JP6694525B2 - Pharmaceutical ophthalmic composition and method for producing the same - Google Patents

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is based on U.S. Patent Application No. 15 / 148,574, filed May 6, 2016, currently pending, and U.S. filed June 10, 2016, currently pending. Claims priority benefit to patent application No. 15 / 178,812. The entire content of each is hereby incorporated by reference.

FIELD OF THE INVENTION The present invention relates generally to the field of ophthalmology, and more specifically to injectable ophthalmic compositions having antibacterial and anti-inflammatory properties, and methods of preparing such compositions.

Background In ophthalmological treatments and procedures, such as cataract surgery, pre- and post-operative eye drops are used to eliminate or reduce negative post-operative complications such as infection, inflammation, and tissue edema. Often used by patients. As many as 8% of all eye surgery patients are infected with latent fulminant endophthalmitis and the risk of blindness after surgery, including inflammatory uveitis, corneal edema, and cystoid macular edema. It has been reported that various negative side effects can be plagued. Typically, topical post-operative medications are prescribed prior to cataract surgery and then prescribed for subsequent home use and are typically self-administered unless the caregiver or family member needs assistance. ..

  These ophthalmic pharmaceutical drops, which contain anti-inflammatory agents and antibiotics, are highly effective but require adherence to therapeutic regimens, which are often difficult for many patients (physical constraints, or It has an aversion to eyelid contact and handling), is often expensive (much more than $ 200 per procedure), and causes patient dissatisfaction. It would be desirable to have an alternative procedure that would allow the avoidance of the need for the use of such post-surgical medication in order to save the associated post-operative troubles and costs.

  One such alternative treatment is intraoperative glass by an atraumatic transpilate route that may achieve patient outcomes comparable to or better than current home eyedrop regimens. Intra-body injections are included, eliminating compliance and drug administration accuracy issues. This patent specification discloses pharmaceutical compositions suitable for intraoperative ocular injection that can achieve such positive patient outcomes, as well as methods of making and administering them.

SUMMARY In accordance with one aspect of the present invention, there is provided a pharmaceutical composition for ophthalmology, which composition comprises essentially a therapeutically effective amount of an antibacterial agent and a therapeutically effective amount of an anti-inflammatory agent. Which comprises a therapeutic component, a combination of at least two pharmaceutically acceptable excipients, and a pharmaceutically acceptable carrier, wherein the composition is via intraocular injection or eye drops. Suitable for delivery via.

  According to another aspect of the invention, the antibacterial agents described herein include quinolones (including fluorinated quinolones), such as moxifloxacin, and their pharmaceutically acceptable salts, hydrates. Compounds, solvates, or compounds selected from the group of N-oxides.

  According to yet another aspect of the invention, the anti-inflammatory agents described herein include corticosteroids such as triamcinolone, as well as their pharmaceutically acceptable salts, hydrates, solvates, It can be an ether, ester, acetal, and ketal.

  According to another aspect of the invention, the pharmaceutical composition described herein further comprises at least two solubilizing and suspending agents, one of which is a nonionic polyoxyethylene-polyoxy. Any of the propylene block copolymers, for example Poloxamer 407®, the other is a water soluble derivative of cellulose (eg carboxymethylcellulose, methylcellulose, hydroxyethylcellulose, or hydroxypropylcellulose), uncrosslinked or partially. Cross-linked polyacrylate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, or a combination thereof. Re is how.

を有する、本発明1003の薬学的組成物。
[本発明1005]
フッ化キノロンが、モキシフロキサシンおよびガチフロキサシンからなる群より選択される、本発明1003の薬学的組成物。
[本発明1006]
フッ化キノロンがモキシフロキサシンである、本発明1005の薬学的組成物。
[本発明1007]
非イオン性ポリオキシエチレン-ポリオキシプロピレンブロック共重合体が、ポリ(エチレングリコール)-ブロック-ポリ(プロピレングリコール)-ブロック-ポリ(エチレングリコール)である、本発明1001の薬学的組成物。
[本発明1008]
セルロースの水溶性誘導体が、カルボキシメチルセルロース、メチルセルロース、ヒドロキシエチルセルロース、およびヒドロキシプロピルセルロースからなる群より選択される、本発明1001の薬学的組成物。
[本発明1009]
第二の可溶化および懸濁化剤が、ポリオキシエチレン(20)ソルビタンモノオレエートである、本発明1001の薬学的組成物。
[本発明1010]
以下を含む、本発明1007の薬学的組成物：
（a）約1.0mg/mLの濃度のモキシフロキサシン；
（b）約15.0mg/mLの濃度のプレドニゾン；および
（c）非イオン性ポリオキシエチレン-ポリオキシプロピレンブロック共重合体は、約5.0質量％の濃度にある。
[本発明1011]
前記組成物が、構成成分（a）によって形成される粒子を含む懸濁液であり、全粒子の約99％が5μMまたはそれ未満の直径を有する、本発明1001の薬学的組成物。
[本発明1012]
粒子の80％を上回る割合が、約1μM〜約4μMの範囲内にあるサイズを有する、本発明1011の薬学的組成物。
[本発明1013]
グリコペプチド系抗生物質が、存在する場合、バンコマイシンである、本発明1001の薬学的組成物。
[本発明1014]
非ステロイド性抗炎症剤が、存在する場合、ブロムフェナクである、本発明1001の薬学的組成物。
[本発明1015]
対象への本発明1001の組成物の送達を含む、眼科学的な疾患、状態、または病状の治療を必要としている哺乳動物対象において眼科学的な疾患、状態、または病状を治療するための方法であって、該送達の方法が、それによって眼科学的な疾患、状態、または病状を治療するために、硝子体内注射、眼球内前房内注射、病巣内注射、関節内注射、結膜下注射、テノン嚢下注射、点眼薬を介した送達、スプレーを介した送達、および小管内送達からなる群より選択される、該方法。
[本発明1016]
前記送達の方法が、点眼薬を介した送達である、本発明1015の方法。
[本発明1017]
（a）対象に対して角膜屈折矯正手術を実施する工程；および
（b）本発明1001の組成物を対象に投与する工程
を含む、眼科学的な疾患、状態、または病状の治療を必要としている哺乳動物対象において眼科学的な疾患、状態、または病状を治療するための方法。
[本発明1018]
角膜屈折矯正手術が、レーザー支援によるインサイチュー手術（LASIK）、レーザー屈折矯正角膜切除術（PRK）、レーザー支援による上皮下角膜切除術（LASEK）、角膜リングセグメント、角膜クロスリンキング、屈折性角膜インレー、および角膜水晶体手術からなる群より選択される、本発明1017の方法。
[本発明1019]
角膜屈折矯正手術がLASIK手術である、本発明1018の方法。
[本発明1020]
前記組成物が、手術後に滴剤によって投与される、本発明1017の方法。 According to another aspect of the invention, the pharmaceutical compositions described herein are of various ophthalmological diseases, conditions, or conditions associated with intraocular surgery, such as cataracts, retinal diseases, and glaucoma diseases. As part of the course of treatment, it can be injected intravitreally into the mammalian subject across the zonules.
[Invention 1001]
(A) prednisone, prednisolone, methylprednisone, corticol, cortisone, fluorocortisone, deoxycorticosterone acetate, aldosterone, budesonide, their derivatives or analogs, and their pharmaceutically acceptable salts, hydrates, and A dispersed phase consisting of solid particles consisting of a therapeutically effective amount of a corticosteroid independently selected from the group consisting of solvates; and
(B) Dispersion medium consisting of:
(B1) at least a therapeutically effective amount independently selected from the group consisting of quinolones, quinolone fluorides, and their pharmaceutically acceptable salts, hydrates, solvates, or N-oxides. 1 antibacterial agent;
(B2) a therapeutically effective amount of a combination of at least two pharmaceutically acceptable solubilizing and suspending agents,
(B2a) a first solubilizing and suspending agent selected from the group consisting of at least one nonionic polyoxyethylene-polyoxypropylene block copolymer, and
(B2b) Water-soluble derivative of cellulose, optionally partially cross-linked polyacrylate, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate A second solubilizing and suspending agent selected from the group consisting of
The combination consisting of;
(B3) optionally at least one therapeutically effective amount of at least one glycopeptide selected from the group consisting of vancomycin, teicoplanin, telavancin, decapranin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim. Antibiotics;
(B4) optionally, bromfenac, ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin, indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexbuprofen, fenoprofen, loxoprofen, loxoprofen. , naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, Firokokishibu, nimesulide , Clonixin, lycoferon, And a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal, and ketal thereof in a therapeutically effective amount of at least one nonsteroidal anti-inflammatory. Agent; and
(B5) pharmaceutically acceptable carrier
A pharmaceutical composition formulated as a suspension consisting of:
The dispersed phase is dispersed in the dispersion medium,
Furthermore, said pharmaceutical composition is an ophthalmic composition which is suitable for delivery via intraocular injection or via eye drops.
[Invention 1002]
The pharmaceutical composition of invention 1001, wherein the corticosteroid is selected from the group consisting of prednisone, prednisolone, methylprednisone, and their derivatives or analogs.
[Invention 1003]
The pharmaceutical composition of invention 1001, wherein the antibacterial agent is a quinolone fluoride.
[Invention 1004]
The antibacterial substance has a chemical structure A:

The pharmaceutical composition of the invention 1003, which comprises:
[Invention 1005]
The pharmaceutical composition of invention 1003, wherein the quinolone fluoride is selected from the group consisting of moxifloxacin and gatifloxacin.
[Invention 1006]
The pharmaceutical composition of invention 1005 wherein the quinolone fluoride is moxifloxacin.
[Invention 1007]
The pharmaceutical composition of the present invention 1001, wherein the nonionic polyoxyethylene-polyoxypropylene block copolymer is poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol).
[Invention 1008]
The pharmaceutical composition of invention 1001, wherein the water-soluble derivative of cellulose is selected from the group consisting of carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
[Invention 1009]
The pharmaceutical composition of invention 1001, wherein the second solubilizing and suspending agent is polyoxyethylene (20) sorbitan monooleate.
[Invention 1010]
A pharmaceutical composition of the invention 1007, which comprises:
(A) Moxifloxacin at a concentration of about 1.0 mg / mL;
(B) prednisone at a concentration of about 15.0 mg / mL; and
(C) The nonionic polyoxyethylene-polyoxypropylene block copolymer is at a concentration of about 5.0% by mass.
[Invention 1011]
The pharmaceutical composition of invention 1001, wherein said composition is a suspension comprising particles formed by component (a), about 99% of all particles having a diameter of 5 μM or less.
[Invention 1012]
The pharmaceutical composition of invention 1011, wherein greater than 80% of the particles have a size in the range of about 1 μM to about 4 μM.
[Invention 1013]
The pharmaceutical composition of invention 1001, wherein the glycopeptide antibiotic, if present, is vancomycin.
[Invention 1014]
The pharmaceutical composition of invention 1001, wherein the non-steroidal anti-inflammatory agent, if present, is bromfenac.
[Invention 1015]
A method for treating an ophthalmic disease, condition, or medical condition in a mammalian subject in need of treatment of the ophthalmic disease, condition, or medical condition, comprising delivery of the composition of the invention 1001 to the subject. A method of delivery for treating an ophthalmologic disease, condition, or medical condition thereby, by intravitreal injection, intraocular intracameral injection, intralesional injection, intraarticular injection, subconjunctival injection. , Sub-Tenon injection, delivery via eye drops, delivery via spray, and intratubular delivery.
[Invention 1016]
The method of invention 1015, wherein said method of delivery is via eye drops.
[Invention 1017]
(A) performing corneal refractive surgery on the subject; and
(B) a step of administering the composition of the present invention 1001 to a subject
A method for treating an ophthalmological disease, condition, or medical condition in a mammalian subject in need of treatment of the ophthalmic disease, condition, or medical condition.
[Invention 1018]
Corneal refractive surgery includes laser-assisted in situ surgery (LASIK), laser refractive keratotomy (PRK), laser-assisted subepithelial keratotomy (LASEK), corneal ring segment, corneal cross-linking, refractive corneal inlay. And the method of invention 1017, which is selected from the group consisting of :, and corneal lens surgery.
[Invention 1019]
The method of invention 1018, wherein the corneal refractive surgery is a LASIK surgery.
[Invention 1020]
The method of invention 1017, wherein said composition is administered by drops after surgery.

Detailed description
A. Terms and Definitions Nomenclature used in connection with analytical chemistry, synthetic organic chemistry, and inorganic chemistry described herein, and their laboratory procedures and techniques, unless specific definitions are provided. Are known in the art. Standard chemical symbols are used interchangeably with the full name represented by such a symbol. 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, formulation of compositions, and testing thereof. The techniques and procedures described above may generally be performed according to conventional methods well known in the art.

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

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

  As used herein, “about” means that the number referred to as “about” includes the listed numbers plus or minus 1-10% of the listed number. For example, "about" 100 degrees can mean 95-105 degrees or a minimum of 99-101 degrees, depending on the context. Whenever it appears in this specification, a numerical range such as `` 1 to 20 '' refers to each integer within a given range, i.e., 1 only, 2 only, 3 only, etc. up to 20. , And 20 are meant to be included.

  The term "pharmaceutical composition" refers to a chemical or biological compound or substance, or two or more compounds, intended for use in the medical diagnosis, cure, treatment, or prevention of a disease or condition. It is defined as a mixture or combination of classes of such compounds or substances.

  The term "intraocular injection" refers to an injection administered by entering the eyeballs of a patient. The term "periocular injection" refers to an injection that is administered deep inside the eye but outside the outer wall of the eye. The term "cross the zonules" refers to an injection that is administered through the zonules, a series of fibers that connect the ciliary body and the lens of the eye.

  The term "intravitreous" refers to an injection that is administered through the eye of a patient directly into the internal cavity of the eye.

  The term "intraoperative" is defined as an act that occurs or is performed during or during surgery.

  The term "suspension" is defined for the purposes of this application as a two-phase dispersion having a first phase and a second phase. It is further provided that dispersions having three, four or more phases are not within the meaning of "suspension" for the purposes of this application.

  Furthermore, said first phase of the suspension consists of a large number of solid particles and is called and defined as the "dispersed phase", said second phase of the suspension being a liquid, "dispersion medium", Interchangeably and synonymously referred to and defined as "continuous phase".

  Further, the dispersed phase is dispersed in the dispersion medium and the term "dispersed" means that the dispersed phase is suspended in various parts of the suspension without statistically significant deviation of the concentration of the dispersed phase. It is defined as meaning that it is distributed statistically evenly throughout the volume of the liquid.

  The term "keratodendroplasty" refers to a surgical procedure by which the refractive state of the cornea is improved. This procedure can be performed as a laser-assisted in situ surgery, also known as "LASIK". Other corneal refractive surgery included in the term "keratometropia" include, but are not limited to, laser refractive keratotomy (PRK), laser-assisted subepithelial keratotomy (LASEK), and cornea. Includes ring segments, corneal cross-linking, refractive corneal inlays (eg, “raindrop”, “Kamra”), and corneal lens surgery (“SMILE”).

  The terms "antimicrobial agent" and "antibiotic" are broadly covered by the term "antimicrobial agent" and are used interchangeably herein to destroy bacteria and / or viruses and / or any mechanism or Refers to a substance or compound that inhibits its growth via a pathway.

  The term "anti-inflammatory agent" refers to a substance or compound that relieves or suppresses inflammation via any mechanism or pathway.

のようにフッ素原子を含む、抗菌性化合物の一類を指す。 The term “quinolone” for the purposes of this application is a derivative of benzopyridine, and in some embodiments has the following structure (“fluoroquinolone”):

As mentioned above, it refers to a class of antibacterial compounds containing a fluorine atom.

を有する。 The terms "corticosteroid" and the closely related "glucocorticoid" are defined as compounds that belong to a subclass of steroids that are derivatives of corticosterone, the latter having the chemical structure:

Have.

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

  The terms "solvate" and "hydrate" refer to a compound or substance that is physically or chemically associated with a solvent for "solvate," such as water (for "hydrate"). Is used herein to indicate that

The term “ether” refers to a chemical compound containing the structure ROR ₁ , where the two organic fragments R and R ₁ are connected via oxygen.

The term “ester” refers to a chemical compound containing an ester group of ROC (O) —R ₁ connecting two organic fragments R and R ₁ .

The terms "acetal" and "ketal" refer to a chemical compound containing a functional group RC (R ₁ ) (OR ₂ ) ₂ , where R and R ₂ are organic fragments and R ₁ is a hydrogen atom. And (for acetals) and in which one R ₂ (other not) is a hydrogen atom, a “hemiacetal”; or where R, R ₁ and R ₂ are both hydrogen Each is not an atom, but an organic fragment (for ketals).

  The term "non-steroidal anti-inflammatory drug" or "NSAID" refers to a substance or compound that does not contain a steroid moiety and that provides an analgesic, antipyretic, and / or anti-inflammatory effect.

  The term "carrier" refers to a substance that acts as a vehicle to improve the efficiency and effectiveness of delivery of pharmaceutical compositions.

  The term "excipient" refers to a pharmacologically inactive substance that is formulated in combination with the pharmacologically active ingredient of a pharmaceutical composition to aid in bulking agents, fillers, diluents, and drug absorption or solubility. Including products used for or for other pharmacokinetic considerations.

  The term "solubilizer" for the purposes of this application broadly refers to a chemical compound that enhances the process of incorporating a sorbizate (ie, the active component described herein) into a micelle; The presence of the solubilizer makes the process of solubilization faster, easier and / or more complete compared to the composition without it.

  The term "suspending agent" for the purposes of this application helps the pharmaceutically active ingredient to remain suspended in the formulation, and can be used to disperse two-phase dispersions as described herein. Broadly refers to chemical compounds that prevent and / or reduce phase separation.

  The term "therapeutically effective amount" refers to a compound or compound that will elicit a biological or medical response in a tissue, system, animal, or human being sought by a researcher, physician, or other clinician. Defined as the amount of pharmaceutical composition.

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

  The terms "administering a composition" or "administering a composition" are defined to include the act of providing a compound of the invention, or pharmaceutical composition, to a subject in need thereof.

B. Aspects of the Invention According to aspects of the invention there is provided a pharmaceutical composition intended to prevent and / or treat inflammation and / or infections. Does the composition comprise or consist essentially of a therapeutically effective amount of an antibacterial agent (ie, an antibiotic) and a therapeutically effective amount of an anti-inflammatory agent (eg, a corticosteroid)? , Or an active ingredient consisting of them. In some embodiments, the pharmaceutical composition may be used for intraocular injection. In other embodiments, the pharmaceutical compositions may be used for intra-articular or intralesional use. In yet other embodiments, the pharmaceutical composition may be used for delivery via eye drops. The composition further comprises one or several pharmaceutically acceptable excipients and one or several pharmaceutically acceptable carriers.

  The concentration of the antimicrobial agent in the pharmaceutical composition can be from about 0.01 mg / mL to about 50.0 mg / mL, such as about 0.5 mg / mL to about 10 mg / mL, for example about 1.0 mg / mL. The concentration of 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, for example about 15.0 mg / mL.

を有する。 According to a further aspect, the antibacterial agents employed in the active components of the compositions include quinolones, including fluoroquinolones, and their suitable forms such as pharmaceutically acceptable salts, hydrates, or solvates thereof. Can be selected from the group of various derivatives. In one embodiment, the fluoroquinolones that may be so employed include 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 is commercially available from Bayer Healthcare Corp., Wayne, NJ under the trade name Aberox®. , And other sources available from other sources such as Alcon Corp. and Bristol-Myers Squibb Co. under the following chemical structures:

Have.

  One non-limiting example of a possible alternative fluoroquinolone antibiotic that may be used instead of or in combination with moxifloxacin is gatifloxacin.

  In some further embodiments, one or several glycopeptide antibiotics, or some or all combinations thereof, are combined with (i.e., in addition to) moxifloxacin to produce one of the antimicrobial agents. It may optionally be used as part. One example of such an acceptable additional glycopeptide antibiotic is vancomycin, which is from about 1.0 mg / mL to about 100.0 mg / mL, such as from about 5.0 mg / mL to about 50.0 mg / mL, e.g. It may be incorporated into the pharmaceutical composition at a concentration of about 10.0 mg / mL. Vancomycin is available from Eli Lilly & Co. of Indianapolis, Ind. Under the trade name Vancosine®. Other acceptable additional glycopeptide antibiotics that may optionally be so included include teicoplanin, telavancin, decapranin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim.

を有する。 According to a further aspect, the anti-inflammatory agent employed in the active component of the composition is a corticosteroid, such as a derivative of corticosterone, as well as pharmaceutically acceptable salts, hydrates, solvates thereof. Can be selected from the group of compounds, ethers, esters, acetals, and ketals. For example, the product resulting from chemically reasonable substitution of any hydrogen and / or hydroxyl groups in the molecule of corticosterone can be used. In one embodiment, corticosteroids that can be so utilized include triamcinolone (chemically (11β, 16α) -9-fluoro-11,16,17,21-tetrahydroxypregna-1,4- Diene-3,20-dione) and has the following chemical formula:

Have.

を有する。 In another embodiment, the corticosteroid that can be so utilized is triamcinolone acetonide (chemically (4aS, 4bR, 5S, 6aS, 6bS, 9aR, 10aS, 10bS) -4b-fluoro-6b-glycoloyl). -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] dioxole-2-one), which is known under the trade name Kenalog® from Bristol-Myers Squibb Co., Princeton, NJ, for example. Is a ketal derivative of triamcinolone available under the other tradenames and from other sources and has the following chemical formula:

Have.

  Other corticosteroids, or some or all combinations thereof, may be used in place of all or a portion of triamcinolone and / or all or a portion of triamcinolone acetonide. Some non-limiting examples of such other acceptable corticosteroids or glucocorticoids include triamcinolone acetate, triamcinolone benetonide, triamcinolone fretonide, triamcinolone hexaacetonide, betamethasone acetate, dexamethasone. , Fluorometholone and fluocinolone acetonide, prednisone, prednisolone, methylprednisone, corticol, cortisone, fluorocortisone, deoxycorticosterone acetate, aldosterone, budesonide, and their derivatives, analogs, or combinations.

  Some of these corticosteroids, such as but not limited to prednisone, prednisolone, dexamethasone, or methylprednisone, perform corneal refractive surgery or corneal refractive surgery (eg, LASIK surgery) as described in more detail below. Are considered to be particularly suitable in the method. One of ordinary skill in the art of ophthalmology or pharmacy will determine which corticosteroid should be used in the particular surgical procedure to be performed.

  According to other embodiments, the pharmaceutical compositions described herein may further optionally include a pharmaceutically effective amount of one or several non-steroidal anti-inflammatory agents or NSAIDs. The concentration of NSAID in the pharmaceutical composition, when used, 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, for example about 15.0 mg / mL.

  When the pharmaceutical compositions disclosed herein include an NSAID, it is envisioned that some compositions should not include the specific NSAID, bromfenac. However, in other embodiments, bromfenac is ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmethine, indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexbuprofen, fenoprofen, loxoprofen, loxoprofen, loxoprofen , oxaprozin, naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, Firokokishibu , Nimesulide, Chronix , Licofelone (licofelone), and salts acceptable their pharmaceutically, hydrates, solvates, ethers, esters, may be used similarly to the NSAID such as any of acetals, and ketals.

  As mentioned above, the pharmaceutical composition which is the subject of this application may optionally further comprise one or several pharmaceutically acceptable excipients. One of ordinary skill in the art will be able to select the appropriate excipient. When moxifloxacin is used in a pharmaceutical formulation, the stability of another product (eg, a corticosteroid such as triamcinolone acetonide) that must be present in the same formulation and in the form of a stable suspension. It is worth mentioning that it is often difficult to obtain a good suspension. Without being bound by any particular scientific theory, such difficulties in obtaining a stable suspension inactivate many suspending agents and result in unacceptable coagulation, flocculation, and flocculation. It is believed to be caused by the propensity of moxifloxacin to bring. As a result, normal delivery through typical 27-29 gauge cannulas is often difficult or even impossible.

  Therefore, corticosteroids such as triamcinolone acetonide are stable in the presence of moxifloxacin and therefore stable suspensions of moxifloxacin are present in the same formulation. It is desirable to select excipients that can be used as solubilizing and suspending agents to ensure successful formation. Numerous attempts by others to produce stable moxifloxacin / triamcinolone acetonide pharmaceutical compositions suitable for intraocular injection have not been successful.

  The presently disclosed embodiments utilize a combination of at least two solubilizing and suspending agents, a first solubilizing and suspending agent and a second solubilizing and suspending agent, of the present invention. It is taught that the excipients used in the composition can be made. According to an embodiment of the present invention, at least one first solubilizing and suspending agent and at least one second solubilizing and suspending agent are present in the composition.

In some embodiments, an excipient that may be used as the first solubilizing and stabilizing agent to overcome the above difficulties and thus obtain a stable suspension of a corticosteroid such as triamcinolone acetonide or prednisolone. Has the following general structure:
HO- (CH ₂ -CH ₂ -O) _x- (C ₃ H ₆ -O) _y- (CH ₂ -CH ₂ -O) _x -H
May be a nonionic polyoxyethylene-polyoxypropylene block copolymer having: where x is an integer having a value of at least 8 and y is an integer having a value of at least 38.

  When the nonionic polyoxyethylene-polyoxypropylene block copolymer is used as the first solubilizing and stabilizing agent in the pharmaceutical composition of the present invention, its content in the entire composition is about 1.0 mass. % To about 8% by weight, such as about 0.01% to about 10.0% by weight, for example about 5.0% by weight.

を有する。 One non-limiting example of a specific nonionic polyoxyethylene-polyoxypropylene block copolymer that can be used as the first solubilizing and stabilizing agent in the pharmaceutical compositions of the present invention is Missouri. A product known under the trade name Poloxamer 407® (Poly (ethylene glycol) -block-poly (propylene glycol) -block-poly (ethylene glycol)) available from Sigma-Aldrich Corp. of St. Louis, It has a molecular weight of the polyoxypropylene moiety of about 4,000 daltons, a polyoxyethylene content of about 70%, a total molecular weight of about 9,840 daltons to about 14,600 daltons, and has the following chemical structure:

Have.

  Excipients that can be used as the second solubilizing and stabilizing agent can be water-soluble derivatives of cellulose, water-soluble, optionally partially cross-linked polyacrylates, and products of the polysorbate family, or combinations thereof.

  Suitable water-soluble derivatives of cellulose that may be used include, but are not limited to, carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, and hydroxypropyl cellulose, available from The Dow Chemical Company of Midland, Mich., Among other sources. Is included. Examples of acceptable water-soluble partially cross-linked polyacrylates that can be used include, but are not limited to, those polymers of the Carbopol® family available from The Lubrizol Corporation of Wickliff, Ohio. included. Typically, cross-linking agents that can be used to cross-link such polyacrylates are allyl sucrose or allyl pentaerythritol.

  Suitable products of the polysorbate family (ie fatty acid esterified ethoxylated sorbitan) that may be used include, but are not limited to, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan. Includes monostearate, or polyoxyethylene sorbitan monooleate, some of which are also known as Tween® products such as Polysorbate 80®, as a second solubilizing and stabilizing agent. Can be used. Such products are available from Croda Americas, L.L.C., Wilmington, Del. Or Sigma-Aldrich Corp., among other sources that make these products available.

を有する非イオン性界面活性剤および乳化剤である、ポリソルベート80（登録商標）（化学的には、ソルビタンモノ-9-オクタデセノエートポリ(オキシ-1,2-エタンジイルとしても知られる、ポリオキシエチレン(20)ソルビタンモノオレエート）、すなわちエチレングリコールに由来する20単位を有するポリエトキシ化ソルビタンおよびオレイン酸の重縮合の産物）である。 One typical product of the latter family that can be used is the structure:

Polysorbate 80®, a nonionic surfactant and emulsifier having a (polyoxy, also known chemically as sorbitan mono-9-octadecenoate poly (oxy-1,2-ethanediyl, Ethylene (20) sorbitan monooleate), ie the polycondensation product of polyethoxylated sorbitan with 20 units derived from ethylene glycol and oleic acid).

  Non-limiting examples of some other excipients and carriers that can be used in preparing the pharmaceutical compositions of the present invention include calcium disodium edetate (EDTA, chelating agents), hydrochloric acid (pH adjustment). Agent) and sterile water.

  According to an aspect of the present application, the pharmaceutical composition described herein is formulated as a stable two-phase suspension as defined above. More specifically, according to these embodiments, the suspension in question consists of two phases, namely the dispersed phase dispersed in the dispersion medium. The dispersed phase consists of solid particles consisting of a therapeutically effective amount of a corticosteroid. No compound other than the corticosteroids mentioned herein above is present in the solid particles forming the dispersed phase.

According to such an embodiment, the dispersion medium is a liquid containing all other compounds present in the pharmaceutical compositions described in this application. This application does not envision the manner in which the corticosteroid may be used outside the dispersed phase, such as in a dispersion medium. Specifically, the dispersion medium contains the following constituent components (a) to (e):
(A) at least one antimicrobial agent of the quinolone family (ie, the quinolones, quinolone fluorides, and derivatives described);
(B) at least two solubilizing and suspending agents (ie nonionic polyoxyethylene-polyoxypropylene block copolymer + polysorbate);
(C) The use of at least one glycopeptide antibiotic (ie vancomycin, or other antibiotic as described herein above), this component in the dispersion medium is optional;
(D) optionally, at least one nonsteroidal anti-inflammatory agent, such as bromfenac, or other NSAIDs described herein above; and (e) a carrier.

  According to a further aspect, there is provided a method for producing the above pharmaceutical composition. If a one-batch formulation method can be used and the components of the pharmaceutical formulation can be combined in a single container, the components can be added to the container simultaneously or sequentially.

  In one exemplary, non-limiting procedure, the process of preparing the pharmaceutical compositions described herein above can be initiated by forming an aqueous dispersion medium. To form the aqueous dispersion medium, an amount of antimicrobial agent, such as moxifloxacin, is placed in a mixing vessel, followed by an amount of sterile water and hydrochloric acid to add a weakly acidic mixture (e.g., (Having a pH of about 6.5), which can be stirred until a clear solution is obtained. In the case of the moxifloxacin / HCl system, the solution is stable and the formulation remains a closed system, thus preventing contamination and loss of sterility.

  After such a clear, stable solution is formed, more components can be added to the solution that will be the dispersion medium for the final suspension, i.e. a certain amount of Poloxamer 407® and / or A quantity of polysorbate 80, a quantity of edetate calcium disodium, an optional quantity of antibiotic (eg vancomycin), and an optional quantity of NSAID (eg bromfenac) are all already prepared moxifloxacin / HCl solution can be added to the same container.

  At the same time, an amount of corticosteroid, such as micronized triamcinolone acetonide, can be added to the solution, followed by a period of time, for example about 6 hours, until a homogeneous suspension is obtained. Are stirred together (eg by rotation). Therefore, two phases are formed in the resulting suspension: a disperse phase of corticosteroids, and a dispersion medium that is a transformation of the above aqueous solution.

  The resulting suspension can then be transferred to single dose vials, capped, sealed, autoclaved, and shaken until cooled. Finally, thorough testing for sterility and the presence of endotoxin can be performed on the product according to well-known methods known to those skilled in the art.

  The pharmaceutical compositions prepared as described above can be used to prevent potential complications following ocular surgery and treatment. For example, prevent or at least substantially prevent the risk of postoperative complications such as the development of endophthalmitis or cystoid macular edema (CME) without requiring patients to use preoperative or postoperative topical eye drops. To reduce, the formulation can be used during any intraocular surgery such as cataract surgery, planned vitrectomy, or glaucoma procedures. Individuals with evidence of endophthalmitis from previous surgical procedures or traumatic eye penetration will benefit from co-injection of these formulations to eliminate infection and reduce damaging inflammation.

  The pharmaceutical formulations described herein may be across the zonules or, if desired, may be delivered via intraocular intravitreal injection, not across the zonules. .. Intraocular intravitreal injections of this formulation, whether administered via transciliary or direct ciliary pars plana (transcleral) injection, Deliver potent broad-spectrum antibiotics directly to purulent tissue without the need for immediate formulation of multiple individual medications or multiple individual injectables.

  Typically, the pharmaceutical compositions described above are administered to a mammalian subject (e.g., human, cat, dog, other pet, domesticated animal) in need of urgent, urgent, or planned ocular surgical treatment. , Wild, or agricultural animals). The effects achieved by such use of the above pharmaceutical composition may last up to 4 weeks. The composition should be injected intravitreally and across the zonules using methods and techniques known to those of skill in the art of ophthalmology. In some embodiments, the injection may be intraoperative.

  Note that delivery through a typical 27-gauge cannula is typically employed utilizing a 1 mL TB syringe, noting that the formulation is resuspended using a quick tap and shaking immediately prior to injection. Can be done. The required effective volume (ie, dosage) of the formulation depends on the type of intraocular treatment, the degree of induced or predicted postoperative inflammation, risk assessment for postoperative infection, and closure. Vary based on anatomical considerations regarding the available volume of injection solution being added to the intraocular space.

  Although the anterior chamber (ie, anterior chamber) injection is within the scope of the invention because the suspension clogs the trabecular meshwork and exacerbates intraocular drainage, resulting in post-operative elevation of intraocular pressure, It is worth mentioning that such injection instead of (intravitreal) injection may be unsatisfactory in some cases. This can be avoided with intravitreal injection, in addition to keeping the formulation components in the protein matrix of the vitreous humor for longer durations. Anterior chamber flushes occur for hours (antibiotics in solution) and for several days (steroids in suspension), while intravitreal injections are kept for weeks.

  In an alternative embodiment, if desired or necessary, but not limited to, where additional medications need to be delivered, especially where local ocular inflammation and extraocular infections require suppression. Alternatively, the formulations may be delivered in the form of eye drops or eye sprays as well as via subconjunctival, intraocular, sub-Tenon, intraarticular, or intralesional injections. Intravitreal delivery of steroids has historically been used to treat clinically significant cystoid macular edema (CME); application of the formulation in the vitreous humor during routine intraocular treatment Results in more active prevention of CME outbreaks. In addition, the suspension of the formulation stains the vitreous humor during planned and unplanned vitrectomy, enhancing the visualization of otherwise clear intraocular tissue, It is useful for improving the outcome of vitrectomy as well as reducing the complications caused by inadequate or tractive vitrectomy. In still a further aspect, intratubular delivery, ie delivery via a lacrimal canaliculus implant, is also envisioned. In yet other embodiments, the formulations can also be delivered via anterior chamber injection of the drug or lens capsule placement. Solutions that can leave bottles, tubing, etc. "sterilized" during surgery can also be added to the perfusate used during cataract surgery. If desired, intracorneal delivery through laser-created corneal channels that can retain the drug may also be used.

  In some further alternative embodiments, instead of delivering the composition comprising both antibacterial and anti-inflammatory agents, continuous injection may be used instead, if desired. For example, triamcinolone or prednisolone may be injected first, followed immediately by injection of moxifloxacin, or vice versa.

  In a still further aspect, the pharmaceutical applications described herein above may be used before or after performing corneal refractive surgery or corneal refractive surgery, such as LASIK surgery. To illustrate, the pharmaceutical composition used for these purposes may include any of the corticosteroids described above and any antimicrobial agent to be selected by the skilled practitioner. By way of further illustration, and not by way of undue limitation, prednisone, prednisolone, or methylprednisone may be chosen as the former and moxifloxacin as the latter. As a further non-limiting example, a formulation used in conjunction with corneal refractive surgery may include about 0.01 mg / mL to about 50.0 mg / mL, such as about 0.5 mg / mL to about 10 mg / mL, for example about 1.0 mg / mL. Moxifloxacin and other antimicrobial agent concentrations; and about 0.1 mg / mL to about 100.0 mg / mL, such as about 5.0 mg / mL to about 50.0 mg / mL, and corticosteroid concentrations, such as prednisone, for example, about 15.0 mg / mL. Can have

  Specific dose levels and frequency of dosing for any particular patient will include the activity of the specific compound employed, the metabolic stability and length of action of the compound, age, weight, general health, sex, It is believed to be variable and dependent on a variety of factors, including eating habits, as well as the severity of the particular ophthalmological condition being treated.

  In an additional aspect, a pharmaceutical kit is provided. The kit comprises a sealed container approved for storage of the pharmaceutical composition, the container containing one of the pharmaceutical compositions described above. Instructions for use of the composition and information about the composition should be included in the kit.

  The following examples are provided to further clarify the advantages and features of the present invention and are not intended to limit the scope of the invention. The examples are merely for purposes of illustration. USP pharmaceutical grade products were used in preparing the formulations described below.

C. Examples Example 1. Preparation of Pharmaceutical Compositions Pharmaceutical compositions were prepared as described below. The following components were used in the amounts and concentrations specified.
(A) at a concentration of about 15.0 mg / mL, about 1.5 g of triamcinolone acetonide;
(B) about 0.1 g of moxifloxacin hydrochloride at a concentration of about 1.0 mg / mL;
(C) at a concentration of about 1.0% by weight, about 1 mL of polysorbate 80;
(D) at a concentration of about 0.2% by weight, about 0.2 g of calcium disodium edetate;
(E) about 1 g of Poloxamer 407® at a concentration of about 1.0% by weight;
(F) Hydrochloric acid to adjust the pH to about 6.5; and (g) about 100.0 mL of sterile water for injection.

  Moxifloxacin hydrochloride was placed in a depyrogenated beaker with a rotating rod. Sterile water for injection was added to approximately 1/3 of the beaker. Moxifloxacin was dissolved by adding hydrochloric acid while spinning until a clear solution with a final pH of about 6.5 was obtained.

  The solution was combined with micronized triamcinolone acetonide, Poloxamer 407®, calcium disodium edetate, and polysorbate 80 and rotated for about 6 hours until a hydrated homogeneous suspension was obtained.

  The suspension was transferred to a depyrogenated single dose vial (2 mL size), capped and sealed, then autoclaved and shaken until cooled. Complete sterility and endotoxin tests were performed by an external laboratory to ensure safety.

  The formulations prepared as described above were tested for particle size and their distribution. The results showed that very fine particles were obtained and the size distribution was fairly uniform. Specifically, about 99% of all particles had a diameter of 5 μM or less, with the majority of sizes in the range of about 1 μM to 4 μM accounting for about 82% of all particles. Only 0.1-0.2% of all particles were larger than about 10 μM in diameter.

  The formulation prepared as described above was also tested for stability after 6 months of storage. After this period of storage, no loss of efficacy was observed (as measured by HPLC); the formulation was visually stable at room temperature and easily resuspended with gentle shaking without increase in particle size or flocculation. It was cloudy.

Example 2. Preparation of Pharmaceutical Compositions Containing Vancomycin Pharmaceutical compositions were prepared as described in Example 1 above. The composition was autoclaved and sonicated for about 60 minutes and about 96 mL of the composition was combined with about 4 mL vancomycin at a concentration of about 250 mg / mL. The pH of the mixture was adjusted to about 6.0-6.5 with hydrochloric acid. The product was then transferred to vials (about 1 mL per vial + 5 drops) and frozen. The product retained its stability and efficacy for at least 6 months.

Example 3. Use of Pharmaceutical Composition The pharmaceutical composition prepared as described in Example 1 above was administered to about 1,600 patients. The composition was introduced into each patient by intravitreal injection across the zonules. The injection was intraoperative. Only about 1 in 4,000 suffered any infectious disease or other side effects requiring further treatment, only a few patients, which did not receive injections A substantial improvement over the typical rate of about 8% for patients.

Example 4. Preparation of Pharmaceutical Compositions Containing Prednisolone Pharmaceutical compositions were prepared as described below. The following components were used in the amounts specified.
(A) about 1.5 g of micronized prednisolone acetate;
(B) about 0.1 g of moxifloxacin hydrochloride;
(C) about 1.0 mL of an aqueous solution of polysorbate 80 at a concentration of about 1.0% by mass;
(D) about 0.2 g calcium disodium edetate;
(E) about 1.2 g of Poloxamer 407®;
(F) Hydrochloric acid to adjust the pH to about 6.5; and (g) about 100.0 mL of sterile water for injection.

  Moxifloxacin hydrochloride was placed in a depyrogenated beaker with a rotating rod. Sterile water for injection was added to approximately 1/3 of the beaker. Moxifloxacin was dissolved by adding hydrochloric acid while spinning until a clear solution with a final pH of about 6.0-6.5 was obtained.

  The solution was combined with micronized prednisolone acetate, Poloxamer 407®, calcium disodium edetate, and polysorbate 80 and spun until a hydrated homogeneous product was obtained. The particle size and their distribution is expected to be similar to that described in Example 1 above. The product is then transferred to a depyrogenated single dose vial (approximately 1 mL of product in a 3 mL size vial), capped and sealed, then autoclaved, shaken, and placed in a vial. Was sonicated for about 1 hour.

  In a second experiment, another prednisolone-based composition was used in which the amount of micronized prednisolone acetate was about 1.0 g (instead of about 1.5 g) and the amount of moxifloxacin hydrochloride was about 0.5 g. Prepared exactly the same way, except g (instead of 0.1 g).

  The prednisolone-based composition obtained as described in this example is then used as an eye drop by, for example, a follow-up care by an ophthalmologist having ordinary skill after performing corneal refractive surgery such as LASIK surgery. Can be administered to the patient as.

Example 5. Preparation of Pharmaceutical Compositions Containing NSAID Bromfenac Pharmaceutical compositions were prepared as described below. The following components were used in the amounts specified.
(A) About 10.0 g of micronized prednisolone acetate;
(B) about 5.454 g of moxifloxacin hydrochloride monohydrate;
(C) About 1.035 g of bromfenac sodium powder;
(D) Polysorbate 80 in an aqueous solution of about 10.0 mL at a concentration of about 1.0% by mass;
(E) About 4.0 g boric acid powder:
(F) about 14.0 g of Poloxamer 407®;
(G) about 3.17 g of sodium chloride granules;
(H) 20% solution of sodium hydroxide to adjust pH; and (i) about 1.0 L of sterile water for injection.

  Moxifloxacin hydrochloride was placed in a depyrogenated beaker with a rotating rod. Sterile water for injection was added in an amount of about 60% of the total volume of water. While rotating, dissolve the moxifloxacin by adding sodium hydroxide to adjust the pH to about 7.4-7.8, followed by additional stirring for about 5 minutes until a clear solution was obtained. It was Bromfenac was then added and stirring was continued until complete dissolution indicated by the solution being visibly clear. The pH was then readjusted to maintain it in the range 7.4-7.8.

  The solution was combined with polysorbate 80, poloxamer 407, and boric acid with continuous stirring, followed by slow addition of micronized prednisolone acetate, the rest of the water to give a hydrated homogeneous product. The rotation continued for about 20 minutes.

  The product is then transferred to a pre-sterilized depyrogenated 100 mL vial, capped and sealed, followed by autoclaving (about 30 minutes, about 121 ° C. and about 15.0 psi pressure) and shaking. The vials were sonicated for about 30 minutes.

  The composition obtained as described in this example is then administered to the patient as an eye drop, for example as follow-up care, by an ophthalmologist of ordinary skill after performing corneal refractive surgery, such as LASIK surgery. Can be administered.

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

Claims (14)

(A) Solid particles consisting of a therapeutically effective amount of a corticosteroid independently selected from the group consisting of prednisone, prednisolone , and their pharmaceutically acceptable salts, hydrates, and solvates. A disperse phase consisting of: and (b) a dispersion medium consisting of:
(B1) full Tsu of quinolones, and their pharmaceutically acceptable salts, hydrates, is selected solvate, or independently from the group consisting of N- oxides, at least a therapeutically effective amount A class of antibacterial agents , wherein the fluorinated quinolone is selected from the group consisting of moxifloxacin and gatifloxacin ;
(B2) a therapeutically effective amount of a combination of at least two pharmaceutically acceptable solubilizing and suspending agents,
A first solubilizing and suspending agent selected from the group consisting of polyoxyethylene-polyoxypropylene block copolymers, the non-ionic polyoxyethylene - - (b2a) at least one non-ionic polyoxyethylene oxypropylene block copolymer, poly (ethylene glycol) - block - poly (propylene glycol) - block - poly first solubilizing and suspending agents (ethylene glycol), and (b2b) polyoxyethylene From a second solubilizing and suspending agent selected from the group consisting of sorbitan monolaurate, polyoxyethylene sorbitan monopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, or combinations thereof. The combination consisting of:
(B3) optionally at least one therapeutically effective amount of at least one glycopeptide selected from the group consisting of vancomycin, teicoplanin, telavancin, decapranin, ramoplanin, gentamicin, tobramycin, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim. Antibiotics;
(B4) optionally, bromfenac, ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin, indomethacin, nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexbuprofen, fenoprofen, loxoprofen, loxoprofen. , naproxen, aspirin, salicylic acid, diflunisal, salsalate, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam, tenoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, Firokokishibu, nimesulide , Clonixin, lycoferon, And a pharmaceutically acceptable salt, hydrate, solvate, ether, ester, acetal, and ketal thereof in a therapeutically effective amount of at least one nonsteroidal anti-inflammatory. An agent; and (b5) a pharmaceutical composition formulated as a suspension comprising a pharmaceutically acceptable carrier,
The dispersed phase is dispersed in the dispersion medium,
Furthermore, said pharmaceutical composition is an ophthalmic composition which is suitable for delivery via intraocular injection or via eye drops. Quinolones fluoride moxifloxacin, wherein pharmaceutical composition of claim 1.   2. The pharmaceutical composition according to claim 1, wherein the second solubilizing and suspending agent is polyoxyethylene (20) sorbitan monooleate. Including the following, wherein pharmaceutical composition of claim 1:
(A) Moxifloxacin at a concentration of about 1.0 mg / mL;
(B) prednisone at a concentration of about 15.0 mg / mL; and (c) the nonionic polyoxyethylene-polyoxypropylene block copolymer is at a concentration of about 5.0% by weight.   2. The pharmaceutical composition of claim 1, wherein the composition is a suspension containing particles formed by component (a) and about 99% of all particles have a diameter of 5 μM or less. 6. The pharmaceutical composition of claim 5 , wherein greater than 80% of the particles have a size in the range of about 1 μM to about 4 μM.   The pharmaceutical composition of claim 1, wherein the glycopeptide antibiotic, if present, is vancomycin.   The pharmaceutical composition of claim 1, wherein the non-steroidal anti-inflammatory agent, if present, is bromfenac. For treating an ophthalmological disease, condition, or medical condition in a mammalian subject in need of treatment of the ophthalmological disease, condition, or medical condition comprising the composition of any of claims 1-8. A pharmaceutical composition of, wherein the method of delivery of the composition to a subject is for treating an ophthalmic disease, condition, or medical condition by intravitreal injection, intraocular intracameral injection, The pharmaceutical composition selected from the group consisting of intralesional injection, intraarticular injection, subconjunctival injection, subtenon injection, delivery via eye drops, delivery via spray, and intratubular delivery. 10. The pharmaceutical composition according to claim 9 , wherein the method of delivery is delivery via eye drops. For treating an ophthalmological disease, condition, or medical condition in a mammalian subject in need of treatment of the ophthalmological disease, condition, or medical condition comprising the composition of any of claims 1-8. A pharmaceutical composition of
The pharmaceutical composition, wherein the subject has undergone corneal refractive surgery. Corneal refractive surgery is laser-assisted in situ surgery (LASIK), laser refractive keratotomy (PRK), laser-assisted subepithelial keratotomy (LASEK), corneal ring segment, corneal cross-linking, refractive corneal inlay. The pharmaceutical composition of claim 11 , selected from the group consisting of :, and corneal lens surgery. 13. The pharmaceutical composition according to claim 12 , wherein the corneal refractive surgery is LASIK surgery. The pharmaceutical composition according to claim 11 , wherein the composition is administered by drops after surgery.