WO2017151664A1 - Compositions pharmaceutiques pour l'administration d'un médicament de type fluoroquinolone - Google Patents

Compositions pharmaceutiques pour l'administration d'un médicament de type fluoroquinolone Download PDF

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WO2017151664A1
WO2017151664A1 PCT/US2017/020019 US2017020019W WO2017151664A1 WO 2017151664 A1 WO2017151664 A1 WO 2017151664A1 US 2017020019 W US2017020019 W US 2017020019W WO 2017151664 A1 WO2017151664 A1 WO 2017151664A1
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composition
gel
drug
weight
fluoroquinolone drug
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PCT/US2017/020019
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Kenneth W. Reed
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Belmont University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels

Definitions

  • 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.
  • the compositions further contain entrapped calcium phosphate nanoparticles.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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) .
  • 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) .
  • Emulsions combined with gels to form an "emulgel” have been used topically for dermal applications with diclofenac.
  • 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) .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the method further comprises adding calcium phosphate nanoparticles to the gel composition.
  • the method further comprises adding calcium phosphate nanoparticles to the emulsion.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present compositions comprise comprising an oil, a surfactant, a polymeric stabilizer, a tonicity component, a gel-forming agent, a fluoroquinolone drug and water.
  • the compositions further comprise calcium phosphate nanoparticles (CaP).
  • 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.
  • 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.
  • any suitable surfactant may be used in the present compositions, and many are known and used in the pharmaceutical arts.
  • surfactants useful in the present compositions include without limitation, surfactant components which may be anionic, cationic, nonionic or amphoteric in nature.
  • the surfactant includes a hydrophobic constituent and hydrophilic constituent.
  • the surfactant is water soluble in the presently useful compositions.
  • the surfactant is nonionic.
  • 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.
  • the surfactant is a polysorbate, such as polysorbate 80, which is commercially available as Tween® 80.
  • 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- methacryloy
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • HPMC hydroxypropyl methyl cellulose
  • HEC hydroxyethyl cellulose
  • HEC hydroxyethyl cellulose
  • hydroxypropyl cellulose hydroxypropyl cellulose
  • carbomers e.g. carbopol, and the like
  • polyvinyl alcohol polyvinyl pyrrolidone
  • alginates e.g.
  • 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
  • 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.
  • Fluoroquinolone drugs have the basic structure of formula I:
  • Ciprofloxacin an exemplary fluoroquinolone drug, has the structure depicted in
  • 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.
  • the drug is ciprofloxacin.
  • 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;
  • 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.
  • the buffering action of tears restores the pH to about 7, thus cause precipitation after administration.
  • ophthalmic administration of such preparations causes discomfort, thereby reducing patient compliance.
  • 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.
  • the compositions may have a pH ranging from about 6 to about 8, and more particularly, about 7 to about 7.3.
  • 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.
  • preservative components in the present compositions also include, but are not limited to, chlorite components.
  • Other useful preservatives include antimicrobial peptides.
  • antimicrobial peptides 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.
  • 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;
  • non-ionic surfactant such as polysorbate surfactant
  • 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;
  • 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 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.
  • composition comprises:
  • castor oil in an amount ranging from about 0.5% to about 10% 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
  • carbomer 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
  • composition has a pH ranging from about 6.0 to about 8.0.
  • 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
  • polysorbate 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
  • carbomer 1342 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
  • carbomer 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.
  • any of the aforementioned compositions further comprise calcium phosphate nanoparticles (CaNP) .
  • CaNP calcium phosphate nanoparticles
  • 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.
  • 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.
  • 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).
  • CaH PC - H20 dibasic calcium phosphate dihydrate
  • CaHP04 dibasic calcium phosphate anhydrous
  • CasfPCU OH hydroxyapatite
  • HP or HAP or HA hydroxyapatite
  • 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.
  • GRAS listed nontoxic and nonirritant material
  • 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 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 Ca 2+ 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.
  • ACP amorphous calcium phosphate
  • HAP crystalline hydroxyapatite
  • 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.
  • the number ratio of C to P in the calcium phosphate nanoparticles in some embodiments ranges from 1 : 1 to 3: 1 .
  • the form of calcium phosphate is dibasic calcium phosphate dihydrate (CaHPO H20).
  • 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.
  • 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).
  • 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.
  • the calcium phosphate nanoparticles useful in the present compositions have an increased surface area compared to stand calcium phosphates used in the pharmaceutical industry.
  • the calcium phosphate particles have a surface area ranging from about 10 m 2 /gm to about 100 m 2 /gm, while in other embodiments, the calcium phosphate particles have a surface area ranging from about 30-60 m 2 /gm.
  • 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.
  • 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.
  • 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.
  • Alternative modes of administration include injection, such as intra-ocular injection, dermal, rectal and vaginal.
  • 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.
  • 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.
  • a buffer such as sodium hydroxide, hydrogen chloride, phosphate, citrate or carbonate.
  • 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.
  • the method further comprises combing the gel of step 2 with calcium phosphate nanoparticles.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Cipro solution 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.
  • 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.
  • 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.
  • 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 were used to determine statistical significance for m3 values of the preparations.
  • 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.
  • 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.

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Abstract

De manière générale, la présente divulgation concerne des hydrogels pharmaceutiques semi-solides contenant des nanoparticules de phosphate de calcium piégées qui font preuve d'une libération ou d'une rétention du médicament et de propriétés esthétiques améliorées. Ces hydrogels sont particulièrement utiles pour des applications topiques de molécules médicamenteuses. Des procédés d'administration d'un agent pharmaceutique par l'intermédiaire d'un hydrogel pharmaceutique semi-solide contenant au moins un agent pharmaceutique et son administration à un sujet en ayant besoin sont en outre décrits.
PCT/US2017/020019 2016-02-29 2017-02-28 Compositions pharmaceutiques pour l'administration d'un médicament de type fluoroquinolone WO2017151664A1 (fr)

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WO2018169967A1 (fr) * 2017-03-14 2018-09-20 Allergan, Inc. Acorafloxacine dans le traitement d'infections oculaires
CN113181125A (zh) * 2021-04-27 2021-07-30 海南通用三洋药业有限公司 一种西他沙星片剂及其制备方法
CN117503701A (zh) * 2023-12-08 2024-02-06 斯坦德医药研发(江苏)有限公司 左氧氟沙星口服混悬液制剂及制剂制造方法

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Publication number Priority date Publication date Assignee Title
WO2018169967A1 (fr) * 2017-03-14 2018-09-20 Allergan, Inc. Acorafloxacine dans le traitement d'infections oculaires
CN113181125A (zh) * 2021-04-27 2021-07-30 海南通用三洋药业有限公司 一种西他沙星片剂及其制备方法
CN113181125B (zh) * 2021-04-27 2022-07-19 海南通用三洋药业有限公司 一种西他沙星片剂及其制备方法
CN117503701A (zh) * 2023-12-08 2024-02-06 斯坦德医药研发(江苏)有限公司 左氧氟沙星口服混悬液制剂及制剂制造方法

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