HK1242223A1 - Stable and soluble formulations of receptor tyrosine kinase inhibitors, and methods of preparation thereof - Google Patents

Description

Stable and soluble formulations of receptor tyrosine kinase inhibitors and methods for their preparation

RELATED APPLICATIONS

This application claims priority to U.S. provisional patent application No. 62/035274, filed 8/2014, the disclosure of which is incorporated herein by reference in its entirety.

Technical Field

The present disclosure relates to stable formulations of receptor Tyrosine Kinase Inhibitors (TKIs), such as pazopanib (pazopanib); a process for the preparation thereof; and the use of the disclosed formulations for sustained delivery of active agents to a target site. The present disclosure further relates to methods of converting one polymorphic form of a TKI to another polymorphic and/or amorphous form.

Background

Preparing formulations of therapeutic agents with low solubility in water and delivering the agents to target tissues is a major challenge for pharmacologists and therapeutic agent delivery scientists. See Gaudana R, et al, Ocular therapeutic Delivery, AAPS J, 12(3): 348-. The combined effects of the unique anatomy and physiology of the eye and the low water solubility of therapeutic agents used to treat ocular diseases or disorders have prevented the delivery of these agents to the desired target site of the eye. See Gaudana. Thus, there is a need for formulations and delivery systems that will allow for high solubility of therapeutic agents and improve stability and efficacy in target tissues.

Protein kinases have been shown to be associated with ocular diseases including, but not limited to, age-related macular degeneration (hereinafter "AMD"), diabetic macular edema, and proliferative diabetic retinopathy. Transmembrane receptor protein kinases exhibit an extracellular domain capable of ligand binding. These ligand binding mechanisms trigger activation of the kinase catalytic domain, which triggers a signaling cascade that controls intracellular functions.

Examples of receptor protein kinases are growth factors such as EGF, FGF, VEGF, PDGF and IGF. Elevated levels of soluble growth factors, such as vascular endothelial growth factor-a (vegf), have been found in ocular tissues and fluids removed from patients with pathological ocular angiogenesis. Various ocular tissues, including sensory neuroretina and Retinal Pigment Epithelium (RPE), are known to respond to hypoxia, inflammation and trauma by increasing VEGF expression which can lead to rupture of the blood-retinal barrier (i.e., enhanced vascular permeability and extracellular edema) and/or pathological Neovascularization (NV).

Delivery of therapeutic agents in the eye is challenging. Current delivery means have major drawbacks due to the repeated intravitreal injections required for long-term maintenance therapy. Repeated intravitreal injections carry risks and burdens on the patient. Endophthalmitis, retinal detachment, traumatic cataract and increased intraocular pressure (IOP) are potential vision-threatening sequelae of intravitreal routes of administration. Furthermore, monthly treatments or even monthly monitoring are a considerable burden on patients, their caregivers, and the medical community, especially when considering that treatment may need to last for the lifetime of a patient. While approximately one-third of patients experience improved vision when treated with repeated intravitreal injections of certain biological VEGF inhibitors, most patients experience only stabilization of reduced vision.

The formulations may provide less than ideal stability in one or more ways when injected into a therapeutic device in at least some instances. For example, in at least some instances, the buffer of the injectable formulation can be released from the device into the vitreous. In addition, the diffusion of hydrogen and hydroxide ions between the reservoir and the vitreous may affect the pH of the formulation within the device.

In at least some instances, buffers of ocular fluids (e.g., vitreous humor) having physiological pH can enter the device and affect the pH of the formulation within the device, such that the stability of the therapeutic agent may be less than ideal in at least some instances.

In at least some instances, formulation components added to increase the solubility of the therapeutic agent may bind the therapeutic agent so strongly that the efficacy of the target tissue may be less than ideal in at least some instances.

In view of the above, it would be desirable to provide improved formulations of therapeutic agents for use in therapeutic devices that overcome at least some of the above-described deficiencies of known formulations, such as having improved release of the therapeutic agent that can be maintained over an extended period of time when implanted.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

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

Disclosure of Invention

The present disclosure generally relates to formulations of therapeutic agents having low solubility in water. Disclosed herein are receptor tyrosine kinase inhibitors (e.g., pazopanib), formulations and methods of preparation and use in the treatment and amelioration of ophthalmic diseases and/or disorders.

The present disclosure provides stable pharmaceutical formulations of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility and one or more formulating agents, wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt, and the one or more formulating agents include a complexing agent, a solubilizing agent, and optionally a buffering agent; wherein the salt of the therapeutic agent is in solution in the formulation. The therapeutic agent is pazopanib.

The present disclosure provides stable pharmaceutical formulations of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility and one or more formulation agents, wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt, and the one or more formulation agents include a complexing agent, a solubilizing agent, and a buffer; wherein the salt of the therapeutic agent is in solution in the formulation. The therapeutic agent is pazopanib.

The present disclosure provides stable pharmaceutical formulations of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility and one or more formulation agents, wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt, and the one or more formulation agents include a complexing agent, a solubilizing agent, but no buffer; wherein the salt of the therapeutic agent is in solution in the formulation. The therapeutic agent is pazopanib.

The pharmaceutically acceptable salt is a monovalent halide salt or a divalent halide salt. The salt is a chloride salt. Monovalent salts are stable in the formulation at concentrations up to about 60 mg/mL. The divalent salt is stable in the formulation at concentrations up to about 70 mg/mL. The divalent salt crystal structure prior to formulation is form XIV as determined by XRPD. The stability of the monovalent salt in the formulation is increased by lyophilizing the therapeutic agent from an organic solvent prior to dissolution with the formulation in solution. The organic solvent is dimethyl sulfoxide (DMSO) or Trifluoroethanol (TFE). The conversion of one crystalline phase form of the therapeutic agent to another form is from the lyophilization of DMSO. Lyophilization from DMSO converts crystalline phase form a to a material containing at least about 70% crystalline phase form G, as determined by XRPD. The crystalline phase form a is converted to a partially or fully amorphous phase from lyophilization of TFE. The pH is adjusted during the formulation of the therapeutic agent or is not adjusted during the formulation of the therapeutic agent.

The solubilizing agents in the formulations and in the methods of making the formulations of the present disclosure are polymers, such as poly (vinyl pyrrolidone) (PVP); when present, the buffer is histidine HCl; the complexing agent is cyclodextrin: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylammonio) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutylether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, or any combination thereof; and the therapeutic agent is a pazopanib (5- [ [4- [ (2, 3-dimethyl-2H-indazol-6-yl) methylamino ] -2-pyrimidinyl ] amino ] -2-methylbenzenesulfonamide) salt, such as pazopanib 1HCl or pazopanib 2 HCl.

The present disclosure provides a method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility, wherein the salt is a divalent salt, comprising (a) dissolving the salt in a solution of one or more formulating agents, wherein the formulating agents comprise a complexing agent, a solubilizing agent, and optionally a buffering agent, and (b) adjusting the pH to an optimum value after dissolving the salt in the formulating agent. The present disclosure provides a method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility, wherein the salt is a divalent salt, the method comprising (a) dissolving the salt in a solution of one or more formulating agents, wherein the formulating agents comprise a complexing agent, a solubilizing agent, and a buffering agent, and (b) adjusting the pH to an optimum value after dissolving the salt in the formulating agent. The present disclosure provides a method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility, wherein the salt is a divalent salt, comprising (a) dissolving the salt in a solution of one or more formulating agents, wherein the formulating agents include a complexing agent and a solubilizing agent, but no buffering agent, and (b) adjusting the pH to an optimum value after dissolving the salt in the formulating agent.

The present disclosure provides a process for preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility, wherein the salt is a monovalent salt, the process comprising (a) treating the salt with a base; (b) dissolving the alkali-treated salt in a solution of one or more formulating agents, wherein the formulating agents include a complexing agent, a solubilizing agent, and optionally a buffering agent, and (c) adjusting the pH to a pH equal to or below about 2 with an acid, wherein the alkali treatment increases the total salt content in the formulation, and the adjusting the pH with the acid increases the solubility of the salt in the formulation.

The present disclosure provides a method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility, wherein the salt is a monovalent salt; the method comprises (a) preparing a solution of the salt in an organic solvent; (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; (d) dissolving a complexing agent in the solution; and (e) adding the lyophilized salts to the solution at or above about ambient temperature and mixing them to dissolve the salts in the solution; wherein the pH of the formulation is optionally adjusted.

The present disclosure provides a method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility, wherein the salt is a monovalent salt; the method comprises (a) preparing a solution of the salt in an organic solvent (e.g., trifluoroethanol-water mixture, or dimethylsulfoxide); (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; (d) dissolving an amount of a complexing agent in the solution, thereby preparing a low viscosity solution; (e) adding the lyophilized salt to the low viscosity solution at or above ambient temperature (about 37 ℃ to about 50 ℃), mixing, and allowing it to dissolve in the solution; adjusting the pH of the low viscosity solution; and (f) adding about 2 times the amount of the complexing agent to the low viscosity solution and dissolving.

Converting crystalline phase form a from lyophilization of a polar aprotic solvent to a material containing at least about 70% form G pazopanib, as determined by XRPD. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃. Converting pazopanib 1HCl in crystalline phase form a from lyophilization of organosulfur compounds to a material containing pazopanib 1HCl up to or at least about 70% form G as determined by XRPD. Lyophilization from dimethyl sulfoxide (DMSO) converts pazopanib 1HCl in crystalline phase form a to a material containing up to or at least about 70% of form G pazopanib 1HCl, as determined by XRPD. Lyophilization from dimethyl sulfoxide (DMSO) converted pazopanib 1HCl in crystalline phase form a to a material containing about 100% of form G pazopanib 1HCl, as determined by XRPD. The conversion of pazopanib 1HCl in crystalline phase form a from the lyophilization step of the alcohol to pazopanib 1HCl in amorphous (or microcrystalline) material form, as determined by XPRD. Lyophilization from an alcohol, such as Trifluoroethanol (TFE), converts pazopanib 1HCl in crystalline phase form a to pazopanib 1HCl in amorphous (or microcrystalline) material form, as determined by XPRD. Pazopanib 1HCl form a is dissolved in an alcohol (e.g., TFE) or TFE/water mixture, and the solution is lyophilized. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃.

The present disclosure provides methods of preparing stable solution pharmaceutical formulations of pharmaceutically acceptable salts of therapeutic agents having low aqueous solubility, wherein the salts are monovalent salts, such as pazopanib 1 HCl; the method comprises (a) preparing a solution of the salt in an organic solvent (e.g., trifluoroethanol-water mixture, or dimethylsulfoxide); (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) continuously mixing at least one solubilizing agent, a buffering agent, a complexing agent, and the lyophilized salt of a therapeutic agent, such as pazopanib 1HCl, at or above about ambient temperature (e.g., about 37 ℃ to about 50 ℃) while adding water. Adjusting the pH of the formulation to about 6 to about 7 with a base.

The present disclosure provides methods of preparing stable solution pharmaceutical formulations of pharmaceutically acceptable salts of therapeutic agents having low aqueous solubility, wherein the salts are monovalent salts, such as pazopanib 1 HCl; the method comprises (a) preparing a solution of the salt in an organic solvent (e.g., trifluoroethanol-water mixture, or dimethylsulfoxide); (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) continuously mixing at least one solubilizing agent, a buffering agent, a complexing agent, and the lyophilized salt of a therapeutic agent, such as pazopanib 1HCl, at or above about ambient temperature (e.g., about 37 ℃ to about 50 ℃) while adding water. The pH of the formulation prepared by this method was not adjusted.

The present disclosure provides methods of converting pazopanib in crystalline form a to a material containing at least about 70% pazopanib in crystalline form G, comprising dissolving form a in DMSO and lyophilizing the resulting solution. The present disclosure provides methods of converting pazopanib in crystalline form a to a material containing 100% pazopanib in crystalline form G, comprising dissolving form a in DMSO and lyophilizing the resulting solution.

The present disclosure provides for the use of a formulation of the present disclosure in a method of treating, preventing progression of, or ameliorating symptoms of a disorder characterized by vascular leakage or Neovascularization (NV) in the retina of the eye of a subject.

The present disclosure provides for the use of a formulation of the present disclosure in the manufacture of a medicament for use in a method of treating, preventing progression of, or ameliorating symptoms of a disorder characterized by vascular leakage or Neovascularization (NV) in the retina of the eye of a subject.

The present disclosure provides a kit comprising a stable formulation of the present disclosure contained in a storage compartment of a therapeutic device, wherein the storage compartment is coupled to a porous structure for controlled release of the therapeutic agent in the vitreous of the eye.

The present disclosure provides a drug delivery formulation of the present disclosure contained in a storage chamber coupled to a porous structure in a therapeutic agent delivery system for controlled release of a therapeutic agent in the vitreous of an eye; and wherein the controlled release of the formulation from the porous structure results in a concentration of the therapeutic agent in the vitreous that is at least two orders of magnitude lower than the concentration of the therapeutic agent in the storage chamber.

The formulations of the present disclosure are used in methods of ocular drug delivery. The formulations of the present disclosure are intravitreal delivery formulations. The formulations of the present disclosure are not eye drops. The formulations of the present disclosure are not topical delivery formulations. The formulations of the present disclosure are not oral delivery formulations or parenteral delivery formulations. The formulations of the present disclosure are not periocular delivery formulations.

The present disclosure provides methods of treating and/or ameliorating an ophthalmic disease or condition of the posterior segment of the eye, the methods comprising delivering a stable pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility and one or more formulation agents from a intravitreal delivery device comprising a storage compartment coupled to a porous structure, wherein the formulation is contained in the reservoir of the device and controlled release of the formulation from the reservoir through the porous structure increases the half-life of the therapeutic agent in the vitreous; wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt and the one or more formulation agents include a complexing agent, a solubilizing agent, and a buffer; wherein the salt of the therapeutic agent is in solution in the formulation. The reservoir chamber is refillable and refillable with the formulation after insertion of the device into the eye.

Refilling the storage chamber with the formulation after the device has been held in the eye for 30-90 days or up to 6 months.

Ophthalmic diseases or conditions for treatment and/or amelioration with the formulations of the present disclosure are: diabetic retinopathy, age-related macular degeneration (AMD), pathological Choroidal Neovascularization (CNV), pathological retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, kotz' disease, sickle cell retinopathy and/or neovascular glaucoma.

The present disclosure provides methods of converting pazopanib in crystalline form (e.g., pazopanib 1HCl) to a material comprising pazopanib in crystalline form G, the methods comprising dissolving the crystalline form in DMSO and lyophilizing the resulting solution; wherein at least about 70% of form G of pazopanib is formed. The present disclosure provides a method of converting pazopanib in crystalline form to a material comprising pazopanib in crystalline form G, the method comprising dissolving the crystalline form in DMSO and lyophilizing the resulting solution; wherein pazopanib is formed in about 100% form G. The present disclosure provides a method of converting pazopanib in crystalline form to a material comprising pazopanib in crystalline form G, the method comprising dissolving the crystalline form in DMSO and lyophilizing the resulting solution; wherein from about 70% to about 100% (e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%) of the form G pazopanib is formed.

The present disclosure provides methods of converting pazopanib in crystalline form a (e.g., pazopanib 1HCl) to a material comprising pazopanib in crystalline form G, comprising dissolving form a in DMSO and lyophilizing the resulting solution; wherein at least about 70% of form G of pazopanib is formed. The present disclosure provides a method of converting pazopanib in crystalline form a to a material comprising pazopanib in crystalline form G, said method comprising dissolving said crystalline form a in DMSO and lyophilizing the resulting solution; wherein pazopanib is formed in about 100% form G. The present disclosure provides a method of converting pazopanib in crystalline form a to a material comprising pazopanib in crystalline form G, said method comprising dissolving said crystalline form a in DMSO and lyophilizing the resulting solution; wherein from about 70% to about 100% (e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%) of the form G pazopanib is formed.

In one aspect, the present disclosure provides a stable pharmaceutical formulation of pazopanib 1HCl for intravitreal delivery from a delivery device, the pharmaceutical formulation comprising a complexing agent, a solubilizing agent, and optionally a buffer. Prior to dissolution, pazopanib 1HCl is lyophilized in DMSO, which converts at least about 70% of the pazopanib 1HCl in crystalline phase form a to crystalline phase form G and increases stability. The pazopanib 1HCl in the thus formed formulation does not precipitate upon dilution and/or during or after at least 50 days of delivery into the vitreous.

In one aspect, the present disclosure provides a stable pharmaceutical formulation of pazopanib 1HCl for intravitreal delivery from a delivery device, the pharmaceutical formulation comprising a complexing agent, a solubilizing agent, and optionally a buffer. Prior to dissolution, pazopanib 1HCl is lyophilized in Trifluoroethanol (TFE), which converts the crystalline phase form a of pazopanib 1HCl into a partially or fully amorphous and/or microcrystalline phase. The pazopanib 1HCl in the thus formed formulation does not precipitate upon dilution and/or during or after at least 50 days of delivery into the vitreous.

The present disclosure provides a process for converting a crystalline form of pazopanib to an amorphous form of pazopanib, the process comprising dissolving the crystalline form in TFE and lyophilizing the resulting solution; wherein up to or at least 96% amorphous pazopanib is formed.

Drawings

In order to understand the invention and to verify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

FIG. 1 shows that the filling is usefulIn vitro drug release profiles of implants of various forms of parecoxib formulated (4.5sccm gas flow). The measured release data is displayed along with the predicted release from the diffusion model.

Fig. 2A shows a treatment device implanted under the conjunctiva and extending through the sclera to release a therapeutic agent into the vitreous humor of the eye to treat the retina according to variations described herein.

Fig. 2B shows a structure of the treatment device as shown in fig. 2A configured for placement in an eye according to variations described herein.

Fig. 2C shows a treatment device loaded into an insertion cannula according to variations described herein, wherein the device comprises an extended narrow shape for insertion into the sclera, and wherein the device is configured to extend to a second extended wide shape for at least partial retention in the sclera.

Fig. 2D shows a treatment device including a reservoir adapted to be loaded in a cannula according to variations described herein.

Fig. 2E shows the treatment device as shown in fig. 2A configured for placement in the eye according to variations described herein.

Fig. 2F shows an access port 180 adapted to be incorporated with the treatment device 100.

Fig. 3 shows a therapeutic device comprising a reservoir having a penetrable barrier disposed on a first end, a porous structure disposed on a second end to release a therapeutic agent over an extended period of time, and a retaining structure projecting outward from the reservoir to couple to the sclera and conjunctiva.

Detailed Description

The materials, compounds, compositions, articles, and methods described herein can be understood more readily by reference to the following detailed description of specific aspects of the disclosed subject matter and the examples included therein. Before the present materials, compounds, compositions, articles, devices, and methods are disclosed and described, it is to be understood that the following aspects are not limited to specific methods or specific reagents, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

In addition, throughout this specification, various publications are referenced. Unless indicated to the contrary, the disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which the disclosed subject matter pertains. The disclosed references are also individually and specifically incorporated by reference herein, in view of the material contained in the reference that is discussed in the sentence in which the reference is relied upon.

Drug delivery formulations of low solubility compounds or active agents (referred to interchangeably in this disclosure) require a significant investment in research and development to ensure that the active agent is not only stable in the formulation, but also active and released at an effective rate over the desired treatment period. Thus, depending on the therapeutic objectives of the disease and/or disorder, it is desirable to develop formulations that meet the desired therapeutic objectives. Delivery of active agents for treating or ameliorating diseases and/or conditions of the posterior segment of the eye is particularly challenging because local delivery of the active, e.g., via eye drops, results in little, if any, optimal amount of active agent delivered to the target site. Furthermore, the concentration required to deliver an effective amount of active to the target site of the posterior ocular segment generally requires high concentrations of the active, which results in at least some systemic side effects due to off-target effects. Delivery of the pharmaceutical formulation by injection avoids the problem of eye drops. Repeated intravitreal injections pose a risk and burden to the patient. Endophthalmitis, retinal detachment, traumatic cataract and increased intraocular pressure (IOP) are potential vision-threatening sequelae of intravitreal routes of administration. Furthermore, monthly treatments or even monthly monitoring are a considerable burden on patients, their caregivers, and the medical community, especially when considering that treatment may need to last for the lifetime of a patient. While approximately one-third of patients experience improved vision when treated with repeated intravitreal injections of certain biological VEGF inhibitors, most patients experience only stabilization of reduced vision.

As described in WO2010/088548, drug delivery formulations developed for delivery by intravitreal delivery devices require that the active agent not only remain in solution (i.e., do not precipitate and/or aggregate) before and during release from the device, but that the active agent remain stable during the same period. And to ensure that the active is delivered to the target site of the posterior segment of the eye for an extended period of time to meet the desired therapeutic goal, the active must be delivered over many days, weeks, and months. As is evident from the lack of therapeutic options for diseases and/or conditions of the posterior segment of the eye, achieving this goal is demanding despite years of research and development, as well as the enormous financial investment of numerous entities.

The present disclosure provides formulations for delivering active agents to the posterior segment of the eye. The active agent formulations of the present disclosure are stable formulations for delivering drugs over an extended period of time. The present disclosure also provides methods of making (and/or manufacturing) drug delivery formulations for delivering active agents that are insoluble or have low solubility in aqueous solutions. Formulations prepared (and/or manufactured) by the methods of the present disclosure are delivered from the intravitreal delivery device of the present disclosure.

Delivery of a therapeutic agent from a diffusion control device requires a source of the therapeutic agent that has a dissolved therapeutic agent concentration that is energetically higher than the therapeutic agent concentration in the target tissue. Delivery of some therapeutic agents is limited by the concentration of dissolved therapeutic agent and thermodynamic energy achievable in the source formulation loaded into the device.

It is desirable to deliver therapeutic levels of therapeutic agents for a period of, for example, three months. This is particularly challenging for therapeutic agents whose aqueous solubility is not as different from the level required to have a therapeutic effect in tissue. For example, as with many therapeutic agents including tyrosine kinase inhibitors, if the solubility of the therapeutic agent in aqueous solution is no greater than 1-10 μ g/mL, a target concentration of about 0.1-10 μ g/mL in the vitreous cannot be obtained from a diffusion-controlled therapeutic device implant.

In addition, some formulation methods increase the amount of therapeutic agent in a formulation that is not in solid form, but the formulated entity in solution is larger in size and has a slower diffusion rate than a single dissolved therapeutic agent molecule. For example, several therapeutic agent molecules may associate or self-assemble into structures such as micelles that have an order of magnitude larger size and an order of magnitude slower diffusion rate than a single therapeutic agent molecule. Furthermore, the size of the diffusing species increases over time in a reproducible or non-reproducible manner, thereby producing a delivery rate profile from the diffusion control device that decreases over time and fails to meet a sustained delivery target profile for a long amount of time.

The present disclosure provides stable pharmaceutical formulations of pharmaceutically acceptable salts and one or more formulating agents of therapeutic agents having low aqueous solubility. The pharmaceutically acceptable salt is a monovalent salt or a divalent salt, and the one or more formulating agents include at least one complexing agent, a solubilizing agent, and a buffer. The salt of the therapeutic agent is dissolved in the pharmaceutical formulation of the present disclosure. The formulations provided in the present disclosure are pazopanib formulations. The formulation is a pharmaceutically acceptable monovalent or divalent salt, such as a halide salt. The present disclosure provides stable pharmaceutical formulations of pazopanib monochloride and/or dichloride salts.

The present disclosure provides that salt molecule (e.g., 1HCl or 2HCl) and polymorphic form amounts affect the solubility and/or stability of the therapeutic agent in the formulation. Obtaining stable and/or soluble formulations of pharmaceutically acceptable salts of therapeutic agents requires different methods of preparing the formulations depending on whether 1HCl or 2HCl and/or polymorphic forms of the salts are present. In addition, the present disclosure provides methods for changing one polymorphic form of a pharmaceutically acceptable salt of a therapeutic agent to another polymorphic form. The methods provide altered polymorphic forms of pharmaceutically acceptable salts of therapeutic agents with higher solubility in the formulation. The method provides for dissolving the active agent in the formulation in a partially and/or fully amorphous form. Accordingly, the present disclosure provides stable and/or highly soluble formulations characterized by polymorphic forms of pharmaceutically acceptable salts of therapeutic agents having low water solubility or being insoluble in aqueous solutions.

The solubility of the therapeutic agent in water or aqueous solvents can vary from sparingly soluble (30 to 100 parts of solvent needed for 1 part of solute), slightly soluble (100 to 1000 parts of solvent needed for 1 part of solute), very slightly soluble (1000 to 10,000 parts of solvent needed for 1 part of solute), and virtually insoluble or insoluble (. gtoreq.10,000). The therapeutic agents of the present invention may be poorly water soluble compounds or compounds with low water solubility. As mentioned herein, a poorly water soluble compound or a compound with low water solubility may have a solubility of, for example, less than 1mg/mL or less than 0.01 mg/mL.

Preparation

The formulations of the present disclosure are formulated to achieve high concentrations (about 1mg/mL to about 300mg/mL) of therapeutic agents characterized by being insoluble or poorly soluble in water.

Complexing agents such as cyclodextrins, which do not readily cross biological membranes and do not affect the PK properties of the therapeutic agent, are used to increase the aqueous concentration of the agent in the memory of the therapeutic device of the present disclosure. Complexing agents of the present disclosure (e.g., cyclodextrin formulations) increase the concentration of a dissolved therapeutic agent by up to 800,000-fold, up to about 10mg/mL to about 100mg/mL for therapeutic agents having an aqueous solubility of 10mg/mL or less, e.g., therapeutic agents having an aqueous solubility of about 0.1 μ g/mL or less.

The present disclosure provides formulations of therapeutic agents (e.g., pazopanib monohydrochloride or dihydrochloride salt) wherein the concentration at the target in the device and/or after delivery is from about 10mg/mL to up to about 70mg/mL (e.g., about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL, about 20mg/mL, about 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL, about 25mg/mL, about 26mg/mL, about 27mg/mL, about 28mg/mL, about 29mg/mL, about 30mg/mL, about 31mg/mL, about 32mg/mL, about, About 33mg/mL, about 34mg/mL, about 35mg/mL, about 36mg/mL, about 37mg/mL, about 38mg/mL, about 39mg/mL, about 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 59mg/mL, about 60mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, about 65mg/mL, about, About 66mg/mL, about 67mg/mL, about 68mg/mL, about 69mg/mL, or about 70 mg/mL). The present disclosure provides about 30mg/mL to about 50mg/mL of pazopanib in a formulation.

Measured at a concentration of about 10mg/mL to up to about 70mg/mL (e.g., about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL, about 20mg/mL, about 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL, about 25mg/mL, about 26mg/mL, about 27mg/mL, about 28mg/mL, about 29mg/mL, about 30mg/mL, about 31mg/mL, about 32mg/mL, about 33mg/mL, about 34mg/mL, about 35mg/mL, about 36mg/mL, about 37mg/mL, about 38mg/mL, about, About 39mg/mL, about 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 59mg/mL, about 60mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, about 65mg/mL, about 66mg/mL, about 67mg/mL, about 68mg/mL, about 69mg/mL, or about 70 mg/mL).

The present disclosure provides for a fill concentration of a therapeutic agent (e.g., pazopanib 1HCL or 2HCL) in a delivery device from about 10mg/mL to up to about 70mg/mL (e.g., about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL, about 20mg/mL, about 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL, about 25mg/mL, about 26mg/mL, about 27mg/mL, about 28mg/mL, about 29mg/mL, about 30mg/mL, about 31mg/mL, about 32mg/mL, about 33mg/mL, about 34mg/mL, about 35mg/mL, About 36mg/mL, about 37mg/mL, about 38mg/mL, about 39mg/mL, about 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 59mg/mL, about 60mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, about 65mg/mL, about 66mg/mL, about 67mg/mL, about 68mg/mL, About 69mg/mL or about 70 mg/mL).

The present disclosure provides monovalent halide salts (e.g., chloride salts) of pazopanib that are stable in the disclosed formulations in a delivery device at about 10mg/ml, about 15mg/ml, about 20mg/ml, about 25mg/ml, about 30mg/ml, about 35mg/ml, about 45mg/ml, about 50mg/ml, about 55mg/ml, about 60mg/ml, about 65mg/ml, about 70mg/ml, about 75mg/ml, or about 80 mg/ml. The present disclosure provides monovalent salts of haloparagonin that are stable in the disclosed formulation in a delivery device between about 10mg/ml up to about 15mg/ml, about 15mg/ml up to about 20mg/ml, about 20mg/ml up to about 25mg/ml, about 25mg/ml up to about 30mg/ml, about 30mg/ml up to about 35mg/ml, about 35mg/ml up to about 45mg/ml, about 45mg/ml up to about 50mg/ml, about 50mg up to about 55mg/ml, about 55mg/ml up to about 60mg/ml, about 60mg/ml up to about 65mg/ml, about 65mg/ml up to about 70mg/ml, about 70mg/ml up to about 75mg/ml, or about 75mg/ml up to about 80mg/ml (e.g., chloride salts). Monovalent halide salts (e.g., chloride salts) of pazopanib that are stable in the disclosed formulations at about 40mg/ml up to about 60 mg/ml.

The present disclosure provides a divalent halide salt (e.g., chloride salt) of pazopanib that is stable in the disclosed formulation in a delivery device at about 10mg/ml, about 15mg/ml, about 20mg/ml, about 25mg/ml, about 30mg/ml, about 35mg/ml, about 45mg/ml, about 50mg/ml, about 55mg/ml, about 60mg/ml, about 65mg/ml, about 70mg/ml, about 75mg/ml, or about 80 mg/ml. The present disclosure provides a divalent salt (e.g., chloride salt) of pazopanib that is stable in the disclosed formulation in a delivery device between about 10mg/ml and about 15mg/ml, between about 15mg/ml and about 20mg/ml, between about 20mg/ml and about 25mg/ml, between about 25mg/ml and about 30mg/ml, up to about 30mg/ml, between about 35mg/ml and about 45mg/ml, between about 45mg/ml and about 50mg/ml, between about 50mg and about 55mg/ml, between about 55mg/ml and about 60mg/ml, between about 60mg/ml and about 65mg/ml, between about 65mg/ml and about 70mg/ml, between about 70mg/ml and about 75mg/ml, or between about 75mg/ml and about 80 mg/ml. A divalent pazopanib halide salt (e.g., chloride salt) of the present invention that is stable in the disclosed formulation at about 60 mg/ml.

The complexing agent is sulfobutyl ether- β -cyclodextrin ("SBE β CD") orThe intravitreal delivery formulations of the present disclosure includeThe complexed therapeutic agent pazopanib monohydrochloride or dihydrochloride. Therapeutic agents pazopanib monohydrochloride or dihydrochloride andthe association of (a) increases the aqueous solubility of the agent by a factor of 10 to 25,000. Therapeutic agents pazopanib monohydrochloride or dihydrochloride andin the interaction ofProvides a beneficial and protected environment for the therapeutic agent, andthe hydrophobic surface of (a) provides effective aqueous solubility, thereby enhancing the solubility and stability of the therapeutic agent. In addition, therapeutic agents andreduces the decomposition of the reagent by protecting the labile region from potential reactants in an aqueous environment.

The formulations of the present disclosure comprise pazopanib or pazopanib monohydrochloride or dihydrochloride in association with a complexing agent (e.g., cyclodextrin ("CD")), which is (without limitation to the list herein) 2-hydroxypropyl- β -cyclodextrin, methyl- β -cyclodextrin, randomly methylated- β -cyclodextrin, ethylated- β -cyclodextrin, triacetyl- β -cyclodextrin, peracetylated- β -cyclodextrin, carboxymethyl- β -cyclodextrin, hydroxyethyl- β -cyclodextrin, 2-hydroxy-3- (trimethylammonio) propyl- β -cyclodextrin, glucosyl- β -cyclodextrin, maltosyl- β -cyclodextrin, sulfobutyl ether- β -cyclodextrin, glucose- β -cyclodextrin, maltosyl- β -cyclodextrin, sodium chloride, sodium, Branched- β -cyclodextrin, hydroxypropyl- γ -cyclodextrin, randomly methylated- γ -cyclodextrin, trimethyl- γ -cyclodextrin, or any combination thereof. The CD in the formulation is present in a ratio of about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1 to the therapeutic agent. The ratio of CD to therapeutic agent is about 2.5: 1. A ratio of CD to therapeutic agent of about 2.2: 1; about 2.5: 1; about 3.7: 1; about 5: 1; about 8: 1; or about 9: 1.

The increase in the concentration of the therapeutic agent in the device is about 100-fold the concentration required at the vitreous for effective treatment, prevention of progression, or amelioration of vascular leakage and Neovascularization (NV) in the retina. Because the required concentration at the vitreous for effective treatment, prevention of progression, or amelioration of vascular leakage and Neovascularization (NV) is above the solubility limit of the therapeutic agent, embodiments of the present disclosure provide a therapeutic agent solubility that is about 1000-fold or more than 1000-fold increase in the intrinsic water solubility of the agent.

The formulations of the present disclosure compriseAs a complexing agent. In thatThe concentration of the therapeutic agent in the drug delivery agent and/or in the vitreous after delivery is from 0.5mg/mL to about 90mg/mL in the presence. For example, inThe concentration of pazopanib monohydrochloride or dihydrochloride, in the presence of the drug, is about 20mg/mL, about 30mg/mL, about 40mg/mL, about 50mg/mL, about 60mg/mL, about 70mg/mL, about 80mg/mL, or about 90 mg/mL.

The formulation further comprises: trehalose, methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium hyaluronate, sodium alginate, chitosan and derivatives thereof, polyethylene glycol, glycerol, propylene glycol, triacetin, N-dimethylacetamide, pyrrolidone, dimethylsulfoxide, ethanol, N- (-beta-hydroxyethyl) -lactamide, 1-methyl-2-pyrrolidone, triglycerides, thioglycerol, sorbitol, lecithin, methyl paraben, propyl paraben, polysorbate, block copolymers of ethylene oxide and propylene oxide, diblock polymers or triblock copolymers of polyethylene oxide and polypropylene oxide, ethoxylated emulsifiers, polyethylene glycol esters, sucrose laurate, tocopherol-PEG-succinate, phospholipids and derivatives thereof, and mixtures thereof, Or other nonionic self-emulsifying agents.

Solubilizing agents in the formulations of the present disclosure include, by way of non-limiting example, trehalose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, sodium hyaluronate, sodium alginate, polyethylene glycol, glycerol, propylene glycol, triacetin, N-dimethylacetamide, polyvinylpyrrolidone), pyrrolidone, or any combination thereof. The solubilizing agent used to prepare the formulations of the present disclosure is poly (vinyl pyrrolidone) (PVP). For example, the formulations of the present disclosure comprise about 0.2% to about 1% PVP. The present disclosure provides formulations having from about 5mg/mL PVP to about 30mg/mL PVP.

The solubilizing agent added to the formulations of the present disclosure comprises from about 0.1% to about 5.0% (e.g., about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3.3%, about 4%, about 4.4%, about 4.5%, about 4%, about 4.6%, about 4%, about 4.7%, about 4.8%, about 4%, about 4.9%, about 4%, PVP. The formulations of the present disclosure comprise, for example, about 1% PVP.

The formulations of the present disclosure comprise a buffering agent, for example, histidine HCl. The formulation comprises about 5mg/mL to about 30mg/mL of a buffer, e.g., histidine HCl (e.g., about 5mg/mL, about 6mg/mL, about 7mg/mL, about 8mg/mL, about 9mg/mL, about 10mg/mL, about 11mg/mL, about 12mg/mL, about 13mg/mL, about 14mg/mL, about 15mg/mL, about 16mg/mL, about 17mg/mL, about 18mg/mL, about 19mg/mL, about 20mg/mL, about 21mg/mL, about 22mg/mL, about 23mg/mL, about 24mg/mL, about 25mg/mL, about 26mg/mL, about 27mg/mL, about 28mg/mL, about 29mg/mL, or about 30 mg/mL).

The formulation has a pH of about 1.0 to about 7.0 (e.g., a pH of about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.9, about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9, about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 4.3, about 5.3, about 5.4.4, about 5, about 5.5, about 6, about 5.6, about 6, about 5.7, about 4.8, about 4.9, about 5.9, about 5.0, about 6, about 5.5, about 6, about 6.5, about 6, about 6.5.0, about 6, about 6.5.5, about 6, about 6.5..

Additional additives included in the formulations of the present disclosure are, by way of non-limiting example, triacetin (about 1x molar ratio to therapeutic agent), L-lysine (about 25mg/mL), ammonium acetate from about 0.1% to about 5% (w/v) (e.g., about 2% (w/v)), or glycerol from about 0.1% to about 5% (w/v) (e.g., about 2% (w/v)).

The formulations of the present disclosure include one or two agents for adjusting pH for increasing the buffering capacity of the formulation in a therapeutic device. One or two pH adjusting agents are selected from (non-limiting examples) sodium hydroxide, hydrochloric acid, citric acid, malic acid, acetate, tartaric acid, histidine, phosphate, or any combination thereof. In one embodiment, the formulation comprises an agent for adjusting pH, but does not comprise a complexing agent. One or both pH adjusting agents are citric acid and/or histidine.

The formulations of the present disclosure comprise a tonicity modifier. For example, tonicity adjusting agents are (non-limiting examples) sodium chloride, sodium phosphate, or any combination thereof.

The formulations of the present disclosure have high stability during use of the PDS implant. For example, the formulation is stable at 37 ℃ for at least 6 months in a PDS storage chamber under physiological conditions. For example, the formulation is stable in PDS in the presence of vitreous components that diffuse from the vitreous.

The formulations of the present disclosure are used in methods of ocular drug delivery. The formulations of the present disclosure are intravitreal delivery formulations. The formulation of the present disclosure is not formulated as eye drops. The preparation of the present disclosure is not formulated for use

In local delivery. The formulations of the present disclosure are not formulated for oral delivery or parenteral delivery. The formulations of the present disclosure are not formulated for periocular local delivery.

Preparation method

The present disclosure provides methods of making and/or manufacturing stable and solution pharmaceutical formulations of pharmaceutically acceptable salts of pazopanib.

The present disclosure provides methods of pharmaceutical formulation that depend on the characteristics of the active agent sample and thus the active in a given sample. The present disclosure provides formulation methods that depend on the salt form and crystallinity of the active agent. Tables 1, 2 and 3 provide a summary of the characteristics of the active pazopanib of the present disclosure.

TABLE 1

Pazopanib with a similar compositionpH comparison of solutions:

based on its XRD pattern, sample-2 has a crystal structure as form a, containing 1HCl per drug molecule.

Comparison of chloride content: table 2 provides the chloride content of various API samples as measured by X-ray fluorescence (XRF). See Evans Analytical Laboratories, X-RAY FLUORESCENCE (XRF) ANALYSIS REPORT, 2.21.2014, JOB NUMBER C0ELG 412.

TABLE 2

From the results of the pH and chloride content analyses it can be concluded that the drug component from sample-1 contains 2HCl per pazopanib molecule compared to the active from sample-2, which contains only 1HCl per drug molecule.

Divalent salt

The present disclosure provides methods for preparing formulations of divalent salts of pazopanib. The method comprises the steps of (a) dissolving a divalent salt of pazopanib in a solution of one or more formulation agents. Formulations used in the method include, but are not limited to, complexing agents, solubilizing agents, and buffers. After dissolving the divalent salt in a solution of the formulation, adjusting the pH of the solution to an optimal pH to maintain stability of the divalent salt in the formulation before and/or after release, solubility of the divalent salt in the formulation before and/or after release, rate of release of the divalent salt from the delivery device in the formulation and/or therapeutic efficacy of the pazopanib after release into the posterior segment of the eye. The pharmaceutically acceptable salt is a divalent halide salt of pazopanib, such as a divalent chloride salt, a divalent bromide salt, a divalent iodide salt or a divalent fluoride salt of pazopanib. The present disclosure provides methods for preparing divalent chloride salts of pazopanib.

The divalent chloride salt in the pazopanib formulation prepared by the methods of the present disclosure is polymorph form XIV having XRPD diffraction peaks at 7.8 ± 0.2 degrees 2 Θ, 12.4 ± 0.2 degrees 2 Θ, 22.9 ± 0.2 degrees 2 Θ, 23.6 ± 0.2 degrees 2 Θ, and 26.9 ± 0.2 degrees 2 Θ (further characterized by peaks at 14.8 ± 0.2 degrees 2 Θ, 17.5 ± 0.2 degrees 2 Θ, 19.0 ± 0.2 degrees 2 Θ, 25.3 ± 0.2 degrees 2 Θ, and 27.4 ± 0.2 degrees 2 Θ); or form I having XRPD diffraction peaks at 6.7 ± 0.2 degrees 2 Θ, 7.4 ± 0.2 degrees 2 Θ, 12.0 ± 0.2 degrees 2 Θ, 14.8 ± 0.2 degrees 2 Θ, 23.6 ± 0.2 degrees 2 Θ (further characterized by peaks at 13.3 ± 0.2 degrees 2 Θ, 14.8 ± 0.2 degrees 2 Θ, 19.0 ± 0.2 degrees 2 Θ, 26.6 ± 0.2 degrees 2 Θ); or a form XV having XRPD diffraction peaks at 6.9 + -0.2 degrees 2 theta, 12.1 + -0.2 degrees 2 theta, 23.6 + -0.2 degrees 2 theta, 26.8 + -0.2 degrees 2 theta, and 27.4 + -0.2 degrees 2 theta (further characterized by peaks at 15.7 + -0.2 degrees 2 theta, 19.4 + -0.2 degrees 2 theta, 23.3 + -0.2 degrees 2 theta, and 25.7 + -0.2 degrees 2 theta). The present disclosure provides methods of preparing a formulation of the polymorphic form XIV pazopanib dihydrochloride having XRPD diffraction peaks at 7.8 ± 0.2 degrees 2 theta, 12.4 ± 0.2 degrees 2 theta, 22.9 ± 0.2 degrees 2 theta, 23.6 ± 0.2 degrees 2 theta, and 26.9 ± 0.2 degrees 2 theta (further characterized by peaks at 14.8 ± 0.2 degrees 2 theta, 17.5 ± 0.2 degrees 2 theta, 19.0 ± 0.2 degrees 2 theta, 25.3 ± 0.2 degrees 2 theta, and 27.4 ± 0.2 degrees 2 theta).

The complexing agent used in the process for the preparation of the divalent salt formulation of pazopanib is a cyclodextrin, for example, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, di-basic-cyclodextrin, di-basic-cyclodextrin, Trimethyl-gamma-cyclodextrin or any combination thereof.

The solubilizing agent used in the method for preparing the formulation of the divalent salt of pazopanib of the present disclosure is poly (vinyl pyrrolidone) (PVP). The buffer used in the method for preparing the formulation of a divalent salt of palozoitinib of the present disclosure is histidine HCl.

The methods of the present disclosure provide for the formulation of 2HCl per pazopanib molecule to formulate drug concentrations of up to about 60 mg/ml. The drug was dissolved in CAPTISOL solution and then the formulation was added before adjusting the pH.

The formulation was prepared by dissolving the required amount of pazopanib 2HCl salt in the cyclodextrin, acid and formulation in water. Pazopanib 2HCl was added and mixed until dissolved. Sodium hydroxide was then added to reach the final pH. The formulation was filtered and then injected into PDS implants for therapeutic agent release testing.

The present disclosure provides formulations of therapeutic agents, such as pazopanib dihydrochloride (2HCl), and their preparation, where the active agent is stable in the formulation for an extended period of time (i.e., over 60 days and/or over 90 days). Formulations with a stable active agent (e.g., pazopanib 2HCl) have up to about 70mg/mL active agent. The present disclosure provides compositions having a total of up to about 10mg/mL, up to about 11mg/mL, up to about 12mg/mL, up to about 13mg/mL, up to about 14mg/mL, up to about 15mg/mL, up to about 16mg/mL, up to about 17mg/mL, up to about 18mg/mL, up to about 19mg/mL, up to about 20mg/mL, up to about 21mg/mL, up to about 22mg/mL, up to about 23mg/mL, up to about 24mg/mL, up to about 25mg/mL, up to about 26mg/mL, up to about 27mg/mL, up to about 28mg/mL, up to about 29mg/mL, up to about 30mg/mL, up to about 31mg/mL, up to about 32mg/mL, up to about 33mg/mL, up to about 34mg/mL, Up to about 35mg/mL, up to about 36mg/mL, up to about 37mg/mL, up to about 38mg/mL, up to about 39mg/mL, up to about 40mg/mL, up to about 41mg/mL, up to about 42mg/mL, up to about 43mg/mL, up to about 44mg/mL, up to about 45mg/mL, up to about 46mg/mL, up to about 47mg/mL, up to about 48mg/mL, up to about 49mg/mL, up to about 50mg/mL, up to about 51mg/mL, up to about 52mg/mL, up to about 53mg/mL, up to about 54mg/mL, up to about 55mg/mL, up to about 56mg/mL, up to about 57mg/mL, up to about 58mg/mL, up to about 59mg/mL, up to about 60mg/mL, A pazopanib 2HCl formulation of a stable active up to about 61mg/mL, up to about 62mg/mL, up to about 63mg/mL, up to about 64mg/mL, up to about 65mg/mL, up to about 66mg/mL, up to about 67mg/mL, up to about 68mg/mL, up to about 69mg/mL, or up to about 70 mg/mL.

Monovalent salt

The present disclosure provides methods for preparing stable and/or soluble formulations of monovalent salts of therapeutic agents. Monovalent salts are highly insoluble in aqueous solutions and are prone to precipitation during storage of the formulation and/or before and/or after delivery of the formulation to the target site. The present disclosure provides methods of increasing the ease of dissolving monovalent salts and/or increasing the stability of monovalent salts in solution. The methods provide increased solubility and/or stability of monovalent salts in formulations such that the salts remain dissolved for extended periods of time during storage and/or before and/or after delivery to a target site.

In order to dissolve a drug (e.g., the monohydrochloride salt of pazopanib), in one method of the present disclosure, a long dissolution time and the addition of additional acid are required; the pH of the formulation was adjusted with hydrochloric acid (HCl) to a pH equal to or below about 2. At a pH below about 2After a long dissolution process (1-3 days) of the drug and excipients in the solution, the pH is adjusted.

NaOH pretreatment (amorphization) of the drug was also successfully employed prior to the dissolution step at low pH. Although the amorphization step reduces the time required to prepare a highly concentrated solution, this step also significantly increases the total salt content of the formulation.

The present disclosure provides methods for stable pharmaceutical formulations of pharmaceutically acceptable salts of therapeutic agents having low aqueous solubility. A method of preparing a stable pharmaceutical formulation of a monovalent salt of a therapeutic agent comprising the steps of: (a) treatment of monovalent salts with alkali (amortization); (b) dissolving the alkali-treated salt in a solution of one or more formulation agents; and (c) adjusting the pH with an acid to a pH of equal to or less than about 4, equal to or less than about 3, equal to or less than about 2, or equal to or less than about 1. Formulations used in the method include, but are not limited to, complexing agents, solubilizing agents, and buffers. The alkaline treatment of monovalent salts increases the total salt content in the formulation. Adjusting the pH with an acid increases the solubility of the salt in the formulation.

The present disclosure provides methods of preparing stable pharmaceutical formulations of pharmaceutically acceptable monovalent salts of pazopanib. A method of preparing a stable pharmaceutical formulation of a monovalent salt of pazopanib (e.g., a monovalent chloride salt of pazopanib, a monovalent bromide salt of pazopanib, a monovalent iodide salt of pazopanib, or a monovalent fluoride salt of pazopanib) comprises the steps of: (a) treating the monovalent salt with a base; (b) dissolving the alkali-treated salt in a solution of one or more formulation agents; and (c) adjusting the pH with an acid to a pH of equal to or less than about 4, equal to or less than about 3, equal to or less than about 2, or equal to or less than about 1. Formulations used in the method include, but are not limited to, complexing agents, solubilizing agents, and buffers. The alkaline treatment of monovalent salts increases the total salt content in the formulation. Adjusting the pH with an acid increases the solubility of the salt in the formulation. The base is, for example, sodium hydroxide (NaOH). The acid is, for example, hydrochloric acid (HCl).

The complexing agent used in the process for preparing the monovalent salt formulation of pazopanib is a cyclodextrin, for example, 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, di-n-butyl ether-beta-cyclodextrin, di-n-butyl ether-cyclodextrin, di-butyl ether-beta-cyclodextrin, trimethyl-gamma-cyclodextrin or any combination thereof.

The solubilizing agent used in the method for preparing the formulation of the monovalent salt of pazopanib of the present disclosure is poly (vinyl pyrrolidone) (PVP). The buffer used in the method for preparing the formulation of monovalent salts of palozoitinib of the present disclosure is histidine HCl.

The solubilizing agent used in the method for preparing the formulation of the monovalent salt of pazopanib of the present disclosure is poly (vinyl pyrrolidone) (PVP) and does not contain any buffering agent.

The present disclosure provides significantly improved stability of 1HCl pazopanib formulations by reducing drug concentrations to below 40 mg/mL.

The active is easily precipitated at high concentrations. The present disclosure provides methods of preparing stable solution formulations of low solubility actives (e.g., pazopanib).

The present disclosure provides formulations of therapeutic agents, such as pazopanib monohydrochloride (1HCl), and methods of making the same, wherein the active agent is stable in the formulation at less than or greater than about 40mg/mL for an extended period of time (i.e., greater than 60 days and/or greater than 90 days). Formulations with a stable active agent (e.g., pazopanib 1HCl) are stable at up to about 60 mg. The present disclosure provides compositions having a total of up to about 10mg/mL, up to about 11mg/mL, up to about 12mg/mL, up to about 13mg/mL, up to about 14mg/mL, up to about 15mg/mL, up to about 16mg/mL, up to about 17mg/mL, up to about 18mg/mL, up to about 19mg/mL, up to about 20mg/mL, up to about 21mg/mL, up to about 22mg/mL, up to about 23mg/mL, up to about 24mg/mL, up to about 25mg/mL, up to about 26mg/mL, up to about 27mg/mL, up to about 28mg/mL, up to about 29mg/mL, up to about 30mg/mL, up to about 31mg/mL, up to about 32mg/mL, up to about 33mg/mL, up to about 34mg/mL, Up to about 35mg/mL, up to about 36mg/mL, up to about 37mg/mL, up to about 38mg/mL, up to about 39mg/mL, up to about 40mg/mL, up to about 41mg/mL, up to about 42mg/mL, up to about 43mg/mL, up to about 44mg/mL, up to about 45mg/mL, up to about 46mg/mL, up to about 47mg/mL, a pazopanib 1HCl formulation of a stable active up to about 48mg/mL, up to about 49mg/mL, up to about 50mg/mL, up to about 51mg/mL, up to about 52mg/mL, up to about 53mg/mL, up to about 54mg/mL, up to about 55mg/mL, up to about 56mg/mL, up to about 57mg/mL, up to about 58mg/mL, up to about 59mg/mL, or up to about 60 mg/mL.

The present disclosure provides methods of improving the stability of a 1HCl pazopanib formulation by lyophilizing an active agent prior to dissolution. The present disclosure provides a formulation method (method of preparing a formulation) for improving the solubility and stability of 1HCl pazopanib in a formulation by lyophilizing an active agent prior to dissolution in the formulation.

The present disclosure provides a test of the effect of lyophilization from two different solvents, Trifluoroethanol (TFE) and dimethyl sulfoxide (DMSO), on the crystal structure and/or amorphous region content of the active agent from sample-2.

The pazopanib salts of the present disclosure are in crystalline and/or amorphous form. A summary of XRPD results for various pazopanib salts used in the formulations of the present disclosure is provided in table 3.

TABLE 3

Lyophilization was performed from Trifluoroethanol (TFE), trifluoroethanol-water (90-10) mixtures, or Dimethylsulfoxide (DMSO) by standard methods in the art.

The lyophilization conditions from DMSO of the present disclosure include the conditions described in table 4 below:

TABLE 4

The present disclosure provides methods for stable pharmaceutical formulations of pharmaceutically acceptable salts of therapeutic agents having low aqueous solubility.

The present disclosure provides a therapeutic agent in a crystalline form that is pre-treated prior to the formulation process. The present disclosure provides for lyophilizing a therapeutic agent (e.g., pazopanib 1HCl) from an alcohol, thereby converting pazopanib 1HCl in a crystalline phase form a to pazopanib 1HCl in an amorphous (or microcrystalline) material form, as determined by XPRD. Lyophilization from an alcohol, such as Trifluoroethanol (TFE), converts pazopanib 1HCl in crystalline phase form a to pazopanib 1HCl in amorphous (or microcrystalline) material form, as determined by XPRD. Pazopanib 1HCl form a is dissolved in an alcohol (e.g., TFE) or TFE/water mixture, and the solution is lyophilized. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃. The present disclosure provides a process for converting pazopanib in crystalline form to pazopanib in amorphous (or microcrystalline) form, comprising dissolving the crystalline form in Trifluoroethanol (TFE) and lyophilizing the resulting solution; wherein up to or at least 96% amorphous pazopanib is formed.

The crystalline form of the therapeutic agent (e.g., pazopanib monohydrochloride) is pre-treated by lyophilization. For example, a solution of about 60mg/mL of a therapeutic agent (e.g., pazopanib monohydrochloride) in TFE is prepared. About 1% to about 30% water (e.g., about 20%) is also added to the therapeutic agent solution (e.g., a solution of pazopanib monohydrochloride in TFE). The solution was then freeze dried (with or without the addition of water) under conditions standard in the art. The solution is allowed to dry at about 35 deg.C to about 50 deg.C (e.g., about 40 deg.C) for about 12 hours to about 24 hours, or at about 50 deg.C to about 65 deg.C (e.g., at about 60 deg.C) for about 4 to about 8 hours. Lyophilization from TFE converts crystalline phase form a to a partially or fully (e.g., up to or at least 96%) amorphous phase. Amorphous (or microcrystalline) pazopanib monohydrochloride (i.e., lyophilized in TFE) is then dissolved in a solution prepared by mixing at least a solubilizing agent, a buffering agent, and a complexing agent, as described in this disclosure.

A method of converting a crystalline form (e.g., form a) of pazopanib to a material containing an amorphous form provides up to about 80%, up to about 81%, up to about 82%, up to about 83%, up to about 84, up to about 85%, up to about 86%, up to about 87%, up to about 88%, up to about 89%, up to about 90%, up to about 91%, up to about 92%, up to about 93%, up to about 94%, up to about 95%, or up to about 96% amorphous pazopanib 1 HCl. Alternatively, the method provides forming at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% amorphous pazopanib 1 HCl. The remaining active agent is in crystalline form, i.e., either in the original form or in the form of a mixture of the original form or another form (e.g., form a and/or form G).

The present disclosure provides for lyophilizing a therapeutic agent (e.g., pazopanib 1HCl) from a polar aprotic solvent for converting pazopanib 1HCl in one crystalline phase form (e.g., crystalline phase form a) to pazopanib 1HCl containing up to or at least about 70% of a different crystalline phase form (e.g., form G), as determined by XRPD. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃. Lyophilization from organosulfur compounds converts pazopanib 1HCl in crystalline phase form a to a material containing at least about 70% of pazopanib 1HCl in form G, as determined by XRPD. Lyophilization from dimethyl sulfoxide (DMSO) converts pazopanib 1HCl in crystalline phase form a to a material containing up to or at least about 70% of form G pazopanib 1HCl, as determined by XRPD. Lyophilization from dimethyl sulfoxide (DMSO) converted pazopanib 1HCl in crystalline phase form a to a material containing about 100% of form G pazopanib 1HCl, as determined by XRPD. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃. The present disclosure provides a method of converting pazopanib in crystalline form to a material comprising pazopanib in crystalline form G, the method comprising dissolving the crystalline form in DMSO and lyophilizing the resulting solution; wherein at least about 70% of form G of pazopanib is formed.

The present disclosure provides a method of converting pazopanib in crystalline form a to a material comprising pazopanib in crystalline form G, the method comprising dissolving form a in DMSO and lyophilizing the resulting solution; wherein up to or at least about 70% of form G of pazopanib is formed. The present disclosure provides a method of converting pazopanib in crystalline form a to a material comprising pazopanib in crystalline form G, said method comprising dissolving said crystalline form a in DMSO and lyophilizing the resulting solution; wherein from about 70% to about 100% (e.g., about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, about 100%) of the form G pazopanib is formed.

A method of converting pazopanib in a crystalline form (e.g., form a) to a material containing crystalline form G provides for the formation of pazopanib in up to about 50%, up to about 51%, up to about 52%, up to about 53%, up to about 54%, up to about 55%, up to about 56%, up to about 57%, up to about 58%, up to about 59%, up to about 60%, up to about 61%, up to about 62%, up to about 63%, up to about 64%, up to about 65%, up to about 66%, up to about 67%, up to about 68%, up to about 69%, or up to about 70% of form G. Alternatively, the method provides forming pazopanib in at least about 70%, at least about 71%, at least about 72%, at least about 73%, at least about 74%, at least about 75%, at least about 76%, at least about 77%, at least about 78%, at least about 79%, at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 100% form G.

The present disclosure provides a therapeutic agent in a crystalline form, e.g., pazopanib monohydrochloride, that is pre-treated prior to the formulation process. The crystalline form of the therapeutic agent (e.g., pazopanib monohydrochloride) is pre-treated by lyophilization (see table 4 for an example of lyophilization conditions from DMSO). A solution of about 20-60mg/mL of a therapeutic agent (e.g., pazopanib monohydrochloride) in DMSO (dimethyl sulfoxide) is prepared. The solution is then lyophilized under conditions standard in the art. The drying conditions of the present disclosure are at a temperature above ambient temperature. For example, the solution of the present disclosure is dried at about 35 ℃ to about 50 ℃ (e.g., about 40 ℃) for about 12 to about 24 hours, and at about 50 ℃ to about 65 ℃ (e.g., about 60 ℃) for about 24 to about 40 hours, and at about 90 ℃ to about 110 ℃ (e.g., about 100 ℃) for about 0.5 to about 2 hours. Lyophilization from DMSO transformed crystalline phase form a to crystalline phase form G as determined by XRPD.

Pazopanib having crystalline phase form a with XRPD peaks at 5.6 ± 0.2 degrees 2 theta, 15.5 ± 0.2 degrees 2 theta, 16.4 ± 0.2 degrees 2 theta, 24.0 ± 0.2 degrees 2 theta, and 24.3 ± 0.2 degrees 2 theta (further characterized by peaks at 10.5 ± 0.2 degrees 2 theta, 16.8 ± 0.2 degrees 2 theta, 17.9 ± 0.2 degrees 2 theta, 26.4 ± 0.2 degrees 2 theta, and 32.9 ± 0.2 degrees 2 theta) is converted from a lyophilization step of DMSO in the methods of the present disclosure to XRPD peaks at 9.6 ± 0.2 degrees 2 theta, 16.8 ± 0.2 degrees 2 theta, 19.6 ± 0.2 degrees 2 theta, 24.7 ± 0.2 degrees 2 theta, and 26.2 ± 0.2 degrees 2 theta (further characterized by peaks at 11.8 ± 0.2 degrees 2 theta, 14.6 ± 0.2 degrees 2 theta, 14.2 degrees 2 theta, and 20.3 ± 0.2 degrees 2 theta from the peak at 10.5 ± 0.2 theta.

The present disclosure provides a method of preparing a stable pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of a therapeutic agent comprising the steps of: (a) preparing a solution of said salt in an organic solvent (TFE or DMSO); and (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent. The method of preparing a stable pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of a therapeutic agent further comprises the steps of: (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; (d) dissolving a complexing agent in an aqueous solution of the solubilizing agent and the buffer, thereby preparing a solution; (e) adding the lyophilized salt to the solution at or above ambient temperature (about 37 ℃ to about 50 ℃), mixing, and allowing it to dissolve in the solution; and (f) optionally adjusting the pH of the formulation. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃ (e.g., at about 37 ℃, about 38 ℃, about 39 ℃, about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃, about 50 ℃).

The solubilizer used in the method is PVP. The buffer used in the method was histidine HCl. The complexing agent used in the process is a cyclodextrin: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, or any combination thereof.

The present disclosure provides a method of preparing a stable pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of pazopanib (e.g., a monovalent chloride salt of pazopanib, a monovalent bromide salt of pazopanib, a monovalent iodide salt of pazopanib, or a monovalent fluoride salt of pazopanib), comprising the steps of: (a) preparing a solution of said salt in an organic solvent (TFE or DMSO); and (b) lyophilizing the solution, thereby preparing a lyophilized salt of pazopanib. A method of preparing a stable pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of pazopanib provides that a lyophilized monovalent halide salt of pazopanib (e.g., a monovalent chloride salt (e.g., the hydrochloride salt), a monovalent bromide salt, a monovalent iodide salt, or a monovalent fluoride salt of pazopanib) is amorphous after lyophilization.

The process for preparing a stable and solution pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of pazopanib further involves: (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; (d) dissolving a complexing agent in an aqueous solution of the solubilizing agent and the buffer, thereby preparing a solution; (e) adding the lyophilized salt to a viscous solution at or above ambient temperature (e.g., about 37 ℃ or 50 ℃), mixing, and dissolving in the solution; and (f) optionally adjusting the pH of the formulation. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃ (e.g., at about 37 ℃, about 38 ℃, about 39 ℃, about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃, about 50 ℃).

The solubilizing agent used in the process for preparing the formulation of monovalent pazopanib is PVP. The buffer used in the same process was histidine HCl. The complexing agents used in the same process are cyclodextrins: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, or any combination thereof.

A method of preparing a stable and solution pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of pazopanib provides a stable formulation of a monovalent halide salt of pazopanib, such as a monovalent chloride salt, a monovalent bromide salt, a monovalent iodide salt, or a monovalent fluoride salt of pazopanib. A method of preparing a stable pharmaceutical formulation of a pharmaceutically acceptable monovalent salt of pazopanib provides a stable formulation of a monovalent chloride salt of pazopanib.

The present disclosure provides methods in which the natural pH of the formulation is used (i.e., no adjustment of the pH of the viscous solution is required). In this method, the dissolution of the pharmaceutical ingredient is carried out in one step. PVP-10k (polyvinylpyrrolidone, MW ═ 10kDa) and histidine HCl were weighed and dissolved by mixingThe solution was dissolved in an appropriate amount of water (vortexed, shaken). Weighing machineAdded to the solution and dissolved prior to shaking, vortexing the solution. Weighing the lyophilized pazopanib, and adding to the viscousIn solution and completely dissolved by vortexing, sonication, shaking at ambient or elevated temperatures (about 37 ℃ to about 50 ℃). The formulation was filtered using a 0.2 μm filter and stored at room temperature and protected from light.

The present disclosure provides methods of preparing stable solution pharmaceutical formulations of pharmaceutically acceptable salts of therapeutic agents having low aqueous solubility, wherein the salts are monovalent salts, such as pazopanib 1 HCl; the method comprises (a) preparing a solution of the salt in an organic solvent (e.g., trifluoroethanol-water mixture, or dimethylsulfoxide); (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; dissolving an amount of a complexing agent in the solution, thereby preparing a low viscosity solution; adding a lyophilized salt to the low viscosity solution at or above ambient temperature (about 37 ℃ to about 50 ℃), mixing, and allowing it to dissolve in the solution; wherein the pH of the low viscosity solution is adjusted; and adding about 2 times the amount of the complexing agent to the low viscosity solution and dissolving it. The lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃ (e.g., at about 37 ℃, about 38 ℃, about 39 ℃, about 40 ℃, about 41 ℃, about 42 ℃, about 43 ℃, about 44 ℃, about 45 ℃, about 46 ℃, about 47 ℃, about 48 ℃, about 49 ℃, about 50 ℃).

The present disclosure provides a method of preparing a formulation of a therapeutic agent, wherein the addition is in two stepsTo reduce the viscosity of the solution during formulation preparation. What is needed isThe method includes, for example, usingHalf of the amountPreparation ofAn aqueous solution of (a); dissolving the therapeutic agent and additives (e.g., PVP, histidine), adjusting the pH of the formulation, and then adding the remaining amountThe two-step process results in a lower viscosity solution that provides faster dissolution and ease of pH measurement than a higher viscosity solution.

The formulation further comprises a buffering agent (e.g., an organic buffer such as histidine or histidine HCl) and a pH adjusting agent (e.g., an inorganic base such as NaOH, an organic base such as meglumine (meglumine), or an organic buffer such as histidine or histidine HCl). In some embodiments, the pH of a formulation of a therapeutic agent (e.g., pazopanib) is adjusted with an inorganic base (e.g., NaOH). In other embodiments, the pH of a formulation of a therapeutic agent (e.g., pazopanib) is adjusted with an organic base (e.g., meglumine). In some embodiments, the present disclosure provides non-precipitating formulations of therapeutic agents (e.g., pazopanib) wherein an organic base, such as meglumine, is used. In some embodiments, additional additives (e.g., triacetin, glycerin) are added for increasing the stability (anti-settling) of the formulation.

The present disclosure provides for this by first weighing approximately half of the requiredAnd dissolving in a vial containing an appropriate amount of water to prepare a stable and solution formulation of a monovalent salt (e.g., monovalent hydrochloride salt) of a therapeutic agent (e.g., pazopanib). Addition of PVP-10k (polyvinylpyrrolidone, MW)10kDa) and histidine HCl, and dissolved into the solution by mixing the solution (vortexing, sonication). Weighing the lyophilized pazopanib, then adding toIn solution. A small amount of hydrochloric acid (HCl) is added to adjust and maintain the pH of the solution at or below about pH 2, if necessary. Adding additives such as triacetin or glycerol. The formulation is stirred and shaken at 37 ℃ or room temperature until the pazopanib is completely dissolved. Dissolution of pazopanib may take several hours. Next, pazopanib-The pH of the solution is to about pH 6-7. Then adding the restAnd dissolved completely by shaking/vortexing the formulation at 37 ℃ or room temperature. The pH was checked and, if necessary, adjusted prior to filtering the formulation using a 0.2 μm filter. The formulations were stored at room temperature and protected from light. The content and purity of the formulation was tested by HPLC and UV.

The present disclosure provides a formulation method in which all solid excipients (A)PVP and histidine-HCl) and a therapeutic agent (e.g., lyophilized pazopanib 1HCl), and are first mixed together in a vial. With continuous mixing, the required water was added gradually. The formed dispersion can be dissolved at ambient or elevated temperatures (e.g., about 37 ℃ or about 50 ℃); the use of elevated temperatures reduces the time required to obtain a homogeneous solution (e.g., from about 24 hours to about 4 hours). The formulation is then used at a natural pH of about 3 to about 4, or after pH adjustment with NaOH solution (pH about 6 to about 7).

The present disclosure provides a method wherein at least the solubilizing agent, the buffer, the complexing agent, and the lyophilized salt are mixed continuously at or above about ambient temperature while adding water. Adjusting the pH of the formulation to about 6-7 with a base.

The present disclosure provides a method wherein at least the solubilizing agent, the buffering agent, the complexing agent, and the lyophilized monohydrochloride salt of pazopanib are continuously mixed at or above about ambient temperature while adding water. Adjusting the pH of the formulation to about 6-7 with a base. The complexing agent in the method is cyclodextrin: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl- β -cyclodextrin, glucosyl- β -cyclodextrin, maltosyl- β -cyclodextrin, sulfobutylether- β -cyclodextrin, branched- β -cyclodextrin, hydroxypropyl- γ -cyclodextrin, randomly methylated- γ -cyclodextrin, trimethyl- γ -cyclodextrin, or any combination thereof; the solubilizing agent is poly (vinyl pyrrolidone) (PVP); and the buffer is histidine HCl.

The present disclosure provides a method wherein at least the solubilizing agent, the buffering agent, the complexing agent, and the lyophilized monohydrochloride salt of pazopanib are continuously mixed at or above about ambient temperature while adding water. In this method, the pH of the formulation was not adjusted. The complexing agent in the method is cyclodextrin: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl- β -cyclodextrin, glucosyl- β -cyclodextrin, maltosyl- β -cyclodextrin, sulfobutylether- β -cyclodextrin, branched- β -cyclodextrin, hydroxypropyl- γ -cyclodextrin, randomly methylated- γ -cyclodextrin, trimethyl- γ -cyclodextrin, or any combination thereof; the solubilizing agent is poly (vinyl pyrrolidone) (PVP); and the buffer is histidine HCl.

Release rate of therapeutic agent

The present disclosure provides a therapeutic agent release rate measured by the amount of therapeutic agent released by PDS into the receiver fluid (PBS buffer) at 37 ℃. The therapeutic agent release test was performed by measuring the amount of therapeutic agent released by the PDS into the fluid representing the vitreous, which was maintained in an incubator at 37 ℃. PDS was suspended in a container containing phosphate buffered saline. Periodically, PDS is transferred to a new container and the concentration of the therapeutic agent is measured in the fluid of the previous container. The rate is calculated from the amount of therapeutic agent released divided by the duration of sample collection. The cumulative percent release is calculated by dividing the cumulative amount of therapeutic agent by the amount of therapeutic agent initially filled into the treatment device (PDS). The half-life was calculated from the percentage of cumulative release at 4 weeks. The present disclosure provides conditions after a small amount of formulation is released into a large amount of buffer solution. If the drug precipitates out after dilution (release), this may lead to clogging of the delivery device and/or loss of drug, as the solid drug will not be measurable in the receiver fluid. Furthermore, precipitation prevents effective treatment with the active as the drug is not accessible in vivo.

The present disclosure provides conditions for testing drug precipitation, where the formulation is diluted 330-fold, e.g., with a phosphate buffered saline solution (with, e.g., 0.1% sodium azide), e.g., about 3 μ Ι _ of formulation is added to 1mL of PBS buffer. The solution is kept in a thermostat (e.g. 37 ℃ C.) and periodically checked for the presence of crystal growth/precipitation. The present disclosure provides that formulations prepared with different drug samples (sample-1 or 2 of pazopanib HCl) exhibit different stability against precipitation upon dilution.

TABLE 5

The drug concentration is mg/mL for pazopanib salt

The release rate of the therapeutic agents of the present disclosure in formulations of about 1mg/mL to about 100mg/mL varies at various fill concentrations: about 100 μ g/mL on day 1 to about 0.01 μ g/mL on day 140. The present disclosure provides that the release rate varies with the HCl content and/or crystalline form of the pharmaceutically acceptable salt of pazopanib. The rate of release of pazopanib 2HCl is higher and can last over 100 days compared to the rate of release of pazopanib 1 HCl.

Lyophilization is believed to convert a highly crystalline drug into a predominantly amorphous solid that has more favorable dissolution properties. As shown in figure 1, the formulations prepared from lyophilized 1HCl salt of pazopanib active agent have significantly improved stability (anti-precipitation/crystallization) compared to the highly crystalline 1HCl form, and also result in comparable drug release characteristics to the 2HCl form.

The present disclosure provides for the lyophilization of pazopanib 1HCl (sample-2) from pazopanib 1Release rate of formulation of solubilizing agent (e.g. PVP) and buffering agent (e.g. histidine HCl): about 12 μ g/day to about 20 days on day 1 or about 1 to about 3 μ g/day over about 20 days, and the pH of the formulation is adjusted to about 6.5. The half-life of drug release is about 99 days. In addition, the non-lyophilized pazopanib 1HCl precipitated out of solution during the drug release. The non-lyophilized pazopanib 1HCl (sample-2) in the formulation is about 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 59mg/mL, about 60.0mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, or about 65 mg/mL. In the preparationThe pazopanib 1HCl ratio is about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2: 1. For example, the ratio of CD to pazopanib 1HCl is about 2.2: 1; about 2.5: 1; about 3.7: 1; about 5: 1; about 8: 1; or about 9: 1. For example, the ratio of CD to pazopanib 1HCl is about 2.5:1 or 2.2: 1.

The present disclosure provides a pharmaceutical composition having about 60mg/mL pazopanib 2HCl, about 660mg/mLA stable formulation of about 1% PVP-10kD, about 6mg/mL histidine HCl, (about pH 6) such that pazopanib 2HCl does not precipitate during ambient storage for up to 1 year and does not precipitate or only minimally precipitates for at least 40-120 days after dilution. After dilution by up to about 350 fold (e.g., about 50-100 fold, about 100-150 fold, about 150-200 fold, about 200-250 fold, about 250-300 fold, about 300-310 fold, about 310-320 fold, about 320-330 fold, about 330-340 fold, or about 340-350 fold), pazopanib 1HCl in the present formulation does not precipitate or minimally precipitates at about 30 ℃ to about 50 ℃ (e.g., about 37 ℃) for at least 40-120 days. Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates for at least 40-120 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides pazopanib 2HCl (sample-1) fromRelease rate of formulation of solubilizing agent (e.g. PVP) and buffering agent (e.g. histidine HCl): about 20 μ g/day to about 140 days on day 1 or about 2 to about 4 μ g/day over about 140 days, and the pH of the formulation is adjusted to about 6.5. The half-life of drug release is about 53 days. Pazopanib 2HCl (sample-1) in the formulation is about 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 59mg/mL, about 60.0mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, or about 65 mg/mL. In the preparationA ratio of pazopanib 2HCl of about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about4:1, about 3:1, or about 2: 1. For example, the ratio of CD to pazopanib 2HCl is about 2.2: 1; about 2.5: 1; about 3.7: 1; about 5: 1; about 8: 1; or about 9: 1. For example, the ratio of CD to pazopanib 2HCl is about 2.5:1 or 2.2: 1.

The present disclosure provides a pharmaceutical composition having about 62mg/mL pazopanib 1HCl, about 660mg/mLA stable formulation of about 1% PVP-10kD, about 6mg/mL histidine HCl (about pH 6), such that pazopanib 1HCl does not precipitate during ambient storage for up to 9 months and does not precipitate or minimally precipitates within 5-10 days upon dilution. After dilution by up to about 350 fold (e.g., about 50-100 fold, about 100-150 fold, about 150-200 fold, about 200-250 fold, about 250-300 fold, about 300-310 fold, about 310-320 fold, about 320-330 fold, about 330-340 fold, or about 340-350 fold), pazopanib 1HCl in the present formulation does not precipitate or minimally precipitates within 5-10 days at about 30 deg.C to about 50 deg.C (e.g., about 37 deg.C). Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates within 5-10 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides a pharmaceutical composition having about 40mg/mL pazopanib 1HCl, about 660mg/mLA stable formulation of about 1% PVP-10kD, about 6mg/mL histidine HCl (about pH 6), such that pazopanib 1HCl does not precipitate during ambient storage for up to at least 9 months and does not precipitate or minimally precipitates for at least 13-20 days upon dilution. After dilution by up to about 350 fold (e.g., about 50-100 fold, about 100-150 fold, about 150-200 fold, about 200-250 fold, about 250-300 fold, about 300-310 fold, about 310-320 fold, about 320-330 fold, about 330-340 fold, or about 340-350 fold), pazopanib 1HCl in the present formulation does not precipitate or minimally precipitates within at least 13-20 days at about 30 deg.C to about 50 deg.C (e.g., about 37 deg.C). Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates for at least 13-20 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides TFE lyophilized pazopanib 1HCl (sample-2) fromRelease rate of formulation of solubilizing agent (e.g. PVP) and buffering agent (e.g. histidine HCl): about 12 μ g/day to about 140 days on day 1 or about 1 to about 2 μ g/day over about 140 days, and the pH of the formulation is adjusted to about 6.5. The half-life of drug release is about 45 days. Pazopanib 2HCl (sample-1) in the formulation is about 30mg/mL, about 31mg/mL, about 32mg/mL, about 33mg/mL, about 34mg/mL, about 35mg/mL, about 36mg/mL, about 37mg/mL, about 38mg/mL, about 39mg/mL, 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about, About 59mg/mL, about 60.0mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, or about 65 mg/mL. In the preparationThe pazopanib 2HCl ratio is about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2: 1. For example, the ratio of CD to pazopanib 2HCl is about 2.2: 1; about 2.5: 1; about 3.7: 1; about 5: 1; about 8: 1; or about 9: 1. For example, the ratio of CD to pazopanib 2HCl is about 4: 1. The PVP in the formulation was about 1%, and the histidine HCl in the formulation was about 25 mg/mL.

The present disclosure provides a release rate from the formulation of about 36.0mg/mL TFE lyophilized pazopanib 1HCl (sample-2): about 12 μ g/day to about 140 days on day 1 or about 1 to about 2 μ g/day over about 140 days, whereinAt about 4:1Ratio of pazopanibA solubilizing agent (e.g., about 1% PVP) and a buffer (e.g., about 25mg/ml histidine HCl) are present and present, and the pH of the formulation is adjusted to about 6.5. The half-life of drug release is about 45 days.

The present disclosure provides pazopanib 1HCl lyophilized from TFE with about 41mg/mL, about 660mg/mLA stable formulation of about 1% PVP-10kD, about 6mg/mL histidine HCl (about pH 7), such that pazopanib 1HCl does not precipitate during ambient storage for up to 6 months and does not precipitate or minimally precipitates for at least 41-120 days upon dilution. After dilution by up to about 350 fold (e.g., about 50-100 fold, about 100-150 fold, about 150-200 fold, about 200-250 fold, about 250-300 fold, about 300-310 fold, about 310-320 fold, about 320-330 fold, about 330-340 fold, or about 340-350 fold), pazopanib 1HCl in the present formulation does not precipitate or minimally precipitates within at least 41-120 days at about 30 deg.C to about 50 deg.C (e.g., about 37 deg.C). Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates for at least 41-120 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides DMSO lyophilized pazopanib 1HCl (sample-2) fromRelease rate of formulation of solubilizing agent (e.g. PVP) and buffering agent (e.g. histidine HCl): about 16 μ g/day to about 140 days on day 1 or about 1 to about 3 μ g/day over about 140 days, and the pH of the formulation is adjusted to about 3.4. The half-life of drug release is about 45 days. Pazopanib 2HCl (sample-1) in the formulation is about 30mg/mL, about 31mg/mL, about 32mg/mL, about 33mg/mL, about 34mg/mL, about 35mg/mL, about 36mg/mL, about 37mg/mL, about 38mg/mL, about 39mg/mL, 40mg/mL, about 41mg/mL, about 42mg/mL, about 43mg/mL, about 44mg/mL, about 45mg/mL, about 46mg/mL, about 47mg/mL, about 48mg/mL, about 49mg/mL, about 50mg/mL, about 51mg/mL, about 52mg/mL, about 53mg/mL, about 54mg/mL, about 55mg/mL, about 56mg/mL, about 57mg/mL, about 58 mg/mL.About 59mg/mL, about 60.0mg/mL, about 61mg/mL, about 62mg/mL, about 63mg/mL, about 64mg/mL, or about 65 mg/mL. In the preparationThe pazopanib 2HCl ratio is about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2: 1. For example, the ratio of CD to pazopanib 2HCl is about 2.2: 1; about 2.5: 1; about 3.7: 1; about 5: 1; about 8: 1; or about 9: 1. For example, the ratio of CD to pazopanib 2HCl is about 3: 1. The PVP in the formulation was about 1%, and the histidine HCl in the formulation was about 6 mg/mL.

The present disclosure provides pazopanib 1HCl having about 60mg/mL lyophilized from DMSO, about 660mg/mLA stable formulation of about 1% PVP-10kD, optionally about 6mg/mL histidine HCl (about pH 6), such that pazopanib 1HCl does not precipitate during ambient storage for up to 40 days and does not precipitate or minimally precipitates for at least 10-14 days upon dilution. After dilution by up to about 350 fold (e.g., about 50-100 fold, about 100-150 fold, about 150-200 fold, about 200-250 fold, about 250-300 fold, about 300-310 fold, about 310-320 fold, about 320-330 fold, about 330-340 fold, or about 340-350 fold), pazopanib 1HCl in the present formulation does not precipitate or minimally precipitates within at least 10-14 days at about 30 deg.C to about 50 deg.C (e.g., about 37 deg.C). Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates for at least 10-14 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides pazopanib 1HCl having about 45mg/mL lyophilized from DMSO, about 660mg/mLA stable formulation of about 1% PVP-10kD, about 6mg/mL histidine HCl (about pH 3.5), such that pazopanib 1HCl does not precipitate during storage at ambient temperature and does not precipitate or minimally precipitates for at least 50 days upon dilution. At a dilution of up to about 350 times (e.g., about 50-1)After a time of 00 times, about 100 times, about 150 times, about 200 times, about 250 times, about 300 times, about 310 times, about 320 times, about 330 times, about 340 times, or about 340 times 350 times, the pazopanib 1HCl in the formulation does not precipitate or precipitates minimally in at least 50 days at about 30 ℃ to about 50 ℃ (e.g., about 37 ℃). Pazopanib 1HCl in the present formulations does not precipitate or minimally precipitates for at least 50 days during and/or after release from the drug delivery device of the present disclosure into a body part (e.g., the vitreous of the eye).

The present disclosure provides a release rate of about 50.0mg/mL DMSO lyophilized pazopanib 1HCl (sample-2) from the formulation from about 16 μ g/day at day 1 to about 140 days or from about 1 to about 3 μ g/day for more than about 140 days, whereinAt about 3:1Pazopanib is present in a ratio and a solubilizing agent (e.g., about 1% PVP) and a buffer (e.g., about 6mg/ml histidine HCl) are present, and the pH of the formulation is adjusted to about 3.4. The half-life of drug release is about 45 days.

The present disclosure provides a release rate of a pazopanib formulation from a delivery device, wherein the formulation is prepared buffer-free and comprises pazopanib 1HCl (about 30mg/mL to about 40mg/mL), about 660 to about 700mg/mL (e.g., about 660mg/mL)Polymer (e.g., PVP) and has a natural pH. The fill concentration is from about 30mg/mL to about 35mg/mL (large scale lyophilized formulation) or from about 35mg/mL to about 45mg/mL (small scale lyophilized formulation). Table 6 provides non-limiting examples of release rates of the formulations of the present disclosure.

TABLE 6

Reagent kit

The present disclosure provides a kit wherein any one of the stable formulations of the present disclosure is contained in a storage compartment of a therapeutic device, wherein the storage compartment is coupled to a porous structure for controlled release of the therapeutic agent in the vitreous of the eye.

Treatment device

The therapeutic device includes a number of configurations and physical attributes, for example, physical features of the therapeutic device include at least one of a therapeutic agent delivery device (port delivery system (PDS)) having sutures, positioning and sizing (sizing) such that vision is not compromised, and a biocompatible material. For example, the device includes a reservoir capacity of about 0.005cc to about 0.2cc (e.g., about 0.01cc to about 0.1cc), and a device volume of no more than about 2 cc. Vitrectomy was performed for device volumes greater than 0.1 cc. The length of the treatment device does not interfere with the patient's vision and depends on the shape of the device and the position of the implanted device relative to the eye. The length of the device also depends on the angle at which the device is inserted. For example, the length of the device comprises about 4mm to 6 mm. Since the diameter of the eye is about 24mm, a device that extends no more than about 6mm from the sclera into the vitreous has minimal impact on the patient's vision.

Variations include many combinations of implanted therapeutic agent delivery devices (port delivery systems (PDS)). The therapeutic device comprises a therapeutic agent and a binding agent. The device further comprises at least one of a membrane, an opening, a diffusion barrier, a diffusion mechanism to release a therapeutic amount of the therapeutic agent over an extended period of time. Several variations of this device are disclosed in WO2012/065006, WO2012/019047, WO2013/003620, WO2012/019136, WO 2012/019176 and us patent No. 8,277,830, each of which is incorporated herein by reference in its entirety.

Fig. 2A shows a treatment device 100 implanted beneath conjunctiva 16 and extending through sclera 24 to release a therapeutic agent into the vitreous humor of the eye to treat the retina of the eye. The treatment device 100 includes a retention structure 120, such as a smooth protrusion, configured to be placed along the sclera and under the conjunctiva such that the conjunctiva covers the treatment device and protects the treatment device 100. When the therapeutic agent 110 is inserted into the device 100, the conjunctiva is lifted, incised or punctured by a needle to access the treatment device. The eye includes insertion of the tendon 27 of the superior rectus muscle to couple the sclera of the eye to the superior rectus muscle. In embodiments, the device 100 is located in many locations in the ciliary zone, for example away from the tendons, and one or more of the following: behind the tendons, under the tendons, or with a therapeutic device placed in the nose or temples.

Although implants can be positioned in the eye in many ways, work related to the variations suggests that placement in the pars plana region releases therapeutic agents into the vitreous to treat the retina, such as therapeutic agents containing active ingredients composed of macromolecules.

Therapeutic agent 110 suitable for use with device 100 includes a number of therapeutic agents, such as those listed in table 1. The therapeutic agent 110 of the device 100 includes one or more of the following: an active ingredient of a therapeutic agent, a formulation of a therapeutic agent, a component of a formulation of a therapeutic agent, a therapeutic agent formulation prepared by a physician, or a therapeutic agent formulation prepared by a pharmacist.

The treatment device 100 may be implanted in the eye for a time that is helpful and beneficial to the patient to treat the eye. For example, the device is implanted for at least about 5 years, e.g., permanently implanted for the life of the patient. Alternatively or in combination, the device is removed when it is no longer helpful or beneficial for the patient's treatment.

Fig. 2B shows the structure of the treatment device 100 configured for placement in the eye as shown in fig. 2A. The device includes a retention structure 120, such as a protrusion disposed on a proximal end of the device, that couples the device 100 to the sclera. The apparatus 100 includes a container 130 attached to the holding structure 120. The active ingredient (e.g., therapeutic agent 110) is contained within a reservoir 140 (e.g., a chamber 132 defined by a reservoir 130 of the device). Vessel 130 includes a porous structure 150, porous structure 150 including a porous material 152, such as a porous frit 154; and a barrier 160, such as an impermeable membrane 162, that inhibits the release of the therapeutic agent. Impermeable membrane 162 includes a substantially impermeable material 164. Impermeable membrane 162 includes openings 166, and openings 166 are sized to release therapeutic amounts of therapeutic agent 110 over an extended period of time. Porous structure 150 includes a thickness 150T and a pore size that, in conjunction with opening 166, is configured to release a therapeutic amount of therapeutic agent over an extended period of time. The container 130 includes a reservoir 140 having a chamber with a volume 142, the volume 142 sized to contain a therapeutic amount of the therapeutic agent 110 for release over an extended period of time. The device includes a needle stop 170. Proteins in the vitreous humor enter the device and compete for adsorption sites on the porous structure, thereby facilitating the release of the therapeutic agent. Therapeutic agent 110 contained in reservoir 140 is in equilibrium with proteins in the vitreous humor such that the system is driven toward equilibrium and therapeutic agent 110 is released in therapeutic amounts.

Impermeable materials such as impermeable membrane 162, porous material 152, reservoir 140, and retaining structure 120 include many configurations for delivering therapeutic agent 110. The impermeable membrane 162 comprises an annular tube that is engaged by a disc having at least one opening formed therein for releasing the therapeutic agent. The porous material 152 includes an annular porous frit 154 and a rounded end disposed thereon. The shape of the memory 140 is varied to facilitate insertion; that is, it is assumed to assume a thin, elongated shape during insertion through the sclera, and then an extended, expanded shape once it is filled with the therapeutic agent.

The porous structure 150 may be configured in a number of ways to release the therapeutic agent according to a desired release profile. The porous structure includes a single hole or a plurality of holes extending through a barrier material (e.g., rigid plastic or metal). Alternatively or in combination, the porous structure comprises a porous structure having a plurality of openings on a first side facing the reservoir and a plurality of openings on a second side facing the vitreous humor with a plurality of interconnecting channels disposed therebetween to couple the openings of the first side with the openings of the second side, such as a sintered rigid material. The porous structure 150 includes one or more of the following: a permeable membrane, a semi-permeable membrane, a material having at least one hole disposed therein, a nanochannel etched in a rigid material, a laser etched nanochannel, a capillary channel, a plurality of capillary channels, one or more curved channels, a curved microchannel, a sintered nanoparticle, an open-cell foam, or a hydrogel such as an open-cell hydrogel.

Fig. 2C shows treatment device 100 loaded into insertion cannula 210 of insertion device 200, wherein device 100 comprises an extended narrow shape for insertion into the sclera, and wherein the device is configured to extend to a second extended wide shape for at least partial retention in the sclera.

Fig. 2D shows a treatment device 100 comprising a reservoir adapted to be loaded in a cannula, wherein the reservoir 140 comprises an expanded configuration when placed in an eye.

Fig. 2E shows treatment device 100 placed in the eye as shown in fig. 2A. The device includes a retention structure 120 to couple to the sclera, e.g., flush with the sclera, and a barrier 160 including a tube 168. Therapeutic agent 110 containing active ingredient 112 is contained within tube 168 containing impermeable material 164. A porous structure 150 comprising a porous material 152 is disposed at the distal end of the tube 168 to provide sustained release of the therapeutic agent at therapeutic concentrations for extended periods of time. An impermeable material 164 extends distally around the porous material 152 to define an opening that couples the porous material 152 to the vitreous humor when the device is inserted into the eye.

Fig. 2F shows an access port 180 adapted to be incorporated with the treatment device 100. The access port 180 is combined with the treatment devices described herein. An access port is disposed on the proximal end of the device. The access port 180 includes an opening formed in the retention structure 120 having a penetrable barrier 184, the penetrable barrier 184 including a septum 186 disposed thereon. The penetrable barrier receives a needle 189 sized to pass through the formulation 190 as described herein. The access port 180 is configured to be placed under the patient's conjunctiva 16 and over the sclera 24.

Delivering therapeutic agents from devices

The drug delivery formulation of the present disclosure is contained in a storage chamber coupled to a porous structure in a therapeutic agent delivery system for controlled release of a therapeutic agent in the vitreous of the eye; and wherein the controlled release of the formulation from the porous structure results in a concentration of the therapeutic agent in the vitreous that is at least two orders of magnitude lower than the concentration of the therapeutic agent in the storage compartment. The reservoir chamber is refillable and refillable with the formulation after insertion of the device into the eye.

Refilling the storage chamber with the formulation after the device has been in the eye for 30-90 days or for up to 6 months. A delivery device for delivering any one of the formulations of the present disclosure is disclosed in WO2010/088548, and the disclosure in the' 548 publication referring only to the delivery device is incorporated herein by reference.

The design of a therapeutic agent delivery formulation for sustained release from the PDS implant of the current embodiment is based on several considerations. For example, elution of therapeutic agents from PDS is based on molecular diffusion through a Release Control Element (RCE) consisting of irregularly shaped channels. Irregularly shaped channels are described in WO2012/065006, wherein the content relating to RCE is incorporated herein in its entirety.

Furthermore, diffusion occurs in two ways, namely, diffusion of the therapeutic agent from the filled PDS into the vitreous and from the vitreous into the PDS. This reversible diffusion allows the formulation contents to equilibrate with the vitreous over time. The formulation designed must be compatible with vitreous components and vitreous pH due to diffusion into and from PDS and vitreous. The formulation must also be compatible with high dilution in the vitreous following release from the PDS reservoir.

The formulations of the present disclosure are compatible with vitreous components and vitreous pH. The formulations described in the current embodiments are compatible with high dilution in the vitreous following release from the PDS reservoir.

The present disclosure provides for adjustment of the therapeutic agent delivery rate from the PDS implant reservoir to achieve a desired sustained release profile and a desired tissue level. In accordance with the present disclosure, tuning is achieved through the design of PDS implants that include a porous structure for controlled release of a therapeutic agent. The porous structure has porosity and tortuosity, further has geometrical dimensions, and is of a material such as titanium, a polymer and/or a coated material, and has a functionality of a surface. Adjustment of the delivery rate is also achieved by changing the reservoir volume.

The adjustment of the therapeutic agent delivery rate depends on the formulation composition, formulation, pH, nature of the complexing agent, concentration of the complexing agent, formulation viscosity, and/or therapeutic agent concentration in the reservoir.

The formulations of the present disclosure are designed to produce robust and highly predictable therapeutic agent delivery profiles and profiles. In some embodiments, the use of selected complexing agents achieves therapeutic agent delivery characteristics (e.g., half-life of the therapeutic agent delivered from PDS storage) that are very similar for a variety of compounds formulated in the selected complexing agents. The present disclosure provides that the half-lives of the different therapeutic agents are similar over a range of complexing agent concentrations in the formulations. The therapeutic agent delivery properties and diffusion through PDS implants for such formulations resemble uncomplexed single molecule entities.

The delivery device of the present disclosure includes a reservoir and a porous structure. This device is for example the device described in WO 2012/019176, where the content relating to the memory is incorporated in its entirety. A porous structure similar to the current embodiment is described in WO2012/065006, where the content relating to the porous structure is incorporated herein in its entirety.

In some embodiments, the porous structure includes a first side coupled to the reservoir and a second side coupled to the glass body. The first side includes a first region and the second side may include a second region.

The volume of the reservoir contains about 5 μ L to about 50 μ L of the therapeutic agent, or for example about 10 μ L to about 25 μ L (e.g., 23 μ L) of the therapeutic agent.

The therapeutic agent stored in the reservoir of the container includes at least one of: a solid comprising a therapeutic agent, a solution comprising a therapeutic agent, a suspension comprising a therapeutic agent, particles comprising a therapeutic agent adsorbed thereon, or particles that reversibly bind a therapeutic agent. The reservoir comprises a suspension of a buffer and a therapeutic agent comprising a solubility in a range of about 1mg/mL to about 100mg/mL (e.g., about 1mg/mL to about 40 mg/mL).

In embodiments, the concentration of the therapeutic agent in the formulation is dependent on increasing the solubility of the agent in water or an aqueous solution by using any one or more of the following: a complexing agent, a pH adjusting agent, a solubilizing/stabilizing agent, an amphiphilic agent, a buffering agent, a non-aqueous solvent, or any combination thereof. The therapeutic agents of these embodiments are inherently sparingly soluble (30 to 100 parts solvent required for 1 part solute), slightly soluble (100 to 1000 parts solvent required for 1 part solute), minimally soluble (1000 to 10,000 parts solvent required for 1 part solute), or nearly insoluble or insoluble (10,000 parts solvent required for 1 part solute).

The release rate index includes a number of values, and for example, in many embodiments, the release rate index of a suspension is slightly higher than a solution.

The porous structure includes a needle stop that limits penetration of the needle. The porous structure includes a plurality of channels configured for extended release of the therapeutic agent. The porous structure comprises a rigid sintered material having characteristics suitable for sustained release of the material.

The reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent in a number of ways. The reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent corresponding to at least about 0.1 μ g/ml of vitreous humor or a concentration of 0.1-25 μ g/day for an extended period of at least about three months. The reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent corresponding to a concentration of at least about 0.1 μ g/ml of vitreous humor and not more than about 10 μ g/ml of vitreous humor for an extended period of at least about three months. In some embodiments, the therapeutic agent is a small molecule therapeutic agent suitable for sustained release.

The reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent corresponding to a concentration of at least about 0.1 μ g/ml of vitreous humor and not more than about 10 μ g/ml of vitreous humor for an extended period of at least about 3 months or at least about 6 months. For example, the reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent corresponding to a concentration of at least about 0.1 μ g/ml of vitreous humor and not more than about 10 μ g/ml of vitreous humor for an extended period of at least about 12 months, or at least about two years, or at least about three years. For example, the reservoir and porous structure are configured to release a therapeutic amount of the therapeutic agent corresponding to a concentration of at least about 0.01 μ g/ml of vitreous humor and not more than about 300 μ g/ml of vitreous humor for an extended period of at least about 3 months or 6 months or 12 months or 24 months.

The added formulation components that increase the solubility of the therapeutic agent bind the therapeutic agent so strongly that the efficacy of the target tissue is less than ideal in at least some instances. For example, complexing agents such as cyclodextrins enable formulations containing high concentrations of therapeutic agents with low water solubility. However, as exemplified by Stella et al, Advanced Drug Delivery Reviews,36:3-16 (1999); and Brewster and Loftsson, Advanced Drug Delivery Reviews,59: 645-. Typically, a dilution of at least 10-fold, typically at least 100-fold or 1000-fold or even 10,000-fold is required to release the majority of the therapeutic agent from the complex with the cyclodextrin.

Therapeutic agent delivery devices (PDS) in combination with formulations containing complexing agents such as cyclodextrins offer unique advantages over all previous applications of cyclodextrins. The reservoir and porous structure of the PDS are configured to achieve the dilution required to release the therapeutic agent from the cyclodextrin complex for an extended period of time. For example, PDS implanted in a human eye with a volume of 23 μ Ι _ and RRI of 0.007mm achieves dilution times of over 10,000 for extended periods (e.g., months). The sustained high dilution is very different from the minimum dilution that occurs when a cyclodextrin formulation is administered as a topical drop to the eye. Furthermore, sustained delivery from PDS at high dilution for a period of months is significantly different from the short duration (e.g., hours) corresponding to intravenous injection of a cyclodextrin formulation.

In embodiments, the porous structure comprises porosity, thickness, channel parameters, and surface area, configured to release therapeutic amounts for an extended period of time. For example, the porous material comprises a porosity corresponding to the fraction of void space of the channels extending within the material. For example, porosity includes values in the range of about 3% to about 70%. In other embodiments, porosity includes having a value ranging from about 5% to about 10%, or from about 10% to about 25%, or for example, from about 15% to about 20%. Porosity is determined by weight and macroscopic volume or measured by nitrogen adsorption.

The porous structure includes a plurality of porous structures, and the area used in the calculation formula includes a combined area of the plurality of porous structures.

Indications and treatment methods

Methods for treating and/or ameliorating diseases or conditions of the eye, particularly retinopathy and ocular neovascularization, are disclosed. Non-limiting examples of such diseases or conditions include diabetic macular edema, AMD, CNV, NV, DR, ocular ischemia, retinal vein occlusion (central or branch), ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, uveitis, and the like. These diseases or conditions are characterized by changes in the ocular vasculature, whether progressive or non-progressive, whether resulting from an acute disease or condition or a chronic disease or condition.

The present disclosure provides for the use of the formulations described herein in the treatment and/or amelioration of atrophic AMD. The formulations are used to treat neovascular (exudative or wet) AMD. The formulations of the present disclosure treat, prevent progression of, or ameliorate symptoms of vascular leakage and/or neovascularization in the retina.

The disclosed methods relate to preventing the progression of or controlling pathological Neovascularization (NV) by administering to a subject one or more of the disclosed therapeutic agents and formulations thereofAngiogenesis (NV), or treating a disease or condition associated with the onset of NV. The disclosed methods relate to treating or preventing the progression of NV by administering to a patient an effective amount of a pharmaceutically acceptable salt of pazopanib with one or more formulations comprising: complexing agents, solubilizing/stabilizing agents, pH adjusting agents, buffering agents, amphiphilic agents, non-aqueous solvents, tonicity agents, or combinations thereof. Complexing agents for use in formulations for treating or preventing NV are cyclodextrins, e.g.

The disclosed methods relate to preventing or controlling ocular neovascularization or treating a disease or condition associated with the onset of ocular neovascularization by intravitreal delivery of a formulation of the present disclosure.

Another method disclosed involves preventing or controlling retinal edema or retinal neovascularization or treating a disease or condition associated with the onset of retinal edema or retinal neovascularization by intravitreal delivery of a formulation comprising a tyrosine kinase inhibitor and a complexing agent (e.g., a cyclodextrin).

The present disclosure relates to methods of delaying or preventing the progression of non-proliferative retinopathy to proliferative retinopathy by intravitreal delivery of formulations comprising a tyrosine kinase inhibitor and a complexing agent (e.g., a cyclodextrin).

Yet another method disclosed relates to treating, preventing progression and/or controlling diabetic retinopathy, or treating a disease or condition associated with or caused by the onset of diabetic retinopathy, by intravitreal delivery of a formulation comprising a tyrosine kinase inhibitor, pazopanib 1HCl or pazopanib 2HCl, and a complexing agent (e.g., a cyclodextrin).

Diabetic proliferative retinopathy is characterized by neovascularization. New blood vessels are fragile and prone to bleeding. The result is scarring of the retina and blockage or complete blockage of the optical path through the eye due to the excessive formation of new blood vessels. Subjects who commonly have diabetic macular edema suffer from a nonproliferative phase of diabetic retinopathy; however, it is not uncommon for a subject to begin exhibiting macular edema only at the beginning of the proliferative phase.

Yet another disclosed method relates to the prevention or control of diabetic macular edema or the treatment of a disease or condition associated with the onset of diabetic macular edema by intravitreal delivery of a formulation comprising a tyrosine kinase inhibitor and a complexing agent (e.g., a cyclodextrin).

General definitions

In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings: all percentages, ratios and proportions herein are by weight unless otherwise specified. All temperatures are in degrees Celsius (. degree. C.) unless otherwise noted.

By "pharmaceutically acceptable" is meant a material that is not biologically or otherwise undesirable, i.e., the material can be administered to an individual with an associated active compound without causing a clinically unacceptable biological effect or interacting in a deleterious manner with any of the other components contained in the pharmaceutical composition.

Unless specifically stated to the contrary, the weight percentages of a component are based on the total weight of the formulation or composition in which it is included.

An "effective amount" as used herein means an amount of one or more of the disclosed compounds that is effective to achieve a desired or therapeutic result within a desired dosage amount and time period. The effective amount may vary according to factors known in the art such as the disease state, age, sex and weight of the human or animal being treated. Although specific dosage regimens may be described in the examples herein, those skilled in the art will appreciate that the dosage regimens may be varied to provide the optimal therapeutic response. For example, several divided doses may be administered daily, or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation. In addition, the compositions of the present disclosure can be administered as frequently as necessary to achieve therapeutic amounts.

"agent" is used herein to include any other compound that may be included in or combined with one or more of the disclosed inhibitors, which is not a therapeutically or biologically active compound. Thus, the agent should be pharmaceutically or biologically acceptable or relevant (e.g., the agent should generally be non-toxic to the subject). "agent" includes a single such compound, and is also intended to include multiple agents. For the purposes of this disclosure, the terms "agent" and "carrier" are used interchangeably throughout the specification of the present disclosure, and the terms are defined herein as "ingredients used in the practice of formulating safe and effective pharmaceutical compositions".

The phrase "pharmaceutically acceptable carrier" is art-recognized and refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, for example, involved in carrying or transporting any supplement or composition or component thereof from one organ or part of the body to another organ or part of the body or delivering an agent to the surface of the eye. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the composition, or not injurious to the patient. In certain embodiments, the pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose and cellulose acetate; (4) tragacanth powder and; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) no heat source water; (17) isotonic saline; (18) ringer's solution; (19) ethanol; (20) a phosphate buffer solution; (21) gums, such as HP-guar; (22) a polymer; and (23) other non-toxic compatible substances used in pharmaceutical formulations.

The term "pharmaceutically acceptable" means that the carrier, diluent or agent must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

As used herein, "subject" means an individual. Thus, "subject" can include domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cows, horses, pigs, sheep, goats, etc.), laboratory animals (e.g., mice, rabbits, guinea pigs, etc.), and birds. "subject" can also include mammals, such as primates or humans.

By "reduce" or other forms of the word such as "reduce" or "mitigating" is meant reducing an event or characteristic (e.g., vascular leakage). It will be appreciated that this is typically associated with some standard or desired value, in other words it is relative, but reference to a standard or relative value is not always required.

The term "treatment" or other forms of the word, such as "treating" or "treating," is used herein to refer to administration of a therapeutic agent of the invention that alleviates a disease or disorder in a host and/or reduces, inhibits, or eliminates a particular feature or event associated with the disorder (e.g., vascular leakage).

To the extent that the methods of the invention are directed to preventing disease, it is understood that the term "preventing" does not require a complete blockage of the disease state. Rather, as used herein, the term prophylaxis refers to the ability of one skilled in the art to identify a population susceptible to a disorder such that administration of a compound of the invention can occur prior to onset of the disease. The term does not imply a complete avoidance of the disease state.

The term "ameliorating a symptom" or other form of the word, such as "alleviating a symptom," is used herein to refer to administration of a therapeutic agent of the invention that alleviates one or more symptoms of a disease or disorder in a host, and/or reduces, inhibits, or eliminates a particular symptom associated with the disease or disorder before and/or after administration of the therapeutic agent.

The disclosed compounds affect vascular leakage by inhibiting receptor tyrosine kinases.

Throughout the description and claims of this specification, the word "comprise", and other forms of the word such as "comprises" and "comprising", means including but not limited to and not intended to exclude, for example, other additives, components, integers or steps.

As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise.

"optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It will also be understood that a number of values are disclosed herein, and that each value is also disclosed herein as "about" that particular value, in addition to the value itself. For example, if the value "10" is disclosed, then "about 10" is also disclosed. It is also understood that when a value is disclosed, the values "less than or equal to," greater than or equal to, "and possible ranges between values are also disclosed, as is well understood by those of skill in the art. For example, if the value "10" is disclosed, then "less than or equal to 10" and "greater than or equal to 10" are also disclosed. It should also be understood that throughout this application, data is provided in many different formats and represents ranges for any combination of endpoints and starting points and data points. For example, if a particular data point "10" and a particular data point "15" are disclosed, it is understood that greater than, greater than or equal to, less than or equal to, and equal to 10 and 15, and 10 through 15 are considered disclosed. It is also understood that each unit between two particular units is also disclosed. For example, if ranges of 10 and 15 are disclosed, 11, 12, 13, and 14 are also disclosed.

The phrase "pharmaceutically acceptable salt" as used herein includes salts of acidic groups or basic groups, unless otherwise specified.

The term "kinase" refers to any enzyme that catalyzes the addition of phosphate groups to protein residues; for example, serine and threonine kinases catalyze the addition of phosphate groups to serine and threonine residues.

The terms "VEGFR kinase", "VEGFR" refer to any vascular endothelial growth factor receptor.

The terms "VEGF signaling" and "VEGF cascade" refer to the upstream and downstream components of the VEGF signaling cascade.

The term "administration of a compound" or "administering a compound" refers to the act of providing a compound or pharmaceutical composition of the invention to a subject in need of treatment.

In the present disclosure, "composition" and "formulation" are used interchangeably and refer to the conventional understanding of a composition or formulation as known in the art. "formulation" as disclosed herein may include solutions, suspensions, semi-solid or semi-liquid mixtures of therapeutic agents and/or formulation excipients or formulations.

A "solution" according to the present disclosure is a clear, homogeneous liquid form containing one or more chemicals dissolved in a solvent or a mixture of mutually miscible solvents. A solution is a liquid formulation containing one or more chemicals dissolved in a suitable solvent or mixture of mutually miscible solvents. Because the molecules of the therapeutic agent substance are uniformly dispersed in the solution, the use of the solution as a dosage form generally provides assurance of a uniform dosage after administration, as well as good accuracy when the solution is diluted or otherwise mixed. "solution" as disclosed herein encompasses any variation based on the state of the art or that which is accomplished by one skilled in the art.

A "suspension" according to the present disclosure is a liquid form containing solid particles dispersed in a liquid vehicle. "suspension" as disclosed herein encompasses any variation based on the state of the art or realized by a person skilled in the art.

"therapeutic agent delivery device" and "port delivery system" ("PDS") are used interchangeably in this specification. As disclosed herein, a "therapeutic agent delivery device" or "port delivery system" ("PDS") encompasses any variation of the disclosed device designed to achieve a similar purpose of targeted specific delivery of a therapeutic agent into a subject. For example, a "therapeutic agent delivery device" or "port delivery system" ("PDS") may have a design that includes a membrane, openings, diffusion barriers, diffusion mechanisms so as to release a therapeutic amount of a therapeutic agent for an extended period of time, e.g., 30 days, 60 days, 90 days, 120 days, or more. Several variations of this device are disclosed in WO2012/065006, WO2012/019047, WO2013/003620, WO2012/019136, WO 2012/019176 and us patent No. 8,277,830, each of which is incorporated herein by reference in its entirety.

The term "acute" as used herein refers to a condition with rapid onset and severe, but short duration symptoms.

The term "analgesic" as used herein means a compound/formulation for the management of intermittent and/or chronic physical discomfort suitable for long-term use.

The term "anesthetic" or "anesthesia" as used herein means a compound/formulation for managing acute body pain suitable for short-term temporary use, which has the effect of producing numbness or reduced sensitivity (e.g., reduced corneal sensitivity of the eye) in the body part/organ to which the compound/formulation is administered.

The term "aqueous" generally denotes an aqueous composition wherein the carrier reaches a level of >50 wt.%, more preferably >75 wt.% and especially 90 wt.% water.

The term "chronic" as defined herein means a condition that is persistent, or characterized by frequent relapses, preferably a condition that persists/relapses for more than 3 months, more preferably more than 6 months, more preferably more than 12 months, and even more preferably more than 24 months.

The term "comfort" as used herein refers to a feeling of physical health or relief as opposed to a physical feeling of pain, burning, stinging, itching, irritation, or other symptoms associated with physical discomfort.

As used herein, the term "symptom" is defined as an indication of a disease, disorder, injury, or abnormality of something in the body. Symptoms are felt or noticed by the individual experiencing the symptoms, but may not be readily noticed by others. Others are defined as non-healthcare professionals.

As used herein, the term "sign" is also defined as an indication that something is abnormal in the body. But signs are defined as something visible to a doctor, nurse or other health care professional.

The term "more" as used in this disclosure does not include an infinite number of possibilities. The term "more" as used in this disclosure is used as understood by those skilled in the art in the context in which it is used.

As used in this disclosure, the terms "comprising" and "including," whether in the transitional phrase or in the subject of the claims, are to be construed in an open-ended sense. That is, the terms should be construed as synonymous with the phrases "having at least" or "including at least". When used in the context of a method, the term "comprising" means that the method includes at least the recited steps, but may include additional steps. The term "comprising" when used in the context of a molecule, compound or composition means that the compound or composition includes at least the recited features or components, but may also include additional features or components.

For the purposes of promoting an understanding of the embodiments described herein, reference will now be made to the preferred embodiments and specific language will be used to describe the same. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. As used throughout this disclosure, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes a plurality of such compositions as well as a single composition, and reference to "a therapeutic agent" is a reference to one or more therapeutic agents and/or medicaments and equivalents thereof known to those skilled in the art, and so forth. All percentages and ratios used herein are by weight unless otherwise indicated.

The following examples are illustrative of, but not limiting to, the methods and compositions of the present invention. Other suitable modifications and adaptations of the various conditions and parameters normally encountered in the synthesis and use of the compounds of the present disclosure and which are obvious to those skilled in the art are within the spirit and scope of the present disclosure.

Further embodiments

1. A stable pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility and one or more formulating agents, wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt and the one or more formulating agents comprise a complexing agent, a solubilizing agent, and optionally a buffering agent; wherein the salt of the therapeutic agent is in solution in the formulation.

2. The formulation of claim 1, wherein the therapeutic agent is pazopanib.

3. The formulation of claim 2, wherein the pharmaceutically acceptable salt is a monovalent halide salt or a divalent halide salt.

4. The formulation of claim 3, wherein the salt is a chloride salt.

5. The formulation of claim 4, wherein the monovalent salt is stable in the formulation at a concentration of up to about 60 mg/mL.

6. The formulation of claim 4, wherein the divalent salt is stable in the formulation at a concentration of up to about 70 mg/ml.

7. The formulation of claim 4, wherein the pre-formulation divalent salt crystal structure is form XIV as determined by XRPD.

8. The formulation of claim 4, wherein the stability of the monovalent salt in the formulation is increased by lyophilizing the therapeutic agent from an organic solvent prior to dissolution with the formulation in solution.

9. The formulation of claim 8, wherein the organic solvent is dimethyl sulfoxide (DMSO) or Trifluoroethanol (TFE).

10. The formulation of claim 9, wherein the conversion of one crystalline phase form of the therapeutic agent to another form is from lyophilization of DMSO.

11. The formulation of claim 10, wherein the lyophilization from DMSO converts crystalline phase form a to a material containing at least 70% crystalline phase form G as determined by XRPD.

12. The formulation of claim 9, wherein the conversion of crystalline form a to a partially or fully amorphous phase is from lyophilization of TFE.

13. The formulation of claim 8, wherein the pH is adjusted during formulation of the therapeutic agent.

14. The formulation of claim 8, wherein the pH is not adjusted during formulation of the therapeutic agent.

15. The formulation of claim 4, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and combinations thereof.

16. The formulation of claim 4, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

17. The formulation of claim 4, wherein the buffer is histidine HCl.

18. A method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent with low water solubility, wherein the salt is a divalent salt, comprising (a) dissolving the salt in a solution of one or more formulating agents, wherein the formulating agents comprise a complexing agent, a solubilizing agent and optionally a buffering agent, and (b) adjusting the pH to an optimum value after dissolving the salt in the formulating agent.

19. The method of claim 18, wherein the therapeutic agent is pazopanib.

20. The method of claim 18, wherein the pharmaceutically acceptable salt is a halide salt.

21. The method of claim 20, wherein the salt is a chloride salt.

22. The method of claim 21, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and combinations thereof.

23. A method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility, wherein the salt is a monovalent salt, comprising (a) treating the salt with a base; (b) dissolving the alkali-treated salt in a solution of one or more formulating agents, wherein the formulating agents include a complexing agent, a solubilizing agent, and optionally a buffering agent, and (c) adjusting the pH to a pH equal to or below about 2 with an acid, wherein the alkali treatment increases the total salt content in the formulation, and the adjusting the pH with the acid increases the solubility of the salt in the formulation.

24. A method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility, wherein the salt is a monovalent salt, comprising (a) preparing a solution of the salt in an organic solvent; (b) lyophilizing the solution, thereby preparing a lyophilized salt of the therapeutic agent.

25. The method of claim 24, wherein the method further comprises dissolving a solubilizing agent and a buffer in water, thereby preparing a solution; dissolving a complexing agent in the solution; adding the lyophilized salt to the solution at or above about ambient temperature, mixing to dissolve the salt in the solution; wherein the pH of the formulation is optionally adjusted.

26. The method of claim 24, wherein the method further comprises dissolving a solubilizing agent and a buffer in water, thereby preparing a solution; dissolving an amount of a complexing agent in the solution, thereby preparing a low viscosity solution; adding the lyophilized salt to the low viscosity solution at or above about ambient temperature, mixing, and dissolving in the solution; wherein the pH of the low viscosity solution is adjusted; and further adding about 2 times the amount of the complexing agent to the low viscosity solution and dissolving it.

27. The method of claim 25 or 26, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

28. The method of claim 25 or 26, wherein the buffer is histidine HCl.

29. The method of claim 25 or 26, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and combinations thereof.

30. The method of claim 25 or 26, wherein the therapeutic agent is pazopanib.

31. The method of claim 30, wherein the monovalent salt is a halide.

32. The method of claim 31, wherein the halide is chloride.

33. The method of claim 32, wherein the lyophilized salt is amorphous.

34. The method of claim 32, wherein the lyophilizing step converts crystalline phase form a to a material containing at least about 70% form G pazopanib, as determined by XRPD.

35. The method of claim 25 or 26, wherein the lyophilized salt is dissolved in the solution at a temperature of about 37 ℃ to about 50 ℃.

36. The method of claim 24, wherein the method further comprises continuously mixing at least the solubilizing agent, the buffer, the complexing agent, and the lyophilized salt at or above about ambient temperature while adding water.

37. The method of claim 36, wherein the pH of the formulation is adjusted to about 6-7 with a base.

38. The method of claim 36, wherein the pH is not adjusted.

39. The method of claim 36, wherein the therapeutic agent is pazopanib.

40. The method of claim 39, wherein the pharmaceutically acceptable salt is a halide salt.

41. The method of claim 40, wherein the salt is a monovalent chloride salt.

42. The method of claim 41, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and combinations thereof.

43. The method of claim 41, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

44. The method of claim 41, wherein the buffer is histidine HCl.

45. The formulation of claim 8, wherein the organic solvent is trifluoroethanol, a trifluoroethanol-water mixture, or dimethylsulfoxide.

46. The method of claim 24, wherein the organic solvent is trifluoroethanol, a trifluoroethanol-water mixture, or dimethylsulfoxide.

47. The formulation of claim 45, wherein the organic solvent is dimethyl sulfoxide.

48. The method of claim 46, wherein the organic solvent is dimethyl sulfoxide.

49. A method of converting pazopanib in crystalline form a into a material comprising at least about 70% pazopanib in crystalline form G, said method comprising dissolving form a in DMSO and lyophilizing the resulting solution.

50. Use of the formulation of any one of claims 1, 18, 23, and 24 in a method of treating, preventing progression of, or ameliorating symptoms of a disorder characterized by vascular leakage or Neovascularization (NV) in the retina of the eye of a subject.

51. Use of the formulation of any one of claims 1, 18, 23, and 24 in the manufacture of a medicament for use in a method of treating, preventing progression of, or ameliorating symptoms of a disorder characterized by vascular leakage or Neovascularization (NV) in the retina of the eye of a subject.

52. A kit comprising the stable formulation of any one of claims 1-48 contained in a storage compartment of a therapeutic device, wherein the storage compartment is coupled to a porous structure for controlled release of the therapeutic agent in the vitreous of the eye.

53. The drug delivery formulation of any one of claims 1-48, wherein the formulation is contained in a storage chamber coupled to a porous structure in a therapeutic agent delivery system for controlled release of a therapeutic agent in the vitreous of the eye; and wherein the controlled release of the formulation from the porous structure produces a concentration of the therapeutic agent in the vitreous body that is at least two orders of magnitude lower than the concentration of the therapeutic agent in the storage chamber.

54. The formulation of any one of claims 1-48, wherein the formulation is used in a method of ocular drug delivery.

55. The formulation of claim 54, wherein the formulation is an intravitreal delivery formulation.

56. The formulation of any one of claims 54, wherein the formulation is not an eye drop.

57. The formulation of claim 54, wherein the formulation is not a topical delivery formulation.

58. The formulation of claim 54, wherein the formulation is not an oral delivery formulation or a parenteral delivery formulation.

59. The formulation of claim 54, wherein the formulation is not a periocular delivery formulation.

60. A method of treating and/or ameliorating an ophthalmic disease or condition of the posterior segment of the eye, the method comprising delivering a stable pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility and one or more formulating agents from a intravitreal delivery device comprising a storage compartment coupled to a porous structure, wherein the formulation is contained in the reservoir of the device and controlled release of the formulation from the reservoir through the porous structure increases the half-life of the therapeutic agent in the vitreous;

wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt and the one or more formulating agents comprise a complexing agent, a solubilizing agent, and a buffer; wherein the salt of the therapeutic agent is in solution in the formulation.

61. The method of claim 60, wherein the disease or disorder is selected from diabetic retinopathy, age-related macular degeneration (AMD), pathological Choroidal Neovascularization (CNV), pathological retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, Kotz's disease, sickle cell retinopathy and neovascular glaucoma.

62. The method of claim 60, wherein the reservoir chamber is refillable and refilled with the formulation after insertion of the device into the eye.

63. The method of claim 62, wherein the storage chamber is refilled with the formulation after the device has been in the eye for 30-90 days or up to 6 months.

64. A method of converting pazopanib in crystalline form to a material comprising pazopanib in crystalline form G, said method comprising dissolving said crystalline form in DMSO and lyophilizing the resulting solution; wherein at least about 70% of form G of pazopanib is formed.

65. The method of claim 64, wherein pazopanib is formed at about 100% form G.

66. The method of claim 64, wherein at least about 70% to about 95% of the pazopanib form G is formed.

67. A method of converting pazopanib in crystalline form a to a material comprising pazopanib in crystalline form G, said method comprising dissolving form a in DMSO and lyophilizing the resulting solution; wherein at least about 70% of form G of pazopanib is formed.

68. The method of claim 67, wherein pazopanib is formed at about 100% form G.

69. The method of claim 67, wherein at least about 70% to about 95% of the form G of pazopanib is formed.

70. A process for converting pazopanib in crystalline form to pazopanib in amorphous form, said process comprising dissolving said crystalline form in TFE and lyophilizing the resulting solution; wherein up to or at least about 96% amorphous pazopanib is formed.

71. The method of claim 70, wherein up to about 96% amorphous pazopanib is formed.

72. The method of claim 70, wherein at least about 96% amorphous pazopanib is formed.

73. A stable pharmaceutical formulation of pazopanib 1HCl for intravitreal delivery from a delivery device, the pharmaceutical formulation comprising a complexing agent, a solubilizing agent, and optionally a buffer; wherein the stability of pazopanib 1HCl in the formulation is increased by converting at least about 70% of the crystalline phase form a of pazopanib 1HCl to the crystalline phase form G by lyophilization from dimethyl sulfoxide (DMSO); wherein the formulation does not precipitate upon dilution and/or during or after at least 50 days of delivery into the vitreous.

74. A stable pharmaceutical formulation of pazopanib 1HCl for intravitreal delivery from a delivery device, the pharmaceutical formulation comprising a complexing agent, a solubilizing agent, and optionally a buffer; wherein the stability of pazopanib 1HCl in crystalline form a in said formulation is increased by converting pazopanib 1HCl in said crystalline form a into a partially or fully amorphous phase and/or a microcrystalline phase by lyophilization from Trifluoroethanol (TFE); wherein the formulation does not precipitate upon dilution and/or during or after at least 50 days of delivery into the vitreous.

75. The stable pharmaceutical formulation of claim 73 or 74, wherein about 30mg/mL to about 70mg/mL pazopanib 1HCl is stable in the formulation in the delivery device.

76. The stable pharmaceutical formulation of claim 75, wherein the complexing agent is a cyclodextrin and the solubilizing agent is a pharmaceutically acceptable carrier.

77. The stable pharmaceutical formulation of claim 76, wherein the pharmaceutically acceptable carrier is poly (vinyl pyrrolidone) (PVP).

78. The stable pharmaceutical formulation of claim 73 or 74, wherein the buffer is histidine HCl.

79. A method of preparing the stable pharmaceutical formulation of claim 73 or claim 74.

Examples

The following examples provide methods for preparing formulations of the present disclosure and evaluating their characteristics at the vitreous following intravitreal delivery.

Example 1

Process for preparing pazopanib 2HCl formulations

An API containing 2HCl per pazopanib molecule was formulated at drug concentrations up to 60mg/ml (from hwasunn biotechnology; distributed by Manus-Aktteva). Dissolving pazopanib in waterIn solution and after addition of all required excipients, the pH is adjusted to the desired value.

By mixing the required amount ofThe acid and the reagent are dissolved in water to prepare the formulation. Pazopanib 2HCl was added and mixed until dissolved. Sodium hydroxide was then added to reach the final pH. The formulation was filtered and then injected into PDS implants for therapeutic agent release testing.

Example 2

Process for preparing pazopanib 1HCl formulations-no lyophilization

About half of the total amount in the vialWeighed and dissolved in an appropriate amount of water. Adding PVP-10k (polyvinylpyrrolidone, MW 10kDa) and histidine HCl,and dissolved by mixing the solution (vortexing, sonication). Pazopanib API (from Hetero Labs, Inc.) was weighed and then added toIn solution. A small amount of hydrochloric acid (HCl) is added to adjust and maintain the pH of the solution at or below pH 2, if necessary. Adding additives such as triacetin or glycerol. The formulation was stirred and shaken at 37 ℃ or room temperature until the pazopanib was completely dissolved. Dissolution of pazopanib may take several hours. Next, pazopanib-The pH of the solution is adjusted to pH 6-7. Then adding the restAnd dissolved completely by shaking/vortexing the formulation at 37 ℃ or room temperature. The pH was checked and, if necessary, adjusted prior to filtering the formulation using a 0.2 μm filter. The formulations were stored at room temperature and protected from light. The content and purity of the formulation was tested by HPLC and UV.

Example 3

High concentration formulations of therapeutic agents (e.g., pazopanib 1HCl) are prepared by stirring and/or shaking the active pharmaceutical ingredient in a dispersion with a base (e.g., NaOH) for about 30 minutes at room temperature. The composition of the dispersion is, for example, about 275mg/mL in 1N NaOH.

In this method, the formulation is prepared by dissolving the required amounts of cyclodextrin, acid and reagent in water. NaOH treated pazopanib 1HCl was added and mixed until dissolved. Sodium hydroxide was then added to reach a pH of 6-7. The formulation was filtered and then injected into PDS implants for therapeutic agent release testing.

Although reasonably high drug concentrations were achieved with both 2HCl and 1HCl pazopanib forms, the 1HCl pazopanib formulation was very unstable. 1HCl pazopanib crystallizes out of the formulation both in the presence of the shelf (i.e., during storage) and upon dilution of the formulation (i.e., during drug release).

The stability of the 1HCl pazopanib formulation was improved by reducing the drug concentration to below 40 mg/mL. See table 5.

Example 4

To improve stability, and for easier formulation processes, lyophilization of pazopanib 1HCl is performed prior to dissolution in one or more formulations. Lyophilization was performed from Trifluoroethanol (TFE), trifluoroethanol-water (90-10) mixtures, or dimethyl sulfoxide (DMSO). Lyophilization is believed to transfer highly crystalline drugs to a predominantly amorphous solid, which has more favorable dissolution properties. XRPD analysis was performed to compare the crystalline structures of 2HCl, 1HCl and 1HCl lyophilized drug products; the results are shown in Table 3. The lyophilization process is summarized in table 4.

Method for preparing pazopanib 1HCl preparation-DMSO freeze-drying

Lyophilization from DMSO; a solution of approximately 20-60mg/mL pazopanib 1HCl in DMSO (dimethylsulfoxide) was prepared. The solution is then freeze-dried under conditions well known within the present invention. The solution is dried at 35 deg.C to 50 deg.C (e.g., at about 40 deg.C) for about 12 hours to about 24 hours, at about 50 deg.C to 65 deg.C (e.g., at about 60 deg.C) for about 24 hours to about 40 hours, and at about 90 deg.C to 110 deg.C (e.g., at about 100 deg.C) for about 0.5 hours to about 2 hours.

Process for preparing pazopanib 1HCl formulation-lyophilization of TFE

Preparation of crystalline form in trifluoroethanol approximately 60mg/mL pazopanib 1 HCl. About 1% to about 30% water (e.g., about 20%) is also added to the solution of the therapeutic agent in trifluoroethanol. The solution was then freeze dried (with or without the addition of water) under conditions standard in the art. The solution is dried at 35 deg.C to 50 deg.C (e.g., about 40 deg.C) for about 12 hours to about 24 hours, or at about 50 deg.C to about 65 deg.C (e.g., at about 60 deg.C) for about 4 hours to about 8 hours.

For both DMSO and TFE lyophilized pazopanib 1HCl, formulations were prepared using either a one-step formulation method or a two-step formulation method.

One step: when a natural pH is used, i.e. without adjusting the pH of the viscous solution, the dissolution of the pharmaceutical ingredient is performed in one step. PVP-10k (polyvinylpyrrolidone, MW ═ 10kDa) and histidine HCl were weighed and dissolved in an appropriate amount of water by mixing the solutions (vortexing, shaking). Weighing machineIt was added to the solution and dissolved before shaking, vortexing the solution. Weighing the lyophilized pazopanib, then adding it toIn solution and completely dissolved by vortexing, sonication, shaking at ambient or elevated (e.g., about 37-50 ℃) temperatures. The formulation was filtered using a 0.2um filter and stored at room temperature and protected from light.

In another formulation method, all solid excipients (A), (B), (C), (PVP and histidine-HCl) and a therapeutic agent (pazopanib 1HCl), and were first mixed together in a vial. Gradual addition of the required water was carried out using continuous mixing. Dissolution of the formed dispersion can be carried out at ambient or elevated temperatures (e.g., about 37 ℃ to 50 ℃); the use of elevated temperatures can reduce the time required to obtain a homogeneous solution (e.g., about 24 hours to 4 hours). The formulation can be used as such (natural pH 3-4) or after pH adjustment with NaOH solution (pH 6-7).

A two-step formulation method using lyophilized therapeutic agents: about half of the total amount in the vialWeighed and dissolved in an appropriate amount of water. PVP-10k (polyvinylpyrrolidone, MW ═ 10kDa) and histidine HCl were added and dissolved by mixing the solutions (vortexing, sonication). Lyophilized pazopanib 1HCl (lyophilized from TFE or DMSO) was weighed and then added toIn solution. A small amount of hydrochloric acid (HCl) is added to adjust and maintain the pH of the solution at or below pH 2, if necessary. Adding additives such as triacetin or glycerol. The formulation was stirred and shaken at 37 ℃ or room temperature until the pazopanib was completely dissolved. Dissolution of pazopanib may take several hours. Next, pazopanib-The pH of the solution is adjusted to pH 6-7. Then adding the restAnd dissolved completely by shaking/vortexing the formulation at 37 ℃ or room temperature. The pH was checked and, if necessary, adjusted prior to filtering the formulation using a 0.2 μm filter. The formulations were stored at room temperature and protected from light. The content and purity of the formulation was tested by HPLC and UV.

Example 5

The therapeutic agent release test was performed by measuring the amount of therapeutic agent released by the PDS into the fluid representing the vitreous, which was maintained in an incubator at 37 ℃. PDS was suspended in a container containing phosphate buffered saline. Periodically, PDS is transferred to a new container and the concentration of the therapeutic agent is measured in the fluid of the previous container. The rate is calculated from the amount of therapeutic agent released divided by the duration of sample collection. The cumulative percent release is calculated by dividing the cumulative amount of therapeutic agent by the amount of therapeutic agent initially filled into the treatment device (PDS). The half-life was calculated from the percentage of cumulative release at 4 weeks.

For use inFormulated pazopanib 1HCl or pazopanib 2HCl for therapeutic agent release. The formulation was filled into a treatment device (PDS) with a reservoir volume of 23 μ Ι _. A comparison of the chloride content of the pazopanib samples is shown in table 2: the XRD results are shown in table 3.

Drug release comparison: the therapeutic agent release rate was tested by measuring the amount of therapeutic agent released by PDS into the receiver fluid (PBS buffer) at 37 ℃. The therapeutic agent release test was performed by measuring the amount of therapeutic agent released by the PDS into the fluid representing the vitreous, which was maintained in an incubator at 37 ℃. PDS was suspended in a container containing phosphate buffered saline. Periodically, PDS is transferred to a new container and the concentration of the therapeutic agent is measured in the fluid of the previous container. The rate is calculated from the amount of therapeutic agent released divided by the duration of sample collection. The cumulative percent release is calculated by dividing the cumulative amount of therapeutic agent by the amount of therapeutic agent initially filled into the treatment device (PDS). The half-life was calculated from the percentage of cumulative release at 4 weeks. The results are shown in fig. 1 and are summarized below:

1.pazopanib-2 HCl (sample-1) (PA-96):

the formulation was 60.0mg/mL pazopanib, 2.2:11％

PVP, 6mg/ml histidine HCl, pH 6.5

Half-life ═ 53 days;

2.pazopanib-1 HCl (sample-2) (PA-110):

the formulation was 60.0mg/mL pazopanib, 2.2:11％

PVP, 6mg/ml histidine HCl, pH 6.5

Half-life 99 days; drug precipitation visible during release

3. Pazopanib-1 HCl-Freeze-dried from TFE (PAL-18)

The preparation is 36mg/mL pazopanib, 4:11％

PVP, 25mg/ml histidine HCl, pH 6.5

Half-life ═ 45 days;

4. pazopanib-1 HCl-Freeze-dried from DMSO (PAD-5)

The preparation is 50mg/mL pazopanib, 3:11％

PVP, 6mg/ml histidine HCl, pH 3.4

Half-life ═ 45 days;

example 6

Precipitation test-comparative results: this test was performed with the aim of modeling the conditions after drug release, i.e. when a small amount of formulation was released into a large amount of buffer solution. In the model, if the drug precipitates out after dilution (release), this may lead to clogging of the device and/or loss of drug, as the solid drug will not be measurable in the receiver fluid (it may also not be accessible when released under in vivo conditions). To perform the assay, the formulation is diluted 330-fold with phosphate buffered saline solution (with about 0.1% sodium azide), e.g., 3 μ L of the formulation is added to 1mL of PBS buffer. The solution was kept in a 37 ℃ thermostat and periodically checked for the occurrence of crystal growth/precipitation. Formulations prepared from different drug sources exhibited different stability against precipitation upon dilution, as summarized in table 5.

Is incorporated by reference

The entire disclosure of each patent document and scientific article referred to herein is incorporated by reference for all purposes. In this disclosure, subject matter is identified with sufficient specificity and materials relevant to this disclosure are explained based on the context of the reference. Citation of publications and patent documents is not intended as an admission that any of the publications and patent documents are pertinent prior art, nor does it constitute any admission as to the contents or date thereof. Having now described the invention by way of a written description, those skilled in the art will recognize that the invention can be practiced in a variety of embodiments, and that the foregoing description and examples are for purposes of illustration and not limitation of the appended claims.

Other embodiments

While the invention has been described in connection with specific embodiments thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (38)

1. A stable pharmaceutical formulation comprising a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility and one or more formulating agents, wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt and the one or more formulating agents comprise a complexing agent, a solubilizing agent and/or a buffering agent; wherein the salt of the therapeutic agent is in solution in the formulation.

2. The formulation of claim 1, wherein the pharmaceutically acceptable salt of the therapeutic agent is a salt of pazopanib.

3. The formulation of claim 2, wherein the pharmaceutically acceptable salt is a monovalent or divalent halide salt of pazopanib.

4. The formulation of claim 3, wherein the monovalent salt or the divalent salt is a chloride salt.

5. The formulation of claim 4, wherein the monovalent salt is stable in the formulation at a concentration of up to about 60 mg/mL.

6. The formulation of claim 4, wherein the divalent salt is stable in the formulation at a concentration of up to about 70 mg/ml.

7. The formulation of claim 4, wherein the monovalent salt is a lyophilized monovalent salt of the therapeutic agent.

8. The formulation of claim 7, wherein the monovalent salt is lyophilized with dimethyl sulfoxide (DMSO), Trifluoroethanol (TFE), or a trifluoroethanol-water mixture.

9. The formulation of claim 1, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and any combination thereof.

10. The formulation of claim 1, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

11. The formulation of claim 1, wherein the buffering agent is histidine HCl.

12. A method of preparing a stable solution pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low aqueous solubility, wherein the salt is a monovalent salt; the method comprises (a) preparing an organic solution of the salt in an organic solvent; (b) lyophilizing the organic solution, thereby preparing a lyophilized salt of the therapeutic agent; (c) dissolving a solubilizer and a buffer in water, thereby preparing a solution; (d) dissolving a complexing agent in the solution, thereby preparing a low viscosity solution; and (e) adding the lyophilized salts to the solution at or above about ambient temperature and mixing them such that the monovalent salt dissolves in the solution, thereby preparing a stable solution pharmaceutical formulation.

13. The method of claim 12, wherein the method further comprises adding and dissolving about 2 times the amount of the complexing agent after step (e).

14. The method of claim 12, wherein the organic solvent is dimethyl sulfoxide (DMSO), Trifluoroethanol (TFE), or a trifluoroethanol-water mixture.

15. The method of claim 14, wherein lyophilization in DMSO converts one crystalline form of the salt of the therapeutic agent to another crystalline form.

16. The method of claim 14, wherein the lyophilization in DMSO converts crystalline phase form a of the salt of the therapeutic agent to a material containing at least 70% crystalline phase form G, as determined by XRPD.

17. The method of claim 14, wherein lyophilization in TEE converts crystalline phase form a of the salt of the therapeutic agent to a partially amorphous phase or a fully amorphous phase.

18. The method of claim 12, wherein the pH is adjusted during the preparation of the stable solution pharmaceutical formulation.

19. The method of claim 12, wherein the pH is not adjusted during the preparation of the stable solution pharmaceutical formulation.

20. The method of claim 12, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

21. The method of claim 12, wherein the buffer is histidine HCl.

22. The method of claim 12, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and any combination thereof.

23. The method of claim 12, wherein the pharmaceutically acceptable salt of the therapeutic agent is a salt of pazopanib.

24. The method of claim 12, wherein the monovalent salt is a halide.

25. The method of claim 12, wherein the halide is chloride.

26. The method of claim 12, wherein the lyophilized salt is dissolved in the solution at step (e) at a temperature of about 37 ℃ to about 50 ℃.

27. The method of claim 13, wherein the method further comprises continuously mixing at least the solubilizing agent, the buffer, the complexing agent, and the lyophilized salt at or above about ambient temperature while adding water.

28. The method of claim 27, wherein the pH of the formulation is adjusted to about 6-7 with a base.

29. A method of treating and/or ameliorating an ophthalmic disease or condition of the posterior segment of the eye, the method comprising delivering a stable pharmaceutical formulation of a pharmaceutically acceptable salt of a therapeutic agent having low water solubility and one or more formulating agents from a intravitreal delivery device comprising a storage compartment coupled to a porous structure, wherein the formulation is contained in the reservoir of the device and controlled release of the formulation from the reservoir through the porous structure increases the half-life of the therapeutic agent in the vitreous;

wherein the pharmaceutically acceptable salt is a monovalent salt or a divalent salt and the one or more formulating agents comprise a complexing agent, a solubilizing agent, and a buffer; wherein the salt of the therapeutic agent is in solution in the formulation.

30. The method of claim 29, wherein the disease or disorder is selected from diabetic retinopathy, age-related macular degeneration (AMD), pathological Choroidal Neovascularization (CNV), pathological retinal neovascularization, uveitis, retinal vein occlusion, ocular trauma, surgery induced edema, surgery induced neovascularization, cystoid macular edema, ocular ischemia, retinopathy of prematurity, kotz's disease, sickle cell retinopathy, and neovascular glaucoma.

31. The method of claim 29, wherein the storage chamber is refillable and the storage chamber is refilled with the formulation after the device is inserted into the eye.

32. The method of claim 31, wherein the storage chamber is refilled with the formulation after the device has been in the eye for 30-90 days or for up to 6 months.

33. The method of claim 29, wherein the solubilizing agent is poly (vinyl pyrrolidone) (PVP).

34. The method of claim 29, wherein the buffer is histidine HCl.

35. The method of claim 29, wherein the complexing agent is a cyclodextrin selected from the group consisting of: 2-hydroxypropyl-beta-cyclodextrin, methyl-beta-cyclodextrin, randomly methylated-beta-cyclodextrin, ethylated-beta-cyclodextrin, triacetyl-beta-cyclodextrin, peracetylated-beta-cyclodextrin, carboxymethyl-beta-cyclodextrin, hydroxyethyl-beta-cyclodextrin, 2-hydroxy-3- (trimethylamino) propyl-beta-cyclodextrin, glucosyl-beta-cyclodextrin, maltosyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, branched-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, randomly methylated-gamma-cyclodextrin, trimethyl-gamma-cyclodextrin, and any combination thereof.

36. The method of claim 29, wherein the pharmaceutically acceptable salt of the therapeutic agent is a salt of pazopanib.

37. The method of claim 29, wherein the monovalent salt is a halide.

38. The method of claim 37, wherein the halide is chloride.