. The mode of administration and its release kinetics can have a profound effect on the therapeutic efficacy. The use of polymeric materials in this regard is well established and has produced many successful methods for controlling drug release and providing sustained release from days to months.

[0010] Polymeric drug delivery devices for in vivo implantation have demonstrated durability and biocompatibility. However, many of these drug delivery devices that provide sustained release of agents are inert under physiological conditions, resulting in the need for surgical removal after complete release of the drug (particularly in the case of larger devices).

[0011] Another challenge is the difficulty in manufacturing materials with therapeutic agents, and particularly maintaining homogeneity between miniaturized devices that are millimeter-sized or smaller. 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 millimeter or sub-millimeter scale.

[0012] Intravitreal implants that deliver a stable concentration of drugs over a period of time have been developed. These implants are injected or surgically implanted into the vitreous of the eye for sustained release of drugs to the back of the eye. Many matrix-based sustained release drug delivery systems are known to be suitable for intraocular (particularly intravitreal) placement for extended treatment of posterior eye indications. The field of sustained drug delivery is clearly described and there are many technologies. For sustained release of implants that release drugs by diffusion through the matrix, release kinetics are generally defined by Fick's diffusion law. Higuchi later described a solution to Fick's law about 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 drugs released from solid systems, such as drugs in polymer matrices. Higuchi also describes a case where the drug is not dissolved in the base material but exists as particles in the base (Higuchi T, Release of medicaments from ointment bases containing drugs in suspension, JPharm Asci. 1961: 50: 874-875).

[0013] 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. In some pharmaceutical dosage forms, this is sufficient, but for other pharmaceutical dosage forms it is desirable to release the drug at a more constant rate, e.g., approximately following zero-order kinetics over most of the release time.

[0014] In an attempt to achieve a more linear release, implants can be made from a matrix of the drug in a bioerodible polymer. "Bioerodible polymer" means a polymer that does not degrade in the body. Bioerodible polymer matrices offer the advantage of mechanical erosion and excretion of unchanged substance by dissolution, whereas biodegradable polymers break down in the body into monomers that can cause toxicological problems. Many biodegradable implants have been prepared, often containing polylactic and polyglycolic acid or copolymers (PLGA). The basic principle is that the drug will be released from these systems as the implant breaks down, rather than by diffusion through the polymer matrix. In practice, this has been difficult to achieve. For implants of any shape, as the implant erodes, the surface area becomes smaller, so even in a perfect system, the release will be non-linear. In addition, the drug still diffuses from the device (especially for water-soluble drugs or implants with high drug content (over 10%)). An example of this is Implant (Allergan). This implant includes dexamethasone in a PLGA matrix and is claimed to be a 6-month device. In fact, it releases more than 99% of its drug within the first month (Chang-Lin JE, Attar M, Acheapong AA et al., Pharmacokinetics and pharmacokinetics 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 decomposition, the net effect of which is a slow initial degradation followed by rapid "bulk" erosion, leading to so-called S kinetics, i.e., an initial release rate determined by diffusion through the matrix, which slows down (square root kinetics of time), followed by a faster release due to device disintegration.

[0015] One attempt to provide a more linear release is to prepare low drug loading (less than 5%) implants in the shape of a wafer so that the surface area will not change significantly with erosion. Devices of this type are commercially available as In vitro, it provides a very linear long-term release, but in vivo data indicate that release occurs via both diffusion and erosion, and the wafer is completely depleted within 5 days (Flemming AB, Saltzman WM, Pharmacokinetics of the carmustine implant, Clin Pharmacokinetics 41(6)403-419 (2002)).

[0016] Non-erodible implants (such as and ) provide a more constant release rate. In these systems, a central drug core such as a tablet or paste (in a polymer matrix) is wrapped in an impermeable polymer. Drug release occurs on both sides of the small hole (diffusion port) in the impermeable layer and can be further controlled by a coating of a permeable polymer above the diffusion port. When immersed in water (or placed in the eye), water diffuses into the central drug core and dissolves some of the drug, which then diffuses through the diffusion port. Because the amount of drug dissolved in the internal water is very small, the amount of water entering the core is also very small, so the release rate is low. In addition, as long as there is excess drug in the drug core, the solution of the drug in the core will be saturated, and the concentration gradient on both sides of the diffusion port will be constant, resulting in linear release. Although these systems have the advantage of providing relatively linear release, they are neither bioerodible nor biodegradable.

[0017] There remains a great need in the medical field for alternative treatments for posterior ocular indications, such as sustained release delivery systems that release therapeutic concentrations of active substances directly to the posterior of the eye from intravitreal implants over long periods of time with great safety and efficacy. Furthermore, any sustained release implant is highly dependent on the selection of polymers, copolymers, drug-polymer interactions, loading homogeneity, porosity, size, surface area to volume ratio, and the like to provide its drug release and degradation characteristics, and the manufacturing techniques used in prior art implants can result in inherent disadvantages in each of these parameters.

[0018] US 5,378,475 describes a sustained release implant for insertion into the vitreous of an 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 above the first coating, including a region where the first coating does not cover the drug reservoir, to provide a location through which the drug can diffuse from the implant. The implant also has a label that can be used to suture the device to a location in the eye. The implant device is prepared by applying a coating solution (by, for example, dipping, spraying or brushing various coatings around the drug reservoir).

[0019] US 8,871,241 discloses a kind of injectable sustained release drug delivery device, it has the cylindrical cross section comprising the core containing one or more drugs and one or more polymers.The core can be surrounded by a polymer outer layer.The device is formed by extruding or otherwise preforming the polymerizable outer layer for the drug core, and the drug core can be coextruded with the outer layer or inserted into the outer layer after extrusion, and curable.The polymer forming the outer layer and the core includes poly (caprolactone), ethylene vinyl acetate polymer, poly (ethylene glycol) (PEG), polyvinyl alcohol (PVA), poly (lactic acid) (PLA), poly (glycolic acid) (PGA), poly (lactic acid-co-glycolic acid) (PLGA), polyalkyl cyanoacrylate, polyurethane, nylon or its copolymer.

[0020] The device can have an outer diameter suitable for injection near the patient's eye (for intraocular or periocular injection) with a 30 gauge (0.3 mm outer diameter according to EN ISO 9626) needle to about a 12 gauge (2.7 mm outer diameter according to EN ISO 9626) needle, or with a needle having an inner diameter ranging from about 0.0055 inches (0.1397 mm) to about 0.0850 inches (2.159 mm).

[0021] The device can 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, wherein, upon injection, this suspension or solution undergoes a phase change and forms a gel. This configuration can provide controlled release of the drug over a longer period of time.

[0022] The device can be manufactured as extended blocks segmented into drug delivery devices, which can be uncoated, leaving the drug core exposed on all sides or (where an outer layer is used) at the ends of each segment, or coated with a layer (such as a drug permeable, semi-permeable, impermeable or bioerodible layer).

[0023] A variety of drugs are disclosed that may be incorporated into the devices, including, among many others, angiogenesis inhibitors, anti-proliferative compounds, and tyrosine kinase inhibitors.

[0024] WO 02 / 074196 discloses ocular implants that administer therapeutic drugs to the eye according to bimodal release kinetics with an initial delivery of a "loading dose" at a high release rate shortly after placement of the implant in or near the eye as a first mode of administration, followed by delivery of the drug via a continuous, sustained lower release rate as a second maintenance dose mode of administration, and using the same implant device within the same treatment regimen. These implants include:

[0025] (a) a composite material substrate layer comprising:

[0026] (i) therapeutic agents, and

[0027] (ii) a polymeric matrix material in which the therapeutic agent is dispersed, the material comprising

[0028] (1) a polymer that is permeable to the therapeutic agent and exists as a bioerodible solid matrix structure, and

[0029] (2) a water-soluble polymer having a greater water solubility than the permeable polymer, and

[0030] (b) Optionally, a discrete solid core containing an additional therapeutic agent, which is surrounded and covered by the composite matrix layer.

[0031] The permeable polymer may be a superhydrolyzed PVA that is not cross-linked, which allows the therapeutic agent to diffuse therethrough and forms 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 slow enough that the polymer material in the implant will dissolve so that the therapeutic agent will only disintegrate after a longer period of time and provide slow sustained drug delivery. The superhydrolyzed polyvinyl alcohol may be a polyvinyl alcohol having at least 98.8 wt% hydrolysis and a weight average molecular weight of about 85,000 to about 150,000. Heating the matrix implant at a temperature above 100° C. will promote PVA cross-linking. This may be desirable for attempting to reduce the drug release rate of a particular implant and also control the rate at which the implant erodes.

[0032] Embodiments of this implant may be installed in the vitreous to deliver 2-methoxyestradiol for the treatment of CNVM, but many other therapeutic agents and drugs are disclosed that may be delivered via these implants, particularly angiogenic compounds such as VEGF antagonists.

[0033] WO 2005 / 110362 discloses a drug delivery system for treating ocular conditions, the system comprising at least one bioerodible implant suitable for insertion into an ocular region, the implant comprising (i) an active agent and (ii) a bioerodible polymer, wherein the bioerodible implant should release a therapeutic amount of the active agent to the ocular region over a period of between about 30 days and about 1 year. Preferably, the active agent is an anti-inflammatory agent and the bioerodible polymer is a PLGA copolymer. The drug delivery system may comprise a plurality of bioerodible implants, each having a unique drug release profile, preferably up to three implants may be implanted into the posterior region of the eye. These implants may be prepared using an extrusion process.

[0034] WO 2006 / 039271 discloses a method for manufacturing a plurality of drug delivery devices for implantation in a patient's eye, the devices being fabricated in part from polyvinyl alcohol using a consistent curing process that results in less variation in drug release rate between devices.

[0035] WO 2018 / 054077 discloses a method for treating an ocular disease (including anterior and posterior ocular indications), the method comprising applying an effective amount of a pharmaceutical composition to the eye of a subject in need thereof, wherein the pharmaceutical composition is a topical preparation (such as an eye drop) and comprises nintedanib or a salt thereof. The disclosure also relates to a pharmaceutical composition or preparation that can be used to treat an ocular disease.

[0036] WO 2020 / 219890 discloses a sustained-release biodegradable ocular hydrogel implant for the treatment of posterior ocular indications, comprising a tyrosine kinase inhibitor (TKI) (including nintedanib and others), a polymer network comprising multiple polyethylene glycol (PEG) units, and a clearance region, wherein the clearance region is free of undissolved TKI particles before TKI release.

[0037] WO 2020 / 243608 discloses an implant comprising a tyrosine kinase inhibitor and a bioerodible polyester polymer, which provides sustained release of a small molecule tyrosine kinase inhibitor (such as axitinib) from the bioerodible polyester polymer implant to treat ophthalmic indications (such as neovascular age-related macular degeneration and diabetic macular edema) by intravitreal injection of the implant. The implant is designed to be preloaded into a small diameter needle and injected through the pars plana via a self-sealing scleral needle.

[0038] WO 2017 / 083779 and WO 2020 / 102758 disclose optional biodegradable solid aggregated microparticles for long-term treatment of ocular diseases, having, for example, an average diameter between 20 and 40 microns, which include an effective amount of a therapeutic agent (such as the VEGFR inhibitor sunitinib) for injection into the bottom of the vitreous. These microparticles are composed of a polymer (such as PLGA, PLGA-PEG or PLA) and aggregate in vivo to form at least one aggregate of at least 500 μm, which provides sustained drug delivery in a manner that allows the aggregate to remain substantially outside the visual axis without significantly impairing vision. Summary of the invention

[0039] In a first aspect, the present invention relates to a long-term sustained release pharmaceutical formulation of an API comprising 80 to 95% (w / w) of the API and 5 to 20% (w / w) of PVA.

[0040] 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, the body optionally having a polymer coating.

[0041] In a third aspect, the present invention relates to a method for preparing a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the present invention, the method comprising the following steps

[0042] (a) preparing a PVA aqueous solution, and

[0043] (b) Mixing the PVA solution with API powder.

[0044] In a fourth aspect, the present invention relates to a method for preparing an IVT implant according to the second aspect of the present invention, the method comprising the following steps

[0045] (a) preparing a PVA aqueous solution,

[0046] (b) mixing the PVA solution with API powder,

[0047] (c) loading the mixture into an extrusion device,

[0048] (d) extruding the mixture through an extruder head to form an extruded strand,

[0049] (e) optionally drying the extruded strand,

[0050] (f) heating the extruded line,

[0051] (g) cutting the extruded strand into implant segments of equal length, and

[0052] (h) sterilizing the implant segment thus obtained,

[0053] Therein, the method may additionally comprise the optional step of coating the extruded wire after step d), e) or f) or coating the implant segments after step g) in a solution of a coating polymer.

[0054] In a fifth aspect, the present invention relates to a method for treating a posterior ocular disease in a patient in need thereof, the method being characterized in that a pharmaceutical formulation according to the first aspect of the invention is administered to the eye of the patient, in particular at least one IVT implant according to the second aspect of the invention is implanted into the vitreous of the eye of the patient.

[0055] Furthermore, the present invention relates to a pharmaceutical formulation according to the first aspect of the invention, in particular to an IVT implant according to the second aspect of the invention, for use in a method of treating a posterior ocular disease in a patient in need thereof.

[0056] Furthermore, the present invention relates to the use of the 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 a posterior ocular disease in a patient in need thereof.

[0057] Other aspects of the present invention will be apparent to those skilled in the art directly from the above and following descriptions.

[0058] General Terms and Definitions

[0059] Terms not specifically defined herein should be given the meanings given by those skilled in the art according to the present invention and content. However, as used in this specification, unless otherwise indicated, the following terms have the indicated meanings and are subject to the following conventions.

[0060] As used herein, the terms "treatment" or "treating" encompass therapeutic, ie, curative and / or palliative, and preventative / prophylactic treatment.

[0061] Therapeutic treatment refers to the treatment of a patient who has developed one or more conditions that are manifest in acute or chronic form. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular indication or causal treatment to reverse or partially reverse the symptoms of that indication or to arrest or slow the progression of the disease.

[0062] Prophylactic treatment ("prevention") refers to treatment of a patient at risk of developing one or more disorders prior to the clinical onset of that disorder, in order to reduce that risk.

[0063] The terms "treatment" or "treating" include the administration of one or more active compounds to prevent or delay the onset of symptoms or complications, and to prevent or delay the development of the disease, disorder or condition, and / or to eliminate or control the disease, disorder or condition, and to alleviate the symptoms or complications associated with the disease, disorder or condition.

[0064] 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) attenuates, ameliorates or eliminates one or more symptoms of the particular disease or condition, or (iii) prevents or delays the onset of one or more symptoms of a particular disease or condition as described herein.

[0065] The expression "intraocular use" refers to use in the eye, which includes use in the vitreous body, suprachoroidal space, anterior chamber of the eye, and subconjunctival space.

[0066] "Long-term sustained release" of a drug means that the drug is released over a long period of time (eg weeks or months, in particular more than 3, 6, 9 or 12 months).

[0067] The expressions "API" and "nintedanib" mentioned herein in relation to any aspect of the invention or in the context of the invention are meant to be interchangeable and include the group consisting of nintedanib (free base), a pharmaceutically acceptable nintedanib salt, and a blend consisting of nintedanib (free base) and a pharmaceutically acceptable nintedanib salt. If not otherwise indicated, the amounts provided herein are generally expressed as nintedanib esylate.

[0068] The term "inactive ingredient" refers to any component other than the active ingredient.

[0069] The phrase "pharmaceutically acceptable" as used herein refers 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 humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications and consistent with a reasonable benefit / risk ratio.

[0070] Pharmaceutically acceptable excipients suitable for use in the preparation of pharmaceutical formulations (eg, for IVT implants) will be known to those skilled in the art.

[0071] The terms "bioerodible" and "biodegradable" refer to the gradual disintegration, dissolution or breakdown of a polymer, formulation or implant in a biological system over a period of time, for example, by one or more physical or chemical degradation processes, such as dissolution by solubility, enzymatic processes or hydrolysis.

[0072] Biodegradable polymers are usually susceptible to hydrolysis under physiological conditions due to the presence of hydrolyzable and / or enzymatically cleavable functional groups (e.g., anhydride, ester, amide bonds). Biodegradation can result in the cleavage of the polymer backbone or the cleavage of water-soluble side chains. The cleavage products can then be metabolized and excreted, allowing them to be completely removed.

[0073] Bioerodible polymers undergo mechanical erosion via a biological process that causes the polymer to dissolve and be absorbed into surrounding tissue.

[0074] A paste as used herein describes a thick, wet mixture of a solid (eg, API) and a solution (eg, PVA solution).

[0075] Viscosity measurements were performed according to the JPE monograph for polyvinyl alcohol (fully hydrolyzed polyvinyl alcohol; viscosity) at 20° C. with a 4% aqueous solution using a rotational viscometer. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] Figure 1 :

[0077] Mean release profile of nintedanib essylate from implant I-6 in PBS at 37°C for 270 days (n=6).

[0078] Figure 2 :

[0079] Release profile of nintedanib essylate in PBS at 37°C over 45 days from implants dried at 130°C for 3 hours.

[0080] Figure 3 :

[0081] Release profile of nintedanib essylate in PBS at 37°C over 45 days from implants dried at 150°C for 3 hours.

[0082] Figure 4 :

[0083] Release profile of nintedanib essylate in PBS at 37°C over 127 days from implants that had been dried at 100°C for 1 hour (disintegrated before day 80).

[0084] Figure 5 :

[0085] Release profile of nintedanib essylate in PBS at 37°C for 135 days from implants dried at 130°C for 3 hours.

[0086] Figure 6 :

[0087] Daily release profile of nintedanib essylate in PBS at 37°C for 135 days from implants dried at 130°C for 3 hours.

[0088] Figure 7 :

[0089] Comparison of extrudates between nintedanib esylate (1), a mixture of nintedanib esylate with 20% esylate and 80% free base (2), and nintedanib free base (3) prepared according to the process of E) 2) above line (I-6) with 12% (w / v) PVA solution before oven heating.

[0090] Figure 8 :

[0091] Comparison of extrudates between nintedanib esylate (1), a mixture of nintedanib esylate with 20% esylate and 80% free base (2), and nintedanib free base (3) prepared according to the process of E) 2) above line (I-6) with 12% (w / v) PVA solution before oven heating. DETAILED DESCRIPTION

[0092] There is a medical need to improve the options for treatment of degenerative or persistent posterior ocular conditions by providing an implantable sustained release delivery device that continuously releases a therapeutic agent to the eye over an extended period of time (e.g., a period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, or longer for a treatment period) at a release rate suitable to maintain therapeutic drug concentrations in the desired posterior ocular region or site.

[0093] Many matrix-based drug delivery systems have been developed to date, however the implant according to the present invention offers a unique combination of the following properties:

[0094] 1) Drug release is dependent on the surface area of ​​the device, which decreases only slightly during the treatment period as drug is released;

[0095] 2) the primary function of the polymer matrix (or coating, if one is used) is not to provide a diffusion barrier for release of the drug, but rather to substantially maintain the surface area of ​​the implant;

[0096] 3) The release rate decreases very slowly throughout the release period, so that the therapeutic concentration of the drug in the vitreous of the eye is maintained throughout the longer treatment period;

[0097] 4) the matrix is ​​bioerodible (not biodegradable);

[0098] 5) The erosion rate can be adjusted by thermal curing methods so that the implant structure decomposes after more than 90% of the drug has been released;

[0099] 6) These implants are able to maintain release and drug concentration in the vitreous within the therapeutic window of the drug while using relatively low concentrations of polymer in the matrix (drug:polymer ratio (w / w) >1:1, more typically >4:1 and ≥6:1 (w / w), for example, up to 10:1 or 20:1).

[0100] Furthermore, as light stress and long-term stability studies have shown, the implant according to the invention is suitable for long-term storage, since it provides sufficient release, physical and chemical stability properties over several months.

[0101] The formulation principle of the present invention is to develop a delivery system with minimal added pharmaceutical excipients and few steps in the manufacturing process. The pharmaceutical excipient selected is polyvinyl alcohol (PVA). This material has a well-known safety profile and has been used in several approved intraocular products. The low percentage of PVA in the formulation (not exceeding 20% ​​(w / w)) allows for high drug loading in the product. PVA dissolves in water to form a viscous solution of the desired concentration, which can be mixed with the API to form a paste.

[0102] The formulation process involves the steps of mixing the API with a PVA solution and extruding the paste (e.g., through a needle tip). The extruded strands are then subjected to heat treatment (e.g., in an oven). Depending on the temperature and time, this process changes the PVA crystallinity in the matrix, which subsequently changes the dissolution rate of the drug in a humid environment.

[0103] The nintedanib IVT implant according to the present invention is bioerodible and provides a long-term almost constant sustained release of nintedanib for intraocular use. It has a very high drug: polymer ratio (drug loading greater than 80 wt %). In ophthalmology, these characteristics are particularly attractive because the implant should be small enough to be injected into the eye via a sufficiently small incision so that no closure is required after injection. This needs to be injected via a needle with a diameter equal to or less than the diameter of a 22-gauge needle. Therefore, high drug content is extremely important.

[0104] Bioerodible IVT implants are particularly advantageous for the treatment of diseases such as macular degeneration and diabetic macular edema, which are considered incurable but must be treated during the patient's life. Unless removed (not an easy surgery), non-erodible implants will accumulate in the eye. Erodible implants do not cause this problem. Biodegradable polymers have a potential problem in that the monomers released by the degradation of these polymers are likely to be inflammatory (Evaluation of the toxicity of intravitreally 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 the polymer itself does not decompose.

[0105] Many ocular diseases must be treated continuously, so maintaining therapeutic concentrations of nintedanib provided by the IVT implant according to the present invention is a substantial advantage, particularly for drugs with a potentially small therapeutic window.

[0106] In a first aspect, the present invention relates to a long-term sustained release pharmaceutical formulation of an API comprising 80 to 95% (w / w) API and 5 to 20% (w / w) PVA.

[0107] According to one embodiment, the pharmaceutical formulation consists of 80 to 95% (w / w) API, 5 to 20% (w / w) PVA (w / w), optional pharmaceutically acceptable inactive ingredients, and optionally trace amounts of water.

[0108] Traces of water may be present in the pharmaceutical preparation, for example, due to incomplete drying of the preparation. They generally involve amounts not exceeding 1% (w / w).

[0109] Preferably, the pharmaceutical formulation consists of 80% to 95% (w / w) API and 5 to 20% PVA (w / w).

[0110] According to another embodiment, the pharmaceutical formulation comprises 85% to 95% API and 5% to 15% PVA (w / w), preferably 87% to 91% API and 9% to 13% PVA (w / w).

[0111] Preferably, the pharmaceutical formulation consists of 85% to 95% API and 5% to 15% PVA (w / w), preferably 87% to 91% API and 9% to 13% PVA (w / w) and optionally trace amounts of water. For example, the mass ratio of API: PVA can be 100: 5, 100: 7, 100: 8, 100: 10, 100: 15, 100: 16.5 or 100: 18, in particular 100: 10 and 100: 15, most preferably 100: 15. In particular, the mass ratios of 100: 15, 100: 16.5 and 100: 18 provide a paste that is still easily extrudable and forms a pharmaceutical formulation and implant with higher long-term integrity (i.e., with late disintegration) and long-term drug release in phosphate buffered saline (PBS) (see the fourth aspect of the invention).

[0112] For the preparation of pharmaceutical formulations and IVT implants providing extended release of therapeutic amounts of a drug substance over several months, a drug substance with low water solubility would be preferred to reduce the risk of premature exhaustion of the implant due to rapid dissolution of the drug substance. Therefore, for the formulations and implants according to the invention, the free base of nintedanib with very poor solubility in water would be a reasonable choice among the different available nintedanib species. However, it has been surprisingly found that an IVT implant according to the invention containing nintedanib esylate with much higher water solubility (2.8 mg / mL) also discloses suitable and desired long-term release properties for the intended clinical use.

[0113] Therefore, the API in the pharmaceutical formulation 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.

[0114] Pharmaceutically acceptable nintedanib salts suitable for any aspect of the present invention include monoethane sulfonate (esylate) and nintedanib salts disclosed in WO 2007 / 141283, such as chloride, bromide, phosphate, sulfate, methanesulfonate, edisylate, benzenesulfonate, toluenesulfonate, camphorsulfonate, naphthalene-1,5-disulfonate, citrate, D-tartrate, L-tartrate, L-lactate, glycolate, glycinate, L-malate, D-malate, malonate, oxalate, benzoate, mandelate, saccharate, salicylate and ascorbate of nintedanib or bis{3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methyl)-piperazin-1-yl)- 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.

[0115] Preferred nintedanib salts for any aspect of the present invention are ethanesulfonate, chloride, bromide, phosphate, sulfate, methanesulfonate, edisylate, benzenesulfonate, toluenesulfonate, citrate, D-tartrate, L-tartrate, L-lactate, glycolate, glycinate, L-malate, D-malate, malonate, oxalate, benzoate, mandelate, salicylate and ascorbate of nintedanib. Particularly preferred nintedanib salts for any aspect of the present invention are ethanesulfonate, chloride, bromide, phosphate, sulfate, methanesulfonate and edisylate of nintedanib. Most preferably, nintedanib ethanesulfonate is used.

[0116] According to one embodiment, with respect to particle size distribution, nintedanib essylate used in the preparation of the above 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 essylate 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.

[0117] More specifically, nintedanib esylate used in the preparation of the above-mentioned formulation may be characterized by 1.2μm≤D10≤2.1μm, 9.5μm≤D50≤14.7μm, 24.3μm≤D90≤31.7μm and 34.3μm≤D98≤42.1μm, for example, 1.4μm≤D10≤1.7μm, 10.5μm≤D50≤12.7μm, 25.4μm≤D90≤28.7μm and 35.2μm≤D98≤39.2μm.

[0118] PVA suitable for pharmaceutical preparations should comply with the requirements of pharmacopoeias (e.g. Ph.Eur., JPE). Various grades of PVA are available, with different degrees of polymerization and hydrolysis (determining the physical properties of different grades). They are characterized by their viscosity and ester value (characterizing the degree of hydrolysis).

[0119] It has been found that the use of PVA with a degree of hydrolysis of 88% for the preparation of the pharmaceutical formulation according to the invention leads to implants which disintegrate rapidly in PBS. Implants with improved long-term release properties are advantageously obtained with PVA having a higher degree of hydrolysis, in particular about 99%.

[0120] According to one embodiment, the average relative molecular weight of PVA is between 20,000 and 150,000, the viscosity is between 3 mPa*s and 70 mPa*s and the ester value is not greater than 280.

[0121] Preferably, the PVA grade is characterized by

[0122] - Viscosity 23.8 to 32.2 mPa*s (4% PVA in aqueous solution) and

[0123] -Highly hydrolyzed (≥97%) or with an ester value of 9 to 11.

[0124] More preferably, the PVA grade is characterized by

[0125] - Viscosity of about 28 mPa*s (4% PVA in aqueous solution) and

[0126] - A degree of hydrolysis of about 99% or an ester value of about 11.

[0127] According to another embodiment, only one grade of PVA is used in the pharmaceutical formulation.

[0128] 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, the body optionally having a polymer coating.

[0129] The long-term sustained release pharmaceutical formulation of the API may be according to any one of the embodiments of the first aspect of the invention described herein before.

[0130] It has been found that implants according to the invention (e.g. containing nintedanib esylate) maintain physical integrity for a long time under moist conditions (e.g. in PBS) even without a coating. In contrast, implants with a coating may be subject to the risk of rapid disintegration due to the high osmotic pressure within the coating membrane.

[0131] According to a preferred embodiment, the IVT implant is uncoated.

[0132] According to another embodiment, the IVT implant is coated.

[0133] The polymer coating of the IVT implant according to the present invention should be biocompatible (not causing any inflammation), bioerodible or biodegradable, and can be selected from the group consisting of PVA, poly(D,L-lactide-co-glycolide) (PLGA), polycaprolactone (PCL), polylactic acid, polyglycolic acid, polyethylene adipate and polyester amide.

[0134] According to another embodiment, the IVT implant is coated, wherein the polymer coating consists of PVA.

[0135] The PVA used in the coating may be the same grade as that used in the pharmaceutical formulation.

[0136] The diameter of the IVT implant (whether coated or not) should be small enough to allow it to be inserted into the vitreous of the eye through an acceptably small incision. For most purposes, it is 22 gauge or smaller, or preferably 24 gauge or smaller, as larger incisions will require sutures to close the wound. Likewise, the overall length of these implants should be less than 10 mm and preferably 6 mm or less to reduce the likelihood that the implant will be on the visual axis.

[0137] According to one embodiment, the IVT implant is shaped and sized in such a way that it can be administered via an inserter having a needle no larger than 22 gauge, particularly no larger than 23, 24, 25, 26 or 27 gauge, for example, via an inserter having a 22, 23, 24, 25, 26 or 27 gauge needle, preferably via an inserter having a needle no larger than 24 gauge (e.g., a 24 gauge ultra-thin wall needle).

[0138] According to another embodiment, the IVT implant is cylindrical in shape.

[0139] According to another embodiment, the diameter of the IVT implant is in the range of 0.2 to 0.4 mm, eg, 0.25 to 0.27 mm or 0.32 to 0.35 mm.

[0140] According to one embodiment, the length of the IVT implant does not exceed 10 mm; for safe clinical use, its length should not exceed 7 mm, and preferably the length does not exceed 6 mm; preferably its length is 1 to 7 mm, and more preferably the length is 1.0 mm to 6.0 mm, for example, the length is 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, and most preferably the length is 2.5 mm, 3.5 mm, 5.0 mm or 6.0 mm.

[0141] According to one embodiment, the IVT implant is characterized in that the nintedanib esylate content is in the range of 100 μg to 250 μg, preferably 120 μg to 160 μg or 180 μg to 220 μg, such as about 140 μg or about 200 μg.

[0142] According to another embodiment, the IVT implant is characterized in that the nintedanib esylate content is in the range of 400 μg to 600 μg, preferably 420 μg to 500 μg or 520 μg to 570 μg, such as about 440 μg, about 475 μg or about 545 μg.

[0143] It has surprisingly been found that, despite the good water solubility of nintedanib essylate, IVT implants containing nintedanib essylate as API reveal suitable and desirable long-term release properties for the intended clinical use.

[0144] According to one embodiment, the IVT implant is characterized in that the in vitro daily release of nintedanib essylate from day 10 to day 30 is 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, most preferably about 1.3 μg / day (equivalent to about 1.1 μg / day of nintedanib base).

[0145] According to another embodiment, the IVT implant is characterized in that the in vitro daily release of nintedanib essylate is not less than about 1.1 μg / day within 6 months, preferably not less than about 1.2 μg / day within 6 months, more preferably not less than about 1.3 μg / day within 6 months.

[0146] According to another embodiment, the IVT implant is characterized by in vitro drug release for greater than 9 months.

[0147] In a third aspect, the present invention relates to a method for preparing a long-term sustained release pharmaceutical formulation of an API according to the first aspect of the present invention, the method comprising the following steps

[0148] a) preparing a PVA aqueous solution, and

[0149] b) Mixing the PVA solution with API powder.

[0150] The long-term sustained release pharmaceutical formulation of the API may be according to any one of the embodiments herein before described according to the first aspect of the invention.

[0151] In step a), an aqueous PVA solution may be prepared by dissolving a desired amount of PVA in deionized water. Optionally, the mixture may be heated and / or stirred to facilitate the dissolution process.

[0152] According to one embodiment, the PVA aqueous 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%.

[0153] In step b), the PVA solution can be mixed with the API powder by placing a weighed amount of the optional micronized nintedanib powder (esylate, base, or a blend of the two) in a mortar and then slowly adding a volume of the PVA solution while mixing the paste with a pestle. On a larger scale, this can be accomplished with a commercial 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 homogenous paste of the components is obtained.

[0154] The PVA and / or the API powder used for the preparation of the pharmaceutical formulation preferably exhibits the features of the first aspect of the invention as hereinbefore described.

[0155] Therefore, the API powder (eg nintedanib esylate) may be micronized before its use in step b) of the process to meet the desired particle size distribution.

[0156] In a fourth aspect, the present invention relates to a method for preparing an IVT implant according to the second aspect of the present invention, the method comprising the following steps

[0157] (a) preparing a PVA aqueous solution,

[0158] (b) mixing the PVA solution with API powder,

[0159] (c) feeding the mixture into an extrusion device,

[0160] (d) extruding the mixture through an extruder head to form an extruded strand,

[0161] (e) optionally drying the extruded strand,

[0162] (f) heating the extruded line,

[0163] (g) cutting the extruded strand into implant segments of equal length, and

[0164] (h) sterilizing the implant segment thus obtained,

[0165] Therein, the method may additionally comprise the optional step of coating the extruded wire after step d), e) or f) or coating the implant segments after step g) in a solution of a coating polymer.

[0166] The IVT implant may be according to any of the embodiments of the second aspect of the invention described herein before.

[0167] Steps a) and b) of the method may be according to any of the embodiments of the third aspect of the invention described hereinabove. In addition, the API powder (e.g. nintedanib esylate) may be micronized before its use in step b) of the method. Preferably, after mixing, the obtained mixture should not be kept in an open container for more than 15 minutes, so as not to negatively affect the extrudability of the paste.

[0168] The extrusion device of step c) comprises an extrusion head (or extrusion tip) as mentioned in step d).

[0169] The extrusion device can be a syringe equipped with a needle, a single screw extruder, a twin screw extruder, a piston pump or a peristaltic pump. The extruder head can be anything with an aperture sized so that the resulting extruded strand has the desired thickness, such as a needle tip.

[0170] The extrusion head may have a rounded profile so that a cylindrical extruded strand is obtained. By using an alternatively shaped extrusion head, different strand geometries may be produced, such as a Toblerone shape, instead of a cylindrical strand.

[0171] The extrusion tip can be of different sizes, and the inner diameter of the tip determines the outer diameter of the implant. It has been found that extrusion using a 23-gauge or 22-gauge tip produces implants (0.25 to 0.27 mm and 0.32 to 0.35 mm in diameter, respectively) that fit well with a 24-gauge ultra-thin wall needle (with an inner diameter of approximately 0.37 mm), which is particularly suitable for the intended clinical use.

[0172] Thus, 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 an inserter no larger than 22 gauge, e.g., 23 or 24 gauge, preferably 24 gauge, particularly via an ultra-thin wall needle of 24 gauge. Thus, after processing, the implant segments can be injected directly into the eye via a sufficiently small incision that does not need to be closed after injection.

[0173] According to one embodiment, the extrusion head has a circular profile.

[0174] According to one embodiment, the inner diameter of the extrusion head does not exceed about 0.5 mm, preferably does not exceed about 0.4 mm, such as about 0.33 mm or about 0.41 mm.

[0175] According to one embodiment, the extruded line is obtained as a cylindrical continuous line.

[0176] According to another embodiment, the diameter of the extruded strand is from 0.2 to 0.4 mm, such as from 0.23 to 0.29 mm or from 0.30 to 0.37 mm.

[0177] For step d), it has surprisingly been found that a mixture prepared according to steps a) to 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), such as 1:9 or 2:8) can be extruded more easily than a mixture prepared from nintedanib free base alone. One example is Figure 8 as shown in .

[0178] Furthermore, the extruded strands formed from the mixtures containing nintedanib esylate revealed good physical properties: for example, these mixtures formed continuous strands with favorable consistency and adhesion, i.e. they did not break easily during the extrusion process. Furthermore, after extrusion and before any drying or heating steps, these extruded strands showed good dimensional stability, in particular they did not flatten under the influence of gravity, but maintained their round profile and cylindrical shape very well. One example is Figure 7 as shown in .

[0179] In optional step e), the extruded lines are allowed to air dry for a suitable time.

[0180] When step e) was performed at ambient temperature, 35°C or 50°C, no significant changes in the measured implant diameters were observed and the in vitro release of these implants was comparable.

[0181] According to a preferred embodiment, step e) is performed without additional heating, for example at ambient temperature.

[0182] According to another embodiment, step e) is carried out under heating (for example at 35°C or 50°C).

[0183] According to another embodiment, the extruded strands are allowed to dry for about 30 minutes to about 24 hours, preferably at least 2 hours, such as from about 2 hours to about 14 hours, for example 2, 4, 6, 10 or 12 hours.

[0184] In a preferred embodiment, the extruded strands are allowed to dry at ambient temperature for at least 2 hours.

[0185] Step f) represents a thermal curing step. This step is intended to increase the crystallinity and hardness of the PVA, thereby reducing the dissolution rate of the API from the implant and improving the integrity of the implant.

[0186] According to one embodiment, the heating is performed for at least 2 hours, preferably at least 3 hours, such as about 3 hours, about 4 hours, about 5 hours or about 8 hours.

[0187] According to another embodiment, the extruded strand is heated to a temperature between 100°C and 180°C, preferably between 120°C and 160°C, for example to about 130°C, about 140°C, about 150°C or about 160°C, more preferably between 130°C and 150°C.

[0188] In a preferred embodiment, the heating is carried out at a temperature between 120°C and 180°C for at least 2 hours, more preferably at about 130°C to 150°C for at least 3 hours, most preferably at about 130°C for about 3 hours.

[0189] In step g), the extruded strand is cut into implants of equal length by suitable means.

[0190] A suitable length of the implant has been described above with respect to the second aspect of the present invention.

[0191] According to one embodiment, the extruded strand is cut into implant segments of equal length not exceeding 10 mm.

[0192] According to a preferred embodiment, the 23G extruded strands are cut into implant segments of equal length ranging from 1 to 7 mm (eg, 2.5, 4.0, 5.0 or 6.0 mm).

[0193] According to another preferred embodiment, the 22G extruded strands are cut into implant segments of equal length ranging from 1 to 7 mm (eg, 3.5, 4.5, 5.0 or 6.0 mm, preferably 5 or 6 mm).

[0194] In the order of the method steps described herein, step g) does not necessarily have to be performed after step f). As an alternative to the order described herein, step g) can also be performed before step f) or even before the optional step e).

[0195] In step h), sterilization of the implant segments may be achieved by gamma or electron beam irradiation.

[0196] According to one embodiment, sterilization is achieved by gamma irradiation.

[0197] According to one embodiment, gamma irradiation can be performed at a dose of up to 25 kGy (eg, about 15 kGy, about 20 kGy, or about 25 kGy, eg, 22.5 to 27.5 kGy).

[0198] No significant differences were observed in the release rates of implants before and after gamma irradiation over a 10-week period.

[0199] Instead of or in addition to step h), the method for preparing an IVT implant may be performed under sterile conditions.

[0200] According to a preferred embodiment, the fourth aspect of the present invention relates to a method for preparing an IVT implant according to the second aspect of the present invention, the method comprising the following steps:

[0201] (a) preparing an aqueous solution of PVA having a mass concentration of PVA between 8% and 15% (w / v) by dissolving PVA in deionized water, optionally with heating and / or stirring,

[0202] (b) mixing the PVA solution with nintedanib ethanesulfonate powder,

[0203] (c) loading the mixture into an extrusion device,

[0204] (d) extruding the mixture through an extruder head of No. 22 or 23 to form extruded strands, preferably continuous strands having a cylindrical shape and a diameter of 0.2 to 0.4 mm,

[0205] (e) optionally allowing the extruded strand to dry at ambient temperature,

[0206] (f) heating the extruded strand at a temperature between 120° C. and 180° C. for at least 2 hours,

[0207] (g) cutting the extruded strand into implant segments of equal length ranging from 1 to 7 mm, and

[0208] (h) sterilizing the implant segment thus obtained,

[0209] Therein, the extruded strand obtained after step d), e) or f) or the implant segment obtained after step g) is optionally coated in a solution of a coating polymer.

[0210] The order of steps g) and f) is interchangeable, step g) can be performed before or after step f) or even before the optional step e).

[0211] In a fifth aspect, the present invention relates to a method for treating a posterior ocular disease in a patient in need thereof, the method being characterized by administering a pharmaceutical formulation according to the first aspect of the invention to the eye of the patient.

[0212] Likewise, the invention relates to a method for treating a posterior ocular disease in a patient in need thereof, the method being characterized by implanting at least one IVT implant according to the second aspect of the invention into the vitreous of the eye of the patient.

[0213] Furthermore, the invention relates to a pharmaceutical formulation according to the first aspect of the invention for use in a method of treating a posterior ocular disease in a patient in need thereof.

[0214] Likewise, the invention relates to an IVT implant according to the second aspect of the invention for use in a method of treating a posterior ocular disease in a patient in need thereof.

[0215] Furthermore, the present invention relates to the use of the API for the preparation of a pharmaceutical formulation according to the first aspect of the present invention for the treatment of a posterior ocular disease in a patient in need thereof.

[0216] Likewise, the invention relates to the use of the API for the preparation of an IVT implant according to the second aspect of the invention for treating a posterior ocular disease in a patient in need thereof.

[0217] The posterior ocular disease may be selected from the group consisting of wet age-related macular degeneration (wAMD), dry macular degeneration, geographic atrophy, diabetic macular edema (DME), non-proliferative diabetic retinopathy (NPDR), cystoid macular edema (CME), choroidal neovascularization (CNV), retinal vein occlusion and retinitis pigmentosa, preferably selected from the group consisting of wAMD, DME or retinal vein occlusion; most preferably, the posterior ocular disease is wAMD.

[0218] The method for treatment may comprise a one-time or repeated implantation of an IVT implant according to the second aspect of the invention in the vitreous of the patient's eye.

[0219] According to one embodiment, the method of treatment comprises repeated implantation of an IVT implant according to the invention in the vitreous of the patient's eye.

[0220] According to another embodiment, implantation of the IVT implant is performed using a 24-gauge ultra-thin wall needle.

[0221] 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, such as 9, 10, 11, 12, 13, 14 or 15 months, most preferably the time interval between repeated implantations is 12 months.

[0222] At each implantation, one or more IVT implants may be implanted into the vitreous of the patient's eye.

[0223] According to a preferred embodiment, the method for treating posterior ocular diseases is characterized in that only one IVT implant is implanted at a time into the vitreous of the patient's eye.

[0224] Examples and experimental data

[0225] The following examples are for the purpose of illustrating the present invention only and are not intended to limit the scope of the present invention in any way.

[0226] A) Method for measuring particle size distribution

[0227] The particle size distribution is determined via laser diffraction. A laser diffraction sensor (e.g. Sympatec's HeNe laser optical system HELOS) with a dry dispersion unit (e.g. Sympatec's RODOS) and a vibrating feed unit (e.g. Sympatec's VIBRI) can be used with the following setup:

[0228] - Semi-circular multi-element photodetector with 31 channels

[0229] -Focal length: 100mm (measuring range 0.5 / 0.9 to 175μm)

[0230] -Time base: 100ms

[0231] - Start: After 0s when concentration ≥ 2.0%, always applicable; Stop: After 3s when concentration ≤ 1.0% or after 30s in real time

[0232] - Pressure: 2.0 bar; Vacuum: max.

[0233] -Mode: HRLD (High Resolution Laser Diffraction Mode)

[0234] -Select concentration: 2 to 20%

[0235] -Feed rate: 80%; Feed height: 1.3mm

[0236] Results are reported as the average of 3 independent sample measurements.

[0237] B) Pharmaceutical preparations

[0238]

[0239] *Removed during the manufacturing process, only trace amounts (i.e., no more than about 1% (w / w) remain in the formulation)

[0240] C) Bioerodible Implants

[0241]

[0242] D) General method for the preparation of coated and uncoated bioerodible nintedanib implants

[0243] The bioerodible nintedanib implant according to the present invention is prepared in a three-step process:

[0244] 1) Preparation of PVA solution

[0245] 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, and the top of the flask is covered with a glass plate or foil to reduce evaporation. When the PVA is completely dissolved, the heat source is turned off and the solution is cooled to room temperature while stirring continuously. During cooling, the volume is adjusted with deionized water to make up for any losses caused by evaporation. The typical mass concentration (w / v) of PVA in the final solution is between 2% and 20%, typically about 10% or about 13.6%. Also preferably, the PVA is a Ph.Eur. / JPE grade with a viscosity of 23.8 to 32.2 mPa*s (4% PVA in aqueous solution) and a high degree of hydrolysis (≥97%).

[0246] 2) Implant preparation

[0247] 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 the PVA solution is slowly added while mixing the paste with a pestle. On a larger scale, this can be accomplished with a commercial mixer (e.g., Hobart). A typical ratio of nintedanib to PVA solution is about 1:1, for example, 100 g of nintedanib powder is mixed with 100 mL of PVA solution.

[0248] The paste is then loaded into a syringe equipped with a needle. The paste is pushed through the needle tip onto the glass disk to form a continuous straight line (line). The inner diameter of the needle determines the diameter of the line. The line is air-dried for more than 2 hours and then heated in an oven between 100°C and 180°C for up to 6 hours, preferably at 130°C to 135°C for 2 to 4 hours, for example 3 hours. After removal from the oven, the line is cut into lengths.

[0249] Alternatively, the line can be coated in a solution of PVA, allowed to dry again and then heated. Other options include heating the dried paste line before dipping and then cutting the implants to length before heating or dipping.

[0250] 3) Loading into applicator, packaging and sterilization

[0251] The implant is loaded into the barrel of a custom applicator. The outer diameter of the barrel should be no larger than and ideally smaller than a 22 gauge needle. After sealing the end of the barrel to prevent the implant from falling off, the applicator is packaged to prevent accidental denting of the plunger or accidental activation of the spring (if spring loaded). The assembly is then bagged for sterilization by gamma (e.g., up to 25 kGy) or electron beam. The bag can be a single bag or (ideally) a double bag (allowing the inner sterile bag to be placed in the sterile field immediately before use).

[0252] E) Specific method for the preparation of an uncoated bioerodible nintedanib implant according to c)

[0253] The specific preparation method of I-6 is described below as an example, but it can be similarly applied to I-3, I-4, I-5, and in a similar manner to other implants according to the present invention, for example, to I-1 and I-2.

[0254] 1) Preparation of PVA solution

[0255] 10% (w / v) and 13.6% (w / v) PVA solutions were prepared by adding 10 g and 13.6 g PVA (Merck Germany, 99% hydrolyzed) respectively to 100 mL water for injection in a glass flask. The flask was placed on a heated stirring plate and heated until the PVA was completely dissolved. After cooling, water was then added under stirring to reach the weight (to correct for evaporation of water during heating).

[0256] 2) Preparation of implant (I-6)

[0257] In a mixing bowl, 5 g of nintedanib ethanesulfonate 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 equipped with a No. 22 blunt tip. The loaded syringe was then placed in a manual spindle press so that the end of the No. 22 tip was facing downward. The arm of the press was lowered to contact the syringe plunger, and then pushed downward with a constant force of no more than 40 N to extrude the API / PVA paste through the No. 22 tip to form an approximately 20 cm line. The syringe was then removed from the press and the line was laid flat on a smooth surface and removed from the tip. This can then be repeated according to the desired batch size.

[0258] The extruded strands were air dried for at least 2 hours and then placed in an oven heated to 130°C for 3 hours. After cooling, the strands were cut into 6.0 mm lengths using a cutting jig and razor blade. The implants were visually inspected for deformities and extraneous material.

[0259] 3) Loading into applicator, packaging and sterilization

[0260] The implant is then loaded into the applicator, which consists of a 24-gauge XTW (ultra-thin wall) needle on an inserter body (similar to a syringe, but with a push rod instead of a plunger, where the push rod is placed at the distal end of the needle). A single (or optionally two) implant is loaded to the distal end of the needle, and the applicator cap is installed on the end to 1) shield the sharp end of the needle and 2) prevent the implant from falling out of the needle. A removable clip is placed on the push rod to prevent it from accidentally denting and the assembly is then loaded into a foil bag and sealed with a stick heat sealer. The loaded foil bag is then placed in a Tyvek (spunbond HDPE fiber material) bag, which is heat sealed with a stick heat sealer. The double bag sealing system is then gamma (25kGy) sterilized.

[0261] F) Specific process for the preparation of coated bioerodible nintedanib implants

[0262] Coated implants similar to the uncoated ones of E) can be prepared by taking the air-dried API / PVA strands of step 2) and dipping them into an aqueous solution of 2% (w / v) or 5% (w / v) PVA. After allowing them to air dry 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 E). This results in a cylindrical implant whose walls are coated with a layer of PVA and the ends are uncoated.

[0263] G) Method for measuring drug release rate from implants in vitro

[0264] The implants were placed individually in vials containing 20 mL of PBS in a 37°C water bath. Samples were taken regularly, for example once a day, and the samples were analyzed by HPLC using a C-18 reverse phase column equipped with UV detection and the buffer was changed to ensure that sinking conditions were maintained. The release rate per day was calculated from the HPLC results and expressed as μg of nintedanib esylate per day.

[0265] Figure 1 An exemplary release profile of implant 1-6 as described hereinabove is shown in FIG.

[0266] H) Effect of formulation properties, implant properties and process parameters on drug release rate The effect of various parameters on the release rate has been determined.

[0267] 1) The role of implant size

[0268] Uncoated Nintedanib esylate implant prototypes of formulation F-4 (Nintedanib esylate: PVA 100: 10 (w / w)) were prepared according to the methods described herein. 22-gauge and 23-gauge needles were used for extrusion and the strands were cut into 1.0 mm or 3.5 mm lengths, respectively. The release rate was determined according to the methods described herein. For each implant, the cumulative amount of released drug was measured over several days and the amount of Nintedanib per mm was calculated. 2 Average release rate over surface area.

[0269] The results show that for a given API:PVA ratio, the release rate of nintedanib from the implant according to the present invention is proportional to its surface area.

[0270]

[0271] 2) Effect of PVA content

[0272] Uncoated Nintedanib esylate implant prototypes of formulations F-4 and F-7 (Nintedanib esylate:PVA mass of 100:10 (w / w) and 100:18 (w / w) respectively) were prepared according to the method described herein. They were extruded through a 23-gauge needle, heated at 130°C for 3 hours and cut into a length of 3.5 mm. The release rate was determined according to the method described herein.

[0273] It can be seen that the higher the PVA content, the lower the release rate.

[0274]

[0275] 3) The effect of temperature during oven drying

[0276] Uncoated Nintedanib esylate implant prototypes of formulations F-4 and F-7 (Nintedanib esylate:PVA mass of 100:10 (w / w) and 100:18 (w / w) respectively) were prepared according to the method described herein. They were extruded through a 23-gauge needle, heated as shown below and cut into a length of 3.5 mm. The release rate was determined according to the method described herein.

[0277] from Figure 2 and Figure 3 As can be seen from the following tables (each showing data for implants of Formulation F-7), the release was relatively constant and the curing temperature had no significant effect on the release rate. Figure 6 Additionally, a surprisingly low initial burst release, less than 5% in the first two days, was shown, which contributed to the relatively constant release.

[0278]

[0279]

[0280] Similar graphs were obtained for implants (23G extrusion needle, length 3.5 mm) of formulation F-4 (nintedanib esylate:PVA 100:10 (w / w)).

[0281]

[0282] Although curing temperature did not affect the release rate, it did affect the disintegration rate of these implants. Implants heated at lower temperatures and in shorter time periods often ruptured during dissolution testing (the above table provides the release rates for those devices that did not disintegrate). When the device disintegrated, drug release increased significantly, followed by a plateau region of measured release rate (see, e.g., Figure 4 and Figure 5 ).

[0283] Disintegration of implants heated at 100°C for 1 hour appeared somewhat random, but all (n=6) implants disintegrated within 120 days ( Figure 4 Only 3 implants were shown to disintegrate before day 80; the overall seemingly low release for one implant was an artifact because this implant disintegrated early). Implants heated to 130°C for 3 hours were much less likely to disintegrate during drug release. (Note: the total drug content of these implants was approximately 200 μg. Therefore, a nearly linear release was maintained until these implants were mostly consumed).

Claims

1. A long-term sustained-release pharmaceutical preparation of an API, comprising 80 to 95% (w / w) of the API and 5 to 20% (w / w) of polyvinyl alcohol (PVA).

2. The pharmaceutical formulation according to claim 1, wherein the formulation consists of 80 to 95% (w / w) API, 5 to 20% (w / w) PVA (w / w) and optionally trace amounts of water.

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

4. The pharmaceutical formulation according to any one of claims 1 to 2, wherein the PVA is characterized by a high degree of hydrolysis (≥97%) and optionally a viscosity of 23.8 to 32.2 mPa*s, as measured by a 4% aqueous solution of PVA.

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, the body optionally having a polymer coating.

6. The IVT implant of claim 5, wherein the implant is cylindrical in shape, 0.2 to 0.4 mm in diameter and no longer than 7 mm.

7. The IVT implant according to any one of claims 5 to 6, wherein the implant is characterized by a nintedanib essylate content in the range of 400 to 600 μg and / or an in vitro daily release of nintedanib essylate of not less than about 1.1 μg / day over 6 months.

8. A method for preparing a pharmaceutical preparation according to any one of claims 1 to 4, comprising the following steps a) preparing a PVA aqueous solution, and b) Mixing the PVA solution with API powder.

9. The method according to claim 8, wherein in step a), the PVA solution has a mass concentration between 8% (w / v) 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, the method comprising the following steps Preparation of a pharmaceutical preparation 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 extrusion head to form an extrusion line, e) optionally drying the extruded strands, f) heating the extruded strands, g) cutting the extruded strands into implant segments of equal length, and h) sterilizing the obtained implant segment, in, The method may further comprise the optional step of coating the extruded strand after step d), e) or f) or coating the implant segment after step g) in a solution of a coating polymer.

11. The method of claim 10, wherein the extrusion head has a circular profile and an inner diameter of no more than about 0.4 mm.

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

13. A method for treating a posterior ocular disease in a patient in need thereof, characterized in that a pharmaceutical preparation according to one or more of claims 1 to 4 is administered to the patient's eye, in particular at least one IVT implant according to one or more of claims 5 to 7 is implanted into the vitreous of the patient's eye.

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

15. The method according to any one of claims 13 to 14, wherein the method comprises repeatedly implanting an IVT implant, preferably using a 24 gauge ultra-thin wall needle, with a time interval of at least 9 months between repeated implantations.

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