Ophthalmic composition comprising poloxamer

Abstract

Ophthalmic compositions having antibacterial and anti-inflammatory properties are described, the compositions comprising an antibacterial agent, an anti-inflammatory agent, and poloxamer 407. Methods for preparing the compositions and medical uses thereof are also described.

Description

Technical Field

[0001] The present invention relates generally to the field of ophthalmology and more particularly to ophthalmic compositions having antimicrobial and anti-inflammatory properties, methods of preparing such compositions, and the medical uses of such compositions. Background Art

[0002] In ophthalmic treatments and surgeries such as cataract surgery, patients often use pre- and postoperative eye drops to eliminate or mitigate negative postoperative complications such as infection, inflammation, and tissue edema. It has been reported that up to 8% of ophthalmic surgery patients may suffer from infections, including the potentially catastrophic endophthalmitis, as well as various vision-threatening side effects after surgery such as inflammatory uveitis, corneal edema, and cystoid macular edema. Typically, topical postoperative medications are initiated for home use before and after cataract surgery and are often self-administered.

[0003] These eye drops include an anti-inflammatory agent and an antibiotic agent. WO 2015012899 A1 describes an ophthalmic preparation.

[0004] It has been observed that certain ophthalmic formulations may exhibit precipitation after preparation, which may have a potential impact on the bioavailability of the anti-inflammatory and antimicrobial agents in the formulation.

[0005] In view of the foregoing, there is therefore a need for new formulations having antibacterial and anti-inflammatory properties for use in patients undergoing ophthalmic treatment and surgery, which formulations exhibit reduced precipitation after preparation. Summary of the invention

[0006] Thus, in a first aspect of the invention, there is provided a pharmaceutical composition comprising: (a) a therapeutic component consisting essentially of: (a1) a therapeutically effective amount of an antibacterial agent independently selected from the group consisting of a fluoroquinolone and a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof; and (a2) a therapeutically effective amount of an anti-inflammatory agent independently selected from the group consisting of a corticosteroid and a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal and ketal thereof; (b) poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)) at a concentration of 1.2 to 2.0% w / v; (c) optionally polysorbate 80; and (d) optionally a pharmaceutically acceptable carrier thereof.

[0007] In a second aspect of the present invention, there is provided a method for preparing a pharmaceutical composition, the method comprising combining components (a) and (b) of the first aspect of the present invention, optionally wherein the antibacterial agent, anti-inflammatory agent, poloxamer 407 and carrier are combined in a one-batch formulation method.

[0008] In a third aspect of the present invention, there is provided a composition according to the first aspect of the present invention for use in medicine.

[0009] In a fourth aspect of the present invention, there is provided a composition of the first aspect of the present invention for use in a method of treating an ophthalmic disease, disorder or pathology, optionally selected from post-op endophthalmitis and ocular inflammation.

[0010] In a fifth aspect of the present invention, a pharmaceutical kit is provided, which comprises a sealed container containing the pharmaceutical composition of the first aspect of the present invention and instructions for use of the composition enclosed in the container.

[0011] It has been unexpectedly discovered that ophthalmic compositions comprising an anti-inflammatory and antibacterial agent at a concentration of 1.2 to 2.0% w / v and poloxamer 407 avoid precipitation for at least 21 days after preparation. It has also been discovered that this beneficial effect is not achieved when the concentration of poloxamer 407 is below 1.2% w / v. Such compositions exhibit antibacterial prevention and suppression of postoperative inflammation, making them suitable for use in patients undergoing ophthalmic treatment and surgery. DETAILED DESCRIPTION

[0012] A. Terms and Definitions

[0013] Unless specific definitions are provided, the nomenclature used for analytical chemistry, synthetic organic and inorganic chemistry described herein, as well as laboratory procedures and techniques, are known in the art. Standard chemical symbols are used interchangeably with the full names represented by these symbols. Thus, for example, the terms "hydrogen" and "H" are understood to have the same meaning. Standard techniques can be used for chemical syntheses, chemical analyses, preparing compositions and testing them. The above techniques and procedures can generally be performed according to conventional methods well known in the art.

[0014] It should be understood that both the general description above and the detailed description below are exemplary and explanatory only and do not limit the invention as claimed. As used herein, unless otherwise specifically stated, the use of the singular includes the plural. The section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0015] As used herein, "or" means "and / or" unless otherwise stated. Furthermore, use of the term "including" as well as other forms, such as "includes" and "included," is not limiting.

[0016] As used herein, "about" means that the number referred to as "about" includes the recited number plus or minus 1% to 5% of the recited number. For example, "about" 100 degrees can mean 95 to 105 degrees or as little as 99 to 101 degrees, depending on the context. Whenever it appears herein, a numerical range such as "1 to 20" refers to each integer in the given range; that is, only 1 is meant, only 2 is meant, only 3 is meant, etc., up to and including only 20 is meant.

[0017] The term "pharmaceutical composition" is defined as a chemical or biological compound or substance, or a mixture or combination of two or more such compounds or substances, which is intended for use in the medical diagnosis, cure, treatment or prevention of a disease or pathology.

[0018] The term "intraocular injection" refers to an injection administered by entering the patient's eyeball.

[0019] The term "transzonal" refers to an injection administered through the ciliary zonules, a series of fibers connecting the ciliary body and lens of the eye.

[0020] The term "intravitreal" refers to injection through the patient's eye directly into the inner cavity of the eye.

[0021] The term "intraoperative" is defined as actions occurring or performed during or during surgery.

[0022] The terms "antibacterial" and "antibiotic" are used interchangeably herein to refer to substances or compounds that destroy bacteria and / or inhibit their growth by any mechanism or pathway.

[0023] The term "anti-inflammatory" refers to substances or compounds that counteract or inhibit inflammation by any mechanism or pathway.

[0024] For the purposes of this application, the term "quinolone" refers to a class of antibacterial compounds that are derivatives of benzopyridine and, in some embodiments, contain a fluorine atom, such as in the following structure ("fluoroquinolone"):

[0025]

[0026] The term "corticosteroids" is defined as compounds belonging to the subclass of steroids that are derivatives of corticosterone, which has the following chemical structure:

[0027]

[0028] The term "salt" refers to an ionic compound that is the neutralization reaction product of an acid and a base.

[0029] The terms "solvate" and "hydrate" are used herein to refer to compounds or substances that are physically or chemically associated with a solvent, for "solvate," such as water (for "hydrate").

[0030] The term "ether" refers to a compound containing the structure RO-R1, wherein two organic fragments R and R1 are linked through an oxygen.

[0031] The term "ester" refers to a compound containing an ester group ROC(O)-R1, which connects two organic fragments R and R1.

[0032] The terms "acetal" and "ketal" refer to compounds containing the functional group RC(R1)(OR2)2, wherein R and R2 are organic fragments and R1 is a hydrogen atom (for acetals), and include "hemiacetals" in which one R2 is (but the other is not) a hydrogen atom; or in which R, R1 and R2 are not hydrogen atoms and each is an organic fragment (for ketals).

[0033] The term "carrier" refers to a substance used as a vehicle to enhance the delivery efficiency and effectiveness of a pharmaceutical composition.

[0034] The term "excipient" refers to a pharmacologically inactive substance formulated in combination with the pharmacologically active ingredients of a pharmaceutical composition, and includes bulking agents, fillers, diluents, and products used to facilitate drug absorption or dissolution or for other pharmacokinetic considerations.

[0035] The term "therapeutically effective amount" is defined as that amount of a compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by a researcher, physician or other clinician.

[0036] The term "pharmaceutically acceptable" is defined as a carrier, whether a diluent or excipient, that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

[0037] The term "administration of a composition" or "administering the composition" is defined to include the act of providing a compound or pharmaceutical composition of the present invention to a subject in need of treatment.

[0038] B. Embodiments of the present invention

[0039] According to an embodiment of the present invention, the pharmaceutical composition may be delivered in the form of eye drops.

[0040] According to an embodiment of the present invention, the pharmaceutical composition may be delivered in the form of an ophthalmic spray.

[0041] According to an embodiment of the present invention, the fluoroquinolone may be moxifloxacin.

[0042] According to an embodiment of the present invention, the fluoroquinolone may be gatifloxacin.

[0043] According to an embodiment of the present invention, the corticosteroid can be selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone diacetate, bentriamcinolone acetonide, furanolone acetonide, hexamcinolone acetonide, betamethasone acetate, dexamethasone, fluorometholone, fluocinolone acetonide, diflupregnant butyl ester (DFBA) and combinations thereof.

[0044] According to an embodiment of the present invention, the antibacterial agent may be moxifloxacin, optionally moxifloxacin hydrochloride.

[0045] According to an embodiment of the present invention, the corticosteroid may be triamcinolone, optionally micronized triamcinolone acetonide (TAC), or a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal or ketal thereof.

[0046] According to an embodiment of the present invention, polysorbate 80 may be present in the pharmaceutical composition at a concentration of 0.8 to 1.2% w / v, preferably about 1% w / v, more preferably 1% w / v.

[0047] According to an embodiment of the present invention, Poloxamer 407 may be present in the pharmaceutical composition at a concentration of about 1.2% w / v, preferably 1.2%.

[0048] According to an embodiment of the present invention, polysorbate 80 may be present in the pharmaceutical composition at a concentration of about 1.0% w / v, and poloxamer 407 may be present in the composition at a concentration of about 1.2% w / v, preferably polysorbate 80 may be present in the pharmaceutical composition at a concentration of 1.0% w / v, and poloxamer 407 may be present in the composition at a concentration of 1.2% w / v.

[0049] According to an embodiment of the present invention, the pharmaceutical composition may include: (a1) moxifloxacin hydrochloride at a concentration of about 0.1% w / v; (a2) micronized triamcinolone acetonide (TAC) at a concentration of about 1.5% w / v; (b) poloxamer 407, optionally at a concentration of about 1.2% w / v; (c) polysorbate 80, optionally at a concentration of about 1% w / v; (d) calcium sodium edetate at a concentration of about 0.2% w / v; (e) hydrochloric acid (HCl); and (f) QS 100ml water.

[0050] According to an embodiment of the present invention, the pharmaceutical composition may further comprise a therapeutically effective amount of an antibiotic selected from the group consisting of vancomycin, teicoplanin, telavanxin, decaplanin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, trimethoprim and a combination thereof.

[0051] According to an embodiment of the present invention, the method may include delivering the pharmaceutical composition to a subject by a method selected from the group consisting of intravitreal injection, intracameral injection, intralesional injection, intraarticular injection, subconjunctival injection, subfascial injection, eye drop delivery, spray delivery and intratubular delivery, optionally, wherein the subject is a mammalian subject.

[0052] According to an embodiment of the present invention, a pharmaceutical composition intended to prevent and / or treat inflammation and / or infection is provided. Said composition comprises an active ingredient, and said active ingredient comprises the following, is substantially composed of or is composed of: an antibacterial agent (i.e., antibiotic) of a therapeutically effective amount and an anti-inflammatory agent (e.g., corticosteroid) of a therapeutically effective amount. In some embodiments, the pharmaceutical composition can be used for intraocular injection. In other embodiments, the pharmaceutical composition can be used for intra-articular or intra-lesional use. Said composition also comprises one or more pharmaceutically acceptable excipients and one or more pharmaceutically acceptable carriers.

[0053] The concentration of the antibacterial agent in the pharmaceutical composition can be about 0.01 mg / mL to about 50.0 mg / mL, such as about 0.5 mg / mL to about 10 mg / mL, such as about 1.0 mg / mL. The concentration of the anti-inflammatory agent in the pharmaceutical composition can be about 0.1 mg / mL to about 100.0 mg / mL, such as about 5.0 mg / mL to about 50.0 mg / mL, such as about 15.0 mg / mL.

[0054] According to a further embodiment, the antibacterial agent used in the active component of the composition can be selected from the group consisting of fluoroquinolones and suitable derivatives thereof, such as pharmaceutically acceptable salts, hydrates or solvates thereof. In one embodiment, the fluoroquinolone that can be used in this way is moxifloxacin (chemically, 1-cyclopropyl-7-[(1S, 6S)-2,8-diazabicyclo-[4.3.0]non-8-yl]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic acid), which can be obtained, for example, under the trade name It is available from Bayer Healthcare Corp., Wayne, N.J., and under other trade names from other suppliers such as Alcon Corp. and Bristol-Myers Squibb Co., and has the following chemical structure:

[0055]

[0056] A non-limiting example of a possible alternative fluoroquinolone antibiotic that can be used in place of or in combination with moxifloxacin is gatifloxacin. In some embodiments, one or more glycopeptide antibiotics or a combination of some or all of them can be optionally used as part of an antibacterial agent in combination with moxifloxacin. An example of such an acceptable additional glycopeptide antibiotic is vancomycin, which can be introduced into the pharmaceutical composition at a concentration of about 1 mg / mL to about 100.0 mg / mL, such as about 5.0 mg / mL to about 50.0 mg / mL, such as about 10.0 mg / mL. Vancomycin can be obtained under the trade name Available from Eli Lilly & Co., Indianapolis, Indiana. Other acceptable additional glycopeptide antibiotics that may be used include teicoplanin, telavancin, decaplanin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim.

[0057] According to a further embodiment, the anti-inflammatory agent used in the active component of the composition can be selected from a group consisting of a corticosteroid, such as a derivative of corticosterone, and a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal and ketal thereof. For example, a product obtained by chemically rationally replacing any hydrogen and / or hydroxyl groups in the corticosterone molecule can be used. In one embodiment, the corticosteroid that can be used in this way is triamcinolone (chemically, (11β, 16α)-9-fluoro-11,16,17,21-tetrahydroxypregnant-1,4-diene-3,20-dione), which has the following chemical formula:

[0058]

[0059] In another embodiment, the corticosteroid that can be used in this way is triamcinolone acetonide (chemically, (4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS)-4b-fluoro-6b-glycolyl-5-hydroxy-4a,6a,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphtho[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one), which is a ketal derivative of triamcinolone, available for example under the trade name Available from Bristol-Myers Squibb Co., Princeton, N.J., and from other suppliers under other trade names, it has the following chemical formula:

[0060]

[0061] Other corticosteroids or some or all of them can be used to replace all or part of triamcinolone and / or all or part of triamcinolone acetonide. Some non-limiting examples of such acceptable other corticosteroids include triamcinolone diacetate, bentriamcinolone acetonide, furanolone acetonide, hexamcinolone acetonide, betamethasone acetate, dexamethasone, fluorometholone, fluocinolone acetonide and diflupregnant butyl ester (DFBA).

[0062] As mentioned above, in addition to poloxamer 407 and polysorbate 80, the pharmaceutical composition as the subject of the present application may also optionally include one or more pharmaceutically acceptable excipients. One of ordinary skill in the art will be able to select suitable excipients. It is worth mentioning that when moxifloxacin is used in pharmaceutical preparations, it is usually difficult to obtain a stable suspension of another product (e.g., corticosteroids, such as triamcinolone acetonide) that is present in the same preparation and needs to exist in the form of a stable suspension. Without being bound by any particular scientific theory, this difficulty in obtaining a stable suspension is considered to be due to the tendency of moxifloxacin to inactivate many suspending agents, resulting in unacceptable coagulation, agglomeration and flocculation. Therefore, it is usually difficult or even impossible to deliver normally by a typical cannula 27-29.

[0063] Therefore, it is necessary to select an excipient that is stable in the presence of moxifloxacin so that the excipient can act as a solubilizer and suspending agent to ensure that a stable suspension can be safely formed even if moxifloxacin is also present in the same formulation as a corticosteroid such as triamcinolone acetonide. Others have made several attempts to produce a stable moxifloxacin / triamcinolone acetonide pharmaceutical composition suitable for intraocular injection, but none have been successful.

[0064] Poloxamer 407 is used as an excipient in the pharmaceutical composition of the present invention, for example, as a solubilizer and stabilizer to obtain a stable suspension of a corticosteroid such as triamcinolone acetonide.

[0065] The term "poloxamers" represents a class of organic structures with certain chain structures and repeating hydrocarbon configurations. More specifically, poloxamers are nonionic triblock copolymers consisting of a central hydrophobic chain of polyoxypropylene (poly(propylene oxide)) (PPO) flanked by two hydrophilic chains of polyoxyethylene (poly(ethylene oxide)) (PEO). Because the length of the polymer blocks can be tailored, poloxamers are a class of molecular structures with a variety of chemical properties (phase behavior, solubility, reactivity, toxicity, etc.). Thousands of poloxamer molecules with a wide range of molecular weights and stereochemical configurations have been created, tested, and explored for various industrial and medical applications. Many of these are clinically toxic and medically unacceptable, including applications for topical use that are significantly limited compared to injectable use.

[0066] Using the generic term "poloxamers", these copolymers are usually named with the letter P (for poloxamer) followed by three digits: the first two digits multiplied by 100 give the approximate molecular weight of the polyoxypropylene core, and the last digit multiplied by 10 gives the percentage of polyoxyethylene content (e.g. P407 = poloxamer with a polyoxypropylene molecular weight of 4000 g / mol and a polyoxyethylene content of 70%). See Schmolka IR. Poloxamers in the pharmaceutical industry. In: Tarcha PJ, ed. Polymers for Controlled Drug Delivery, CRC Press, Boca Raton, FL 1991, pp 189-214.

[0067] The naming system for poloxamers sold under the Pluronics brand is slightly different. In the Pluronic nomenclature, the first letter represents solid ("F"), pasty ("P"), or liquid ("L"). As in the general poloxamer nomenclature, the last digit approximates the weight content of the EO block, expressed in ten weight percents. The remaining first one or two digits encode the molecular mass of the central PPO block. To decipher the code, the corresponding number should be multiplied by 300 to obtain the approximate molecular mass in Da. Thus, for example, the code "Pluronic F127" defines a block copolymer that is solid, has a PO block of 3600 Da (12 x 300) and 70% wt PEO. See Kabanov et al., " Appendix A of "blockcopolymers: novel functional molecules for gene therapy," Advanced Drug Delivery Reviews, 54: 223-233 (2002). Pluronic codes can be converted to general poloxamer codes by multiplying the first two digits by 3. Thus, Pluronic F127 would correspond to poloxamer 367.

[0068] Poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)) is a specific nonionic polyoxyethylene-polyoxypropylene block copolymer having a molecular weight of about 4,000 Daltons for the polyoxypropylene portion, a polyoxyethylene content of about 70%, an overall molecular weight of about 9,840 Daltons to about 14,600 Daltons, and having the following chemical structure:

[0069]

[0070] Where the approximate block lengths may be X = 101, Y = 56, and Z = 101. Poloxamer 407 is available, for example, from Sigma-Aldrich Corp., St. Louis, MO.

[0071] The concentration of poloxamer 407 in the composition of the present invention is in the range of 1.2% w / v to 2.0% w / v, preferably about 1.2% w / v, more preferably 1.2% w / v. The concentration of poloxamer 407 in the composition can also be 1.3, 1.4, 1.5, 1.6, 1.7, 1.8 or 2.0% w / v.

[0072] Polysorbate 80 can be used as an excipient in the pharmaceutical compositions of the present invention, for example as an emulsifier. Polysorbates are a class of emulsifiers that are oily liquids derived from hydroxyethylated sorbitan (a derivative of sorbitol) esterified with fatty acids. The number following the "polysorbate" portion of the name is related to the type of fatty acid associated with the polyoxyethylene sorbitan portion of the molecule. Polysorbate 20 is polyoxyethylene (20) sorbitan monolaurate. Polysorbate 40 is polyoxyethylene (20) sorbitan monopalmitate. Polysorbate 60 is polyoxyethylene (20) sorbitan monostearate. Polysorbate 80 is polyoxyethylene (20) sorbitan monooleate.

[0073] The concentration of polysorbate 80 in the composition of the present invention may be 0.6% w / v to 1.4% w / v, preferably 0.8% w / v to 1.2% w / v, more preferably about 1.0% w / v, even more preferably 1.0% w / v. The concentration of polysorbate 80 in the composition may be 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 or 1.4% w / v.

[0074] Non-limiting examples of some other excipients and carriers that can be used to prepare the pharmaceutical compositions of the present invention include calcium sodium edetate (EDTA, a chelating agent), hydrochloric acid (pH adjuster), and sterile water.

[0075] According to a further embodiment, the pharmaceutical composition may comprise (or preferably consist of): diflupregnant butyl ester (DFBA) (preferably 0.01% w / v), moxifloxacin hydrochloride (preferably 0.1% w / v), poloxamer 407 (preferably 0.06 to 0.2% w / v), polysorbate 80 (preferably 0.08 to 0.12% w / v), calcium sodium edetate (preferably 0.2% w / v), hydrochloric acid (preferably adjusting the pH of the composition to 6.5 to 7.6, more preferably adjusting the pH of the composition to 7.0) and water (preferably QS to 100 ml).

[0076] According to a further embodiment, the pharmaceutical composition may comprise (or preferably consist of): micronized triamcinolone acetonide (TAC) (preferably 1.5% w / v), moxifloxacin hydrochloride (preferably 0.1% w / v), sodium carboxymethylcellulose (preferably 0.3 to 0.4% w / v), polysorbate 80 (preferably 0.00001 to 0.00003% w / v), calcium sodium edetate (preferably 0.2% w / v), sodium chloride (preferably 0.6% w / v), hydrochloric acid (preferably to adjust the pH of the composition to 6.5 to 7.6, more preferably to adjust the pH of the composition to 7.0) and water (preferably QS to 100 ml).

[0077] According to a further embodiment, the pharmaceutical composition may comprise (or preferably consist of): micronized triamcinolone acetonide (TAC) (preferably 1.5% w / v), moxifloxacin hydrochloride (preferably 0.1% w / v), sodium carboxymethylcellulose (preferably 0.3 to 0.4% w / v), polysorbate 80 (preferably 0.01 to 0.03% w / v), calcium sodium edetate (preferably 0.2% w / v), sodium chloride (preferably 0.6% w / v), hydrochloric acid (preferably to adjust the pH of the composition to 6.5 to 7.6, more preferably to adjust the pH of the composition to 7.0) and water (preferably QS to 100 ml).

[0078] Also provided herein is a method for treating an ophthalmic disease, disorder or pathology in a mammalian subject in need of such treatment, comprising delivering to the subject a pharmaceutical composition described herein, wherein the delivery method is selected from the group consisting of intravitreal injection, intracameral injection, intralesional injection, intraarticular injection, subconjunctival injection, subfascial injection, eye drop delivery, spray delivery and intratubular delivery, thereby treating the ophthalmic disease, disorder or pathology.

[0079] According to a further embodiment, a method of manufacturing the above pharmaceutical composition is provided.A one-shot formulation method may be used, wherein the components of the pharmaceutical formulation may be combined in a single container; the components may be added to the container simultaneously or sequentially.

[0080] In an exemplary non-limiting procedure, a certain amount of an antibacterial agent such as moxifloxacin can be placed in a mixing container, and then a certain amount of sterile water and hydrochloric acid are added to obtain a slightly acidic mixture (e.g., pH is about 6.5), and the mixture is stirred until a clear solution is obtained. In the case of the moxifloxacin / HCl system, the solution is stable, allowing the formulation to remain a closed system, thereby preventing contamination and loss of sterility.

[0081] Next, an amount of a corticosteroid such as micronized triamcinolone acetonide, an amount of poloxamer 407, an amount of edetate calcium sodium, and an amount of polysorbate 80 can all be added, combined with the prepared moxifloxacin / HCl solution in the same container, and stirred together (e.g., by rotation) for a period of time, such as about 6 hours, until a uniform suspension is obtained. The resulting suspension can then be transferred to a single-dose vial, capped, sealed, autoclaved, and shaken until cooled. Finally, the product can be fully tested for sterility and the presence of endotoxins according to common methods known to those of ordinary skill in the art.

[0082] The pharmaceutical compositions prepared as described above can be used to prevent complications that may occur after ophthalmic surgeries and procedures. For example, the formulations can be used during any intraocular surgery, such as cataract surgery, planned vitrectomy, or glaucoma surgery, to prevent or at least significantly reduce the risk of postoperative complications, such as the development of endophthalmitis or cystoid macular edema (CME), without requiring the patient to use topical eye drops before or after surgery. Individuals with evidence of endophthalmitis due to previous surgical procedures or traumatic ocular penetration will benefit from simultaneous injection of these formulations to eliminate infection and reduce destructive inflammation.

[0083] The pharmaceutical formulations described herein can be delivered by intravitreal injection, which can be transzonal or, if desired, non-zonal. Intravitreal injection of the formulation, whether by transzonal or direct pars plana (transscleral) injection, can deliver potent broad-spectrum antibiotics directly to purulent tissues without the need for urgent mixing of multiple separate drugs or multiple separate injections into the eye.

[0084] Typically, the pharmaceutical composition is administered intraocularly to a mammalian subject (e.g., a human, cat, dog, other pet, domestic animal, wild animal, or farm animal) that requires critical, urgent, or planned ophthalmic surgery. The effect achieved by using the pharmaceutical composition can last up to four weeks. The composition is injected intravitreally and through the zonules using methods and techniques known to those of ordinary skill in the field of ophthalmology. In some embodiments, the injection can be performed intraoperatively.

[0085] Typically, delivery can be performed using a 1 mL TB syringe through a typical 27-gauge cannula, taking care to resuspend the formulation using a brief flick and shake prior to injection. The volume of drug (i.e., dosage) required for this formulation varies depending on the type of intraocular surgery, the degree of postoperative inflammation induced or anticipated, the risk assessment for postoperative infection, and anatomical considerations regarding the volume available for injection into the closed intraocular space.

[0086] It is worth mentioning that, although intracameral (i.e., anterior chamber) injection is within the scope of the present invention, such injection instead of posterior chamber (intravitreal) injection may be unsatisfactory in some cases because the suspension blocks the trabecular meshwork and exacerbates intraocular drainage, leading to postoperative intraocular pressure elevation. Intravitreal injection avoids this and allows the formulation components to be retained in the protein matrix of the vitreous for a longer period of time. Anterior chamber flushing occurs within hours (antibiotic solutions) and days (steroids in suspension), while intravitreal injection is reserved for weeks.

[0087] The pharmaceutical compositions described herein can be injected intravitreally, transzonal, into a mammalian subject as part of a process for treating a variety of ophthalmic diseases, disorders or pathologies associated with intraocular surgery, such as cataracts, retinal and glaucoma diseases.

[0088] In alternative embodiments, if desired or necessary, the preparation may preferably be delivered in the form of eye drops or eye sprays. In alternative embodiments, if desired or necessary, the preparation may be delivered by subconjunctival injection, intracameral injection, subfascial injection, intraarticular injection or intralesional injection, particularly, but not limited to, in certain cases, when local ocular inflammation and extraocular infection need to be suppressed and additional drugs need to be delivered. Intravitreal injection of steroids has historically been used to treat clinically significant cystoid macular edema (CME); application of the preparation to the vitreous during conventional intraocular surgery can more actively prevent the occurrence of CME. In addition, a suspension of the preparation can be used to stain the vitreous during planned and unplanned vitrectomy, improving the visualization of this originally transparent intraocular tissue, improving vitrectomy results and reducing complications caused by insufficient vitrectomy or traction. In yet further embodiments, intraductal delivery is also envisioned, i.e., delivery via lacrimal canaliculus implants.

[0089] In some other alternative embodiments, if necessary, continuous injection can be used instead of delivering the above-mentioned composition comprising an antibacterial agent and an anti-inflammatory agent. For example, triamcinolone can be injected first, followed immediately by moxifloxacin, or vice versa.

[0090] It will be understood by those of ordinary skill in the art that the specific dosage level and frequency of administration for any particular patient may vary and will depend on a variety of factors, including the activity of the specific compound used, the metabolic stability and duration of action of the compound, age, body weight, general health, sex, diet, and the severity of the specific ophthalmic condition being treated.

[0091] In another embodiment, a pharmaceutical kit is provided. The kit includes a sealed container approved for storing a pharmaceutical composition containing one of the above-mentioned pharmaceutical compositions. The kit should include instructions for use of the composition and information about the composition.

[0092] The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the present invention. These examples are for illustrative purposes only. USP pharmaceutical grade products are used to prepare the following formulations.

[0093] C. Examples

[0094] Example 1. Preparation of pharmaceutical composition

[0095] The pharmaceutical composition was prepared as described below. The following products were used in the specified amounts and concentrations:

[0096] (a) micronized triamcinolone acetonide (TAC), concentration of about 1.5% w / v;

[0097] (b) moxifloxacin hydrochloride at a concentration of about 0.1% w / v;

[0098] (c) polysorbate 80, at a concentration of about 1% w / v;

[0099] (d) calcium sodium edetate, at a concentration of about 0.2% w / v;

[0100] (e) Poloxamer 407, at a concentration of about 1.2% w / v (variable in Example 3 below);

[0101] (f) hydrochloric acid, to adjust the pH; and

[0102] (g) Approximately 100.0 mL of sterile water for injection.

[0103] Example 1A. Preparation method 1

[0104] Place moxifloxacin hydrochloride in a depyrogenated beaker with a rotating rod. Add sterile water for injection to about 1 / 3 of the beaker volume. While rotating, dissolve moxifloxacin by adding hydrochloric acid until a clear solution with a final pH of about 6.5 is obtained.

[0105] This solution was mixed with micronized triamcinolone acetonide, poloxamer 407, edetate calcium sodium, and polysorbate 80 and rotated for about 6 hours until a hydrated and homogeneous suspension was obtained.

[0106] The suspension was transferred into depyrogenated single-dose vials (2 mL size), capped and sealed, then autoclaved and the vials shaken until cool. Complete sterility and endotoxin testing was performed by an external laboratory to ensure safety.

[0107] The formulation prepared as described above was subjected to stability testing after 6 months of storage. No loss of potency (measured by HPLC) was observed over time; the formulation was visually stable at room temperature and could be resuspended with gentle shaking without particle size increase or flocculation.

[0108] Example 1B Preparation method 2

[0109] Moxifloxacin was dissolved in 1 / 3 of water in a beaker, HCl was added until pH = 6, and the resulting composition was mixed until clear.

[0110] The other ingredients in Example 1 were added to the composition, the QS was adjusted to a final volume of 100 ml, and the resulting composition was homogenized at 5,000 RPM for 30 minutes.

[0111] The composition was then transferred to an autoclave bottle and autoclaved at 121°C, 15 psi for 30 minutes and then shaken until cool.

[0112] Example 2. Characterization of pharmaceutical compositions

[0113] In Example 3 below, each formulation prepared according to Example 1 / 1B was tested for pH stability, viscosity, turbidity, flocculation, precipitation (aggregation by contact adhesion), product and drug stability after sterilization, injectability (delivered by ophthalmic cannula), and the expected clinical efficacy of each batch. These tests include observation of the sedimentation, flocculation, aggregation, injectability and chromatographic chemistry of the composition at one week, one month and three months. pH was measured using a Horiba ion selective electrode device. Viscosity was measured using an Anton-Parr rheometer. Turbidity was visually assessed and measured using a Malvern multi-angle light scattering (MALS) detector. Flocculation and particle size were measured using a Malvern multi-angle light scattering (MALS) detector. Over time, precipitation (solution stratification) was visually assessed, noting the aggregation at the bottom of the test tube. Product stability was assessed in various ways: drug integrity, chromatographic analysis, injectability, etc. Syringe and cannula delivery was assessed by syringe delivery through cannulas of various specifications. Drug and product integrity after sterilization was assessed in various ways: drug integrity, chromatographic analysis, injectability, etc. Clinical efficacy was assessed by physicians based on a range of findings, surgical functionality, and expected performance for the patient.

[0114] Example 3. Effect of different poloxamer 407 concentrations

[0115] In this example, compositions were prepared according to Example 1 / 1B, wherein the poloxamer 407 concentration was varied, and characterized according to Example 2.

[0116] Formulations of triamcinolone and moxifloxacin (Tri-Moxi) in the relative amounts described in Example 1 were tested using 1% w / v polysorbate 80 with varying concentrations of the preferred poloxamer 407. The results are summarized in Table 1 below.

[0117] Conclusion: Poloxamer 407 must be present at concentrations below 2.2% w / v to form a clinically effective formulation. Poloxamer 407 concentrations of 2.2%, 5%, and 10% w / v were clinically failed formulations for ophthalmic applications. Poloxamer 407 concentrations ranging from 0.8% w / v to 2.0% w / v were functional formulations for clinical applications required for this novel drug combination. Surprisingly, poloxamer 407 concentrations ranging from 1.2% w / v to 2.0% w / v showed no precipitation for at least 21 days, compared to minimal precipitation at poloxamer 407 concentrations below 1.2% w / v.

[0118] Table 1

[0119] Testing of Tri-Moxi with different concentrations of Poloxamer 407

[0120]

[0121] These experiments demonstrate that Poloxamer 407 has surprising and unexpected beneficial precipitation properties when incorporated into formulations at concentrations of 1.2 to 2.0% w / v. The beneficial precipitation properties result in a preservative-free therapeutic drug combination (antibiotic and corticosteroid) with excellent storage properties suitable for injection into the intraocular space as well as for topical application to provide protection and prevention of post-op endophthalmitis and ocular inflammation.

[0122] Example 4. Preparation of a pharmaceutical composition containing vancomycin

[0123] Pharmaceutical compositions were prepared as described in Example 1 / 1A above. The compositions were autoclaved and ultrasonically treated for approximately 60 minutes, and approximately 96 mL of the compositions were combined with approximately 4 mL of vancomycin at a concentration of approximately 250 mg / mL. Hydrochloric acid was used to adjust the pH of the mixture to approximately 6.0 to 6.5. The product was then transferred to a vial (5 drops per bottle of approximately 1 mL) and frozen. The product has maintained its stability and effectiveness for at least six months.

[0124] Example 5. Use of pharmaceutical composition

[0125] The pharmaceutical composition prepared as described above in Example 1 was administered to approximately 1600 patients. For each drug, it was introduced by intravitreal transzonal injection. The injection was performed intraoperatively. Only a very small number of patients (approximately only one in four thousand) developed any infection or other side effects requiring further treatment, which is a significant improvement over the typical incidence of approximately 8% in patients who did not receive the injection.

[0126] Although the present invention has been described with reference to the above embodiments, it will be understood that modifications and variations are encompassed within the spirit and scope of the present invention. Accordingly, the present invention is limited only by the appended claims.

Claims

1. A pharmaceutical composition comprising: (a) a therapeutic component consisting essentially of: (a1) a therapeutically effective amount of an antibacterial agent independently selected from the group consisting of fluoroquinolones and pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof; and (a2) a therapeutically effective amount of an anti-inflammatory agent independently selected from the group consisting of a corticosteroid and pharmaceutically acceptable salts, hydrates, solvates, ethers, esters, acetals and ketals thereof; (b) Poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)) at a concentration of 1.2% w / v to 2.0% w / v; (c) optionally polysorbate 80; and (d) optionally, a pharmaceutically acceptable carrier thereof.

2. The pharmaceutical composition according to claim 1, wherein the composition is delivered in the form of eye drops or eye spray.

3. The pharmaceutical composition according to claim 1 or 2, wherein the fluoroquinolone is selected from the group consisting of moxifloxacin and gatifloxacin.

4. The pharmaceutical composition according to any one of the preceding claims, wherein the corticosteroid is selected from the group consisting of triamcinolone, triamcinolone acetonide, triamcinolone diacetate, bentriamcinolone acetonide, furanolone acetonide, hexamcinolone acetonide, betamethasone acetate, dexamethasone, fluorometholone, fluocinolone acetonide, diflupregnant butyl ester (DFBA), and combinations thereof.

5. A pharmaceutical composition according to any one of the preceding claims, wherein: (a) the antibacterial agent is moxifloxacin, optionally moxifloxacin hydrochloride; and / or (b) The corticosteroid may be triamcinolone, optionally micronized triamcinolone acetonide (TAC), or a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal or ketal thereof.

6. A pharmaceutical composition according to any one of the preceding claims, wherein the concentration of polysorbate 80 is 0.8% w / v to 1.2% w / v.

7. The pharmaceutical composition according to any one of the preceding claims, wherein the concentration of Poloxamer 407 is about 1.2% w / v.

8. The pharmaceutical composition of any one of the preceding claims, wherein the concentration of polysorbate 80 is about 1.0% w / v and the concentration of poloxamer 407 is about 1.2% w / v.

9. A pharmaceutical composition according to any one of the preceding claims, comprising: (a1) moxifloxacin hydrochloride, at a concentration of about 0.1% w / v; (a2) micronized triamcinolone acetonide (TAC), concentration about 1.5% w / v; (b) Poloxamer 407, optionally at a concentration of about 1.2% w / v; (c) polysorbate 80, at a concentration of about 1% w / v; (d) calcium sodium edetate, at a concentration of about 0.2% w / v; (e) hydrochloric acid (HCl); and (f) QS 100ml water.

10. The pharmaceutical composition according to any one of the preceding claims, further comprising a therapeutically effective amount of an antibiotic selected from the group consisting of vancomycin, teicoplanin, telavansin, decaplanin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, trimethoprim, and combinations thereof.

11. A method for preparing a pharmaceutical composition comprising combining components (a) and (b) as claimed in any one of the preceding claims, optionally wherein the antibacterial agent, the anti-inflammatory agent, the poloxamer 407 and the carrier are combined in a single formulation.

12. A composition according to any one of claims 1 to 10 for use in medicine.

13. A composition according to any one of claims 1 to 10 for use in a method of treating an ophthalmic disease, disorder or pathology, optionally selected from post-op endophthalmitis and ocular inflammation.

14. A composition for use according to claim 13, wherein the method comprises delivering the composition to a subject by a means selected from the group consisting of intravitreal injection, intracameral injection, intralesional injection, intraarticular injection, subconjunctival injection, subfascial injection, eye drop delivery, spray delivery and intratubular delivery, optionally, wherein the subject is a mammalian subject.

15. A pharmaceutical kit comprising a sealed container containing the pharmaceutical composition according to any one of claims 1 to 10 and instructions for use of the composition enclosed in the container.

16. A pharmaceutical composition comprising: (a) difluoropregnantate butyl ester (DFBA), at a concentration of about 0.01% w / v; (b) moxifloxacin hydrochloride at a concentration of about 0.1% w / v; (c) Poloxamer 407 at a concentration of about 0.06% w / v to 0.2% w / v; (d) polysorbate 80 at a concentration of about 0.08% w / v to 0.12% w / v; (e) edetate calcium sodium, at a concentration of about 0.2% w / v; (f) hydrochloric acid (HCl); and (g) QS 100ml water.

17. A pharmaceutical composition comprising: (a) micronized triamcinolone acetonide (TAC), concentration of about 1.5% w / v; (b) moxifloxacin hydrochloride at a concentration of about 0.1% w / v; (c) sodium carboxymethylcellulose at a concentration of about 0.3% w / v to 0.4% w / v; (d) polysorbate 80 at a concentration of about 0.01% w / v to 0.03% w / v; (e) edetate calcium sodium, at a concentration of about 0.2% w / v; (f) sodium chloride, at a concentration of about 0.6% w / v; (g) hydrochloric acid (HCl); and (h) QS 100 water.

Images