WO2017151664A1

WO2017151664A1 - Pharmaceutical compositions for fluoroquinolone drug delivery

Info

Publication number: WO2017151664A1
Application number: PCT/US2017/020019
Authority: WO
Inventors: Kenneth W. Reed
Original assignee: Belmont University
Current assignee: Belmont University
Priority date: 2016-02-29
Filing date: 2017-02-28
Publication date: 2017-09-08
Anticipated expiration: 2018-08-29

Abstract

The present disclose generally provides pharmaceutical semi-solid hydrogels with entrapped calcium phosphate nanoparticles that demonstrate enhanced drug release, retention, and esthetic properties. The hydrogels are particularly useful for topical applications of drug molecules. The present disclosure also relates to methods of administering a pharmaceutical agent by providing a pharmaceutical semi-solid hydrogel containing at least one pharmaceutical agent and administering it to a subject in need thereof.

Description

DESCRIPTION

PHARMACEUTICAL COMPOSITIONS FOR FLUOROQUINOLONE DRUG DELIVERY RELATED APPLICATION

[0001 ] This application claims the benefit of priority to U.S. Provisional Application No. 62/301 ,218 filed on February 29, 201 6, which is hereby incorporated by reference in its entirety.

TECH NICAL FIELD

[0002] The present disclose generally relates to pharmaceutical fluoroquinolone compositions that are particularly suitable for topical administration, including ophthalmic and dermal administration. The compositions combine an emulsion and a gel to provide compositions having advantageous drug retention, thixotropic and rheologic properties. In some embodiments, the compositions further contain entrapped calcium phosphate nanoparticles.

BACKGROUND

[0003] Fluoroquinolones are a family of synthetic broad-spectrum antibiotics having a fluorine atom attached to the central ring system. These drugs are effective against both gram-negative and gram-positive bacteria, and play an important role in the treatment of serious bacterial infections. Common side effects of fluoroquinolones include gastrointestinal effects such as nausea, vomiting, and diarrhea, as well as headache and insomnia. Some of the more common fluoroquinolones include ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin.

[0004] Ophthalmic ciprofloxacin, in particular, is an antibiotic commonly used to treat a number of bacterial infections. For example, it is commonly used as the initial treatment for bacterial conjunctivitis and corneal ulcerations (Ciprofloxacin, ophthalmic. Lexi-Drugs Online. Lexi-Comp Online [database online] . Hudson, Ohio: Lexi- Comp, Inc.; Updated April 24, 201 5) . Ciprofloxacin is active against many gram negative organisms including Pseudomonas aeruginosa, and Enterobacteriaccea as well as gram positive MRSA making it ideal for patients who obtain these infections while wearing contact lenses. Topical delivery is the preferred method of administration for these ophthalmic conditions. Nevertheless, topical administration of ophthalmic medication has many problems, including difficulty controlling contact time and release of the drug with the eye and side effects due to systemic absorption (Guzman-Aranguex A, Colligris B, Pinto J. Contact Lenses: Promising Devices for Ocular Drug Delivery. J Ocul Pharmacol Ther. 2013; 29: 189-199) . Common side effects include nausea, vomiting, diarrhea, and rash. Ciprofloxacin also can increase the risk of tendon rupture and worsening muscle weakness in people with the neurological disorder myasthenia gravis.

[0005] During ophthalmic administration, the active drug component can quickly flow out of the eye due to rapid tearing. After administration, a 10-fold reduction in drug concentration on the cornea is observed within 4-20 minutes, thereby necessitating multiple daily doses to get any therapeutic effect (Ciprofloxacin hydrochloride solution/ drops. DailyMed. http://dailymed.nlm. nih.gov/dailymed/druglnfo.cfm?se†id=6d401 184-2ff2-4950-820d- ac800469a04f. Updated June, 201 1 ). Multiple daily doses can be difficult for patients who live active lifestyles or have difficulty administering medication leading to poor adherence. Drug absorption through the nasolacrimal tube leads to an average of 5ng/mL of ciprofloxacin being reported in the body after 7 days of therapy. This systemic absorption can be what causes the reported side effects such as unpleasant taste and gastrointestinal upset.

[0006] Ophthalmic ointments, as opposed to eye drop solutions, are sometimes used to prevent this problem as well as administration errors in populations that have difficulty applying eye drops. Nevertheless, ointment tends to leave vision blurry for about 20 minutes after administration making it less than ideal for daytime use (Jacobs DS. Conjunctivitis- Bacterial Conjunctivitis Treatment. In Park L, Trobe J, eds. UpToDate. Waltham, MA: UpToDate; 2015. http://www.uptodate.com) .

[0007] Ophthalmic gels have the potential to increase the corneal contact time of drugs while decreasing the amount of drug systemically absorbed by increasing viscosity of the vehicle (Bourlais CL, Acar L, Hosen Z, et al. Ophthalmic drug delivery systems— Recent advances. Prog Retin Eye Res. 1998; 1 7 ( 1 ) : 33-58. http://www.sciencedirect.com/science/article/pii/S 1350946297000025) . Yet, if the viscosity is too high, the same problems encountered with the ointment may result (i.e. blurry vision) .

[0008] An ophthalmic emulsion of cyclosporine is currently on the market as Restasis®, used in the treatment of dry eye. The emulsion has been shown to improve ocular bioavailability for lipophilic drugs (Utine C, Stern M, Akpek E. Clinical review: topical ophthalmic use of cyclosporine A. Ocul Immunol Inflamm. October 2010; 18(5) : 352- 361 ) .

[0009] Emulsions combined with gels to form an "emulgel" have been used topically for dermal applications with diclofenac. When used with an emulsion-gel formulation, diclofenac has a higher bioavailability and better clinical results compared to microemulsions (Shevachman M, Garti N, Shani A, et al. Enhanced percutaneous permeability of diclofenac using a new u-†ype dilutable microemulsion. Drug Dev Ind Pharm. 2008; 34: 403-412) .

[0010] Another problem with ophthalmic ciprofloxacin administration is that the drug is insoluble at a physiologic pH (~pH 7) . Specifically, ciprofloxacin HCI dissolves at approximately 40 mg/mL at a pH of 4-5. Therefore, many pharmacologically prepared ciprofloxacin solutions exist at a pH of about 4.5. When applied to an eye, the buffer action of tears restores the pH of the eye to around 7. This may explain why approximately 1 7% of patients experience crystalline precipitates after ophthalmic administration of Ciprofloxacin HCI solutions (Bozkir A, Denli ZF, Basaran B. Effect of Hydroxy propyl- beta- cyclodextrin on the solubility, stability and in-vitro release of ciprofloxacin for ocular drug delivery. Polish Pharmaceutical Society. 2012 69(4) : 719- 724) . In addition when applied to the eye at this acidic pH, the patient experiences pain and burning, decreasing the chances of treatment compliance.

[001 1 ] In summary, there is a need for a pH neutral formulation for fluoroquinolone drug delivery, particularly ciprofloxacin. It would further be useful to provide a delivery system capable of improving ocular fluoroquinolone drug absorption while decreasing systemic absorption. The present disclosure addresses these needs.

SUMMARY OF THE INVENTION

[0012] The present disclosure provides a pharmaceutical fluoroquinolone combined emulsion-hydrogel composition. While not being bound by theory, it is believed that the present compositions provide a sustained released of the drug while minimizing systemic absorption and exposure. Additionally, the emulsion-hydrogel composition is transparent and has beneficial thixotropic properties, making it particularly suitable for ophthalmic use. The formulations are also useful for other modes of administration, including injection, oral, dermal application.

[0013] Accordingly, the present disclosure provides a pharmaceutical composition for fluoroquinolone drugs comprising an emulsion of the fluoroquinolone drug and a hydrogel. More particularly, the present disclosure provides a pharmaceutical composition comprising an oil, a surfactant, a polymeric stabilizer, a tonicity component, a gel-forming agent, a fluoroquinolone drug and water. Fluoroquinolone drugs useful in the composition include ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin.

[0014] The oil may be selected from the group consisting of vegetable oils, mineral oils, synthetic oils and mixtures thereof. Useful surfactants include nonionic surfactants such as the polysorbate surfactants. The polymeric stabilizer is, in some embodiments, a hydrophobically modified cross-linked polyacrylate, such as a carbomer, e.g., carbomer 1342. In some embodiments, the nonionic tonicity agent may be selected from the group consisting of glycerin, mannitol, sorbitol and mixtures thereof.

[0015] In some embodiments, the composition further comprises about 0.1 % to about 5% of calcium phosphate nanoparticles by weight of the composition. The calcium phosphate nanoparticles may have a size ranging from about 5 nm to about 200 nm, and more particularly, from about 10 nm to about 100 nm, and even more particularly, from about 10 nm to about 80 nm.

[0016] The present disclosure further provides a method of administering a fluoroquinolone to a patient in need thereof comprising administering any of the above-described compositions to the eye.

[0017] The present disclosure further provides a method of preparing the above described fluoroquinolone drug compositions comprising i) preparing an emulsion comprising an oil, a surfactant, a polymeric stabilizer, a tonicity component, a fluoroquinolone drug and water ii) preparing a gel comprising a gel-forming agent and water; and iii) combining the emulsion and the gel to form the fluoroquinolone drug composition. In some embodiments, the method further comprises adding calcium phosphate nanoparticles to the gel composition. In other embodiments, the method further comprises adding calcium phosphate nanoparticles to the emulsion.

[0018] It is to be understood that both the foregoing general description and the following detailed description present embodiments of the disclosure are intended to provide an overview or framework for understanding the nature and character of the disclosure as it is claimed. The description serves to explain the principles and operations of the claimed subject matter. Other and further features and advantages of the present disclosure will be readily apparent to those skilled in the art upon a reading of the following disclosure. BRIEF DESCRIPTION OF TH E DRAWINGS

[0019] Figure 1 depicts a Beer's Law calibration curve created by dissolving 3 mg of ciprofloxacin base in 200 mL of buffer solution composed of sodium lauryl sulfate, docusate sodium, polyethylene glycol 400, and TR 1 . Concentrations of ciprofloxacin in experimental samples were determined using this standard curve.

[0020] Figure 2 is a graph of the average ciprofloxacin release rates from a solution, an emulsion, an emulsion-gel, 2% CaP emulsion-gel and 5% CaP emulsion-gel as defined by the logistic fit parameters: Ml , M2, M3, and M4. All release rate lines were terminated at 8300 minutes as this was the last data point for the fastest vehicle, the emulsion-gel.

[0021 ] Figure 3 is a graph of a rheology study (shear rate 1 /s vs log [viscosity (Pa*s)] ) . The measured viscosity values for each preparation were fitted by the Ostwald de Waele and Bingham models. The n values were less than one, which indicates that all preparations exhibited pseudoplastic properties.

DETAILED DESCRIPTION

[0022] Reference now will be made in detail to the embodiments of the present disclosure, one or more examples of which are set forth herein below. Each example is provided by way of explanation of the compositions of the present disclosure and is not a limitation. In fact, it will be apparent to those skilled in the art that various modifications and variations can be made to the teachings of the present disclosure without departing from the scope or spirit of the disclosure. For instance, features illustrated or described as part of one embodiment, can be used with another embodiment to yield a still further embodiment.

[0023] Thus, it is intended that the present disclosure covers such modifications and variations as come within the scope of the appended claims and their equivalents. Other objects, features and aspects of the present disclosure are disclosed in or are obvious from the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments only and is not intended as limiting the broader aspects of the present disclosure.

[0024] The present disclosure provides emulsion-gel compositions that are particularly suitable for use with the fluoroquinolone class of drugs. While the present compositions are useful for many different modes of administration, they are particularly advantageous for ophthalmic and dermatological use. Ophthalmically acceptable compositions are compatible with ocular tissue, for example by not causing cause significant or undue detrimental effects when brought into contact with ocular tissues. The present compositions advantageously combine emulsions with hydrogels to take advantage of features of both types of delivery vehicles, and in some embodiments, to provide synergistic effects of the combined delivery vehicles. In some embodiments, the present compositions comprise comprising an oil, a surfactant, a polymeric stabilizer, a tonicity component, a gel-forming agent, a fluoroquinolone drug and water. In some embodiments, the compositions further comprise calcium phosphate nanoparticles (CaP).

[0025] Oils useful in the present compositions include, without limitation, vegetable oils, mineral oils, synthetic oils and the like and mixtures thereof. Further examples of oils that may be used in the compositions include corn oil, peanut oil, olive oil, arachis oil, castor oil, mineral oil, silicone fluid and the like and mixtures thereof. Higher fatty acid glycerides such as olive oil, peanut oil, castor oil and the like and mixtures thereof may also be used. In more particular embodiments, the oil comprises castor oil.

[0026] The oil, such as castor oil, may be present in an amount of greater than about 0.5% by weight of the composition. More specifically, the oil may be present in an amount ranging from about 0.5 % to about 10% by weight, about 0.5% to about 5% by weight, about 1 % to about 5% by weight, or about 2% to about 5% by weight.

[0027] Any suitable surfactant may be used in the present compositions, and many are known and used in the pharmaceutical arts. Examples of surfactants useful in the present compositions include without limitation, surfactant components which may be anionic, cationic, nonionic or amphoteric in nature. In general, the surfactant includes a hydrophobic constituent and hydrophilic constituent. Advantageously, the surfactant is water soluble in the presently useful compositions. Preferably, the surfactant is nonionic. Specific examples of suitable surfactants include, without limitation, polysorbate surfactants, such as polysorbate 80, polyoxyalkylene alkylene ethers, polyalkylene oxide ethers of alkyl alcohols, polyalkylene oxide ethers of alkylphenols, other emulsifiers/surfactants, preferably nonionic emulsifiers/surfactants, useful in ophthalmic compositions, and the like and mixtures thereof. In particular embodiments, the surfactant is a polysorbate, such as polysorbate 80, which is commercially available as Tween® 80.

[0028] The surfactant, in some embodiments, is present in an amount effective in forming an emulsion. In some embodiments, the surfactant is present in an amount ranging from about 0.1 % to about 10%, about 0.1 % to about 5%, about 0.2% to about 5%, about 0.5% to about 5%, about 1 % to about 5% or about 1 % to about 3% by weight of the composition

[0029] The present compositions further comprise a amphoteric polymeric stabilizer composed both of charged functional groups and non-polar lipophilic functional groups. Polymeric stabilizers include, in some embodiments, anionic cellulose derivatives, anionic acrylic acid-containing polymers, anionic methacrylic acid- containing polymers, anionic amino acid-containing polymers and the like and mixtures thereof. A particularly useful class of polymeric stabilizers include one or more polymeric materials having multiple anionic charges. Examples include, but are not limited to: metal carboxy methylcelluloses, metal carboxy methylbydroxyethylcelluloses, metal carboxy methylstarchs, metal carboxy methylhydroxyethylstarchs, hydrolyzed polyacrylamides and polyacrylonitriles, heparin , glycosaminoglycans, hyaluronic acid, chondroitin sulfate, dermatan sulfate, peptides and polypeptides, alginic acid, metal alginates, homopolymers and copolymers of one or more of acrylic and methacrylic acids metal acrylates and methacrylates vinylsulfonic acid metal vinylsulfonate amino acids, such as aspartic acid, glutamic acid and the like metal salts of amino acids p-s†yrenesulfonic acid metal p- styrenesulfonate 2-me†hacryloyloxye†hylsulfonic acids metal 2- methacryloyloxethylsulfonates 3-me†hacryloyloxy-2-hydroxpropylsulonic acids metal 3- me†hacryloyloxy-2-hydroxypropylsulfona†es 2-acrylamido-2-me†hylpropanesulfonic acids metal 2-acrylamido-2-me†hylpropanesulfona†es allylsulfonic acid metal allylsulfonate and the like. In some embodiments, the polymeric stabilizer comprises crosslinked polyacrylates, such as carbomers and Pemulen®. Carbomers useful as stabilizing polymers include carbomer 1342 (commercially available as Caropol® 1342 from The Lubrizol Corporation). Pemulen® is a registered trademark of B.F. Goodrich for polymeric emulsifiers available commercially from B.F. Goodrich Company, Specialty Polymers & Chemicals Division, Cleveland, Ohio. Pemulen® and carbomer 1342 include acryla†e/C 10-30 alkyl acrylate cross-polymers, or high molecular weight, copolymers of acrylic acid and a long chain alkyl methacrylate crosslinked with allyl ethers of pentaerythritol.

[0030] The stabilizing polymer may be present in the composition, in some embodiments, in an amount ranging from about 0.01 % to about 1 % by weight, about 0.01 % to about 0.5%, 0.01 % to about 0.1 %, 0.01 % to about 0.05%, or about 0.01 % to about 0.03% by weight of the composition. [0031] The present compositions further include a tonicity component. Any suitable tonicity component may be employed in accordance with the present invention. Preferably, such tonicity component is non-ionic, for example, in order to avoid interfering with the other components in composition and to facilitate maintaining the stability of the composition. Useful tonicity agents include, without limitation, glycerin, mannitol, dextrose, sorbitol and the like and mixtures thereof. In certain embodiment, the tonicity component is glycerin.

[0032] The tonicity component, such as glycerin, may be present in the compositions in and amount of about 0.1 % to about 5%, 0.1 % to about 3%, or about 0.5% to about 3% by weight of the composition.

[0033] The present compositions comprise a gel-forming agent, which is capable of forming a hydrogel in an aqueous medium. Hydrogels are three-dimensional, cross- linked networks of water-soluble polymers. Drugs can be loaded into hydrogel matrices due to porosity of the gel, and subsequent drug release occurs at a rate dependent on the diffusion coefficient of the small molecule or macromolecule through the gel network. A depot formulation is created from which drugs slowly elute, maintaining a high local concentration of drug in the surrounding tissues over an extended period. Biocompatibility is promoted by the high water content of hydrogels. Therefore, it can be seen that hydrogels are an advantageous dosage form, especially for ocular administration.

[0034] In general, the rate of drug release from a linear polymer matrix is inversely proportional to its viscosity. (Hydrogels in drug delivery: Progress and challenges by Todd R. Hoare and Daniel S. Kohane, Polymer 49: 1 1993-2007 (2008).) This causes a difficulty in that very large unworkable viscosities may be needed to affect a desired prolonged release. Water-soluble polymer hydrogels that are not cross-linked swell and subsequently dissolve in the aqueous in vivo environment. (Hydrogels in drug delivery: Progress and challenges by Todd R. Hoare and Daniel S. Kohane, Polymer 49: 1 1993- 2007 (2008).) Thus, if the polymers can be cross linked, it is likely they will stay longer in an in vivo environment such as the area of the eye.

[0035] Cross-links between the different polymer provide networks that have visco- elastic and sometimes pure elastic behavior. Polymers can be cross linked physically in addition to chemically. Alginate, for example, can be cross linked by ionic interactions, such as through calcium ions. (Novel Crosslinking methods to design hydrogels by W.E. Hennink and C.R. van Nostrum, Advanced Drug Delivery Reviews 64:223-236 (2012).) [0036] Gel-forming agents useful in the present compositions may be selected from the group consisting of cellulose polymers, including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; carbomers (e.g. carbopol, and the like); polyvinyl alcohol; polyvinyl pyrrolidone; alginates; carrageenans; and guar, karaya, agarose, locust bean, tragacanth and xanthan gums. In particular embodiments, the gel-forming agent is carbomer 980 (commercially available as Carbopol® 980 from the Lubrizol Corporation). Carbopol 980 is readily available commercially and can be used in ophthalmic applications. Jain S, Shah S, Rajadhyaksha N, Singh PSP, Amin P. Insitu ophthalmic gel of ciprofloxacin hydrochloride for once a day sustained delivery. Drug Dev Ind Pharm. 2008; 34 (4): 445-452; http://www.accessdata.fda.gov/scripts/cder/iig/getiigWEB.cfm. Carbopol is a water soluble mucoadhesive polymer that is stable at a neutral pH, which is particularly useful in ophthalmic drug administration Pharmaceutical Bulletin 21. Lubrizol. https://www.lubrizol.com/Life-Science/Documents/Pharmaceutical/Bulletins/Bulletin- 21— Formulating-Semisolid-Products.pdf. Published May 31 , 201 1 . Accessed May 5, 2015.

[0037] Carbomer displays non-Newtonian shear thinning flow properties which will permit less resistant while blinking and improve patient tolerability. Also of benefit, is that carbomers generally do not support the growth of micro-organisms, potentially giving a longer half-life to such products (Pharmaceutical Bulletin 21 . Lubrizol. https://www.lubrizol.com/Life-Science/Documents/Pharmaceutical/Bulletins/Bulletin- 21— Formulating-Semisolid-Products.pdf. Published May 31 , 201 1 ).

[0038] The gel-forming agent may advantageously be present in an amount ranging from about 0.2% to about 5%, about 0.5% to about 5%, about 0.5% to about 3% or about 0.5% to about 1 .5%, or about 1 % by weight of the composition.

[0039] Fluoroquinolone drugs have the basic structure of formula I:

[0041] Ciprofloxacin, an exemplary fluoroquinolone drug, has the structure depicted in

[0043] In some embodiments, fluoroquinolone drug is selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin. In particular embodiments, the drug is ciprofloxacin.

[0044] The fluoroquinolone drug may be present in an effective amount, which may vary depending on the specific pharmacological activity of the individual drug and condition to be treated. In some embodiments, the fluoroquinolone drug is present in an amount ranging from about 0.05% to about 5% by weight, 0.1 % to about 5% by weight, about 0.1 % to about 1 % by weight, or about 0.1 to about 0.5% by weight of the composition;

[0045] One problem with ciprofloxacin, and potentially other drugs in this class, is that it is insoluble at physiologic pH. Ciprofloxacin HCI dissolves at approximately 40mg/mL at a pH of 4-5. Therefore, pharmaceutical solutions of ciprofloxacin have a pH of 4.5 in order to solubilize the drug completely. When applied to the eye, the buffering action of tears restores the pH to about 7, thus cause precipitation after administration. Thus, ophthalmic administration of such preparations causes discomfort, thereby reducing patient compliance.

[0046] Accordingly, in some embodiments, the compositions advantageously have a relatively neutral pH, suitable for ophthalmic application, while preventing the drug from precipitating out of the emulsion-gel carrier composition. In particular, the compositions may have a pH ranging from about 6 to about 8, and more particularly, about 7 to about 7.3.

[0047] Typically a buffer is used to adjust the pH of ophthalmic solution products. The polymers selected in this application have buffer capacity due to their anionic functional groups and are utilized as buffers. Sodium hydroxide and/or hydrochloric acid may be used†o adjust pH along with typical non-electrolyte pH adjusters such as tromethamine.

[0048] The present compositions may in some embodiments further comprise a preservative. Any preservative or combination of preservatives routinely used in the art may be employed. Examples of suitable preservatives include, without limitation, sorbic acid, chlorobutanol, phenylethanol, edetate and its salts, benzalonium chloride, methyl and ethyl parabens, hexetidine, phenyl mercuric salts and the like and mixtures thereof. The amounts of preservative components included in the present compositions are such to be effective in preserving the compositions and can vary based on the specific preservative component employed, the specific composition involved, the specific application involved, and the like factors. Preservative concentrations often are in the range of about 0.00001 % to about 0.05% or about 0.1 % (w/v) of the composition, although other concentrations of certain preservatives may be employed.

[0049] Examples of preservative components in the present compositions also include, but are not limited to, chlorite components. Other useful preservatives include antimicrobial peptides. Among the antimicrobial peptides which may be employed include, without limitation, defensins, peptides related to defensins, cecropins, peptides related to cecropins, magainins and peptides related to magainins and other amino acid polymers with antibacterial, antifungal and/or antiviral activities. Mixtures of antimicrobial peptides or mixtures of antimicrobial peptides with other preservatives are also included within the scope of the present invention.

[0050] In particular embodiments, the emulsion-gel composition comprises:

an oil selected from the group consisting of selected from the group consisting of vegetable oils, mineral oils, synthetic oils and mixtures thereof;

a non-ionic surfactant such as polysorbate surfactant;

a polymeric stabilizer comprising hydrophobically modified acryla†e/C 10-30 alkyl acrylate cross-polymers, or high molecular weight, co-polymers of acrylic acid and a long chain alkyl methacrylate crosslinked with allyl ethers of pentaerythritol;

a tonicity agent selected from the group consisting of glycerin, mannitol, sorbitol and mixtures thereof;

a gel-forming agent is selected from the group consisting of cellulose polymers, including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; carbomers (e.g. carbopol, and the like); polyvinyl alcohol; polyvinyl pyrrolidone; alginates; carrageenans; and guar, karaya, agarose, locust bean, tragacanth and xanthan gums;

a fluoroquinolone drug is selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin; and

optionally a buffer.

[0051] In yet another embodiment, the composition comprises:

an oil selected from the group consisting of selected from the group consisting of vegetable oils, mineral oils, synthetic oils and mixtures thereof in an amount ranging from about 0.5% to about 10% by weight of the composition;

a polysorbate surfactant in an amount ranging from about 0.1 % to about 10% by weight of the composition;

a polymeric stabilizer comprising acryla†e/C 10-30 alkyl acrylate cross-polymers, or high molecular weight, co-polymers of acrylic acid and a long chain alkyl methacrylate crosslinked with allyl ethers of pentaerythritol in an amount ranging from about 0.01 % to about 1 % by weight of the composition ;

a tonicity agent selected from the group consisting of glycerin, mannitol, sorbitol and mixtures thereof in an amount ranging from about 0.1 % or to about 5% by weight of the composition;

a gel-forming agent selected from the group consisting of cellulose polymers, including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; carbomers (e.g. carbopol, and the like); polyvinyl alcohol; polyvinyl pyrrolidone; alginates; carrageenans; and guar, karaya, agarose, locust bean, tragacanth and xanthan gums in an amount ranging from about 0.2% to about 5% by weight of the composition;

a fluoroquinolone drug selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin in an amount ranging from about 0.05 to about 5% by weight of the composition; and optionally a buffer, wherein the composition has a pH ranging from about 6.0 to about 8.0.

[0052] In yet another embodiment, the composition comprises:

castor oil in an amount ranging from about 0.5% to about 10% by weight of the composition;

polysorbate 80 (e.g. Tween® 80) in an amount ranging from about 0.1 % to about 10% by weight of the composition;

carbomer 1342 (e.g., Carbopol® 1432), in an amount ranging from about 0.01 % to about 1 % by weight of the composition;

glycerin in an amount ranging from about 0.1 % or to about 5% by weight of the composition;

carbomer 980 (e.g., Carbopol® 980) in an amount ranging from about 0.2% to about 5% by weight of the composition;

ciprofloxacin in an amount ranging from about 0.05 to about 5% by weight of the composition; and

optionally a buffer, wherein the composition has a pH ranging from about 6.0 to about 8.0.

[0053] In yet another embodiment, the composition comprises:

castor oil in an amount ranging from about 0.5% to about 5% by weight, about 1 % to about 5% by weight, or about 2% to about 5% by weight of the composition; polysorbate 80 (e.g. Tween® 80) in an amount ranging from about 0.1 % to about 10% by weight, about 0.1 % to about 5% by weight, about 0.2% to about 5% by weight, about 0.5% to about 5% by weight, about 1 % to about 5% by weight, or about 1 % to about 3% by weight of the composition;

carbomer 1342 (e.g., Carbopol® 1432), in an amount ranging from about 0.01 % to about 0.5% by weight, about 0.01 % to about 0.1 % by weight, about 0.01 % to about 0.05% by weight, or about 0.01 % to about 0.03% by weight of the composition;

glycerin in an amount ranging from about 0.1 % or to about 3% by weight, 0.5% to about 3% by weight of the composition;

carbomer 980 (e.g., Carbopol® 980) in an amount ranging from about 0.5% to about 5% by weight, about 0.5% to about 4% by weight, about 0.5% to about 3% by weight, about 0.5% to about 1 .5% by weight of the composition;

ciprofloxacin in an amount ranging from about 0.05% to about 5% by weight, 0.1 % to about 5% by weight, about 0.1 % to about 1 % by weight, or about 0.1 to about 0.5% by weight of the composition; and optionally a buffer, wherein the composition has a pH ranging from about 6.0 to about 8.0.

[0054] In certain embodiments, any of the aforementioned compositions further comprise calcium phosphate nanoparticles (CaNP) . While not being bound by any particular theory, the addition of calcium phosphate nanoparticles in the present compositions is expected to increase the tortuosity and viscoelastic properties of the emulsion-gel composition. This is anticipated to result in a more prolonged and controllable sustained release of active drug molecules. Additionally, the composition should remain transparent and thus be more acceptable as a topical dosage form (especially as an ophthalmic dosage form). The composition described herein should also be more aesthetically pleasing for gels that are applied in locations other than the eye (e.g., dermatologically). It is anticipated that this type of composition could also be administered orally.

[0055] Dibasic calcium phosphate dihydrate [7789-77-7] has been used as a tablet and capsule diluent for a number of years (Pharmaceutical Excipients, 3^rd ed. © 2000 American Pharmaceutical Association and Pharmaceutical Press. CD-ROM) . Calcium phosphates are useful as pharmaceutical tablet fillers and binders due to their good binding properties, flowability, low cost, chemical purity and compatibility with pharmaceutical drugs."

[0056] Calcium phosphates that are useful in pharmaceutical tableting include dibasic calcium phosphate dihydrate (CaH PC - H20; DCP or DCPD), dibasic calcium phosphate anhydrous (CaHP04; DCPA or ACP) and hydroxyapatite (CasfPCU OH"; HP or HAP or HA). (Calcium phosphates in pharmaceutical tableting. (Physico- pharmaceutical Properties by P.C. Schmidt and R. Herzog. Pharmacy World & Science, 15(3) : 105-1 1 5, 1993.)

[0057] Dibasic calcium phosphate dihydrate is generally regarded as a nontoxic and nonirritant material (GRAS listed). It is included in the FDA Inactive Ingredients Guide (oral capsules and tablets) and in non-parenteral medicines licensed in Europe, the UK, and the US. However, oral ingestion of large quantities may cause abdominal discomfort.

[0058] The calcium phosphates are insoluble in water as defined by the USP. ⁽Physical and Chemical Properties of Calcium Phosphates for Solid State Pharmaceutical Formulations by J.R. Carstensen and C. Ertell. Drug Development and Industrial Pharmacy, 1 6(7) : 1 121 -1 133, ( 1990) .) Dicalcium phosphate is only soluble at low pH values and is insoluble at physiological pH (0.002g in 100 gm of water). In general, the calcium phosphates become increasingly soluble below pH environments that are less than 6.5. (Calcium Phosphate Nanocomposite Particles for In Vitro Imaging and Encapsulated Chemotherapeutic Drug Delivery to Cancer Cells by Mark Kester et.al., Nano Letters, 8 (12):41 1 6-4121 , (2008).)

[0059] Calcium phosphates are also a major component of bone and tooth enamel, where it is seen in the form of amorphous calcium phosphate (ACP) as well as crystalline hydroxyapatite (HAP), the major component of bone and tooth enamel. Additionally, both Ca²⁺ and PO4^3" are found in relatively high concentrations at typically 1 -5 mM in the bloodstream. Encapsulation of Organic Molecules in Calcium Phosphate Nanocomposite Particles for Intracellular Imaging and Drug Delivery by Thomas T. Morgan et.al., Nano Letters, 8 ( 12):4108-41 15, (2008).) As a biomineral, CP safely biodistributes, with dissolved material regulated via the kidneys. CP is relatively insoluble at physiological pH but has increasing solubility in the acidic environments that can occur in the body, such as in endolysosomes. It is suggested that calcium phosphate nanoparticles dissolve when the endosomes carrying them fuse with lysosomes where they experience low pH.

[0060] The number ratio of C to P in the calcium phosphate nanoparticles in some embodiments ranges from 1 : 1 to 3: 1 . In an embodiment, the form of calcium phosphate is dibasic calcium phosphate dihydrate (CaHPO H20). In another embodiment, the form of calcium phosphate is tncaicium diphosphate (Ca3(P04)2) because it is readily available in nanometer size. Favored forms of calcium phosphate include dibasic calcium phosphate anhydrous (CaHP04) and hydroxylapatite (Ca5(P04)30H) because of their common pharmaceutical use. All Calcium Phosphates (chemical bond between calcium and phosphorus atoms, the phosphorus atom is further bonded to oxygen atoms that may or may not be bonded to hydrogen) that are insoluble at pH of 6.5 to 8.0 are considered to be appropriate for the pharmaceutical compositions described herein

[0061] Discrete nanoparticles are expected to be transparent when dispersed in water. This is believed to result in less blurred vision when administered to the eye. Additionally, it should be more aesthetically pleasing if used as a dermatological dosage form. If a dermatological form is used as a film forming bandage, the transparency would enable inspections of wounds and abrasions without removing the protective film (bandage).

[0062] In some embodiments, the calcium phosphate nanoparticles have a size ranging from about 5 nm to about 200 nm. In other embodiments, the calcium phosphate nanoparticles have a size ranging from about 10 nm to about 100 nm, while in still other embodiments, the calcium phosphate nanoparticles have a size ranging from about 10 to about 80 nm.

[0063] The calcium phosphate nanoparticles useful in the present compositions have an increased surface area compared to stand calcium phosphates used in the pharmaceutical industry. For example, in some embodiments, the calcium phosphate particles have a surface area ranging from about 10 m²/gm to about 100 m²/gm, while in other embodiments, the calcium phosphate particles have a surface area ranging from about 30-60 m²/gm.

[0064] Tortuosity is understood in the art as referring to a property of a curve being tortuous (twisted; having many turns). There have been several attempts to quantify this property. Tortuosity is commonly used to describe diffusion in porous media. It is commonly invoked in hydrogels to explain why the release of drug molecules is slowed when dissolved in a hydrogel network. That is, the drug molecule must work its way through the polymer network in order to be released out of the system. The use of CaP NPs will result in multitudes of NPs blocking the pathway of the drug molecule, thus slowing its release even more. Additionally, most drug particles would adsorb onto CaP NP and the need to desorb would result in additional slowing of their release from the hydrogel.

[0065] It is anticipated that just as adsorbing Na citrate onto CaP NP resulted in dispersions, that the same dispersive events will occur when hydrophilic polymers adsorb onto CaP NPs. Agglomerations of the CaP NPs would result in a loss of transparency and significantly decrease the overall strength of the interactions between solid phase and solvated polymer.

[0066] It is anticipated that the binding of CaP NPs to hydrophilic polymer strands present in the gel-forming agent will result in an increase in viscosity (resistance to flow) and elasticity (resistance to deformation) of the resulting hydrogel. Examples were given in the literature where by physical crosslinking of polymers resulted in such effects.

[0067] Again not being bound by theory, an increase in viscosity would resist tear flow in the eye and increase retention time of an ophthalmic gel. An increase in elasticity may increase ocular retention time by absorbing the energy of blinking, much as a contact lens does. An increase in elasticity may assist in setting up a dermatological gel so that it stays in place until a film forms from evaporation. An increase in elasticity could help to insure that a capsule filled with such a gel would empty out of the stomach intact and then break into micro hydrogels in the gastro intestinal tract. [0068] The present disclosure further provides methods of administering a fluoroquinolone drug opthalmically to a patient in need thereof using the present emulsion-gel compositions. The administration may be in the form of eye drops or a similar form to facilitate administration to the surface of the eye of the patient in need thereof. The frequency of administration will vary depending on the dose of the drug and the condition to be treated. Nevertheless, it is believed that the present compositions advantageously reduce the amount of systemic exposure to the drug agent compared to administration of a solution of the drug. Furthermore, because precipitates and acidic pH are avoided with the present compositions, patient comfort and compliance should be greatly improved.

[0069] Alternative modes of administration include injection, such as intra-ocular injection, dermal, rectal and vaginal. Again, the present compositions are expected to provide a more localized application of the fluoroquinolone drug at a site in need thereof, thereby reducing systemic absorption.

The present disclosure further provides methods for preparing the aforementioned compositions. The method comprises the steps of providing and emulsion of the fluoroquinolone drug and combining it with a hydrogel composition to form the emulsion gel. More particularly, the methods comprises the steps of i) preparing an emulsion comprising an oil, a surfactant, a polymeric stabilizer a tonicity component, a gel-forming agent, fluoroquinolone drug and water; 2) preparing a gel comprising a gel-forming agent and water; and 3) combining the emulsion and the gel to form the fluoroquinolone drug composition. In some embodiments, the method of preparing further comprises adjusting the pH of the emulsion-gel compositions using a buffer, such as sodium hydroxide, hydrogen chloride, phosphate, citrate or carbonate. In certain embodiments, the buffer is sodium hydroxide and the pH is adjusted to within a range of about 6.0 to about 8.0, or about 6.5 to about 7.5, or about 7.0 to about 7.3.

[0070] In embodiments further comprising calcium phosphate nanoparticles, the method further comprises combing the gel of step 2 with calcium phosphate nanoparticles.

[0071] Examples below are provided to illustrate some embodiments of the compositions of the present disclosure but should not be interpreted as any limitation thereon. Other embodiments within the scope of the claims herein will be apparent to one skilled in the art from the consideration of the specification or practice of the compositions or methods disclosed herein. It is intended that the specification, together with the example, be considered to be exemplary only, with the scope and spirit of the disclosure being indicated by the claims which follow the examples.

EXAMPLES

[0072] A Beer's Law calibration curve was created by dissolving 3 mg of ciprofloxacin base in 200 mL AJAX buffer solution (sodium lauryl sulfate, docusate sodium, polyethylene glycol 400, and TR1 ). Next, volumetric dilutions were performed to obtain the desired concentrations, 100%, 60%, 40%, 20%, 10%, 2%, 1 %. The absorbance was read on a UV-Visable Spectrophotometer at a wavelength of 280. The curve was not forced through the Y intercept of zero and had an R2 of 0.9988 (Fig. 1 ). Concentrations of ciprofloxacin in experimental samples were determined using the standard curve.

[0073] Next, the dialysis tubing was prepared. The tubing selected was cellulose ester dialysis membrane with a molecular weight between 500-1000D. The tubing was soaked approximately one hour in Dl water. Then soaked another 24 hours in the AJAX buffer. When prepped, the tubing was cut into 10 cm segments then crimped at one end and secured with a plastic paper clip. The cut and paper-clipped tubing was placed back in the AJAX buffer to await filling with the Cipro vehicles.

[0074] The first vehicle prepared was a ciprofloxacin emulsion. The components for the emulsion were obtained from the FDA inactive ingredient list for Restasis®. These were: 2.2 grams of glycerin, 5 grms of castor oil, 4 gms of Tween 80®, and 0.05 gm of carbomer 1342 combined with 0.3 gm of ciprofloxacin base. These were mixed together by hand and pH adjusted with 0.1 N NaOH to 7.12 and qs'd to a final volume of 100 mL. The mixture was then combined with a homogenizer for 5 minutes to create the emulsion. It was allowed to sit out overnight to determine if it would break. While creaming was noted, the emulsion easily distributed again after little agitation.

[0075] Next, the emulsion-gel was created. A 2% stock carbomer gel was made from 4 gm of carbomer 980 in 200 mL of Dl water. The solution was allowed to saturate overnight and pH adjusted to 7.05. Next, a 0.6% stock Cipro emulsion was created as described above but doubled amounts of the components. 100 mL of the 2% emulsion was combined with 100 mL of the 2% carbomer gel in a Beville open top mixer and mixed until uniform. The final concentration of the emulsion-gel is 1 % carbomer gel and 0.3% ciprofloxacin emulsion.

[0076] A ciprofloxacin solution similar to what is marketed was prepared for this study. Therefore, the inactive ingredients of the Cipro solution were obtained from the FDA inactive drug list. It was determined for a 100 mL solution, it needed 0.1 mL acetic acid, 5 gm of dextrose, and pH adjust using HCI and NaOH as needed for a final pH of 4.5.

[0077] To create the calcium phosphate nanoparticle gels, the emulsion was created as above, but before the final qs, 5 gm of calcium phosphate nanoparticles were added. Then 50 mL of the 2% carbomer stock gel were added and mixed together by hand. The solution was pH adjusted using 0.1 N NaOH to a final pH of 7.1 5. The emulgel with nanoparticles was mixed with the homogenizer for 5 minutes. This procedure was repeated but with 2 gm of nanoparticles as well and had a final pH of 7.06.

[0078] Next, rheology studies were conducted. The gels were assessed on a Haake 550 viscotester to determine, thixotropic and viscosity characteristics of the gels. The gels were tested between 20-22 degrees Celsius. The Ostwald de Waele curve fit calculated the flow consistency index, K, and flow behavior index, n determined using the equation T=ky ^'Λη, where τ is shear stress. The higher the k value, the more viscous the preparation is. Fluids are considered shear thinning if n is less than 1 and considered more shear thinning as n decreases. The Bingham curve fit calculated the yield.

[0079] In order to determine the release rate, the dialysis tubing was filled with 1 mL of ciprofloxacin vehicle and normalized on a pan balance to 1 gm of vehicle. The tubing was then crimped closed and secured with a plastic clip. The tubing was then placed into a beaker containing 200 mL of AJAX vehicle and a stir bar. The beakers were covered with parafilm and corrections for water loss were made on an as needed basis. Beakers were placed on stir plates to normalize concentration of drug throughout the system and maintenance of sink condition. Six beakers were set up for each vehicle type for an n of 6. Samples were drawn from the vehicle frequently and concentration was assessed via UV-Visible Spectroscopy. The results were then plotted on a time vs. percent theory concentration graphs.

[0080] Statistical analysis was performed by normalizing percent absorbance values vs the time at which they were measured. The data was fit with the general form of the logistic function. The sigmoid curve fit data as defined in kaleidaGraph is Y=M1 + (M2 - Μ1 )/( 1 + (Χ/Μ3)^ΛΜ4 ) . In this equation, y is the percent theory released at X or time in minutes. Ml was defined as the concentration at infinity. Ml was allowed to float, as the release amount varied from formulation to formulation. M2 is defined as the concentration before the run beings, or 0% theory The m3 parameter is the time at which 50% of the ciprofloxacin has been released. Ml and M3 are an effective measure of release rate. . The four equation parameters were averaged for each preparation and was used to create a single curve representing ciprofloxacin release rate from different preparations. One way ANOVA and Tukey's post hoc tests (p<0.05) were used to determine statistical significance for m3 values of the preparations.

[0081 ] When all the Cipro solution that was going to diffuse had left the tubing, an assay of the final amount left in the tube was taken to make sure none was stuck inside the tubing membrane. 1 mL of solution inside the tubing was measured out. This was diluted with 10 mL of vehicle. The absorbance was taken and this was compared to the amount that had diffused out of the tubing.

Results

[0082] It is important to note, that by day 2 of release studies, crystals developed in the ciprofloxacin solution beakers. The precipitate remained for approximately a week, dissolving slowly in the test vehicle, likely increasing the apparent release rate demonstrated by the dialysis tubing methodology.

Release Rates

[0083] A linear curve fit sigmoid model was used to evaluate each experimental run for concentration released vs sampling time. The R2 values obtained for all the individual curve fits ranged from 0.98 to 0.99 with the average at 0.99. The Ml and M3 values were averaged and listed in Table 1 . Larger Ml values indicate more drug released, and larger M3 indicate a slower ciprofloxacin release rate. M4 is a shape parameter but was not assessed at this time.

[0084] One way ANOVA results indicate that there were statistically significant difference between the groups at Ml with a p value O.0001 (not including 2% at this time due to incompleteness) . Tukey's post-hoc test also indicated there were statistically significant differences between each formulation with the other formulation which can be found in Table 2. In addition, ANOVA demonstrated statistically significant difference M3 values. However Tukey's post-hoc did not show a difference in 5% emulgel vs emulgel and 5% vs. solution.

[0085] Table 1

[0086] Table 2 Comparison Mean | q | P 95% CL

Difference

solution vs emulsion 0.008804 28.286 < .0001 0.0075718 to 0.010036 solution vs 5% 0.00384 12.3376 < .0001 0.002608 to 0.005072 solution vs emulgel 0.001836 5.8992 0.0024 0.00060409 to

0.0030681

emulgel vs emulsion 0.006968 22.3868 < .0001 0.0057357 to 0.0081997 emulgel vs 5% 0.002004 6.4384 0.001 0.00077193 to

0.0032359

5% vs emulsion 0.004964 15.9484 < .0001 0.0037318 to 0.0061958

[0087] The graph of the average release rates as defined by the Ml , M2, M3, and M4 values is displayed in Fig. 2. All lines were terminated at 8300 minutes as this was the last data point for the fastest vehicle, the emulgel. Include time to diffuse of other formulations here

[0088] The assay of the tubing showed an absorbance of 68% theory. This equals approximately 0.01 mg. The expected was approximately 0.009 mg. This difference could be due to experimental error. It is assumed all Cipro is present in either the vehicle or still in the tube and not bound in the tubing membrane.

Rheology

[0089] The measured viscosity values for each gel preparation were fitted by the

Ostwald de Waele and Bingham models and results are reported in Table 3. The n values were less than one, which indicates that all preparations exhibited pseudoplastic properties. As expected, the 5% CaP emulgel has the highest viscosity. The lowest the viscosity gel, the 2% CaP emulgel, displayed more pseudoplastic properties. However, the 2% CaP emulgel actually has a lower viscosity than the emulgel but both experience a similar yield value. Thixotropic values were significantly different between all three preparations, the 5% being the highest and the emulgel displaying the lowest. The 5% CaP emulgel and the emulgel also displayed similar flow behavior index (n) values. The rheology study is shown in Graph A as shear rate 1 /s vs log[viscosi†y (Pa*s)].

Table 3 Emulgel 2% CaP emulgel 5% CaP emulgel

K 3.720 0.08567 28.8

n 0.3102 0.8964 0.3889 Thixotropy -2661 2523 22270

Yield value 5.220 8.7964 1 13.1

Discussion

[0090] The four parameter sigmoidal model was used as the descriptor for the release results. This provided a good description of the release rates, as indicated by the excellent R2 values provided by the program. The experiment is set up to allow for sink conditions with a linear rate of release. The equations clearly demonstrate this is Graph X in all formulations but that of the emulsion. This could be because the emulsion is so lipophilic, the ciprofloxacin is not compelled to exit the environment for the much more aqueous environment of the vehicle. As the experiment progresses, the curve begins to flatten out at a much lower concentration than sink conditions would be compromised due to the large volume of receiving fluid even for the ciprofloxacin in solution. Again, this could be explained by the ciprofloxacin not diffusing into the vehicle due to its chemical properties or by binding the cellulose membrane itself. The ciprofloxacin with a molecular weight of 331 D should easily be able to flow through the tubing therefore size is not an issue.

[0091] Per the ANOVA one way test, the difference between Ml and M3 values were statistically different for each formulation. All formulations displayed a lower release than the solution. Again, the emulsion would not diffuse due to the characteristics of the ciprofloxacin. Clinically, when applied to the eye, the solution must have a high concentration to rapidly diffuse into the cornea before being almost immediately washed away. A formulation that would have a longer residence time, say an emulgel, would need to have a lower concentration or risk toxicity and/or side effects to the eye tissue. Therefore, a lower release would be preferable in the clinical setting.

[0092] In addition, all formulations except the emulgel succeeded in slowing the release of ciprofloxacin as compared to the solution as indicated by the statistically different M3 values. Initially, the emulgel displayed a faster release than the solution despite the solution releasing more drug. However, due to the increased viscosity of the emulgel compared to the solution, it can be theorized the emulgel will have a longer residence time on the eye, and therefore deliver more drug to the eye as the solution would be quickly washed away. An slower release is ideal for an extended release product. More importantly, all formulations were of a neutral pH and successfully released product into the vehicle. These products could reside on the eye for a long period of time and not cause pain and burning to the patient. Neither would the drug precipitate out into the cornea as it was already contained in a pH neutral environment.

[0093] Rheology

[0094] As expected, the 5% CaP emulgel had the highest viscosity. However, the emulgel had a higher viscosity than the 2% CaP emulgel. This could be due to the CaP nanoparticles disrupting some potential interactions in the gel. This could also explain the increased thioxtrophy experienced by the emulgel. All gels would be easily thinned by a blinking eye and provide a protective film to the eye. The emulgel and the 2% CaP emulgel are thin enough as well that they could conceivably be placed into a dropper bottle for easy patient administration. The addition of the 2% nanoparticles did not increase shear thinning and therefore would not cause the "sticky" feeling disliked by many patients.

[0095]

[0096] Conclusions

[0097] It appears the emulsion-gel compositions described herein may be used to control drug release and provide a pH neutral drug vehicle for ciprofloxacin. This may be a useful finding for ophthalmics because an increased residence time on the eye would necessitate a neutral pH to provide patient comfort and prevent precipitants in the eye. The emulsion-gel compositions did decrease the amount of drug released, however, in an extended release format where the drug is not being quickly washed away, less drug would need to be released.

[0098] Rheology studies demonstrate release can be further controlled by increasing and decreasing the amount of nanoparticles in the formulation. It was demonstrated that an addition of 2% nanoparticles did not increase shear thinning compared to the emulgel. Both formulations would easily be spread by the patient's eyelid, increasing patient comfort still further.

[0099] All patent and non-literature documents cited hereinabove are hereby incorporated by reference in their entirety.

Claims

CLAIMS We claim:

1 . A pharmaceutical composition comprising an oil, a surfactant, a polymeric stabilizer, a tonicity component, a gel-forming agent, a fluoroquinolone drug and water.

2. The composition of claim 1 , wherein the oil is selected from the group consisting of vegetable oils, mineral oils, synthetic oils and mixtures thereof.

3. The composition of claim 2, wherein the oil is castor oil.

4. The composition of any one of claims 1 to 3, wherein the oil is present in an amount greater than about 0.5% by weight.

5. The composition of claim 1 , wherein the surfactant is a polysorbate surfactant.

6. The composition of any one of claims 1 to 5, wherein the surfactant is present in an amount of about 0.1 % to about 10%.

7. The composition of any one of claims 1 to 6, wherein the polymeric stabilizer is a cross-linked polyacrylate.

8. The composition of any one of claims 1 to 7, wherein the polymeric stabilizer is carbomer 1342.

9. The composition of any one of claims 1 to 8, wherein the polymer is present in an amount ranging from about 0.01 % to about 1 % by weight of the composition.

10. The composition of any one of claims 1 to 9, wherein the tonicity agent is selected from the group consisting of glycerin, mannitol, sorbitol and mixtures thereof.

1 1 . The composition of claim 10, wherein the tonicity agent is glycerin.

12. The composition of any one of claims 1 to 1 1 , wherein the tonicity component is present in an amount ranging from about 0.1 % or to about 5%.

13. The composition of any one of claims 1 to 12, wherein the gel-forming agent is selected from the group consisting of cellulose polymers, including hydroxypropyl methyl cellulose (HPMC), hydroxyethyl cellulose (HEC), ethyl hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose and carboxymethyl cellulose; carbomers (e.g. carbopol, and the like); polyvinyl alcohol; polyvinyl pyrrolidone; alginates; carrageenans; and guar, karaya, agarose, locust bean, tragacanth and xanthan gums.

14. The composition of claim 14, wherein the gel-forming agent is carbomer 980.

1 5. The composition of any one of claims 1 to 14, wherein the gel-forming agent is present in an amount ranging from about 0.2% to about 5% by weight of the composition.

1 6. The composition of any one of claims 1 to 15, wherein the fluoroquinolone drug is selected from the group consisting of ciprofloxacin, norfloxacin, ofloxacin, gemifloxacin, levofloxacin and moxifloxacin, enoxacin, fleroxacin, lomefloxacin, nadifloxacin, pefloxacin, rufloxacin, balofloxacin, pazufloxacin, sparfloxacin, tosufloxacin, clinafloxacin, gatifloxacin, sitafloxacin, prulifloxacin, delafloxacin, JNJ-Q2, and nemonoxacin.

1 7. The composition of claim 1 6, wherein the fluoroquinolone drug is ciprofloxacin.

18. The composition of any one of claims 1 to 1 7, wherein the fluoroquinolone drug is present in an amount ranging from about 0.05 to about 5% by weight of the composition.

1 9. The composition of any one of claims 1 to 18, further comprising a buffer.

20. The composition of claim 1 9, wherein the buffers comprises the polymeric stabilizer and/or the gel forming polymer.

21 . The composition of any one of claims 1 to 20, wherein the composition has a pH ranging from about 6.0 to about 8.0.

22. The composition of any one of claims 1 to 21 , further comprising calcium phosphate nanoparticles in an amount ranging from about 0.1 % to about 5% by weight.

23. A method for administering a fluoroquinolone drug to the eye of a patient in need thereof comprising:

providing a composition comprising a composition according to anyone of claims 1 to 18, and

contacting the composition with the eye.

24. The method of claim 23, wherein the administration is topical administration to the surface of the eye.

25. The method of claim 23 or 24, wherein the method demonstrates a reduction in systemic exposure to the fluoroquinolone drug compared to administration of an aqueous formulation of a fluoroquinolone drug.

26. A method for administering a fluoroquinolone drug to the skin of a patient in need thereof comprising: providing a composition comprising a composition according to anyone of claims 1 to 18, and

contacting the composition with the skin.

27. A method for administering a fluoroquinolone drug to the skin of a patient in need thereof comprising:

contacting the composition with the skin.

28. The method of claim 26, wherein the administration is topical administration to the surface of the skin or used to treat abrasions or cuts of the skin.

29. A method of preparing a fluoroquinolone drug composition comprising: preparing an emulsion comprising an oil, a surfactant, a polymeric stabilizer a tonicity component, a gel-forming agent, a fluoroquinolone drug and water;

preparing a gel comprising a gel-forming agent and water; and

combining the emulsion and the gel to form the fluoroquinolone drug composition.

30. The method of claim 29, further comprising adding a sodium hydroxide solution to the composition to adjust the pH to a range of about 6.0 to about 8.0.

31 . The method of claim 29 or 30, further comprising adding calcium phosphate nanoparticles to the emulsion.

32. The method of claim 29 or 30, further comprising adding calcium

phosphate nanoparticles to the gel.