EA041985B1 - OPHTHALMIC MICROSUSPENSIONS BASED ON SOLID CYCLODEXTRIN COMPLEXES OF DEXAMETHASONE, METHODS FOR THEIR PREPARATION AND THEIR APPLICATION - Google Patents

Description

The technical field to which the invention belongs

The present invention relates to ophthalmic compositions containing solid complexes of an active pharmaceutical ingredient and a cyclodextrin, to a process for their preparation and to their use. The present invention also relates to the preparation of novel aqueous eye drop formulations containing drug/cyclodextrin nanoparticles using a bottom-up approach.

Prerequisites for the creation of the invention

In this specification, to the extent that a document, act, or knowledge item is mentioned or discussed, this reference or discussion is not an admission that such document, act, or knowledge item, or any combination thereof, was publicly available, known to the public, or part of the general knowledge or otherwise constitute prior art under applicable law; or recognition of the notoriety that they were involved in an attempt to solve any problem to which this description relates.

According to the National Institute of Ophthalmology, a division of the National Institutes of Health, eye diseases cause an economic burden estimated at $139 billion in America alone. This number is not surprising given that 2.1 million Americans have been diagnosed with age-related macular degeneration (AMD), 2.7 million Americans have been diagnosed with glaucoma, 7.7 million Americans have been diagnosed with diabetic retinopathy, and 24 million Americans have been diagnosed with cataracts. Eye disease is not just a problem in the United States. In fact, it is estimated that around 285 million people worldwide have visual impairments.

Most eye conditions can be treated and/or controlled to reduce negative effects, including total blindness. To combat this serious problem, the World Health Organization (WHO) has approved an action plan aimed at reducing by 2019 25% of all avoidable visual impairment in the world. In its efforts, WHO plans to reduce the impact of eye diseases such as diabetic retinopathy, glaucoma and retinitis pigmentosa, which are responsible for the majority of cases of irreversible blindness worldwide. However, current treatments for ocular diseases are limited by the difficulty in delivering effective doses of drugs to target tissues in the eye.

In current therapies, topical eye drops are the preferred means of administering drugs to the eye due to the convenience and safety of eye drops compared to other routes of administration of ophthalmic drugs such as intravitreal injections and implants (Le Bourlais, C., Acar, L. , Zia, H., Sado, P.A., Needham, T., Leverge, R., 1998. Ophthalmic drug delivery systems-Recent advances. Progress in Retinal and Eye Research 17, 33-58). Drugs are mainly transported by passive diffusion from the surface of the eye to the eye and surrounding tissues, where, according to Fick's law, the drug enters the eye via a gradient of dissolved drug molecules. Passive diffusion of drugs into the eye is hampered by three main obstacles (Gan, L., Wang, J., Jiang, M., Bartlett, H., Ouyang, D., Eperjesi, F., Liu, J., Gan, Y., 2013. Loftsson, T., Sigurdsson, H.H., Konradsdottir, F., Gisladottir, S., Jansook, P., Stefansson. , E., 2008. Topical drug delivery to the posterior segment of the eye: anatomical and physiological considerations. Pharmazie 63, 171-179; Urtti, A., 2006. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv. Drug Del Rev. 58, 1131-1135).

The first big hurdle is the solubility of the drug in water. In hitherto known ophthalmic compositions, only dissolved drug molecules can penetrate biological membranes into the eye. Accordingly, ophthalmic drugs must have sufficient solubility in aqueous lacrimal fluid to penetrate the eye.

The second big obstacle is the high turnover rate of tear fluid and, as a consequence, the decrease in the concentration of dissolved drug molecules. After instillation of eye drops (25-50 µl) in the area in front of the cornea, most of the drug solution quickly drains from the surface of the eye, and the tear volume returns to the normal resident volume of about 7 µl. Thereafter, the volume of the tear remains constant, but the concentration of the drug decreases due to dilution due to the turnover of the tear fluid and absorption of the drug in the cornea and other tissues. The value of the first order rate constant for drainage of eye drops from a surface is typically about 1.5 min ^-1 in humans after initial rapid drainage. Normal tear turnover in humans is about 1.2 µl/min, and the precorneal half-life of topically applied drugs is 1 to 3 minutes (Sugrue, MF, 1989. The pharmacology of antiglaucoma drugs. Pharmacology & Therapeutics 43, 91-138).

The third major obstacle is the slow penetration of the drug through the membrane barrier, i.e. cornea and/or conjunctiva/sclera. Drug molecules must be released from the water surface into the interior of the membrane before they can passively permeate the membrane barrier. As a result, typically only a few percent of the applied dose of drug is delivered to

- 1 041985 eye tissues. The main part (50-100%) of the administered dose will be absorbed from the nasal cavity into the systemic circulation, which can cause various side effects.

The present invention seeks to contribute to the WHO plan to reduce preventable visual impairment by providing an ophthalmic composition and a method of making an ophthalmic composition that overcomes barriers to passive drug diffusion into the eye. As a result of these efforts, Applicants propose a process for the preparation of an ophthalmic composition that overcomes major barriers to passive drug diffusion by (1) increasing the solubility of poorly soluble drugs; (2) increasing the half-life of topical drugs from the area in front of the cornea; and (3) separating drug molecules from the external aqueous medium into the membrane to allow passive permeation through the membrane barrier. In exemplary embodiments, ophthalmic compositions are provided having a combination of such features.

Brief summary of the invention

It is well known that cyclodextrins increase the solubility and bioavailability of hydrophobic compounds. In aqueous solutions, cyclodextrins form inclusion complexes with many active pharmaceutical ingredients. The preparation of active pharmaceutical ingredient/cyclodextrin complexes by the bottom-up method involves suspending the active pharmaceutical ingredient and cyclodextrin in an aqueous medium and heating the resulting suspension. When the active pharmaceutical ingredient and the cyclodextrin are dissolved, complexes of the active pharmaceutical ingredient and the cyclodextrin are formed. The hot solution is then cooled to precipitate solid complexes of the active pharmaceutical ingredient and the cyclodextrin.

Applicants have surprisingly found that the particle diameter and viscosity of the composition can be adapted using heating and cooling steps and using stabilizing polymers in an aqueous environment. Applicants have found that in order to prevent or significantly inhibit or reduce the formation of impurities such as a degradation product derived from the active pharmaceutical ingredient and/or excipients, excessive heating of the medium should be avoided and the hot solution should be rapidly cooled to room temperature.

In addition, the composition of the present invention exhibits an increased viscosity which prevents the microparticles from settling during storage and also advantageously increases the contact time of the particles on the ocular surface, thus improving the bioavailability of the active pharmaceutical ingredient.

Applicants have discovered an exemplary ophthalmic composition and a method for making such a composition that overcomes known major barriers to passive drug diffusion.

The first object of the present invention is an ophthalmic microsuspension containing in an ophthalmologically acceptable medium a solid complex comprising dexamethasone and γ-cyclodextrin, where the solid complex has a D50 diameter of from 1 to 25 μm and where the microsuspension contains less than 0.5 wt.% dexamethasone enol aldehydes based on the weight of dexamethasone.

Compositions containing natural α-cyclodextrin, β-cyclodextrin or γ-cyclodextrin and the methods described herein provide an increase in the concentration of the dissolved active pharmaceutical ingredient by about 10-100 times compared to conventional ophthalmic compositions obtained by previously known methods. In addition, illustrative methods provide an ophthalmic composition with a reduced concentration of impurities and/or increased viscosity.

The invention also discloses methods for preparing ophthalmic compositions having a high concentration of microparticulate dexamethasone/cyclodextrin complex. In addition, the methods of the invention provide an ophthalmic composition with a reduced concentration of impurities and/or increased viscosity.

As such, the second object of the invention is a process for the preparation of an ophthalmic composition comprising the steps of:

a) suspending γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension and sterilizing said suspension in an autoclave;

b) suspending dexamethasone in an ophthalmologically acceptable medium to form a suspension and sterilizing said suspension in an autoclave;

c) mixing the compositions from steps (a) and (b) and heating the mixture at a temperature T1 below 120°C for a time t;

d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of dexamethasone and γ-cyclodextrin, where the ophthalmic composition contains less than 0.5 wt.% dexamethasone enol aldehydes based on the mass of dexamethasone, where the solid complex has a diameter D ₅₀ of 1 up to 25 microns.

The third object of the invention is an ophthalmic composition obtained by the method according to

- 2 041985 invention.

The fourth object of the invention is the use of an ophthalmic composition according to the invention or obtained according to the method according to the invention as a solution for eye drops.

The ophthalmic composition is in the form of a microsuspension containing an active agent complex having a diameter of 1 to 25 microns. The compositions and methods provided in illustrative embodiments provide an increase in the concentration of the dissolved active agent (i.e., dexamethasone) by about 10-100 times the concentration of the agent available in the case of conventional ophthalmic compositions obtained using previously known methods. In addition, illustrative methods provide an ophthalmic composition with a reduced concentration of the degradation product.

Used in this application, the term active agent may also be referred to, for example, as a pharmaceutical ingredient, active pharmaceutical ingredient, ophthalmic active pharmaceutical ingredient or drug (or variations of these expressions). As used herein, these terms (and variations thereof) may be considered equivalent and interchangeable. Exemplary embodiments provide methods for preparing ophthalmic compositions having a high concentration of active agent/cyclodextrin complex microparticles that do not generate or produce a by-product and/or degradation product for at least about 90 days when stored at room temperature.

In one method of the invention, at least one cyclodextrin is suspended in water or an aqueous eye drop vehicle to form a suspension having a milky appearance. Separately, dexamethasone is suspended in water or a cyclodextrin-free eye drop vehicle to form a suspension having a milky appearance. The two suspensions are sterilized, for example, by heating in an autoclave at 121° C. for 20 minutes. The two slurries or hot solutions are then allowed to cool to about 95° C. before mixing to form a substantially clear solution, with no or substantially no decomposition and/or formation of a by-product. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing the dexamethasone/cyclodextrin microparticulate complex.

In a non-limiting embodiment, at least one cyclodextrin is suspended in water or an aqueous eye drop vehicle to form a suspension having a milky appearance. Separately, dexamethasone is suspended in water or a cyclodextrin-free eye drop vehicle to form a suspension having a milky appearance. The two suspensions are heated or sterilized, for example by heating in an autoclave at 121° C. for 20 minutes. The two suspensions or hot solutions are then mixed together and the temperature is brought to about 90-95° C. to form a substantially clear solution with no or substantially no decomposition and/or by-product formation. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing the dexamethasone/cyclodextrin microparticulate complex.

Brief description of the drawings

These and other features of the present invention will now be described with reference to the drawings of some embodiments, which are intended to illustrate and not limit the present disclosure.

In FIG. 1 shows the structures of natural α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin.

In FIG. 2 shows the effect of self-aggregation of γ-cyclodextrin on the solubilization of the active pharmaceutical ingredient (dexamethasone). Phase solubility profiles of dexamethasone and natural γ-cyclodextrin (γCD) in aqueous eye drops. The solid curve is the solubility of the active pharmaceutical ingredient (·), the dotted curve is the solubility of γCD (ο), and the straight line is the theoretical amount of dissolved γCD in the aqueous medium of the eye drops. Excess dexamethasone was added to a solution containing 0 to 20% (w/v) γCD in an ophthalmologically acceptable medium containing benzalkonium chloride (0.02% w/v), sodium edetate (0.1% w/v). ./vol.) and a sufficient amount of sodium chloride to obtain an isotonic solution.

Thus, the amount of drug dissolved in solution is constant at γCD concentrations above 3% (w/v). The amount of γCD dissolved in the solution increases more slowly than the amount of γCD added to the medium, the change becomes linear only after 10% (w/v). This shows that at a concentration of γCD between 3-10% (w/v), all γCD added to the medium forms solid complexes with the drug and precipitates. At γCD concentrations above 10% (w/v), the amount of dissolved γCD again shows a linear increase.

Detailed description of the invention

Additional aspects, features, and advantages of exemplary embodiments will become apparent from the following detailed description.

The patents, published applications, and scientific literature referenced herein establish the knowledge of those skilled in the art and are hereby incorporated by reference.

- 3 041985 in their entirety to the same extent as if each of them were specifically and individually indicated as being incorporated by reference. Any conflict between any reference given in this document and the specific provisions of this specification shall be resolved in favor of the latter. Likewise, any conflict between a definition of a word or phrase accepted in the art and a definition of a word or phrase as specifically set forth herein should be resolved in favor of the latter.

Used in this application, the terms contains and containing, both in the transition phrase and in the text of the claims, should be interpreted as having an open meaning. That is, these terms are to be interpreted as synonymous with 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 listed steps, but may include additional steps. When used in the context of a composition, the term comprising means that the composition includes at least the listed features or components, but may also include additional features or components.

The terms consists essentially of or consists essentially of have a partially closed meaning, i.e. they do not allow the inclusion of steps, features or components that may significantly change the essential characteristics of the method or composition; for example, steps or features or components that can significantly affect the desired properties of the compounds or compositions described herein; those. the method or composition is limited to the specified steps or materials, as well as those materials and steps that do not significantly affect the basic and new characteristics of the method or composition.

The terms consists of and consists of are closed terminology and allow only the presence of the listed steps, features, or components.

As used herein, the singular terms also cover the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

The term approximately is used herein to mean approximately, in the area, roughly, or about. When a term is roughly used in conjunction with a numeric range, it modifies that range by extending the boundaries above and below the specified numeric values. In general, the term approximately or approximately is used herein to change a numerical value above and below the stated value by an amount of 20%.

The term dissolved or substantially dissolved is used herein to refer to the solubilization of a solid in solution. A solid may be considered to be dissolved or substantially dissolved in a solution when the resulting solution is clear or substantially clear.

The term transparent is used in this application to mean a translucent or translucent solution. The clear solution thus has a haze of <100 nephelometric turbidity units (NTU) according to ISO standards, preferably <50 NTU.

The term substantially transparent is used herein to refer to an almost transparent or translucent solution. Thus, a substantially clear solution has an ISO turbidity of <100 nephelometric turbidity units (NTU).

As used herein, the term cloudy or substantially cloudy refers to a solution having a haze of greater than 100 NTU according to ISO standards.

As used herein, the term milky or substantially milky refers to a solution having a turbidity, measured according to ISO standards, greater than 100 NTU, preferably greater than 200 NTU.

In this document, specifying a numeric range for a variable is intended to indicate that the variable can be equal to any value within that range. Thus, for a variable that is discrete in nature, the variable can be equal to any integer value in the numeric range, including the endpoints of the range. Similarly, for a variable that is inherently continuous, the variable can be equal to any real number in the numeric range, including the ends of the range. As an example, a variable that is described as having values from 0 to 2 may be 0, 1, or 2 for variables that are discrete in nature, and may be 0.0; 0.1; 0.01; 0.001 or any other real number for variables that are inherently continuous.

In the description and claims, terms in the singular include references to the plural, unless the context clearly dictates otherwise. Unless specifically stated otherwise, as used in this application, the term or is used in the inclusive sense and/or, and not in the exclusive sense of either/or.

The technical and scientific terms used in this document have the meanings usually

- 4 041985 understood by experts in the field of technology to which this description relates, unless otherwise indicated. Reference is made here to various methodologies and materials known to those skilled in the art. Standard reference works outlining the general principles of pharmacology and pharmacy include The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill Companies Inc., New York (2001) by Goodman and Gilman, and Remington, The Science and Practice of Pharmacy , 22nd Ed., Philadelphia (2013).

Used in this application, the term % by weight of compound X based on the volume of the composition, also abbreviated as % wt./vol., corresponds to the amount of compound X in grams, which is injected into 100 ml of the composition.

Used in this application, the term microparticle refers to a particle having a diameter D ₅₀ from 1 μm or more to about 200 μm. The term nanoparticle refers to a particle having a D ₅₀ diameter of less than 1 µm.

In exemplary embodiments, the diameter, which may be D ₅₀ , is from 1 µm or more to about 200 µm; and the term nanoparticle refers to a particle having a D50 of less than about 1 micron.

As used herein, the term eye disease is a disease, ailment, or other condition that affects or affects the eye, one of the parts or regions of the eye, or surrounding tissues such as the lacrimal glands. Generally speaking, the eye includes the eyeball and the tissues and fluids that make up the eyeball, the periocular muscles (such as the oblique and rectus muscles), the part of the optic nerve that is in or near the eyeball, and surrounding tissues such as the lacrimal glands and eyelids. .

As used herein, an anterior eye disease is a disease, ailment, or condition that affects or affects the anterior (i.e., anterior to the eye) ocular region, or a region such as the periocular muscle, eyelid, lacrimal gland, or tissue or eyeball fluid, which is located in front of the back wall of the lens capsule or ciliary muscles.

Thus, anterior eye disease primarily affects or affects one or more of the following: the conjunctiva, cornea, anterior chamber, iris, lens or lens capsule, and the blood vessels and nerves that vascularize or innervate the anterior or part of the eye. Disease of the anterior part of the eye is also considered here as extending to the lacrimal apparatus, in particular the lacrimal glands, which secrete tears, and their excretory ducts, which carry tear fluid to the surface of the eye.

In addition, the anterior eye condition affects or affects the posterior chamber, which is behind the retina but in front of the posterior wall of the lens capsule.

Posterior eye disease is a disease, ailment or condition that primarily affects or affects the posterior region or part of the eye such as the choroid or sclera (in a position behind the plane passing through the back wall of the lens capsule), the vitreous body, the vitreous chamber body, retina, optic nerve (ie, optic disc), and blood vessels and nerves that vascularize or innervate the posterior region or part of the eye.

Thus, the posterior eye disease may include a disease, ailment, or condition such as, for example, macular degeneration (such as non-exudative age-related macular degeneration and exudative age-related macular degeneration); choroidal neovascularization; acute macular neuroretinopathy; macular edema (such as cystoid macular edema and diabetic macular edema); Behçet's disease, retinal diseases, diabetic retinopathy (including proliferative diabetic retinopathy); occlusive lesion of the retinal artery; occlusion of the central retinal vein; retinal disease associated with uveitis; retinal disinsertion; an eye injury that affects the back region or part of the eye; disease of the back of the eye caused or mediated by laser eye treatment; diseases of the back of the eye caused or mediated by photodynamic therapy, photocoagulation; radiation retinopathy; disorders of the epiretinal membrane; occlusion of the branch of the retinal vein of the retina; anterior ischemic optic neuropathy; non-retinopathic diabetic retinal dysfunction, retinitis pigmentosa and glaucoma. Glaucoma can be considered a disease of the back of the eye, since the therapeutic goal is to prevent loss or reduce the frequency of loss of vision due to damage or loss of retinal or optic nerve cells (ie, in neuroprotection).

Disease of the anterior part of the eye includes a disease, ailment, or condition such as, for example, aphakia; pseudophakia; astigmatism; blepharospasm; cataract; diseases of the conjunctiva; conjunctivitis; corneal diseases; corneal ulcer; dry eye syndromes; eyelid diseases; diseases of the lacrimal apparatus; obstruction of the lacrimal duct; myopia; presbyopia; pupil disorders; refractive error and strabismus. Glaucoma can also be considered a disease of the anterior part of the eye, since the clinical goal of treating glaucoma may be to reduce the hypertension of the aqueous fluid in the anterior chamber of the eye (ie, lower intraocular pressure).

- 5 041985

The present disclosure relates to and is directed to ophthalmic compositions for topical drug delivery to the eye(s) and methods of treating an eye disease such as an anterior eye disease or a posterior eye disease or an eye disease that can be characterized as an anterior eye disease and disease of the back of the eye.

Solid complex of cyclodextrin and active pharmaceutical ingredient.

The composition of the invention contains a solid complex comprising an active pharmaceutical ingredient and a cyclodextrin. A complex comprising an active pharmaceutical ingredient and a cyclodextrin may be referred to as an active pharmaceutical ingredient/cyclodextrin complex or a drug/cyclodextrin complex. When the active pharmaceutical ingredient is dexamethasone and the cyclodextrin is γ-cyclodextrin, the complex comprising dexamethasone and γ-cyclodextrin may be referred to as a dexamethasone/γ-cyclodextrin complex.

The solid complex of the composition of the present invention may be an aggregate of complexes. An aggregate of complexes may correspond to an aggregate of a plurality of complexes, in particular a plurality of inclusion complexes containing an active pharmaceutical ingredient and a cyclodextrin.

According to one embodiment, the ophthalmic composition of the present invention is a microsuspension. The term microsuspension is intended to refer to a composition containing microparticles of solid complexes suspended in a liquid phase.

In particular, the ophthalmic composition of the present invention contains a solid complex that has a D ₅₀ diameter of less than about 100 microns, in particular from about 1 to about 100 microns. In one embodiment, the diameter D ₅₀ may range from about 1 to about 25 microns, in particular from about 1 to about 20 microns, more specifically from about 1 to about 10 microns, even more specifically from about 2 to about 10 microns, even more particularly from about 2 to about 5 microns, or from about 3 to about 8 microns. The diameter D ₅₀ can be measured in accordance with the test method described in this document.

The European Pharmacopoeia (01/2008: 1163) states that eye drops in the form of a suspension must meet the following requirements: for every 10 µg of solid active substance, not more than about 20 particles having a maximum size exceeding about 25 µm, and not more than about 2 of these particles have a maximum size in excess of about 50 microns. None of the particles can have a maximum size greater than about 90 microns. The compositions according to the invention comply with the requirements of the European Pharmacopoeia (01/2008: 1163).

In general, it is recommended that the particle sizes in aqueous eye drop suspensions be as small as possible, preferably below about 10 µm, to prevent eye irritation. In addition, the settling rate in aqueous suspensions is proportional to the particle diameter, with the settling rate of large particles being higher than that of fine particles, provided that all other factors remain constant.

Cyclodextrin.

The composition according to the invention contains a cyclodextrin. The composition according to the invention may contain a mixture of cyclodextrins.

Cyclodextrins, which are also known as cycloamyloses, are obtained by the enzymatic conversion of starch. They have a cyclic structure that is hydrophobic on the inside and hydrophilic on the outside. Due to the amphiphilic nature of the ring, cyclodextrins are known to increase the solubility and bioavailability of hydrophobic compounds.

As shown in FIG. 1, cyclodextrins are cyclic oligosaccharides containing 6 (α-cyclodextrin), 7 (β-cyclodextrin) and 8 (γ-cyclodextrin) glucopyranose monomers linked by a-1,4-glycosidic bonds, α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin are natural products resulting from the microbial degradation of starch. The outer surface of donut-shaped cyclodextrin molecules is hydrophilic, bearing numerous hydroxyl groups, but their central cavity is somewhat lipophilic (Kurkov, S.V., Loftsson, T., 2013. Cyclodextrins. Int. J. Pharm. 453, 167-180; Loftsson, T., Brewster, M. E., 1996. Pharmaceutical applications of cyclodextrins 1. Drug solubilization and stabilization Journal of Pharmaceutical Sciences 85, 1017-1025). In addition to the three natural cyclodextrins, numerous water-soluble cyclodextrin derivatives, including cyclodextrin polymers, have been synthesized and tested as drug carriers (Stella, V.J., He, Q., 2008. Cyclodextrins. Tox. Pathol. 36, 30-42).

Cyclodextrins increase the solubility and bioavailability of hydrophobic compounds. In aqueous solutions, cyclodextrins form inclusion complexes with many drugs by absorbing the drug molecule, or more commonly some lipophilic portion of the molecule, into the central cavity. This property has been used to formulate and deliver drugs. Reviews have been made of the formation of drug/cyclodextrin inclusion complexes, their effects on physicochemical

- 6 041985 properties of drugs, their effect on the ability of drugs to penetrate biomembranes, and the use of cyclodextrins in pharmaceutical products (Loftsson, T., Brewster, M.E., 2010. Pharmaceutical applications of cyclodextrins: basic science and product development. Journal of Pharmacy and Pharmacology 62 Loftsson, T., Brewster, M. E., 2011. Pharmaceutical applications of cyclodextrins: effects on drug permeation through biological membranes, J. Pharm. Pharmacol. 63, 1119-1135; Loftsson, T., Jarvinen, T. , 1999. Cyclodextrins in ophthalmic drug delivery Advanced Drug Delivery Reviews 36, 59-79).

Cyclodextrins and drug/cyclodextrin complexes are able to self-assemble in aqueous solutions to form nano- and micro-sized aggregates and micellar-like structures, which are also able to solubilize poorly soluble active pharmaceutical ingredients through non-inclusion complexation and micellar-like solubilization (Messner, M., Kurkov, SV, Jansook, P., Loftsson, T. 2010. Self-assembled cyclodextrin aggregates and nanoparticles Int. J. Pharm. 387, 199-208). In general, the tendency of cyclodextrins to self-assemble and form aggregates increases with the formation of drug/cyclodextrin complexes, and aggregation increases with increasing concentration of active pharmaceutical ingredient/cyclodextrin complexes. Generally, hydrophilic cyclodextrin derivatives such as 2-hydroxypropyl-β-cyclodextrin and 2-hydroxypropyl-γ-cyclodextrin and their complexes are freely soluble in water. On the other hand, natural α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin and their complexes have limited solubility in pure water or 129.5±0.7; 18.4 ± 0.2 and 249.2 ± 0.2 mg / ml, respectively, at 25 ° C (Sabadini E., Cosgrovea T. and do Carmo Egidio F., 2006. Solubility of cyclomaltooligosaccharides (cyclodextrins) in H ₂ O and D ₂ O: a comparative study Carbohydr Res 341, 270-274). It is known that their solubility increases somewhat with increasing temperature (Jozwiakowski, MJ, Connors, K.A., 1985. Aqueous solubility behavior of three cyclodextrins. Carbohydr. Res., 143, 51-59). Due to the limited solubility of their complexes, natural cyclodextrins most often exhibit B _s type or Bj type phase dissolution diagrams (Brewster ME, Loftsson T., 2007, Cyclodextrins as pharmaceutical solubilizers. Adv. Drug Deliv. Rev., 59, 645-666 ). It has been observed that the solubility of natural cyclodextrins can decrease below their pure water solubility upon formation of active pharmaceutical ingredient/cyclodextrin complexes (Fig. 2) (Jansook, P., Moya-Ortega, MD, Loftsson, T., 2010. Effect of selfaggregation of y-cyclodextrin on drug solubilization Journal of Inclusion Phenomena and Macrocyclic Chemistry 68, 229-236). The low concentration of dissolved active pharmaceutical ingredient/cyclodextrin complexes prevents the formation of nano- and microparticles containing active pharmaceutical ingredient/cyclodextrin complexes. In addition, other excipients, such as water-soluble polymers used to stabilize nano- and microsuspensions, can form complexes with cyclodextrins and thus further hinder the formation of active pharmaceutical ingredient/cyclodextrin complexes.

Applicants have previously described the preparation and study of cyclodextrin-based eye drops containing dexamethasone (Johannesson, G., Moya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014 Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid Acta Ophthalmologica 92, 550-556 Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery, US Pat. Thorsteinn Loftsson and Einar Stefansson, Cyclodextrin nanotechnology for ophthalmic drug delivery, US Pat. No. 8,633,172 (Jan. 21, 2014) )), dorzolamide (Johannesson, G., Moya-Ortega, M.D., Asgrimsdottir, G.M., Lund, S.H., Thorsteinsdottir, M., Loftsson, T., Stefansson, E., 2014. Kinetics of γ-cyclodextrin nanoparticle suspension eye drops in tear fluid. ica 92, 550-556; Gudmundsdottir, B.S., Petursdottir, D., Asgrimsdottir, G.M., Gottfredsdottir, M.S., Hardarson, S.H., Johannesson, G., Kurkov, S.V., Jansook, P., Loftsson, T., Stefansson, E. 2014 nanoparticle eye drops with dorzolamide: effect on intraocular pressure in man. J. Ocul. Pharmacol. Ther. 30, 35-41), irbesartan (Muankaew, C, Jansook, P., Stefansson, E., Loftsson, T., 2014. Effect of γ-cyclodextrin on solubilization and complexation of irbesartan: influence of pH and excipients. Int. J. Pharm. 474, 80-90), telmisartan (C. Muankaew, P. Jansook, H.H. Sigur6sson, T. Loftsson, 2016, Cyclodextrin-based telmisartan ophthalmic suspension: Formulation development for water-insoluble drugs. Int. J. Pharm 507, 21-31) and cyclosporin A (S. J0hannsd0ttir, P. Jansook, E. Stefansson, T. Loftsson, 2015, Development of a cyclodextrin-based aqueous cyclosporin A eye drop formulation. Int. J. Pharm. 493( 1-2), 86-95) in cyclodextrin nanoparticles. Studies have shown that nanoparticles increase the contact time of the drug with the ocular surface and the bioavailability of the drug in the eye. Nano- and microparticles of active pharmaceutical ingredient/cyclodextrin not only adhere to the surface of the eye, but also improve the solubility of the drug in aqueous lacrimal fluid. Nano- and microparticles composed of active pharmaceutical ingredient/γ-cyclodextrin complexes have been shown to be particularly effective drug carriers for topical delivery of the active pharmaceutical ingredient to the eye.

There are two approaches for obtaining nano- and microparticles and for obtaining nano- and microstructures: a top-down approach and a bottom-up approach. Approach to obtaining nanoparticles and microparticles

- 7 041985 active pharmaceutical ingredient / cyclodextrin from top to bottom usually involves grinding solid complexes of the active pharmaceutical ingredient / cyclodextrin to obtain nanoparticles and microparticles of the required diameter. The top-down approach can lead to surface defects and contamination. The bottom-up approach to the preparation of active pharmaceutical ingredient/cyclodextrin nanoparticles involves the assembly of individual molecules or individual active pharmaceutical ingredient/cyclodextrin complexes into microparticles of the required diameter. The bottom-up approach often results in microparticles with fewer defects and more uniform chemistry.

Applicants have surprisingly discovered the bottom-up preparation of drug/cyclodextrin nanoparticles, which can be performed in the presence or absence of stabilizing polymers. According to the claimed method, the drug and the cyclodextrin are suspended in an aqueous medium, such as an aqueous eye drop medium, and heated. At high temperature, the active compounds as well as cyclodextrin and other pharmaceutical excipients completely or almost completely dissolve in the aqueous medium, and the concentration of drug/cyclodextrin complexes and excipient/cyclodextrin complexes is much lower than at room temperature. The hot solution is then cooled at a predetermined rate to promote the formation of particles consisting of drug/cyclodextrin complexes with a diameter of less than about 100 microns. The particle diameter can also be controlled by the heating and cooling cycle and the presence of stabilizing polymers in the aqueous environment. To prevent or significantly inhibit or reduce degradation of the drug and/or excipient, excessive heating of the medium followed by relatively rapid cooling to room temperature is avoided.

Under controlled heating/cooling conditions, the aqueous solution containing the cyclodextrin is heated at such a temperature and for such a length of time as to limit the formation of a degradation product or sedimentation. The initial aqueous solution, if necessary, additionally contains an active drug agent and/or a stabilizing polymer. During the heating cycle, the initial milky white cyclodextrin solution turns into a clear solution. Heating is carried out using any method or means known to those skilled in the art. In preferred embodiments, the heating is carried out in an autoclave. For example, the autoclave may be cycled at about 90°C to about 120°C for about 20 to about 30 minutes.

In an exemplary embodiment, under controlled heat/cool conditions, an aqueous solution containing cyclodextrin is heated at such a temperature and for such a length of time as to limit degradation product formation or precipitation. The initial aqueous solution optionally additionally contains an active pharmaceutical ingredient and/or a stabilizing polymer. During the heating cycle, the initial milky white cyclodextrin solution turns into a clear solution. Heating is carried out using any method or means known to those skilled in the art. In preferred embodiments, heating is carried out using an autoclave or steam jacketed reactors. For example, the autoclave may be cycled at about 121°C for about 10 to about 30 minutes.

The heated solution is then cooled at a sufficient rate to provide a drug/cyclodextrin complex having a diameter of less than about 100 microns. Upon cooling, the drug/cyclodextrin complex precipitates to form the desired microsuspension. The microsuspension contains from about 70% to about 99% of the drug in microparticles and from about 1% to about 30% of the drug in nanoparticles as a carrier for eye drops. The microparticles have an average diameter of from about 1 to about 100 microns. The average microparticle diameter may range from about 1 to about 20 microns, from about 1 to about 25 microns, from about 1 to about 10 microns, or from about 2 to about 5 microns. In a typical embodiment, the microsuspension comprises about 80% drug in microparticles having an average diameter of about 1 to about 10 microns and about 20% drug in nanoparticles.

In one embodiment, the heated solution is then cooled at a sufficient rate to produce aggregates of drug/cyclodextrin complexes having a diameter of less than about 100 microns. Upon cooling, the drug/cyclodextrin complex precipitates to form the desired microsuspension. The microsuspension contains from about 40% to about 99% of the drug in microparticles and from about 1% to about 60% of the drug in nanoparticles or water-soluble drug/cyclodextrin complexes. The microparticles have an average diameter of from about 1 to about 100 microns. The average microparticle diameter may range from about 1 to about 20 microns, from about 1 to about 25 microns, from about 1 to about 10 microns, or from about 2 to about 5 microns. In a typical embodiment, the microsuspension comprises about 80% of the drug in microparticles having an average diameter of about 1 to about 10 microns and about 20% of the drug in nanoparticles.

- 8 041985

Microsuspensions obtained in accordance with the claimed method are characterized by an increase in the concentration of the dissolved drug by about 10-100 times compared with microsuspensions obtained in accordance with known methods in the form of water-soluble nanoparticles, individual drug/cyclodextrin complexes and dissolved drug molecules. For example, known compositions of dexamethasone contain a concentration of dexamethasone of about 1 mg/ml, where only 0.1 mg/ml is in solution. However, a dexamethasone/cyclodextrin composition prepared according to the claimed process may contain a dexamethasone concentration of about 15 mg/ml, where about 4 mg/ml is in solution.

In a preferred embodiment, the cyclodextrin is a-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, or combinations thereof.

In a particularly preferred embodiment, the cyclodextrin is a γ-cyclodextrin. Indeed, γ-cyclodextrin has a higher water solubility compared to the solubility of α-cyclodextrin and β-cyclodextrin. In addition, γ-cyclodextrin is prone to hydrolysis with the formation of glucose and maltose subunits by a-amylase in the lacrimal fluid and the gastrointestinal tract.

The amount of cyclodextrin in the ophthalmic composition of the present invention may be from 1 to 25%, in particular from 5 to 20%, more specifically from 10 to 18%, even more specifically from 12 to 16% by weight of the cyclodextrin based on the volume of the composition.

In addition to cyclodextrin, the ophthalmic composition of the invention may further comprise a water-soluble cyclodextrin derivative selected from the group consisting of 2-hydroxypropyl-a-cyclodextrin, 2-hydroxypropyl-b-cyclodextrin, 2-hydroxypropyl-γ-cyclodextrin, sulfobutyl ether α-cyclodextrin, sulfobutyl ether β -cyclodextrin, sulfobutyl ether γ-cyclodextrin, methylated α-cyclodextrin, methylated β-cyclodextrin, methylated γ-cyclodextrin and combinations thereof. The water-soluble cyclodextrin derivative can in particular be used to further increase the solubility of the active pharmaceutical ingredient, i.e. the amount of active pharmaceutical ingredient that is dissolved in the composition.

Active pharmaceutical ingredient.

The composition of the invention contains an active pharmaceutical ingredient.

An active pharmaceutical ingredient may be referred to as a drug. In the context of the invention, the active pharmaceutical ingredient is an ophthalmic drug, i. a compound which exhibits a therapeutic effect when administered in a sufficient amount to a patient suffering from an eye disease.

In particular, the ophthalmic composition may contain an active pharmaceutical ingredient selected from the group consisting of a steroid such as dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone and rimexolone; a kinase inhibitor such as axitinib, BMS-794833 (N-(4-((2-amino-3-chloropyridin-4yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1, 4-dihydropyridine-3-carboxamide), carbozantinib, cediranib, crizotinib, dasatinib, dovitinib, everolimus, lapatinib, lenvatinib, motesanib, nilotinib, nintedanib, orantinib, PD173074 (K-[2-[[4-(diethylamino)butyl]amino ]-6-(3,5dimethoxyphenyl)nirido[2,3-d]nirimidin-7-yl]-N'-(1,1-dimethylethyl)ureaα), pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, temsirolimus, tofacitinib , vandetanib, vemurafenib, and ZM323881 (5-((7-benzyloxyquinazolin-4-yl)amino)-4-fluoro-2-methylphenol); an angiotensin II receptor antagonist such as candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan; an aldose reductase inhibitor such as 2-methylsorbinol; an immunosuppressant such as sirolimus; a carbonic anhydrase inhibitor such as acetazolamide, brinzolamide, dorzolamide, ethoxzolamide and methazolamide; an antimicrobial or antiviral agent such as acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline and zidovudine; an antihistamine such as levocabastine; and a non-steroidal anti-inflammatory active pharmaceutical ingredient such as bromfenac, diclofenac, indomethacin and nepafenac; and their combinations.

The active drug agent for use in nano- and microparticles in exemplary embodiments may be selected from the group consisting of a steroid such as dexamethasone, difluprednate, estradiol, fluocinolone, fluorometholone, hydrocortisone, loteprednol etabonate, prednisolone, triamcinolone, and rimexolone; a kinase inhibitor such as axitinib, BMS-794833 N-(4-((2amino-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-5-(4-fluorophenyl)-4-oxo-1,4 -dihydropyridine-3-carboxamide), carbozantinib, cediranib, dovitinib, lapatinib, lenvatinib, motesanib, nintedanib, oratinib, PD173074 (R-[2-[[4-(diethylamino)butyl]amino]-6-(3,5- dimethoxyphenyl)pyrido[2,3-d]pyrimidin-7-yl]N'-(1,1-dimethylethyl)urea), pazopanib, regorafenib, sorafenib, tofacitinib and ZM323881 (5-((7benzyloxyquinazolin)-4-yl) amino)-4-fluoro-2-methylphenol); an angiotensin II receptor antagonist such as candesartan, irbesartan, losartan, olmesartan, telmisartan and valsartan; Aldose inhibitors

- 9 041985 ductases such as 2-methylsorbinol; an immunosuppressant such as sirolimus, a carbonic anhydrase inhibitor such as acetazolamide, brinzolamide, dorzolamide, ethoxzolamide and methazolamide; an antimicrobial and antiviral agent such as acyclovir, chloramphenicol, chlortetracycline, ciprofloxacin, fusidic acid, ganciclovir, norfloxacin, ofloxacin, tetracycline and zidovudine; an antihistamine such as levocabastine; and a non-steroidal anti-inflammatory drug such as, but not limited to, bromfenac, diclofenac, indomethacin, nepafenac, or combinations thereof.

According to a preferred embodiment, the ophthalmic composition comprises an active pharmaceutical ingredient selected from the group consisting of dexamethasone, axitinib, cediranib, dovitinib, motesanib, pazopanib, regorafenib, losartan, olmesartan, dorzolamide, diclofenac, nepafenac, and combinations thereof. More preferably the active pharmaceutical ingredient is dexamethasone.

The concentration of the active pharmaceutical ingredient in the ophthalmic composition of the invention may be from about 0.1 to about 100 mg/ml, in particular from about 1 to about 100 mg/ml, in particular from about 1 mg/ml to about 50 mg/ml, more specifically from about 1 mg/ml to about 20 mg/ml, even more specifically from about 5 mg/ml to about 25 mg/ml, even more specifically from about 10 mg/ml to about 20 mg/ml.

In illustrative embodiments, the active pharmaceutical ingredient (i.e., drug) is present in the original aqueous solution at a concentration of from about 1 mg/mL to about 100 mg/mL. In addition, the desired final concentration of the active pharmaceutical ingredient/cyclodextrin complex can be obtained with an initial concentration of the active pharmaceutical ingredient from about 1 mg/ml to about 50 mg/ml and from about 1 mg/ml to about 20 mg/ml.

In other illustrative embodiments, the active pharmaceutical ingredient is present in the original aqueous solution at a concentration of from about 0.01 mg/mL to about 10 mg/mL.

Compositions of the present invention can be characterized by an increase in the concentration of the dissolved active pharmaceutical ingredient by 10-100 times compared to compositions obtained in accordance with known methods.

In particular, from 60 to 95 wt.%, more specifically from 70 to 90 wt.% of the active pharmaceutical ingredient in the composition may be in the form of a solid complex of the active pharmaceutical ingredient and cyclodextrin.

Even more specifically, from 5 to 40 wt.%, in particular from 10 to 30 wt.%, of the active pharmaceutical ingredient in the composition may be in dissolved form. The dissolved form includes an uncomplexed active pharmaceutical ingredient that dissolves in the liquid phase, and complexes of the active pharmaceutical ingredient and cyclodextrin that dissolve in the liquid phase, as well as water-soluble nanoparticles consisting of aggregates of drug/cyclodextrin complexes.

Preferably, from 0 to 0.5% by weight of the active pharmaceutical ingredient in the composition may be in a non-complexing solid form. As such, the composition of the present invention may be substantially free of solid, non-complexing active pharmaceutical ingredient particles.

In one embodiment, the microsuspension may contain from about 70% to about 99% active pharmaceutical ingredient in microparticles and from about 1% to about 30% active pharmaceutical ingredient in nanoparticles. More specifically, the microsuspension may contain about 80% of the active pharmaceutical ingredient in microparticles having a diameter of from about 1 micron to about 10 microns, and about 20% of the active pharmaceutical ingredient in nanoparticles.

In another embodiment, the microsuspension may contain from about 40% to about 99% active pharmaceutical ingredient in microparticles and from about 1% to about 60% active pharmaceutical ingredient in nanoparticles or water-soluble active pharmaceutical ingredient/cyclodextrin complexes. In particular, the microsuspension may comprise from about 80% to about 90% of the active pharmaceutical ingredient in microparticles having a diameter of from about 1 μm to about 10 μm, and from about 10% to about 20% of the active pharmaceutical ingredient in nanoparticles or water-soluble active pharmaceutical ingredient complexes. ingredient/cyclodextrin.

Polymer.

The composition of the present invention may further comprise a polymer.

In particular, said polymer may be a water-soluble polymer. Moreover, the specified polymer may be a polymer that increases the viscosity. The term viscosity-increasing polymer is intended to mean a polymer that increases the viscosity of a fluid. The polymer increases the viscosity of the composition of the invention. Increasing the viscosity leads to an increase in the physical stability of the composition. As such, the composition of the invention is less prone to settling

- 10 041985 solid complex when it contains a polymer. Thus, the polymer can be considered as a polymeric stabilizing agent.

In particular, the polymer may be a surface active polymer. The term surface active polymer is intended to mean a polymer that exhibits the properties of a surfactant. Surface active polymers may, for example, contain hydrophobic chains grafted onto a hydrophilic backbone polymer; hydrophilic chains grafted onto a hydrophobic backbone; or alternating hydrophilic and hydrophobic segments. The first two types are called graft copolymers and the third type is called block copolymer.

In one embodiment, the ophthalmic composition of the present invention contains a polymer selected from the group consisting of a polyoxyethylene fatty acid ester; polyoxyethylene alkylphenyl ether; polyoxyethylene alkyl ether; a cellulose derivative such as alkylcellulose, hydroxyalkylcellulose and hydroxyalkylalkylcellulose; a carboxyvinyl polymer such as a carbomer such as Carbopol 971 and Carbopol 974; polyvinyl polymer; polyvinyl alcohol; polyvinylpyrrolidone; a copolymer of polyoxypropylene and polyoxyethylene; tyloxapol; and their combinations.

Examples of suitable polymers include polyethylene glycol monostearate, polyethylene glycol distearate, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyoxyethylene lauryl ether, polyoxyethylene octyl dodecyl ether, polyoxyethylene stearyl ether, polyoxyethylene myristyl ether, polyoxyethylene oleyl ether, sorbitan esters, polyoxyethylene hexadecyl ether (e.g. polyoxyethylene sorbitan and fatty acids (eg Tween 20 and Tween 80 (ICI Specialty Chemicals)); polyethylene glycols (e.g. Carbowax 3550 and 934 (Union Carbide)), polyoxyethylene stearates, calcium carboxymethylcellulose, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, cellulose, polyvinyl alcohol (PVA), poloxamers (e.g. Pluronic F68 and F108), which are block- copolymers of ethylene oxide and propylene oxide); poloxamines (for example, Tetronic 908, also known as Poloxamine 908, which is a tetrafunctional block copolymer obtained by sequentially adding propylene oxide and ethylene oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany, NJ)); Tetronic 1508 (T-1508) (BASF Wyandotte Corporation), Tritons X-200, which is an alkylaryl polyethersulfonate (Rohm and Haas); Phospholipid PEG derivative, Cholesterol PEG derivative, Cholesterol PEG derivative, Vitamin A PEG derivative, Vitamin E PEG derivative, vinylpyrrolidone-vinyl acetate random copolymers, combinations thereof, and the like, but are not limited to.

Particularly preferred examples of polymers according to the invention are tyloxapol and a copolymer of polyoxypropylene and polyoxyethylene.

More specifically, the polyoxypropylene-polyoxyethylene copolymer may be a triblock copolymer having a hydrophilic block-hydrophobic block-hydrophilic block configuration.

In one embodiment, the composition according to the invention contains a polymer that is a poloxamer. Poloxamers may include any type of poloxamer known in the art. Plaxamers include a shelter 101, a shelter 105, a shelter 108, a shelter 122, a shelter 123, a shelter 124, a shelter 181, a shelter 182, a shelter 184, a shelter 184, a shelter 185, a shelter 188, a shelter 212, a shelter 215, a shelter 217, a shelter of 231, a shelter Poloxamer 234, shelter 235, shelter 237, shelter 238, shelter 282, shelter 284, shelter 288, shelter 331, shelter 333, shelter 334, shelter 335, shelter 338, shelter 401, shelter 402, shelter 403, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405. benzoate and poloxamer 182 dibenzoate. Poloxamers are also referred to by their trade name Pluronic, such as Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F 108, Pluronic F 108NF, Pluronic F 127, Pluronic F 127 NF 3, Pluronic F 3, Pluronic F 3 Pluronic F 68, Pluronic F 77, Pluronic F 87, Pluronic F 88, Pluronic F 98, Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L 35, Pluronic L 43, Pluronic L 44, Pluronic L 61, Pluronic L 62, Pluronic L 62LF, Pluronic L 62D, Pluronic L 64, Pluronic L 81, Pluronic L 92, Pluronic L 44, Pluronic N 3, Pluronic R 103, Pluronic R 104, Pluronic R 105, Pluronic R 123, Pluronic R 65, Pluronic R 84, Pluronic R 85, their combinations, etc.

Particularly useful polymers as stabilizers are poloxamers. Poloxamers may include any type of poloxamer known in the art. Plaxamers include a shelter 101, a shelter 105, a shelter 108, a shelter 122, a shelter 123, a shelter 124, a shelter 181, a shelter 182, a shelter 184, a shelter 184, a shelter 185, a shelter 188, a shelter 212, a shelter 215, a shelter 217, a shelter of 231, a shelter Poloxamer 234, shelter 235, shelter 237, shelter 238, shelter 282, shelter 284, shelter 288, shelter 331, shelter 333, shelter 334, shelter 335, shelter 338, shelter 401, shelter 402, shelter 403, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405, shelter 405. benzoate and poloxamer 182 dibenzoate. Poloxamers also mention

- 11 041985 sold under their trade name Pluronic, such as Pluronic 10R5, Pluronic 17R2, Pluronic 17R4, Pluronic 25R2, Pluronic 25R4, Pluronic 31R1, Pluronic F 108 Cast Solid Surfacta, Pluronic F 108NF, Pluronic F 108 Pastille , Pluronic F 108 Pastille Poloxamer 338, Pluronic F 127, Pluronic F 127NF, Pluronic F 127NF 500 BHT Prill, Pluronic F 127NF Prill Poloxamer 407, Pluronic F 38, Pluronic F 38 Pastille, Pluronic F 68, Pluronic F 68 Pastille, Pluronic F 68 LFille F 68 NF, Pluronic F 68 NF Prill Poloxamer 188, Pluronic F 77, Pluronic F 77 Micropastille, Pluronic F 87, Pluronic F 87 NF, Pluronic F 87 NF Prill Poloxamer 237, Pluronic F 88, Pluronic F 88 Pastille, Pluronic F 98 , Pluronic L 10, Pluronic L 101, Pluronic L 121, Pluronic L 31, Pluronic L 35, Pluronic L 43, Pluronic L 44 NF Poloxamer 124, Pluronic L 61, Pluronic L 62, Pluronic L 62 LF, Pluronic L 62D, Pluronic L 64, Pluronic L 81, Pluronic L 92, Pluronic L44 NF INH surfactant Poloxamer 124 View, Pluron IR N 3, Pluronic R 103, Pluronic R 104, Pluronic R 105, Pluronic R 123 Surfactant, Pluronic R 65, Pluronic R 84, Pluronic R 85, their combinations, etc.

Another polymeric stabilizing agent compatible with the compositions and methods described herein is tyloxapol. In preferred embodiments, the stabilizer and co-solvent is tyloxapol, which is a 4-(1,1,3,3-tetramethylbutyl)phenol polymer with formaldehyde and oxirane.

Solutions and microsuspensions prepared in accordance with the method of the applicants, if necessary, contain additional additives. For example, the solution and/or microsuspension is expected to additionally contain ethylenediaminetetraacetic acid (EDTA). EDTA can be used, for example, to reduce degradation or as a stabilizer. It is also assumed that the solution and/or microsuspension are isotonic, for example with the addition of sodium chloride.

In a typical embodiment, the EDTA may be the disodium salt of ethylenediaminetetraacetic acid.

In one method, the active drug agent and at least one cyclodextrin are suspended in an aqueous eye drop carrier to form a suspension having a milky appearance. The suspension is then heated for a sufficient period of time at a sufficient temperature until the drug and the cyclodextrin are dissolved in the aqueous solution of the eye drops and no degradation product is formed. Once the drug and cyclodextrin are dissolved, the milky suspension turns into a substantially clear solution. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing a drug/cyclodextrin microparticulate complex.

In another embodiment, the active drug agent, at least one cyclodextrin and at least one polymer are suspended in an aqueous eye drop vehicle to form a suspension having a milky appearance. The suspension is then heated for a sufficient period of time at a sufficient temperature until the drug, cyclodextrin and polymer are dissolved in the aqueous solution of the eye drops and no degradation product is formed. Once the drug, cyclodextrin and polymer are dissolved, the milky suspension turns into a substantially clear solution. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing a drug/cyclodextrin/polymer microparticulate complex. In this alternative embodiment, the drug/cyclodextrin/polymer complex comprises a polymer coating.

In an alternative method, at least one cyclodextrin is suspended in an aqueous eye drop carrier to form a suspension having a milky appearance. The cyclodextrin suspension is heated for a sufficient period of time at a sufficient temperature to dissolve the cyclodextrin in the aqueous solution of the eye drops. The active drug agent is added to the heated aqueous suspension while stirring the solution until the drug is dissolved in the solution. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing a drug/cyclodextrin microparticulate complex.

In yet another method, the cyclodextrin and at least one polymer are suspended in an aqueous eye drop vehicle to form a suspension having a milky appearance. After dissolution of the cyclodextrin and the polymer, the milky suspension turns into a substantially clear solution. The active drug agent is added to the heated aqueous suspension while stirring the solution until the drug is dissolved in the solution. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing a drug/cyclodextrin/polymer microparticulate complex. The resulting drug/cyclodextrin/polymer complex contains a polymer coating.

In another method, at least one polymer and the drug are suspended in an aqueous eye drop carrier to form a suspension having a milky appearance. In another container, at least one cyclodextrin is suspended in water to form a suspension having a milky appearance. Both suspensions are heated for a sufficient period of time at a sufficient temperature until the cyclodextrin solution is clear, the polymer/drug suspension is still a milky suspension, and no (or virtually no) degradation product is formed. The cyclodextrin solution is added to the polymer/drug phase and the mixture becomes clear

- 12 041985 as the drug dissolves and the solution is stirred for a sufficient period of time at the same temperature. The resulting solution is cooled at a rate sufficient to obtain a microsuspension containing a drug/cyclodextrin microparticulate complex.

The polymer that can be incorporated into the composition of the present invention may have a weight average molecular weight of 2000 g/mol or higher, in particular a weight average molecular weight of from 2000 to 50000 g/mol, more specifically 5000 to 25000 g/mol, even more specifically from 9000 to 15000 g/mol.

The amount of polymer in the composition of the present invention may be from 0.5 to 5%, in particular from 1 to 4%, more specifically from 2 to 3%, more specifically from 2.2 to 2.8% by weight of the polymer on a volume basis. compositions.

When the composition contains a polymer, the viscosity of the composition may be 4 to 14 centipoise, preferably 5 to 13 centipoise, more preferably 6 to 12 centipoise.

Part of the polymer that is introduced into the composition according to the invention may be contained in solid complexes of the active pharmaceutical ingredient and cyclodextrin. As such, a portion of the polymer may be absorbed into the solid complex and/or a portion of the polymer may be applied to the surface of the solid complex. Thus, the microsuspension may include a drug/cyclodextrin/polymer microparticle complex. Said drug/cyclodextrin/polymer complex may contain a polymer coating.

Ophthalmologically acceptable environment.

The composition of the invention contains an ophthalmologically acceptable medium.

The term ophthalmologically acceptable medium is intended to mean a medium suitable for ophthalmic use of the composition. The ophthalmologically acceptable medium is preferably a liquid. The ophthalmologically acceptable medium may in particular contain water. In a particular embodiment, the ophthalmologically acceptable medium does not contain any solvent other than water. Thus, the ophthalmologically acceptable medium may correspond to an aqueous vehicle for eye drops.

According to a preferred embodiment, the ophthalmologically acceptable medium contains water and, if necessary, an additive selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffering agent, and combinations thereof.

In particular, the ophthalmologically acceptable medium may contain a preservative. A preservative may be used to limit the growth of bacteria in the composition.

Suitable examples of preservatives are sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkonium chloride, chlorobutanol, merthiolate, phenylmercury acetate, phenylmercury nitrate, methylparaben, phenylethyl alcohol, and combinations thereof. Preferably the preservative is benzalkonium chloride.

The amount of preservative in the composition according to the invention may be from 0 to 1%, in particular from 0.001 to 0.5%, more specifically from 0.005 to 0.1%, even more specifically from 0.01 to 0.04% by weight of the preservative in calculating the volume of the composition.

In particular, the ophthalmologically acceptable medium may contain a stabilizing agent. A stabilizing agent may be used to reduce degradation or stabilize the composition during storage.

An example of a suitable stabilizing agent is disodium edetate.

The amount of stabilizing agent in the composition according to the invention may be from 0 to 1%, in particular from 0.01 to 0.5%, more specifically from 0.08 to 0.2% by weight of the stabilizer, based on the volume of the composition.

In particular, the ophthalmologically acceptable medium may contain an electrolyte. The electrolyte can especially be used to render the composition isotonic.

Examples of suitable electrolytes include sodium chloride, potassium chloride, and combinations thereof. Preferably the electrolyte is sodium chloride.

The amount of electrolyte in the composition according to the invention may be from 0 to 2%, in particular from 0.1 to 1.5%, more specifically from 0.5 to 1% by weight of the electrolyte, based on the volume of the composition.

impurities.

The composition according to the present invention may in particular have a low concentration of impurities. The low amount of impurities in the composition of the invention results from the specific preparation process described below, in particular the specific heating and cooling steps used in the preparation process.

Accordingly, the composition according to the present invention may contain less than 2%, in particular less than 1%, more specifically less than 0.8% by weight of impurities, based on the weight of the active pharmaceutical ingredient.

The term impurities is intended to refer to a product that has not been specifically introduced into the composition according to the invention, but was obtained in situ during the manufacture of the composition. As such, the term impurity covers any product other than the active pharmaceutical ingredient.

- 13 041985 ent, cyclodextrin, complex of active pharmaceutical ingredient and cyclodextrin, polymer, water, preservative, stabilizing agent and electrolyte, as defined herein above. Impurities usually correspond to a by-product or degradation product of the active pharmaceutical ingredient. The amount of impurities in the composition can be determined by conventional analytical methods, including, for example, liquid chromatography, mass spectrometry and/or NMR. The amount of impurities can be measured soon after, for example less than 24 hours after preparation of the composition, or after storage of the composition, for example up to 2 years of storage of the composition at 25°C.

Surprisingly, applicants have found that compositions of the present invention containing particular active pharmaceutical ingredients were particularly prone to the formation of impurities when aqueous solutions or suspensions thereof were heated in the presence of cyclodextrins, such as γ-cyclodextrin, at temperatures above 120°C. However, when the compositions were prepared in accordance with the disclosure below, only minor amounts of impurities were obtained.

Accordingly, according to one embodiment, the present invention relates to an ophthalmic composition comprising, in an ophthalmologically acceptable medium, a solid complex containing an active pharmaceutical ingredient and a cyclodextrin; where the composition contains less than 2%, in particular less than 1%, more specifically less than 0.8 wt.% impurities based on the weight of the active pharmaceutical ingredient; where the active pharmaceutical ingredient is selected from the group consisting of dexamethasone, axitinib, cediranib, dovitinib, motesanib, pazopanib, regorafenib, losartan, olmesartan, dorzolamide, diclofenac, nepafenac and combinations thereof; and where the cyclodextrin is γ-cyclodextrin.

In particular, when the active ingredient is dexamethasone, the composition of the present invention may contain less than 0.5%, in particular less than 0.3%, more particularly less than 0.2% of dexamethasone enol aldehydes (i.e. mixtures of Z- and E -isomers) based on the weight of dexamethasone.

Dexamethasone enol aldehydes are dehydrated dexamethasone which has the following structures:

Z-isomer of enol aldehyde dexamethasone E-isomer of enol aldehyde dexamethasone

In addition, when the active ingredient is dexamethasone, the composition of the present invention may contain less than 0.5%, in particular less than 0.3%, more particularly less than 0.2% by weight of 16,17-unsaturated dexamethasone, based on the weight of dexamethasone. .

16,17-Unsaturated dexamethasone is a dehydrated dexamethasone that has the following structure:

He

16,17-unsaturated dexamethasone

In particular, when the active ingredient is dexamethasone, the composition of the present invention may contain less than 0.5%, in particular less than 0.3%, more particularly less than 0.2% by weight of dehydrated dexamethasone, i.e. enol aldehydes of dexamethasone (i.e. mixtures of isomers Z and E) and 16,17-unsaturated dexamethasone, based on the weight of dexamethasone.

It is known that dexamethasone can undergo base-catalyzed and photochemical degradation in aqueous solutions (E.M. Cohen, 1973, Dexamethasone. Analytical Profiles of Drug Substances, 2, 163-197) and that the active pharmaceutical ingredient is susceptible to oxidative degradation (R.E. Conrow, G.W. Dillow, L. Bian, L. Xue, O. Papadopoulou, J. K. Baker, B. S. Scott, 2002, Corticosteroid decomposition via a mixed anhydride, J. Org. Chem. 67, 6835-6836). The monograph on dexamethasone in the European Pharmacopoeia (01/2014: 0388) lists 11 impurities and degradation products and describes a method for

- 14 041985 detection. The British Pharmacopoeia (2015, version 19.0) contains a monograph on dexamethasone eye drop suspension and lists 5 impurities and degradation products and how to detect them. For maximum chemical stability in aqueous solutions, the pH of dexamethasone eye drop suspensions should be maintained between about 5.0 and about 6.0. It is believed that the main degradation product formed during the preparation of an aqueous suspension of dexamethasone eye drops containing cyclodextrin and sterilization of the eye drops in an autoclave contains 16,17 unsaturated dexamethasone and a mixture of the E- and Z-isomers of dexamethasone enol aldehydes formed by the Mattox rearrangement upon dehydration dexamethasone (B. Chen, M. Li, M. Lin, G. Tumambac, A. Rustum, 2009, A comparative study of enol aldehyde formation from betamethasone, dexamethasone, beclomethasone and related compound under acidic and alkaline conditions. Steroids, 74, 30-41). Due to steric limitations, in the case of dexamethasone, the Z-isomer of the enol aldehyde of dexamethasone is considered to be the main product. This degradation product is not listed in pharmacopoeias. Previously, 16,17-unsaturated dexamethasone has been found in parenteral dexamethasone solutions that have been heated to about 75°C for about 10 days (M. Spangler, E. Mularz, 2001, A validated, stability-indicating method for the assay of dexamethasone in drug substance and drug product analyses, and the assay of preservatives in drug product. Chromatographia, 54, 329-334), which is also a dehydrated degradation product of dexamethasone, and since the authors did not analyze the product, they probably found enol aldehydes. Previously, a Japanese group described two enol aldehydes and 16-17-unsaturated degradation products of betamethasone, both by acid catalysis (T. Hidaka, S. Huruumi, S. Tamaki, M. Shiraishi, H. Minato, 1980, Studies on betamethasone: behavior of betamethasone in acid or alkaline medium, photolysis and oxidation Yakugaku Zasshi, 100, 72-80). The apparent activation energy for the rate of degradation of dexamethasone to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in an aqueous solution of γ-cyclodextrin is unusually high, and thus these degradation products are essentially not formed at ambient room temperature. The presence of cyclodextrin in aqueous eye drops appears to promote dehydration of dexamethasone upon autoclaving to form 16,17-unsaturated dexamethasone and a mixture of E and Z isomers of dexamethasone enol aldehydes.

In aqueous solutions, diclofenac is relatively stable at room temperature when protected from light and oxygen (R. Chadaha, N. Kashid, D. V. S. Jain, 2003, Kinetics of degradation of diclofenac sodium in aqueous solution determined by a calorimetric method. Pharmazie, 58, 631- 635). Although β-cyclodextrin has been shown to stabilize diclofenac in aqueous solutions at about pH 7, we have found that γ-cyclodextrin can accelerate decomposition upon autoclaving, causing intense coloration of diclofenac aqueous solutions.

In doing so, Applicants have surprisingly found that the claimed method provides solutions and microsuspensions containing active pharmaceutical ingredient/cyclodextrin complexes that are stable in aqueous solution. For example, the inventive method provides a solution of dexamethasone/γ-cyclodextrin eye drops in which very low amounts of 16,17 unsaturated dexamethasone and dexamethasone enol aldehydes are formed. In addition, this invention provides a diclofenac/γ-cyclodextrin solution in which no degradation or precipitation product is observed for at least about 12 months. These aqueous eye drops containing γ-cyclodextrin also have the advantage of increasing the concentration of the dissolved active pharmaceutical ingredient by 10-100 times, in the case of dexamethasone by about 30 times, and have the necessary particle size to achieve maximum drug diffusion.

Dexamethasone composition.

According to a particularly preferred embodiment, the present invention relates to a dexamethasone ophthalmic composition comprising, in an ophthalmologically acceptable medium, a solid complex comprising dexamethasone and γ-cyclodextrin.

In one embodiment, the dexamethasone ophthalmic composition of the present invention contains less than 0.5%, in particular less than 0.3%, more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes, based on the weight of dexamethasone.

In another embodiment, the dexamethasone ophthalmic composition of the invention comprises a polymer as defined herein above. The viscosity of said dexamethasone ophthalmic composition may be 4 to 14 cps, preferably 5 to 13 cps, more preferably 6 to 12 cps.

In another embodiment, the dexamethasone ophthalmic composition of the present invention contains less than 0.5%, in particular less than 0.3%, more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes based on the weight of dexamethasone; the dexamethasone ophthalmic composition of the invention contains a polymer; and the viscosity of the dexamethasone ophthalmic composition is 4 to 14 cps, preferably 5 to 13 cps, more preferably 6 to 12 cps.

- 15 041985

The concentration of dexamethasone in the ophthalmic composition according to the invention may be from 10 to 20 mg/ml. Thus, the amount of dexamethasone in the composition of the present invention is much higher than in known dexamethasone compositions, which contain a concentration of dexamethasone of about 1 mg/ml, where about 0.1 mg/ml is in solution. In particular, the concentration of dexamethasone in the ophthalmic composition of the present invention may be about 15 mg/ml, where about 4 mg/ml is in solution.

In particular, from 60 to 95 wt.%, more specifically from 70 to 90 wt.% dexamethasone in the composition may be in the form of a solid complex of dexamethasone and γ-cyclodextrin.

More specifically, from 5 to 40 wt.%, in particular from 10 to 30 wt.% dexamethasone in the composition may be in dissolved form. The dissolved form includes non-complexing dexamethasone, which is dissolved in the liquid phase, complexes of dexamethasone and cyclodextrin, which are dissolved in the liquid phase, and water-soluble nanoparticles consisting of aggregates of dexamethasone/cyclodextrin complexes.

Preferably, 0 to 0.5% by weight of the dexamethasone in the composition may be in a non-complexing solid form. As such, the composition of the present invention may be substantially free of solid non-complexing particles of dexamethasone.

In one embodiment, the microsuspension may contain from about 70% to about 99% dexamethasone in microparticles and from about 1% to about 30% dexamethasone in nanoparticles. More specifically, the microsuspension may contain about 80% dexamethasone in microparticles having a diameter of about 1 to about 10 microns and about 20% dexamethasone in nanoparticles.

In another embodiment, the microsuspension may contain from 40 to 99% dexamethasone in microparticles and from about 1 to about 60% dexamethasone in nanoparticles or water-soluble dexamethasone/γ-cyclodextrin complexes. In particular, the microsuspension may contain from about 80 to about 90% dexamethasone in microparticles having a diameter of from about 1 μm to about 10 μm, and from about 10 to about 20% dexamethasone in nanoparticles or water-soluble dexamethasone/γ-cyclodextrin complexes.

The amount of γ-cyclodextrin in the dexamethasone ophthalmic composition may be from 1 to 25%, in particular from 5 to 20%, more particularly from 10 to 18%, even more particularly from 12 to 16% by weight of γ-cyclodextrin based on the volume of the composition.

In addition to γ-cyclodextrin, the ophthalmic composition of the present invention may further comprise α-cyclodextrin, β-cyclodextrin and/or a water-soluble cyclodextrin derivative as defined above.

The dexamethasone ophthalmic composition of the invention contains an ophthalmologically acceptable medium as defined above.

According to a preferred embodiment, the ophthalmologically acceptable medium comprises water and, if necessary, an additive selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffering agent, and combinations thereof, as defined above.

In a particularly preferred embodiment, the dexamethasone ophthalmic composition contains 1 to 2% dexamethasone, for example 1.5% dexamethasone;

12 to 16% γ-cyclodextrin, for example 14% γ-cyclodextrin;

2.2 to 2.8% polymer, for example 2.5% poloxamer;

0 to 0.2% stabilizing agent, for example 0.1% disodium edetate;

0 to 1% electrolyte, such as 0.57% sodium chloride; as well as water;

where % represent wt.% based on the volume of the composition.

Method for preparing ophthalmic compositions according to the invention

Compositions of the present invention can be obtained or obtained by the following methods. All embodiments, preferred statements and specific examples given in the previous sections apply equally to the methods of the invention and compositions obtained using the methods of the invention.

In the first embodiment, the method for obtaining an ophthalmic composition includes the steps:

a) suspending the active pharmaceutical ingredient and the cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension at a temperature T1 below 120° C. for a time t until the active pharmaceutical ingredient and the cyclodextrin are substantially dissolved in an ophthalmologically acceptable medium; And

c) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of the active pharmaceutical ingredient and cyclodextrin.

In the method of the first embodiment, the active pharmaceutical ingredient and the cyclo

- 16 041985 dextrin can be suspended in an ophthalmologically acceptable medium to obtain a suspension having a milky appearance. The suspension can then be heated for a sufficient period of time at a sufficient temperature until the active pharmaceutical ingredient and the cyclodextrin are dissolved in the ophthalmologically acceptable medium without the formation of a degradation product. Once the active pharmaceutical ingredient and the cyclodextrin are dissolved, the milky suspension may turn into a substantially clear solution. The resulting solution can then be cooled at a rate sufficient to obtain a microsuspension containing a solid active pharmaceutical ingredient/cyclodextrin complex.

In the second embodiment, the method for obtaining an ophthalmic composition includes the steps:

a) suspending the cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension until the cyclodextrin is completely dissolved in an ophthalmologically acceptable medium;

c) adding the active pharmaceutical ingredient in solid form to the solution in step (b) at a temperature T1 below 120°C and heating the mixture at a temperature T1 below 120°C for a time t until the active pharmaceutical ingredient becomes essentially dissolved in an ophthalmologically acceptable medium; And

d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of the active pharmaceutical ingredient and cyclodextrin.

In the method of the second embodiment, the cyclodextrin may be suspended in an ophthalmologically acceptable medium to obtain a suspension having a milky appearance. The cyclodextrin suspension can be heated for a sufficient period of time at a sufficient temperature until the cyclodextrin is dissolved in an ophthalmologically acceptable medium. The active pharmaceutical ingredient may be added in solid form to the heated aqueous solution while stirring the solution. Heating can be carried out for a sufficient period of time at a sufficient temperature until the active pharmaceutical ingredient is dissolved in an ophthalmologically acceptable medium, and no degradation product is formed. The resulting solution may be cooled at a rate sufficient to form a microsuspension containing the solid pharmaceutical ingredient/cyclodextrin complex.

In a third embodiment, the method for preparing an ophthalmic composition includes the steps of:

a) suspending the active pharmaceutical ingredient in an ophthalmologically acceptable medium to form a suspension and heating said suspension until the active pharmaceutical ingredient is substantially dissolved in the ophthalmologically acceptable medium;

b) suspending the cyclodextrin in an ophthalmologically acceptable medium to form a suspension and heating said suspension until the cyclodextrin is substantially dissolved in the ophthalmologically acceptable medium;

c) mixing the compositions from steps (a) and (b) at a temperature T1 below 120°C and heating the mixture at a temperature T1 below 120°C for a time t; And

d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of the active pharmaceutical ingredient and cyclodextrin.

In the method of the third embodiment, the active pharmaceutical ingredient may be suspended in an ophthalmologically acceptable cyclodextrin-free medium. The resulting suspension may have a milky appearance. Separately, the cyclodextrin may be suspended in an ophthalmologically acceptable medium free of the active pharmaceutical ingredient. The resulting suspension may have a milky appearance. The two suspensions can be heated or sterilized, for example by heating in an autoclave at 121° C. for 20 minutes. The two suspensions or hot solutions may then be mixed together and the mixture may be heated until the active pharmaceutical ingredient and cyclodextrin are complexed and no degradation product is formed. The resulting solution may be cooled at a rate sufficient to form a microsuspension containing the solid pharmaceutical ingredient/cyclodextrin complex.

The ophthalmic composition obtained by the methods of the first, second and third embodiments may contain less than 2%, in particular less than 1%, more specifically less than 0.8% by weight of impurities based on the weight of the active pharmaceutical ingredient.

The present invention also provides methods for preparing dexamethasone ophthalmic compositions according to the invention.

Accordingly, in a fourth embodiment, a method for preparing an ophthalmic composition is provided, comprising the steps of:

a) suspending dexamethasone and γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

- 17 041985

b) heating the suspension at a temperature T1 below 120° C. for a time t until the dexamethasone and γ-cyclodextrin are substantially dissolved in an ophthalmologically acceptable medium; And

c) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of dexamethasone and γ-cyclodextrin.

In a fifth embodiment, the method for preparing an ophthalmic composition comprises the steps of:

a) suspending the γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension;

b) heating the suspension until the γ-cyclodextrin dissolves in an ophthalmologically acceptable medium;

c) adding dexamethasone in solid form to the solution in step (b) at a temperature T1 below 120°C and heating the mixture at a temperature T1 below 120°C for a time t until the dexamethasone is substantially dissolved in the ophthalmologically acceptable environment; And

d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of dexamethasone and γ-cyclodextrin.

In the sixth embodiment, the method for obtaining an ophthalmic composition includes the steps:

a) suspending dexamethasone in an ophthalmologically acceptable medium to form a suspension and heating said suspension until the dexamethasone is substantially dissolved in the ophthalmologically acceptable medium;

b) suspending the γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension and heating said suspension until the γ-cyclodextrin is substantially dissolved in the ophthalmologically acceptable medium;

c) mixing the compositions from steps (a) and (b) at a temperature T1 below 120°C and heating the mixture at a temperature T1 below 120°C for a time t; And

d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of dexamethasone and γ-cyclodextrin.

The ophthalmic compositions obtained by the methods of the third, fourth and fifth embodiments may contain less than 0.5%, in particular less than 0.3%, more specifically less than 0.2% by weight of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in based on the weight of dexamethasone.

The heating step of the methods of the present invention is carried out at a T1 temperature below 120° C. to avoid the formation of impurities. In particular, the temperature T1 may be from 80 to 110°C, more specifically from 85 to 105°C, even more specifically from 90 to 100°C.

The heating step of the methods of the present invention is carried out for a time t. In particular, the heating time t is 5 minutes to 2 hours, more specifically 10 minutes to 1 hour, even more specifically 15 to 30 minutes.

During the heating cycle, the active pharmaceutical ingredient and/or the cyclodextrin are dissolved and a complex of the active pharmaceutical ingredient and the cyclodextrin is formed. Heating is carried out using any method or means known to those skilled in the art. In preferred embodiments, heating is carried out in an autoclave or steam jacketed reactor.

The cooling step in the methods of the present invention lowers the temperature of the composition from a T1 temperature to a T2 temperature to precipitate a solid complex of the active pharmaceutical ingredient and the cyclodextrin. In particular, the temperature T2 may be from 10 to 40°C, more specifically from 15 to 35°C, even more specifically from 20 to 30°C.

The cooling rate in the methods of the present invention can be maintained by lowering the temperature T1 to the temperature T2 at a rate of from 1 to 25°C/min, in particular from 2 to 20°C/min, more specifically from 5 to 18°C/min.

Cooling may be performed using any method or means known to those skilled in the art. In preferred embodiments, cooling is carried out using an ice bath or jacketed reactor with cooling liquid.

In the methods of some exemplary embodiments, such as the first, second, third, fourth, fifth, and sixth embodiments, the slurry from step (a) may further comprise a polymer as defined above. In the methods of the third and sixth embodiments, the slurry from step (b) may further comprise a polymer as defined above. When the initial slurry contains a polymer, a portion of the polymer may be absorbed into the solid complex and/or a portion of the polymer may be applied to the surface of the solid complex. Thus, the microsuspension obtained by the process of the invention may contain a drug/cyclodextrin/polymer microparticulate complex. Said drug/cyclodextrin/polymer complex may contain a polymer coating.

- 18 041985

When the polymer is introduced into the initial suspension in the methods of the present invention, the ophthalmic composition obtained by these methods may have a viscosity of 4 to 14 cps, preferably 5 to 13 cps, more preferably 6 to 12 cps.

The viscosity of the compositions obtained by the methods of the invention is higher than that of the compositions obtained by known production methods. Without wishing to be bound by any theory, Applicants believe that the implementation of the stage of controlled cooling of the process, in particular, with a cooling rate of from 1 to 25°C/min, after the stage of heating allows you to include less solid polymer in the solid complex, and, therefore, more polymer is in solution, thereby increasing the viscosity of the composition. Thus, the original manufacturing process disclosed herein makes it possible to obtain new compositions with increased viscosity with similar amounts of polymer, cyclodextrin and active pharmaceutical ingredient, as in the compositions of the prior art.

In the methods of the illustrative embodiments, for example, in the first, second, third, fourth, fifth and sixth embodiments, the ophthalmologically acceptable medium may contain water and, if necessary, an additive selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffer agent and their combinations.

In illustrative methods, for example in the first, second, fourth and fifth embodiments, the ophthalmologically acceptable medium in step (a) may contain water and, if necessary, an additive selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffering agent, and their combinations.

In other illustrative methods, such as in the third and sixth embodiments, the ophthalmologically acceptable medium in step (a) may contain only water, and the ophthalmologically acceptable medium in step (b) may contain water and, if necessary, an additive selected from the group consisting of a preservative, a stabilizing agent, an electrolyte, a buffering agent, and combinations thereof.

In alternative embodiments, for example in the methods of the third and sixth embodiments, the ophthalmologically acceptable medium of step (b) may contain only water, and the ophthalmologically acceptable medium of step (a) may contain water and, if necessary, an additive selected from the group consisting of of a preservative, a stabilizing agent, an electrolyte, a buffering agent, and combinations thereof.

The use of the composition according to the invention

The ophthalmic compositions of the present invention can be used to treat an eye disease, in particular an anterior or posterior eye disease, in particular uveitis, macular edema, macular degeneration, retinal detachment, eye tumors, fungal or viral infections, multifocal choroiditis, diabetic retinopathy, proliferative vitreoretinopathy (PVR), sympathetic ophthalmia, Vogt Koyanagi-Harada syndrome (FCH), histoplasmosis, uveal effusion and vascular occlusion. Compositions of the invention may be particularly useful in the treatment of uveitis, macular edema, diabetic retinopathy, proliferative vitreoretinopathy (PVR), and vascular occlusions.

The dexamethasone ophthalmic composition according to the present invention can in particular be used for the treatment of macular edema. In this case, the dexamethasone ophthalmic composition of the present invention may be locally administered to the eye in the amount of 1 drop of the composition three times a day. The amount of dexamethasone in said composition may be from 1 to 2%, in particular 1.5% by weight of dexamethasone, based on the volume of the composition.

Compositions of the present invention do not need to be administered as frequently as known topical dexamethasone formulations, i. 1 drop of the composition six times a day. Indeed, due to the increased viscosity of the composition, the solid complexes in the composition of the invention show a higher contact time on the ocular surface compared to known compositions, which increases the bioavailability of the active pharmaceutical ingredient.

The present disclosure also covers the use of the ophthalmic composition of the invention as an eye drop solution.

Measurement methods.

Diameter.

The diameter of a particle, such as a solid complex of an active pharmaceutical ingredient and a cyclodextrin, may correspond to a diameter D ₅₀ of the particle. The D ₅₀ diameter is also known as the median diameter or the mean value of the particle size distribution. The diameter D ₅₀ corresponds to the value of the particle diameter at 50% of the total distribution. For example, if D ₅₀ is 5 µm, then 50% of the particles in the sample are larger than 5 µm and 50% are less than 5 µm. The diameter D ₅₀ is generally used to represent the particle size of a group of particles.

The diameter and/or size of a particle or complex can be measured according to any method known to those skilled in the art. For example, the diameter D ₅₀ is measured using laser diffraction particle size analysis. There is usually a limited number

- 19 041985 methods for measuring/estimating the diameter and/or size of a particle or cyclodextrin/drug complex. In particular, those skilled in the art will recognize that physical properties (eg, particle size, diameter, median diameter, median particle size, etc.) are typically estimated/measured using such limited, exemplary known techniques. For example, such known techniques are described in Int. J Pharm. 493 (2015), 86-95, mentioned above, which is incorporated herein by reference in its entirety. In addition, such limited, known measurement/evaluation techniques were known in the art, as evidenced by other technical references such as, for example, European Pharmacopoeia (2.9.31 Particle size analysis by laser diffraction, January 2010) and Saurabh Bhatia, Nanoparticles types, classification, characterization, fabrication methods and drug delivery applications, Chapter 2, Natural Polymer Drug Delivery Systems, pp. 33-94, Springer, 2016, which are also incorporated herein by reference in their entirety.

For the particle size of complexes containing an active pharmaceutical ingredient other than dexamethasone, the particle size is measured using laser diffraction particle size analysis according to Eur. farm. 2.9.31.

For the particle size of the complexes containing dexamethasone, the particle size is measured using laser diffraction particle size analysis according to Eur. farm. 2.9.31 with the following parameters:

system: Malvern Mastersizer 3000 with hydro-MV distributor, Fraunhofer approximation, dispersant: water, dispersant refractive index: 1.33, measurement time: 1 s, background measurement time: 10 s, stirrer speed: 1200 rpm, light blocking range: 1-20%, model: standard, sample preparation: homogenize the eye drops by shaking, sample size: add 0.5 ml of eye drops to the dispersant, cleaning: rinse twice with the dispersant (water) and start the measurement, checking that the beam strength is less than 120 units in the first channels, and download background.

Viscosity.

The viscosity of the composition corresponds to the dynamic viscosity of said composition. Viscosity is measured at 25°C using a Brookfield digital viscometer. The viscosity of the composition is measured shortly after, i. less than 24 hours after preparation of the composition.

The percentage of drug in the solid complex and the percentage of dissolved drug.

The amount of drug in the form of solid complexes and the amount of dissolved drug are determined by centrifugation of the composition at 6000 rpm at a temperature of 22-230°C for 20-30 minutes.

The amount of drug dissolved corresponds to the amount of drug in the supernatant measured by high performance liquid chromatography.

The percentage of the drug in the form of a solid complex is obtained by the following formula:

(general drug - diluted drug) „„

Then drugs in solid complex =----------------------X TUU about total drug where total drug is the total amount of drug administered in the composition, in mg/ml; and dissolved drug is the amount of drug in the supernatant, in mg/mL.

The percentage of drug dissolved is obtained by the following formula:

% drug dissolved = 100 - % drug in solid complex.

Examples

The following examples are detailed by way of illustration only and should not be construed as limiting the spirit or scope of the invention; many modifications, both in materials and methods, will be apparent to those skilled in the art.

Example 1

The composition of dexamethasone aqueous eye drops is as follows: dexamethasone (1.50%), γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), benzalkonium chloride (0.02%), disodium edetate (0.10%) , sodium chloride (0.57%) in purified water, all w/v%. Five different methods were used.

F1: Dissolve or suspend the ingredients, including dexamethasone, in pure water and autoclave the mixture in a sealed vial at 121°C for 20 minutes. Vials containing a substantially clear aqueous solution were removed from the autoclave and became cloudy upon cooling to room temperature. Solid particles were analyzed by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and X-ray diffraction (XRD), showing that the solid particles contain dexamethasone/γ-cyclodextrin complexes.

F2: Dissolving or suspending ingredients, including dexamethasone, in pure water and heating

- 20 041985 stirring the mixture for 30 minutes to 90°C to form a clear solution. After further heating at 90°C for 15 min, the solution was allowed to cool and became cloudy at ambient temperature, reaching room temperature in about 3 h.

F3: dissolving or suspending the pharmaceutical excipients in pure water, heating the mixture to 90° C. to form a clear solution, and then adding dexamethasone solid powder to the hot solution. When the dexamethasone was dissolved (with stirring for 15 minutes), the solution was allowed to cool and became cloudy at ambient temperature, reaching room temperature within approximately 3 hours.

F4: Dissolve or suspend the pharmaceutical excipients in pure water and autoclave the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95° C., solid powder of dexamethasone was added to the solution. When the dexamethasone was dissolved (with stirring for 15 minutes), the solution was allowed to cool and became cloudy at ambient temperature, reaching room temperature within approximately 3 hours.

F5: Dissolving or suspending the pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95° C., solid powder of dexamethasone was added to the solution. When the dexamethasone was dissolved (with stirring for 15 minutes), the solution was quickly cooled to room temperature (within 20 minutes) and it became cloudy on cooling.

F6: excipients were divided into two parts, A and B. In part A, all excipients except γ-cyclodextrin were dissolved in pure water at 80°C, and in part B, γ-cyclodextrin was suspended (or dissolved) separately in pure water at 80°C. Dexamethasone was added to the mixture of excipients just before sterilization. Two parts of a mixture of excipients in water containing dexamethasone (part A) and γ-cyclodextrin suspended (or dissolved) in water (part B) were sterilized at 121° C. for 15 minutes. After sterilization, sterile γ-cyclodextrin was added to the remaining sterile excipients at 95°C. In other words, parts A and B were mixed. After stirring for 15 minutes, the solution was rapidly cooled to room temperature (over 20 minutes) to form a cloudy suspension. F6 did not contain benzalkonium chloride.

Table 1

Microparticle Formation Results Mean of Three Measurements ± Standard Deviation

Compound F1 F2 F3 F4 F5 F6 pH 4.5 5.1 5.0 5.0 4.7 4.7 Solid fraction of dexamethasone (%) 87.6±0.0 70.8±0.0 68D±0D 73.0±0.2 87D±0D 83.9±0.6 Solid fraction of γ-cyclodextrin (%) 91.6±0.0 89.6±3.4 90D±3.4 88.8±0.0 89.9±0.0 - Viscosity at 25°C (cP) 3.68±0.29 6.48±0.07 6.64±0.12 8.18±0.05 8.67±0.30 11.1±0.1 The average size particles (µm) 4.4±2.7 3.6 3.3

The results show that rapid cooling (F5) produces a microsuspension where more than about 80% of the active pharmaceutical ingredient and γ-cyclodextrin are in the solid phase as active pharmaceutical ingredient/γ-cyclodextrin complexes, and where most of the polymer is in aqueous solution ( i.e. has the highest viscosity). F1 settles over time but can redisperse with some agitation. However, F5 has a low tendency to settle over time and is easily redispersible with agitation. Thus, F5 exhibits significantly greater physical stability than F1.

Example 2

The composition of irbesartan aqueous eye drops is as follows: irbesartan (2.0%), γ-cyclodextrin (10.0%), HPMC (0.20%), tyloxapol (0.10%), benzalkonium chloride (0.02%), disodium edetate (0.10%), sodium chloride (0.50%) in purified water, all w/v%. Three different methods were used:

F7: Dissolve or suspend the ingredients including irbesartan in pure water and autoclave the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. The clear aqueous solution was allowed to cool to room temperature and became cloudy.

F8: Dissolving or suspending the pharmaceutical excipients in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 min to form a clear

- 21 041985 solution. After cooling to 95°C, the solid powder of irbesartan was added to the solution. When irbesartan dissolved (15 min), the solution was allowed to cool and became cloudy at ambient temperature, reaching room temperature within approximately 3 h.

F9: Dissolve or suspend the pharmaceutical excipients in pure water and autoclave the mixture in a sealed vial at 121°C for 20 minutes to form a clear solution. After cooling to 95°C, the solid powder of irbesartan was added to the solution. When irbesartan dissolved (15 min), the solution was rapidly cooled to room temperature (over 20 min) and it became cloudy.

For formulation F7, the formulation may have a solid drug content of 54%, a viscosity at 25°C (cp) of 4.36, and an average particle size (µm) of 2.44.

Example 3

Dexamethasone dehydration during the preparation of the aqueous dexamethasone eye drops described in Example 1 (formulations F1, F2, F3, F4, F5 and F6) was measured by quantifying 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in the eye drops after manufacture. Formulations F12, F13 and F14 were prepared as described in F1, ie. by dissolving or suspending the ingredients, including dexamethasone, in pure water and autoclaving the mixture in a sealed vial at 121°C for 20 minutes. Vials with a substantially clear aqueous solution were removed from the autoclave and became cloudy upon cooling at ambient conditions. The composition of F12 is identical to F1, but does not contain γ-cyclodextrin. F13 contains dexamethasone and γ-cyclodextrin suspended in pure water. F14 contains dexamethasone suspended in pure water. The effect of excipients and methods of preparation on the formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes is presented as the proportion (in%) of dexamethasone decomposed to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes.

table 2

Compound F1 F2 F3 F4 F5 F6 F12 F13 F14 Autoclaving at 121 °C for 20 min with dexamethasone X X X X X Heating at 90°C for 15 min with dexamethasone X X X X X Contains γcyclodextrin Yes Yes Yes Yes Yes Yes No Yes No pH 4.5 5.1 5.0 5.0 4.7 4.8 Fraction of dexamethasone in solution (%) 12.4 29.2 31.9 27.0 12.9 16.1 1.17 4.16 5.73 Proportion degraded to 16,17-unsaturated dexamethasone and enol aldehydes (%) 1.45 0.16 oh p oh p 0.08 0.20 0.18 1.34 0.13

The results presented in Table 2 show that the formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes was catalyzed by the presence of γ-cyclodextrin during heating in the autoclave of formulation F1 (contains all excipients) and F13 (includes γ-cyclodextrin but no other auxiliaries). substances). Much less 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes were formed in aqueous eye drops when γ-cyclodextrin was removed from the formulation (F12) or when the eye drops were prepared by heating to 90°C for 15 min (F2, F3 and F4) . Little or no formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes was formed in eye drops when stored at room temperature (22-23°C) for more than 12 months. During the preparation of F6, the aqueous suspension of γ-cyclodextrin and separately the aqueous suspension containing dexamethasone and all other ingredients except γ-cyclodextrin were autoclaved at 121°C for 15 min. After autoclaving, the two suspensions/two solutions were cooled to 95°C before mixing, and then cooled further to ambient temperature (see example 1). Only a small amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes formed in the aqueous eye drop formulation when dexamethasone was sterilized in the absence of γ-cyclodextrin.

Example 4

Amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes formed, expressed as the proportion (in %) of dexamethasone degraded to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in aqueous eye drops

- 22 041985 in the absence of autoclaving (i.e. heating to 121 ° C for 20 minutes) and autoclaving one, two and three times, shown in table. 3.

Table 3

pH Number of autoclaving cycles 0 1 2 h 2.5 0.085 1.06% 2.29% 3.12% 4.0 0.08% 1.14% 2.19% 3.03% 5.5 0.08% 1.22% 2.27% 3.46% 7.0 0.08% 0.86% 1.64% 2.57%

Amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes formed, expressed as the proportion (in %) of dexamethasone degraded to form 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes, in aqueous eye drops without autoclaving (i.e. heating to 121°C for 20 min) and after autoclaving one, two and three times, shown below.

The formation of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes is observed at all four pH values tested. Although less 16.17 unsaturated dexamethasone and dexamethasone enol aldehydes are formed at pH 7.0 than at pH 5.5, other degradation products appear. According to the British Pharmacopoeia 2015 (version 19.0), the pH value of an aqueous suspension of dexamethasone eye drops should be between 5.0 and 6.0.

Example 5

Decomposition of dexamethasone in F1 was studied at 25, 40, 60, 70 and 95°C. Apparent first order rate constants for the disappearance of dexamethasone were determined and the apparent activation energy was calculated using the Arrhenius equation. The equation was also used to estimate the rate constant of the first order of the disappearance of dexamethasone at 25°C. The decomposition time of 10% (t ₉₀ ; expiration date) and 0.5% (t ₉₉ , ₅ ) was also calculated from the rate constants.

Table 4 First order rate constant for degradation of dexamethasone in an aqueous eye drop formulation containing γ-cyclodextrin (i.e. F5) at pH 7.0

25°С 40°С 60°С 70°C 95°C First order rate constant (k in h' ¹ ) ^{1.442-10'7 2.483-10'6} 2.476-10' ^{5 2.044-10'4 3.277-10'3} Shelf life (t90 in days) 30.444 1.768 177 21.5 1.3 Time for 0.5% decomposition (t99.5 in hours) 34.761 2.018 202 24.5 1.5 Apparent activation energy (Ea) 3.2 kcal/mol = 134.5 kJ/mol Specified SHELF LIFE (t90) at 25°C 83.4 years Set time for 0.5% decomposition (t99.s) at 25°C 4.0 years

As a rule, E _a values are in the range of approximately 50 to 85 kJ/mol, and values exceeding 100 kJ/mol are very rare. The apparent value of E _a for dehydration of dexamethasone in an aqueous solution of γ-cyclodextrin with the formation of 16,17-unsaturated dexamethasone and enol aldehydes of dexamethasone is 134.5 kJ / mol and, thus, 16,17-unsaturated dexamethasone and enol aldehydes of dexamethasone are formed only in aqueous solutions of γ-cyclodextrin at extremely high temperatures.

Example 6

The influence of the cooling rate on the size of microparticles was studied. The solvent for dexamethasone eye drops contained γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), benzalkonium chloride (0.02%), disodium edetate (0.10%), sodium chloride (0.57% ) in purified water, all in w/v%. The solvent was heated in an autoclave (121° C. for 20 min) in a sealed vial to form a substantially clear solution. After cooling to 95° C., solid powder of dexamethasone (1.50% w/v) was added to the solution. After dissolution of dexamethasone (with stirring for 15 min), the solution was divided into small portions (about 5 ml) and placed in thermostated water set at different temperatures. Temperature changes were recorded over time. The particle size and viscosity of the resulting suspension were determined.

- 23 041985

Example 7

The influence of time and temperature of sterilization and the influence of mixing time were evaluated in the case of formulation F6. Formulations were prepared as described in Example 1. During the preparation of F6, an aqueous suspension of γ-cyclodextrin (part B) and separately an aqueous suspension containing dexamethasone and all other ingredients except γ-cyclodextrin (part A) were autoclaved at 121°C for 15 minutes. After autoclaving, the two suspensions/two solutions were cooled to 95°C before mixing, and then cooled further to ambient temperature (see examples 1 and 3).

The modified process parameters during sterilization and mixing of γ-cyclodextrin with other excipients and the resulting amounts of the fraction decomposed to 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes are shown in Table 1. 5.

Table 5

Compound Sterilization Mixing with UCD solution at 95°C The amount of 16.17 unsaturated dexamethasone and enol aldehydes of dexamethasone (%) F6 15 min, 121°C 15 minutes 0.20 F6a 15 min, 121°C No UCD 0.05 F6b 2x15 min, 121°C No UCD 0.10 F6c 15 min, 121°C 30 min 0.28 F6d 2x15 min, 121°C 15 minutes 0.25 F6e 15 min, 135°C 15 minutes 0.34

Formulations F6a and F6b did not contain γCD and showed only the effect of the sterilization step. F6a was sterilized in an autoclave once for 15 min at 121°C, while F6b underwent two cycles of sterilization under the same conditions. One sterilization cycle added 0.05% 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes (% of total dexamethasone in eye drops), and two sterilization cycles added 0.10% 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes.

Composition F6c showed the effect of double mixing time at 95°C after addition of γCD. An additional 15 minutes of mixing was added with an additional 0.08% 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes 0.20% F6.

Formulation F6d shows the effect of double autoclaving (two sterilization cycles) in combination with stirring for 15 minutes at 95° C. after addition of γCD. Double sterilization added 0.05% 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes to 0.20% F6, consistent with the results for γCD-free formulations F6a and F6b.

Formulation F6e shows the effect of sterilization at 135°C instead of 121°C for 15 minutes followed by 15 minutes of stirring at 95°C after addition of γCD.

The amount of 16,17-unsaturated dexamethasone and enol aldehydes of dexamethasone increased from 0.20 to 0.34%.

The results show that the manufacturing method is reliable and small changes in process parameters do not substantially affect the amount of 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes in the finished product.

Example 8

The F6 manufacturing process has been implemented on an industrial scale. The composition of dexamethasone aqueous eye drops is as follows: dexamethasone (1.50% w/v), γ-cyclodextrin (14.00% w/v), poloxamer 407 (2.50% w/v), disodium edetate (0.10% w/v), sodium chloride (0.57% w/v) in purified water. The batch size was 400 L (F15).

F15: Dexamethasone and all excipients except γ-cyclodextrin were dissolved or suspended in pure water at 80° C. (solution A). γ-cyclodextrin was dissolved separately in pure water at 80°C (solution B). Solution A and solution B were sterilized at 121° C. for 15 minutes. After sterilization and cooling, solution A and solution B were mixed. Then the mixture was again heated to 95°C and kept at this temperature with stirring for 15 min. The solution was cooled to 40° C. in less than 40 minutes and then to room temperature (for another 40 minutes). The resulting microsuspension was then filled into unit dose containers. See table. 6.

- 24 041985

Table 6

Parameter Compound F15 pH 4.5 D50 (µm) 7.2 Proportion degraded to 16,17-unsaturated dexamethasone and dexamethasone enol aldehydes 0.3% Uniformity of dosage form (L 1<15 in accordance with Evr.Pharm.) L1 =3.9

Example 9

The composition of dexamethasone aqueous eye drops (F16) is as follows: dexamethasone (1.50%), γ-cyclodextrin (14.00%), poloxamer 407 (2.50%), disodium edetate (0.10%), sodium chloride (0. 57%) in purified water, all w/v%. The excipients were divided into two parts, A and B. In A, all excipients except γ-cyclodextrin were dissolved in pure water at 80°C, and in B, γ-cyclodextrin was dissolved separately in pure water at 80°C. Dexamethasone was added to the mixture of excipients just before sterilization. A mixture of excipients in water containing dexamethasone (A) and γ-cyclodextrin dissolved in water (B) was sterilized at 121°C for 15 min. After sterilization, A and B were mixed at 95°C. After stirring for 15 min, the solution was cooled from 95 to 40° C. at three different cooling rates (ΔT/Δt). The cooling rate of F16a was 17.7°C/min, F16b 1.3°C/min and F16c 1.2°C/min (Table 7).

Table 7

F16a F16b F16c ΔΤ/Δΐ (°С/min) 17.7 1.3 1.2 D50 (µm) h, h 7.2 8.8 Viscosity (cP) 11.1 9.0 Not defined

The table shows how the average particle size is controlled by the cooling rate. The higher the cooling rate, the smaller the particles and the higher the viscosity.

Example 10

The kinase inhibitors were suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) led to degradation of kinase inhibitors up to 50%, while heating to 95°C for 15 min and rapid cooling to 25°C led to significantly less decomposition and provided suspension of microparticles. The solubility of the kinase inhibitors in pure water (S ₀ ) and the stability constant (K _1:1 ) of the active pharmaceutical ingredient/γ-cyclodextrin complexes were determined from the initial linear level of the phase solubility profiles (Table 8).

Table 8

Kinase inhibitor So (mg/ml) Κ1:1 (Μ' ¹ ) axitinib 0.0004 260 Cediranib 1.2 23 dovitinib 0.006 680 Motesanib 0.014 140 Pazopanib 0.0006 13 regorafenib 0.0001 94

Example 11.

The kinase inhibitors were suspended in an aqueous medium consisting of pure water, an aqueous solution of γ-cyclodextrin, an aqueous solution containing γ-cyclodextrin and tyloxapol (1% w/v), and an aqueous eye drop medium containing γ-cyclodextrin, benzalkonium chloride (0.02% w/v), disodium edetate (0.10% w/v) and sodium chloride (0.05% w/v). The concentration of γ-cyclodextrin varied depending on the kinase inhibitor. Solubility was determined as described in example 10. In table. 9 shows the concentration of γ-cyclodextrin and the effect of tyloxapol and a mixture of eye drop excipients on the solubilization of γ-cyclodextrin from kinase inhibitors.

- 25 041985

Table 9

Kinase inhibitor γcyclodextrin concentration (% w/v) Solubility (mg/ml) γcyclodextrin Tyloxapol Eye drops axitinib 4 0.003 0.008 0.007 Cediranib 12 2.0 2.8 4.1 Motesanib 8 0.09 0.04 0.07 Pazopanib 16 0.007 0.006 0.01 regorafenib 4 0.0005 0.005 0.0008

The results show that excipients can have a significant effect on the solubilization of the kinase inhibitor.

Example 12.

Dovitinib is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should result in decomposition of dovitinib, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a formulation containing solid dovitinib/γcyclodextrin complexes, and significantly less degradation of dovitinib.

Example 13

Losartan is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should lead to the decomposition of losartan, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a composition containing solid losartan/γ-cyclodextrin complexes, and much less degradation of losartan.

Example 14

Olmesartan is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should lead to the decomposition of olmesartan, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a composition containing solid olmesartan/γcyclodextrin complexes, and significantly less degradation of olmesartan.

Example 15

Dorzolamide is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should lead to decomposition of dorzolamide, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a composition containing solid dorzolamide/γcyclodextrin complexes, and much less degradation of dorzolamide.

Example 16

Diclofenac is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should lead to the decomposition of diclofenac, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a composition containing solid diclofenac/γ-cyclodextrin complexes, and much less degradation of diclofenac.

Example 17.

Nepafenac is suspended in aqueous solutions containing 1% (w/v) to 15% (w/v) γ-cyclodextrin. Heating the suspensions formed in the autoclave (121°C for 15 min) should lead to the decomposition of nepafenac, while heating to 95°C for 15 min and cooling to 25°C for 20 min should result in a composition containing solid nepafenac/γ-cyclodextrin complexes, and significantly less degradation of nepafenac.

Any numbers expressing quantities of ingredients, components, reaction conditions, etc., used in the description, should be understood as modified in all cases by the term approximately. Although the numerical ranges and parameters used in defining the broad scope of the invention herein are approximate values, the numerical values given are as accurate as possible. Any numerical value, however, may inherently have a certain amount of error or inaccuracy, which manifests itself in the form of a standard deviation found in the respective measurement procedures. None of the characteristics listed in this document should be interpreted as falling under 35 U.S.C. §112(f) or pre-AIA 6, unless the term facility is used explicitly.

Although the present invention has been described in connection with its illustrative embodiments, it will be appreciated by those skilled in the art that additions may be made.

- 26 041985 additions, exceptions, modifications and substitutions, which are not specifically described, but which do not deviate from the essence and scope of the invention.

Claims (20)

1. An ophthalmic microsuspension containing, in an ophthalmologically acceptable medium, a solid complex comprising dexamethasone and γ-cyclodextrin, wherein the solid complex has a D ₅₀ diameter of 1 to 25 μm, and wherein the microsuspension contains less than 0.5 wt% of dexamethasone enol aldehydes based on the weight of dexamethasone . 2. An ophthalmic microsuspension according to claim 1, containing in an ophthalmologically acceptable medium a solid complex comprising dexamethasone and γ-cyclodextrin, where the composition contains less than 0.2 wt.% dexamethasone enol aldehydes based on the weight of dexamethasone. 3. Ophthalmic microsuspension according to claim 1 or 2, additionally containing a poloxamer. 4. An ophthalmic microsuspension according to claim 3, wherein the amount of poloxamer is from 0.5 to 5% by weight of the poloxamer based on the volume of the composition. 5. An ophthalmic microsuspension according to any one of claims 1 to 4, wherein dexamethasone is present in the composition at a concentration of 10 to 20 mg/ml. 6. An ophthalmic microsuspension according to any one of claims 1 to 5, wherein 60 to 95% by weight of the dexamethasone in the composition is in the form of solid complexes. 7. An ophthalmic microsuspension according to any one of claims 1 to 6, wherein the amount of γ-cyclodextrin is from 1 to 25 wt% of γ-cyclodextrin based on the volume of the composition. 8. Ophthalmic microsuspension according to any one of paragraphs.1-7, including from 1 to 2% dexamethasone; 12 to 16% γ-cyclodextrin; 2.2 to 2.8% polymer; from 0 to 0.04% preservatives; 0 to 0.2% stabilizing agent; 0 to 1% electrolyte and water; where % are weight percent based on the volume of the composition. 9. Ophthalmic microsuspension according to any one of claims 1 to 8, including: 1.5% dexamethasone; 14% γ-cyclodextrin; 2.5% poloxamer; 0.02% benzalkonium chloride; 0.1% disodium edetate; 0.57% sodium chloride and water; where % are weight percent based on the volume of the composition. 10. A method for producing an ophthalmic composition, comprising the steps: a) suspending the γ-cyclodextrin in an ophthalmologically acceptable medium to form a suspension and sterilizing said suspension in an autoclave; b) suspending dexamethasone in an ophthalmologically acceptable medium to form a suspension and sterilizing said suspension in an autoclave; c) mixing the compositions from steps (a) and (b) and heating the mixture at a temperature T1 below 120°C for a time t; d) cooling the resulting solution to a temperature T2 to obtain an ophthalmic composition containing a solid complex of dexamethasone and γ-cyclodextrin, where the ophthalmic composition contains less than 0.5 wt.% dexamethasone enol aldehydes based on the mass of dexamethasone, where the solid complex has a diameter D ₅₀ of 1 up to 25 microns. 11. The method according to claim 10, in which the temperature T1 is from 80 to 110°C. 12. The method according to claim 10 or 11, in which the temperature T2 is from 10 to 40°C. 13. The method according to any one of claims 10 to 12, wherein the temperature T1 is reduced to the temperature T2 at a rate of 1 to 25°C/min. 14. Ophthalmic composition obtained by the method according to any one of claims 10 to 13 and containing less than 0.5 wt.% dexamethasone enol aldehyde based on the mass of dexamethasone, where the solid complex of dexamethasone and γ-cyclodextrin has a diameter D ₅₀ from 1 to 25 μm. - 27 041985 15. Use of the ophthalmic composition according to claim 14 as an eye drop solution, wherein the solid complex of dexamethasone and γ-cyclodextrin has a D ₅₀ diameter of 1 to 25 µm. 16. Use according to claim 15, wherein the composition is used in the treatment of an eye disease. 17. Use according to claim 15, wherein the ophthalmic composition is used in the treatment of uveitis or macular edema. 18. Use of an ophthalmic microsuspension according to any one of claims 1 to 9 as an eye drop solution, wherein the solid complex of dexamethasone and γ-cyclodextrin has a D ₅₀ diameter of 1 to 25 µm. 19. Use according to claim 18, wherein the microsuspension is used in the treatment of an eye disease. 20. Use according to claim 18, wherein the ophthalmic microsuspension is used in the treatment of uveitis or macular edema.