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WO2024233921A1 - Compositions pour l'administration transtympanique d'antibiotiques et leurs procédés d'utilisation - Google Patents

Compositions pour l'administration transtympanique d'antibiotiques et leurs procédés d'utilisation Download PDF

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Publication number
WO2024233921A1
WO2024233921A1 PCT/US2024/028845 US2024028845W WO2024233921A1 WO 2024233921 A1 WO2024233921 A1 WO 2024233921A1 US 2024028845 W US2024028845 W US 2024028845W WO 2024233921 A1 WO2024233921 A1 WO 2024233921A1
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composition
compound
therapeutic compound
concentration
therapeutic
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Inventor
Rong Yang
Sophie S. LIU
Michelle CALABRESE
Joanna White
Frank Bates
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Cornell University
University of Minnesota Twin Cities
University of Minnesota System
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Cornell University
University of Minnesota Twin Cities
University of Minnesota System
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    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A61K9/0046—Ear
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • 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
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant

Definitions

  • the present invention relates to compositions suitable for the transdermal, transmembrane, transmucosal, and/or transtympanic administration of a therapeutically effective amount of a therapeutic compound such as an antibiotic for treating a subject.
  • a therapeutic compound such as an antibiotic for treating a subject.
  • the compositions of the present invention are stable hydrogels.
  • Chemical permeation enhancers are broadly categorized as solvents (e.g., water, dimethylsulphoxide, pyrrolidones), surfactants, terpenes, azones, fatty acids, urea, phospholipids, etc. (see Ref 5).
  • solvents e.g., water, dimethylsulphoxide, pyrrolidones
  • surfactants e.g., water, dimethylsulphoxide, pyrrolidones
  • terpenes e.g., azones, fatty acids, urea, phospholipids, etc.
  • Ionic surfactants such as sodium dodecyl sulfate (SDS) can also interact with the therapeutic agents such as ciprofloxacin (see Refs 10-11), resulting in aggregate that cannot diffuse through a hydrogel or do so very slowly (see Refs 12-14).
  • ionic surfactants make up a significant class of commonly chemical permeation enhancers (for example, sodium alkyl sulfates and quaternary alkyl ammonium salts (see Refs 1, 3, and 15)
  • surfactant-drug- hydrogel interactions present a significant challenge in the development of hydrogel compositions for drug delivery.
  • the current standard of care for otitis media is a non-local, oral antibiotic course (Refs. 16-18), which is undesirable due to: (1) the need for a multi-day, multidose administration, (2) the resulting systemic exposure (Ref. 19), and (3) the high risk of antibiotic resistance due to patient non-compliance or frequent antibiotic use to treat recurring infections (Refs. 20-22).
  • Local otitis media treatment options exist, as there are currently a limited number of FDA- approved otic drops, e.g. Ciprodex® (0.3% ciprofloxacin, 0.1% dexamethasone) (Refs. 27-28) and Cetraxal® (0.2% ciprofloxacin) (Ref. 29).
  • Otiprio® is an FDA-approved solution of 6% ciprofloxacin in P407 for sustained drug release, but it is also limited to patients with tympanostomy tube or requires an invasive intra-tympanic injection (Refs. 43, 66, 69).
  • the present invention is directed to compositions suitable for administration of a therapeutic compound across a biological barrier.
  • the present invention is directed to a composition to facilitate transtympanic delivery of a therapeutic compound comprising the therapeutic compound, a first compound comprising a permeation enhancer that comprises a fatty acid methyl ester having a Cio to C20 n-alkyl or branched alkyl chain, and a second compound comprising a hydrophilic non-ionic surfactant; wherein the therapeutic compound has a molecular weight of about 200 g/mol to about 1,000 g/mol and is at least one of: ionized at pH 3 to 8, contains a Hydrogen-bond donor functional group; contains a Hydrogen-bond acceptor functional group, or a combination thereof.
  • the present invention is directed to a composition for delivering a therapeutic compound to a patient comprising: a therapeutic compound having a molecular weight of about 200 g/mol to about 1,000 g/mol that is at least one of:
  • a combination thereof a first compound comprising one or more ester groups and one or more optionally substituted Cio to C20 chains, wherein the first compound and therapeutic compound interact form a pseudo-surfactant assembly; a second compound comprising a non-ionic surfactant or a hydrogel precursor that forms a micelle, liposome, or vesicle with water, wherein the pseudo-surfactant assembly is incorporated into the micelle, liposome, or vesicle, and wherein the composition has a pH of 3 to 8.
  • the present invention is directed to a composition
  • a composition comprising: a therapeutic compound having a molecular weight of about 200 g/mol to about 1,000 g/mol that is:
  • compositions of the present invention are suitable for administering therapeutic compounds having a molecular weight of about 200 g/mol to about 1,000 g/mol and that are at least one of: anionic, cationic, include a Hydrogen-bond donor functional group, include a Hydrogen-bond acceptor functional group, or a combination thereof.
  • the therapeutic compound is selected from a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, an aminoglycoside, a steroid, derivatives thereof, or a combination thereof.
  • the therapeutic compound has a solubility of less than 0.1 g/L in water at 20 °C.
  • the therapeutic compound is a quinolone antibiotic or a salt thereof.
  • the therapeutic compound is a quinolone antibiotic selected from: ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, salts thereof, and combinations thereof.
  • the therapeutic compound is ciprofloxacin.
  • the therapeutic compound is present in a concentration of about 0.1% w/v to about 10% w/v, preferably about 1% w/v to about 8% w/v, or more preferably about 2% w/v to about 6% w/v.
  • compositions of the present invention further comprise one or more additional therapeutic compounds.
  • Additional therapeutic compounds suitable for use with the present invention include analgesics such as bupivacaine, lidocaine, tetracaine, benzocaine, and prilocaine.
  • the therapeutic compound and first compound are present in the compositions of the present invention at a molar ratio of about 1:2 to about 2:1, or about 1:1.
  • the first compound is selected from an ester, a diester, or an oligo-ester comprising a Ce to C20 carbon chain. In some embodiments, the first compound is a C ⁇ > to C20 fatty acid ester.
  • the first compound is a fatty acid ester having a Ce to C20 n-alkyl or branched alkyl chain and a methyl, ethyl, propyl, isopropyl, or butyl ester group, or preferably a fatty acid ester having a Ce to Cis n-alkyl or branched alkyl chain and a methyl, ethyl, propyl, isopropyl, or butyl ester group.
  • the first compound is a Ce to C20 fatty acid methyl ester. In some embodiments, the first compound consists essentially of a fatty acid methyl ester having a C ⁇ > to C20 n-alkyl or branched alkyl chain. In some embodiment, the fatty acid methyl ester comprises methyl laurate. In some embodiments, the permeation enhancer consists essentially of methyl laurate.
  • the first compound comprises a fatty acid methyl ester present in a concentration of about 0.5% w/v to about 5% w/v, more preferably about 1% w/v to about 4% w/v, and most preferably about 2% w/v.
  • the therapeutic compound comprising a Hydrogen-bound donor functional group, a Hydrogen-bond acceptor functional group, or a combination thereof; and the first compound comprises a Hydrogen-bond acceptor functional group, a Hydrogen-bond acceptor functional group, or a combination thereof, and the therapeutic compound and first compound interact via one or more Hydrogen-bonds to form a pseudosurfactant assembly.
  • the pseudo-surfactant assembly formed by the therapeutic compound and first compound further interacts with the second compound to form a micelle assembly, a hydrogel, or a combination thereof.
  • the second compound comprises a hydrophilic non-ionic surfactant having the structure of formula I: wherein a is independently an integer of about 50 to about 150, preferably about 75 to about 125, and most preferably about 100; and b is independently an integer of about 40 to about 70, and preferably about 50 to about 60, and most preferably about 55.
  • a is an integer of about 50 to about 150 and b is an integer of about 40 to 70, preferably a is an integer of about 75 to about 125 and b is an integer of about 50 to about 60, and more preferably a is an integer of 100 and b is an integer of 55.
  • the second compound is a non-ionic surfactant or a neutral surfactant.
  • the second compound is selected from a poloxamer or a derivative thereof, a reverse poloxamer or a derivative thereof, a polyethylene glycol polymer, and a combination thereof.
  • the second compound is selected from a polysorbate, sodium lauryl sulfate, poloxamer, polyoxyl 40 hydrogenated castor oil, lauroyl polyoxyl-32 glycerides, mannide monooleate, propylene glycol monocaprylate, and a combination thereof.
  • the second compound is selected from P407, P188, P338, MAKON 17R2, MAKON 17R4, poloxamer/pluronic diacrylate, poloxamer dimethacrylate, PEGDA, PEGMA, PLGA-PEG-PLGA, PEG-PCL-PEG, and a combination thereof.
  • the second compound is a thermoresponsive polymer, a thermoresponsive block copolymer, or a combination thereof.
  • the composition is thermosensitive with a transition from a liquid at a first temperature to a hydrogel at a second temperature.
  • the compositions of the present invention form a stable hydrogel at a temperature of about 20 °C to about 40 °C.
  • the compositions of the present invention have a solgel transition temperature at about 4 °C to about 35 °C.
  • the second compound comprises a hydrophilic non-ionic surfactant is present in a concentration of about 10% w/v to about 25% w/v, or more preferably about 15% w/v to about 25% w/v.
  • the first compound is methyl laurate in a concentration of about 1% w/v to about 4% w/v
  • the second compound is a hydrophilic non-ionic surfactant in a concentration of about 15% w/v to about 25% w/v.
  • compositions of the present invention comprise the therapeutic compound in a concentration of 0.005% w/v to 20% w/v, the first compound in a concentration of 0.005% w/v to 30% w/v, and the second compound in a concentration of 12% w/v to 50% w/v.
  • the composition comprises 0.005% w/v to 10% w/v of the therapeutic compound, 0.1% w/v to 10% w/v of the first compound, 15% w/v to 25% w/v of the second compound, and 30% w/v to 50% w/v of water.
  • the composition comprises 1% w/v to 8% w/v of the therapeutic compound, 0.5% w/v to 8% w/v of the first compound, 15% w/v to 25% w/v of the second compound, and 30% w/v to 50% w/v of water.
  • the composition comprises 2% w/v to 6% w/v of the therapeutic compound, 1% w/v to 6% w/v of the first compound, 15% w/v to 25% w/v of the second compound, and 30% w/v to 50% w/v of water.
  • the compositions of the present invention further comprise one or more additives.
  • Additives suitable for use with the compositions of the present invention include an alcohol, a terpene, a terpenoid, bupivacaine, an alkanol, a phenols, a sulfoxide, a glycol, a fatty acid or a derivative thereof, and combinations thereof.
  • Alcohols suitable for use with the compositions of the present invention include one or more Ci to Cs linear or branched alcohols, preferably one or more Ci to Ce linear or branched alcohols, and most preferably one or more Ci to C4 linear or branched alcohols.
  • Terpenes and terpenoids suitable for use with the compositions of the present invention include limonene, myrcene, menthol, carvone, linalool, and combinations thereof, with limonene being preferred.
  • compositions of the present invention further comprise limonene or bupivacaine, or a combination thereof.
  • the present invention is also directed to methods of administering a therapeutically effective amount of the compositions of the present invention to a subject in need thereof.
  • a subject in need of treatment suffers from otitis media.
  • Data are mean ⁇ SD, statistical analysis performed using two-way analysis of variance (ANOVA) with Dunnetf s test vs. [P407 + cip], ** indicates a statistically significant result with p ⁇ 0.005.
  • Data are mean ⁇ SD, statistical analysis performed using two-way analysis of variance (ANOVA) with Dunnetfs test vs. [P407 + cip], * p ⁇ 0.05, ** p ⁇ 0.005, *** p ⁇ 0.0005.
  • FIG. 3A is an illustration of the supported lipid bilayer (SLB) formed on a PEDOT:PSS-coated electrode and its equivalent electrical circuit.
  • FIG. 3B is a graphic representation of illustrative impedance data showing the signature “chair- like” signal for SLB.
  • FIGs. 4A-4D provide graphic representations of impedance measurements taken for the bare electrode (baseline); after formation of a supported lipid bilayer using 1- palmitoyl-2-oleoyl-glycero-3-phosphocholine (“POPC”); and after 30 min of treatment with diluted hydrogel compositions containing: P407 alone (FIG. 4A); P407 and methyl laurate (“ML”) (P407+ML, FIG. 4B); P407 and ciprofloxacin (“cip”) with no permeation enhancer (P407+cip, FIG. 4C); and P407, ciprofloxacin (“cip”), and methyl laurate (“ML”) (P407+cip+ML, FIG. 4D).
  • P407 alone P407 and methyl laurate (“ML”)
  • cip ciprofloxacin
  • cip ciprofloxacin
  • ML methyl laurate
  • FIG. 5 provides a graph of representative microelectrode EIS measurements for before SLB formation (baseline), after SLB formation (POPC SLB), and after SLB was incubated with diluted [P407], [P407 + cip], [P407 + ML], or [P407 + cip + ML] compositions.
  • FIG. 6 provides a graphic representation of the timeline utilized for in vivo experiments performed using a chinchilla otitis media model.
  • FIGs. 7A-7D are photographs of: a healthy chinchilla tympanic membrane (FIG. 7A); a chinchilla tympanic membrane infected with Nontypeable Haemophilus influenzae (“NTHi”) (FIG. 7B); a chinchilla tympanic membrane infected with NTHi following application of a hydrogel composition containing P407, ciprofloxacin (“cip”), and 2% methyl laurate onto the tympanic membrane through the outer ear canal (P407 + cip + 2% ML, FIG.
  • FIG. 7C a chinchilla tympanic membrance infected with NTHi following application of a hydrogel composition containing P407, ciprofloxacin (“cip”), and a combination of bupivacaine, limonene, and SDS (“3CPE(SDS)”) (P407 + cip + 3CPE(SDS), FIG. 7D), which gelled during the injection before reaching the tympanic membrane.
  • the arrow points towards the tympanic membrane.
  • the scale bar in all images FIGs. 7A-7D is 2 mm.
  • Statistical analysis were performed using two-way ANOVA with Dunnett’s test vs. [untreated] for day 7, ** p ⁇ 0.005.
  • FIG. 8B provides a graphic representation of the CFU count of NTHi in middle ear fluids extracted from the same animals as FIG. 8A.
  • the LoglO value for CFU measurements of zero was represented as one instead of negative infinity. All data are median and interquartile range.
  • FIG. 8C provides a graphic representation of the concentration of ciprofloxacin in the middle ear fluid extracted from the same animals used for the data in FIGs. 8A-8B. Data are mean ⁇ Standard Error of Mean (SEM).
  • FIGs. 9A-9E provide representative images showing section tympanic membrane from healthy and NTHi-infected chinchillas after 7 days of treatment, with Gram staining.
  • FIGs. 10A-10E provide representative images showing section tympanic membrane from healthy and NTHi-infected chinchillas after 7 days of treatment, with Gram staining. The black arrows indicate clusters of bacteria.
  • ME middle ear
  • OE outer ear
  • scale bar 200 pm.
  • FIG. 11 provides a graphic representation of the observed phenomenon that with increasing temperature, a solution containing 18% P407 is disorders “unimers” at temperatures at or below 20 °C, then forms spherical micelles that are disordered in the temperature range of 25 °C to 26.5 °C, and which then order into a physical hydrogel at temperatures at about 27 °C, as seen by rheology (plotted on logarithmic scale).
  • the PPO block within P407 dehydrates, as shown by the endothermic peak in the differential scanning calorimetry (DSC) curve, as temperature increases.
  • DSC differential scanning calorimetry
  • FIG. 12 provides a graphic representation of Small Angle X-ray Scattering (SAXS) measurements for neat P407 every from 10 °C to 50 °C measured every 5 °C (indicated by symbols), where the ID traces show broad features indicative of disordered micelles at 25 °C (black) prior to ordering onto an Face Centered Cubic (“FCC”) lattice with increasing temperature. The position of the Bragg peaks and corresponding Miller indices for the FCC-structure are highlighted with black triangles.
  • SAXS Small Angle X-ray Scattering
  • FIGs. 13A-13B provide a graphic representation of rheology data (plotted on a linear scale) for solutions containing P407, P407+2% SDS, P407+2% ML (FIG. 13A) and P407, P407+cip, P407+2% ML, and P407+cip+2% ML (FIG. 13B).
  • FIG. 14 provides a graphic representation of Differential Scanning Calorimetry (DSC) data showing that in 18% P407 solutions with 2% SDS, the temperature-dependent thermodynamic micellization transition was not observed while in 18% P407 solutions with 2% methyl laurate (“ML”), the transition was preserved.
  • DSC Differential Scanning Calorimetry
  • FIGs. 15A-15B provide a graphic representation of 1-dimensional SAXS traces and 2-D patterns at 35 °C.
  • FIG. 15C provides a graphic representation of micelle radius (R m ic) determined via SAXS as a function of ML concentration for compositions containing 18% (w/v) P407 and 4% (w/v) CIP.
  • FIG. 16 provides a graphical representation of the decay coefficient (F) determined via multi-angle Dynamic Light Scattering (DLS) plotted as a function of q- squared (“q 2 ”) for compositions containing 1% P407 with 0.1% methyl laurate (“ML”) or 0.1% SDS. Linear fitting of these data bound to an intercept of zero (dashed lines) were used to extract the diffusion coefficient which is related to Rh via the Stokes-Einstein relationship. Addition of SDS dramatically decreases the Rh relative to compositions with P407 or P407 + ML.
  • DLS Dynamic Light Scattering
  • FIGs. 17A-B are representative images of a gel containing neat 18% P407 at 37 °C (FIG. 16A), which are optically clear, and a gel containing 18% P407 and 2% methyl laurate (“ML”) (FIG. 16B), which are cloudy.
  • a representative optical microscopy image of the gel containing 18% P407 and 2% methyl laurate (“ML”) shows that the presence of ML resulted in the formation of micron-sized oil droplets.
  • Scale bar 200 m in both insets.
  • compositions and methods of using the compositions refers to compositions and methods of using the compositions.
  • a feature or embodiment associated with a composition such a feature or embodiment is equally applicable to the methods of using the compositions.
  • a feature or embodiment associated with a method of using a composition e.g., a method of treatment, method of administration, and/or other method of use
  • such a feature or embodiment is equally applicable to the compositions disclosed herein.
  • compositions and methods which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination.
  • composition refers to a composition, pharmaceutical composition, and/or unit dosage form suitable for administration to a subject.
  • compositions of the present invention refers to a salt form, carrier, diluent, adjuvant, or excipient that is compatible with the compositions of the present invention and the other ingredients of a pharmaceutical composition such that the composition is suitable for pharmaceutical use and not deleterious to the recipient thereof.
  • administering refers to providing a composition described herein to a subject in need thereof by ototopical or topical application, or other means that enables the compositions of the present invention to have beneficial effect(s) or to have a targeted effect(s) on a specific location of the body.
  • administering a composition may be accomplished by any method that provides a localized administration of the compositions to an area of the body requiring such treatment by known techniques.
  • a “therapeutically effective amount” or “effective amount” of a composition of the present invention is a predetermined amount calculated to achieve a desired effect.
  • a desired effect can be to inhibit, block, or reverse the activation, migration, proliferation, or alteration of cellular function, while preserving the normal function of normal cells.
  • the activity contemplated by the compositions and methods described herein includes both medical therapeutic and/or prophylactic treatment, as appropriate, and the compositions and methods of the invention can be used to provide improvement in any of the conditions described. It is also contemplated that the compositions described herein may be administered to healthy subjects or individuals not exhibiting symptoms but who may be at risk of developing a particular disorder.
  • a therapeutically effective amount of a composition of this invention is typically an amount such that when administered it is sufficient to achieve a beneficial effect on the subject.
  • the terms “treat,” “treated,” and/or “treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological condition, disorder, or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder, or disease; stabilization (i.e., not worsening) of the state of the condition, disorder, or disease; delay in onset or slowing of the progression of the condition, disorder, or disease; amelioration of the condition, disorder, or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder, or disease.
  • the term “subject,” as used herein, describes an organism, including mammals, to which treatment with the compositions and compounds according to the subject disclosure can be administered.
  • Mammalian species that can benefit from administration of the compositions of the present invention by the disclosed methods include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and other animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters.
  • the subject is a human.
  • the compositions of the present invention comprise a “pseudo-surfactant assembly” between the therapeutic compound and the first compound.
  • a “pseudo-surfactant assembly” is a reversible complex that enhances tissue permeability of the therapeutic compound while retaining the bulk structure and rheological properties of the composition that are attributable to the second compound.
  • the pseudo-surfactant assembly can be formed by ionic and/or Hydrogen-bonding interactions between the therapeutic compound and the first compound.
  • a pseudo-surfactant assembly is formed by Hydrogen-bonding interaction(s) between the therapeutic compound and first compound.
  • a pseudo-surfactant assembly between the therapeutic compound and first compound can be characterized using a variety of analytical techniques, including, but not limited to differential scanning calorimetry (DSC), dynamic light scattering (DLS), optical microscopy, small-angle X-ray scattering (SAXS), and/or small- amplitude oscillatory rheology.
  • DSC differential scanning calorimetry
  • DLS dynamic light scattering
  • SAXS small-angle X-ray scattering
  • small-amplitude oscillatory rheology small-amplitude oscillatory rheology
  • compositions of the present invention are generally suitable for use with any therapeutic compound having a molecular weight of about 200 g/mol to about 1,000 g/mol, and that is at least one of: ionized in aqueous solution at a pH of 3 to 8, and/or includes a Hydrogen-bond donor, and/or includes a Hydrogen-bond acceptor functional group.
  • the therapeutic compound has a molecular weight of 225 g/mol to about 900 g/mol, about 250 g/mol to about 800 g/mol, or about 300 g/mol to about 1,000 g/mol.
  • the therapeutic compound has low solubility in water or is substantially insoluble in water. In some embodiments, the solubility of the therapeutic compound in water is less than 0.1 g/L at 20 °C, or less than 0.01 g/L at 20 °C.
  • the therapeutic compound is a quinolone antibiotic, a tetracycline antibiotic, a macrolide antibiotic, an aminoglycoside, a steroid, or a combination thereof any of which is ionized in aqueous solution at a pH of 3 to 8, and/or includes a Hydrogen-bond donor and/or Hydrogen-bond acceptor functional group.
  • the therapeutic compound is a quinolone antibiotic or a pharmaceutically acceptable salt thereof.
  • the therapeutic compound is a quinolone antibiotic selected from the group consisting of: ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, a pharmaceutically acceptable salt thereof, and combinations thereof.
  • the therapeutic compound is ciprofloxacin or a pharmaceutically acceptable salt thereof.
  • the therapeutic compound is a tetracycline antibiotic or a salt thereof.
  • the therapeutic compound is a tetracycline antibiotic selected from: tetracycline, chlortetracycline, oxytetracycline, demeclocycline lymecycline, methacycline, minocycline, rolitetracycline, doxycycline, tigecycline, eravacycline, sarecycline, omadacycline, salts thereof, and combinations thereof.
  • the therapeutic compound is a macrolide antibiotic or a salt thereof.
  • the therapeutic compound is a macrolide antibiotic selected from: erythromycin, azithromycin, clarithromycin, dirithromycin, roxithromycin, telithromycin, cethromycin, solithromycin, Carbomycin A, josamycin, kitasamycin, midecamycin, oleandomycin, spiramycin, troleandomycin, tylosin, boromycin, tacrolimus, sirolimus, pimecrolimus, amphotericin B, nystatin, natamycin, rimocidin, filipin, candicin, hamycin, perimycin, dermostatin, salts thereof, and combinations thereof.
  • the therapeutic compound is an aminoglycoside or a salt thereof.
  • the therapeutic compound is an aminoglycoside selected from: gentamicin, amikacin, tobramycin, neomycin B, neomycin C, neomycin E, streptomycin, plazomycin, kanamycin, vancomycin, amikacin, tobramycin, dibekacin, gentamicin, sisomicin, netilmicin, salts thereof, and combinations thereof.
  • the therapeutic compound is a steroid or a salt thereof.
  • the therapeutic compound is a steroid selected from: dexamethasone, hydrocortisone, cortisone, prednisone, prednisolone, methylprednisolone, betamethasone, triamcinolone, deflazacort, fludrocortisone, deoxycorticosterone, aldosterone, beclomethasone, triamcinolone, paramethasone, fluprednisolone, salts thereof, and combinations thereof.
  • Pharmaceutically acceptable salts of the therapeutic compounds for use with the present invention include acid-addition salts.
  • Suitable pharmaceutically-acceptable acid addition salts of compounds within the scope of the present invention may be prepared from anions derived from inorganic or organic acids, or a combination thereof.
  • Examples of salts derived from inorganic acids include but are not limited to chloride, bromide, iodide, nitrite, nitrate, carbonate, sulfate, phosphate, tetrafluoroborate, and combinations thereof.
  • Suitable organic acids include aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, sulfonic, and combinations thereof.
  • organic acids include but are not limited to formate, acetate, propionate, succinate, glycolate, gluconate, lactate, malate, tartrate, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilate, mesylate, salicylate, 4-hydrobenzoate, phylacetate, mandelate, embonate, methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, 2- hydroxyethanesulfonate, toluenesulfonate, sulfanilate, cyclohyexylaminosuflonate, stearate, algenate, hydrobutyrate, galactarate and galactumoate, and combinations thereof.
  • a hydrochloride salt of a therapeutic compound is preferred.
  • the therapeutic compound is present in a concentration of about 0.005% w/v to about 10% w/v, about 0.5% w/v to about 10% w/v, preferably about 1% w/v to about 6% w/v, or most preferably about 4% w/v.
  • compositions of the present invention further comprise one or more additional therapeutic compounds.
  • Additional therapeutic compounds suitable for use with the present invention include analgesics such as bupivacaine, lidocaine, tetracaine, benzocaine, and prilocaine.
  • an additional therapeutic compound is present in a concentration of about 0.005% w/v to about 10% w/v, about 0.5% w/v to about 10% w/v, about 1% w/v to about 8% w/v, or about 2% w/v to about 6% w/v.
  • the inventive compositions comprise a “first compound” which is generally a neutral or non-ionized compound having permeation enhancing functionality, which refers to an ability to increase the flux of a therapeutic compound through a biologic barrier.
  • the first compound is selected from an ester, a diester, or an oligo-ester having 3-10 ester groups (e.g. 3, 4, 5 ester groups).
  • the first compound is selected from an ester, a diester, or an oligo-ester comprising a Ce to Cis carbon chain
  • esters, diesters, and oligo-esters comprising a Ce to Ci6 carbon chain, a Ce to Cu carbon chain, or a Ce to C12 carbon chain can also be used.
  • esters, diesters, and oligo-esters comprising a Cs to Cis carbon chain, a C10 to Cis carbon chain, or a C12 to Cis carbon chain can also be used.
  • the first compound comprises a Ce to Cis fatty acid ester, a Ce to Ci6 fatty acid ester, a Ce to C14 fatty acid ester, a Ce to Cis fatty acid ester, a Cs to Cis fatty acid ester, a C10 to Cis fatty acid ester, or a combination thereof.
  • Fatty acid esters for use with the inventive compositions can include an n-alkyl or branched alkyl chain and a methyl, ethyl, propyl, isopropyl, or butyl ester group, or a mixture thereof.
  • the first compound comprises a Ce to Cis fatty acid methyl ester, a Ce to Cie fatty acid methyl ester, a Ce to C14 fatty acid methyl ester, a Cs to Cis fatty acid methyl ester, a C10 to Cis fatty acid methyl ester, a C12 to Cis fatty acid methyl ester, or a combination thereof.
  • the fatty acid methyl ester comprises methyl laurate.
  • the first compound consists essentially of a Ce to Cis fatty acid methyl ester, a Ce to Cie fatty acid methyl ester, a Ce to C14 fatty acid methyl ester, a Cs to C is fatty acid methyl ester, a C10 to Cis fatty acid methyl ester, a C12 to Cis fatty acid methyl ester, or a combination thereof.
  • the permeation enhancer consists essentially of methyl laurate.
  • the first compound consists of a Ce to Cis fatty acid methyl ester, a Ce to Cie fatty acid methyl ester, a Ce to C14 fatty acid methyl ester, a Ce to C12 fatty acid methyl ester, a Cs to Cis fatty acid methyl ester, a C10 to Cis fatty acid methyl ester, a C12 to Cis fatty acid methyl ester, or a combination thereof.
  • the first compound comprises a fatty acid short chain ester.
  • short chain refers to a Ci to C4 alkyl chain, which is optionally branched.
  • the fatty acid short chain ester is selected from: methyl caprate, ethyl caprate, propyl caprate, iso-propyl caprate, butyl caprate, methyl laurate, ethyl laurate, propyl laurate, iso-propyl laurate, butyl laurate, methyl myristate, ethyl myristate, propyl myristate, iso-propyl myristate, butyl myristate, methyl palmitate, ethyl palmitate, propyl palmitate, iso-propyl palmitate, butyl palmitate, methyl stearate, ethyl stearate, propyl stearate, iso-propyl stearate, butyl stearate, and combinations thereof.
  • the fatty acid short chain ester is methyl laurate.
  • the first compound is generally present in any concentration suitable to facilitate the permeation of the therapeutic compound through a biologic barrier, such as the skin, a membrane, eardrum, or other barrier.
  • a biologic barrier such as the skin, a membrane, eardrum, or other barrier.
  • the first compound is present in a concentration of about 0.1% w/v to about 20% w/v, about 0.2% w/v to about 18% w/v, about 0.5% w/v to about 15% w/v, or preferably about 1% w/v to about 10% w/v, about 1% w/v to about 5% w/v, or about 1% w/v to about 4% w/v.
  • the first compound comprises a fatty acid methyl ester and is present in the composition in a concentration of about 0.5% w/v to about 10% w/v, about 0.5% w/v to about 5% w/v, or about 0.5% w/v to about 4% w/v.
  • the first compound is a fatty acid methyl ester present in the composition in a concentration of about 1% w/v to about 4% w/v.
  • the first compound is a fatty acid methyl ester present in the composition in a concentration of about 2% w/v.
  • the first compound comprises a fatty acid methyl ester present in a concentration of about 0.5% w/v to about 5% w/v, more preferably about 1% w/v to about 4% w/v, and most preferably about 2% w/v.
  • the amounts of the therapeutic compound and first compound can also be selected on the basis of a molar ratio suitable for the formation of a pseudo-surfactant assembly.
  • the therapeutic compound and first compound are present in the compositions of the present invention at a molar ratio of about 1:4 to about 4:1 and any values therewith and any subranges therebetween, and preferably about 1:3 to about 3:1 or about 1:2 to about 2:1, or most preferably about 1:1.
  • the therapeutic compound comprising a Hydrogen-bound donor functional group, a Hydrogen-bond acceptor functional group, or a combination thereof; and the first compound comprises a Hydrogen-bond acceptor functional group, a Hydrogen-bond acceptor functional group, or a combination thereof, and the therapeutic compound and first compound interact via one or more Hydrogen-bonds to form a pseudosurfactant assembly.
  • the therapeutic compound interacts with the one or more functional groups of the first compound via one or more hydrogen bonds to form an assembly.
  • the therapeutic compound comprises one or more Hydrogen bound donors having N, O, F, or any combination
  • the first compound comprises one or more Hydrogen bound acceptors (e.g. an ester group) to interact with the hydrogen bound donors of the therapeutic compound to form a pseudo-surfactant assembly.
  • the therapeutic compound comprises one or more Hydrogen bound acceptor and the first compound comprises one or more Hydrogen bound donor to interact with the therapeutic compound to form a pseudo-surfactant assembly.
  • compositions of the present invention contain 2% w/v or less of an ionic surfactant, 1% w/v or less of an ionic surfactant, 0.5% w/v or less of an ionic surfactant, 0.2% w/v or less of an ionic surfactant, or 0.1% or less of an ionic surfactant.
  • compositions of the present invention are substantially free of an ionic surfactant, for example, 100 ppm or less of an ionic surfactant, 50 ppm or less of an ionic surfactant, or 20 ppm or less of an ionic surfactant. In some embodiments, the compositions of the present invention do not contain an ionic surfactant, for example, in any detectable amount.
  • SDS sodium dodecyl sulfate
  • compositions of the present invention contain 0.5% w/v or less of SDS, 0.2% w/v or less of SDS, or 0.1% or less of SDS.
  • the compositions of the present invention are substantially free of SDS, for example, 100 ppm or less of SDS, 50 ppm or less of SDS, or 20 ppm or less of SDS.
  • the compositions of the present invention do not contain SDS, for example, in any detectable amount.
  • compositions comprise a “second compound” which is generally a hydrophilic, non-ionic or neutral surfactant.
  • the second compound forms a hydrogel.
  • the second compound comprises a hydrophilic non-ionic surfactant having the structure of formula I: wherein a is independently an integer of about 50 to about 150, preferably about 75 to about 125, and most preferably about 100; and b is independently an integer of about 40 to about 70, and preferably about 50 to about 60, and most preferably about 55.
  • a is an integer of about 50 to about 150 and b is an integer of about 40 to 70, preferably a is an integer of about 75 to about 125 and b is an integer of about 50 to about 60, and more preferably a is an integer of 100 and b is an integer of 55.
  • a is 156 and b is 101.
  • the second compound is a non-ionic surfactant or a neutral surfactant selected from a poloxamer or a derivative thereof, a reverse poloxamer or a derivative thereof, a polyethylene glycol polymer, and a combination thereof.
  • the second compound is a non-ionic surfactant selected from a polysorbate, sodium lauryl sulfate, poloxamer, polyoxyl 40 hydrogenated castor oil, lauroyl polyoxyl-32 glycerides, mannide monooleate, propylene glycol monocaprylate, and a combination thereof.
  • the second compound is a non-ionic surfactant is selected from one or more polysorbates (e.g. polysorbate 20, polysorbate 80), one or more poloxamers (e.g. P407, P188, and/or P338), reverse poloxamers and any derivatives, polyoxyethylene (160), polyoxypropylene (30) glycol, MAKON 17R2, MAKON 17R4, pluronic diacrylate, poloxamer dimethacrylate, a PEG-based polymer (e.g. PEGDA, PEGMA, PLGA-PEG- PLGA, PEG-PCL-PEG), and/or any combinations thereof.
  • polysorbates e.g. polysorbate 20, polysorbate 80
  • poloxamers e.g. P407, P188, and/or P3308
  • reverse poloxamers and any derivatives polyoxyethylene (160), polyoxypropylene (30) glycol, MAKON 17R2, MAKON 17R4, pluronic diacrylate, po
  • the second compound is selected from P407, P188, P338, MAKON 17R2, MAKON 17R4, poloxamer/pluronic diacrylate, poloxamer dimethacrylate, PEGDA, PEGMA, PLGA-PEG-PLGA, PEG-PCL-PEG, and a combination thereof.
  • the second compound can be present in the compositions in any concentration that forms a stable hydrogel.
  • the second compound comprises a hydrophilic non-ionic surfactant and is present in the compositions in a concentration of about 10% w/v to about 25% w/v, or about 12% w/v to about 25% w/v, or preferably about 15% w/v to about 25% w/v.
  • the second compound comprises a hydrophilic non-ionic surfactant and is present in the compositions in a concentration of about 12% w/v to about 30% w/v.
  • the second compound comprises a hydrophilic non-ionic surfactant and is present in the compositions in a concentration of about 15% w/v to about 25% w/v, or about 15% w/v to about 25% w/v. In some embodiments, the second compound comprises a hydrophilic non-ionic surfactant and is present in the compositions in a concentration of about 18% w/v.
  • first compound methyl laurate
  • second compound P407
  • topical pharmaceuticals such as transdermal patches containing fentanyl or testosterone (see Refs. 28, 29, 69, 77, 78).
  • the compositions of the present invention do not require further regulatory review and approval in order to be administered to mammals, and in particular humans.
  • the second compound is a thermoresponsive polymer, a thermoresponsive block copolymer, or a combination thereof.
  • a “thermoresponsive” or “temperature-responsive” polymer refers to polymers that undergo discontinuous changes in their physical properties as a function of temperature. Relevant properties for the inventive compositions disclosed herein include, but are not limited to, solubility, three-dimensional packing, hydrogen bonding, hydrogel formation, micelle formation, phase separation, and the like.
  • the compositions of the present invention include P407 as the second compound, which is a thermoresponsive polymer that undergoes gelation in aqueous solutions with increasing temperature, which is driven by changes in polymer solubility.
  • P407 is an ABA triblock polymer composed of poly(ethylene oxide) (PEO) endblocks and a polypropylene oxide) (PPO) midblock. With increasing temperature, the interactions between water and the PPO midblock become less favorable, driving the formation of spherical micelles composed of PPO cores and PEO coronas (see Refs. 32, 44- 49). When a critical volume fraction of micelles is achieved, the micelles order into cubic packings, causing the low-viscosity solutions to gel (see Refs. 32, 50, 51).
  • the inventive composition is thermosensitive with a transition from a liquid at a first temperature to a hydrogel at a second temperature.
  • the compositions of the present invention form a stable hydrogel at a temperature of about 20 °C to about 40 °C, about 25 °C to about 45 °C, or about 25 °C to about 40 °C.
  • the compositions of the present invention have a sol-gel transition temperature at about 4 °C to about 35 °C, about 6 °C to about 32 °C, or about 8 °C to about 30 °C.
  • the pseudo-surfactant assembly formed by the therapeutic compound and first compound further interacts with the second compound to form a micelle assembly, a hydrogel, or a combination thereof.
  • the pseudo-surfactant assembly interacts with the second compound to form a micelle assembly in a solution or a hydrogel with water.
  • the composition and/or the second compound is thermosensitive with a transition from a liquid at a first temperature (e.g less than 15 °C such as 4 °C) to a hydrogel at a second temperature (e.g. greater than 20 °C such as 30 °C to 37 °C).
  • the composition is a stable hydrogel in a temperature of about 20 °C to about 40 °C, including any values therewithin and/or any subranges therebetween, preferably about 30 to about 37 °C.
  • the composition and/or the second compound has a sol-gel transition temperature in a range of about 1 °C to about 35 °C, including any values therewithin and/or any subranges therebetween, preferably about 5 °C to about 2 °C.
  • the composition further comprises one or more additives, one or more additional therapeutic compounds, or any combinations thereof.
  • the one or more additives are selected from one or more terpenes (e.g. limonene), alcohols, alkanols, phenols, sulfoxides, glycols, fatty acids and fatty acid derivatives.
  • one or more additional therapeutic compounds is bupivacaine, or other small molecule analgesics.
  • the present disclosure is also directed to methods of treating disorders that require or benefit from the transdermal, transmembrane, and/or transtympanic administration of an antibiotic.
  • the present invention is directed to methods of treating otitis media, the methods comprising transtympanically administering a therapeutically effective amount of a composition to a subject in need thereof.
  • the composition of the present invention comprises 0.1% w/v to 20% w/v of the therapeutic compound including any values therewith and any subranges therebetween, 0.1% w/v to 20% w/v of the first compound including any values therewith and any subranges therebetween, 10% w/v to 30% w/v of the second compound including any values therewith and any subranges therebetween, and optionally 30% w/v to 50% % w/v of water including any values therewith and any subranges therebetween.
  • the present invention is directed to a composition
  • a hydrophilic non-ionic surfactant having the structure of Formula I: wherein a is an integer from about 75 to about 125, and b is an integer from about 50 to about 60, and wherein the hydrophilic non-ionic surfactant is present in a concentration of about 15% w/v to about 25% w/v; methyl laurate, in a concentration of about 1% w/v to about 4% w/v; a quinolone antibiotic selected from the group consisting of: ciprofloxacin, garenoxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, and combinations thereof, present in a concentration of about 0.5% w/v to about 6% w/v; and water.
  • More embodiments include:
  • compositions further comprise a permeation enhancer.
  • the additional permeation enhancer is selected from: limonene, bupivacaine, and combinations thereof.
  • compositions further comprise a Ci to Cs alcohol. In some embodiments, the compositions further comprise a C2 or C3 alcohol, or a combination thereof.
  • the present invention is directed to method of administering the compositions described herein to a subject in need of treatment with a therapeutic compound.
  • the compositions of the present invention are particularly suitable for administering a therapeutic compound to a subject suffering from a condition that would benefit from localized (i.e., non-systemic) administration of a therapeutically effective amount of the therapeutic compound.
  • the methods of the present invention include administering a composition as described herein once, twice, three times, or four times per day or on an as-needed basis to treat the subject’s condition.
  • Example 1 Ex vivo Drug Permeation with Ciprofloxacin-Containing Compositions
  • the transtympanic drug flux was measured for three compositions, each containing 18% w/v P407 and 4% w/v ciprofloxacin: (i) [P407 + cip], which served as the baseline for the transtympanic flux of ciprofloxacin without CPEs, (ii) [P407 + cip + 2% ML], which additionally contained 2% w/v ML, and (iii) [P407 + cip + 3CPE(SDS)], which additionally contained the three chemical permeation enhancers SDS (1% w/v), limonene (2% w/v), and bupivacaine (0.5% w/v).
  • 3CPE(SDS) has been previously identified as the gold standard and thus served as a benchmark in this experiment (see Ref. 30).
  • chinchilla model was used to measure the transtympanic drug flux.
  • Tympanic membranes from healthy chinchillas were harvested following euthanization under CO2 inhalation in accordance with IACUC guidelines, and the auditory bullae were removed from the skull. Each bulla was excised to expose the middle ear chamber and the tympanic membrane. Immediately following dissection, the tympanic membranes were visually examined, and their electrical impedance was measured using a previously described protocol to test tissue integrity see Ref. 18).
  • the saline in the receiving chamber was retrieved for analysis and each insert was placed into a new well with the same amount of fresh saline (i.e., 1.5 mL).
  • Samples were diluted in MilliQ water as needed, filtered with a 0.45-pm (pore size) PTFE membrane, then analyzed by high- performance liquid chromatography (HPLC) to determine the concentration of ciprofloxacin hydrochloride.
  • HPLC-grade acetonitrile, methanol, and water were obtained from Fisher Chemical and HPLC-grade trifluoroacetic acid (TFA) was obtained from Sigma- Aldrich.
  • the HPLC was performed on a Shimadzu LC-2030C 3D with a Cl 8 column, 4.6 x 100 mm, 2.7 pm (Agilent).
  • the mobile phase contained acetonitrile with 0.1% TFA (solvent A) and water with 0.1% TFA (solvent B).
  • Lipid bilayers constitute the most likely path of diffusion through the stratum comeum, i.e., the uppermost layer in skin and tympanic membrane that is largely impermeable to most drugs (see Refs. 23-26). Supported lipid bilayers have been widely used as cell membrane surrogates to study the biophysical properties of membranes and their interactions with signaling molecules (see Refs. 35, 36). The effect of CPEs on the structural integrity of SLB thus provides a good prediction of their effect on tympanic membrane permeability.
  • the supported lipid bilayers were formed using l-palmitoyl-2-oleoyl-glycero-3- phosphocholine (POPC, FIG. 3A), a widely used phosphatidylcholine model lipid to recapitulate the phospholipids present in the cell membrane (see Refs. 38-40).
  • POPC l-palmitoyl-2-oleoyl-glycero-3- phosphocholine
  • the supported lipid bilayers were subsequently treated by the hydrogel compositions used in the ex vivo experiment, i.e., [P407 + cip] and [P407 + cip + ML].
  • the compositions were diluted 20-fold in Tris-KCl buffer to minimize the mechanical perturbations to the supported lipid bilayers.
  • Otitis media infections were established by inoculating Nontypeable Haemophilus influenzae (“NTHi”) into the bulla of chinchillas.
  • NHi Non-typeable haemophilus influenzae
  • HBSS sterile Hanks’ balanced salt solution
  • the solution 100 pL, 25-75 CFU was inoculated directly into the middle ear of chinchillas through the bulla, using aseptic techniques. Once pathogen inoculation was completed, chinchillas were monitored, and their TMs examined via otoscopy.
  • middle ear infection was established (usually at 3 days post inoculation), 200 pL of the formulations were administered through the external ear canal using a soft-tipped 22-gauge angiocatheter (without needle, MonojectTM), and the animals underwent surgery for middle ear sample collection.
  • the animals were anesthetized under isoflurane inhalation, placed in ventral recumbency, and had their tympanic bullae surgically prepped. A small surgical opening was created at the most palpable region of the tympanic bulla with a scalpel blade. Direct samples of the middle ear culture were obtained with sterile cotton swabs, and immediately streaked onto chocolate agar plates.
  • the middle ear fluid was retrieved through the surgical opening with a 22-gauge angiocatheter (without needle) connected to a 1 mL tuberculin syringe, without hampering TM integrity.
  • the MEF was sampled before the treatment on day 0, and after the administration of the formulations on day 1, day 3, and day 7.
  • the MEF (10- 20 pL) was diluted in HBSS with 10-fold serial dilution and plated onto chocolate agar plates. The number of colonies was counted to calculate the CFU of NTHi, with the lower limit of detection being 100 CFU/mL.
  • the middle ear fluid (“MEF”) was sampled before inoculation on day 0, and after the administration of the compositions on day 1, day 3, and day 7.
  • Infection was defined as non-zero NTHi colony forming units (“CFU”) count from the middle ear fluid or a direct cotton swab from the bulla.
  • CFU non-zero NTHi colony forming units
  • FIGs. 7 A and 7B provide images of hydrogel administered to healthy and infected chinchilla tympanic membranes. Seven days after the administration, animals were euthanized under CO2 inhalation in accordance with IACUC guidelines. The bullae were retrieved and excised to expose the TM, while the bone and tissue around the tympanic ring were carefully removed. The excised samples were immediately fixed in 10% neutral buffered formalin overnight.
  • compositions were administered via the outer ear canal and placed as close to the tympanic membrane as possible.
  • the [P407 + cip + 2% ML] composition eradicated otitis media in 83% of the treated animals within the first 24 1 hours, which was maintained through day 7 (p ⁇ 0.005 vs. untreated).
  • the P407 + cip composition had no measurable effect on otitis media.
  • [0148] Referring to FIG. 7D and FIG. 8A, [P407 + cip + 3CPE(SDS)] proved difficult to administer due to its low gelation temperature, which caused the composition to transition from a liquid to a hydrogel as it was being extruded, before reaching the tympanic membrane. [0149] Referring to FIG. 8B, the CFU count of NTHi culture recovered from the MEF showed a sharp decrease on day 1 after the treatment from a median of 1.75 x 107 to 0, which was also maintained throughout the 7-day treatment.
  • NTHi was not eradicated in one of the six animals treated with [P407 + cip + 2% ML], but the MEF CFU count for this animal did show a 3-log reduction from day 0 to day 7, corresponding to a 99.9% reduction of the bacterial count in the middle ear, which has been considered an indication of cure.
  • treatment with [P407 + cip + 3CPE(SDS)] led to a 50% cure rate by day 7, with a median CFU count 7.25 x 105.
  • the animals that were untreated or treated with [P407 + cip] remained 100% infected through day 7, with a median CFU count of 1.02 x 107 and 1.06 x 105, respectively.
  • the concentration of ciprofloxacin in the MEF over the course of treatment indicated a clear enhancement of drug permeation across the TM with the addition of 2% ML.
  • the average tympanic membrane thickness in FIG. 9B was measured to be 42 + 21 pm.
  • FIGs. 10A-10E provide representative microscope images under a cross-sectional view.
  • FIGs. 10A-10E provide representative microscope images under a cross-sectional view.
  • Example 5 Compositions Comprising Methyl Laurate, Limonene, and Bupivacaine
  • SDS was previously used in a synergistic combination of CPE called 3CPE(SDS), consisting of 0.5% bupivacaine, 1% SDS, and 2% limonene (see Refs. 18, 33).
  • 3CPE(SDS) consisting of 0.5% bupivacaine, 1% SDS, and 2% limonene
  • compositions containing 18% P407, 3CPE(SDS), and 4% ciprofloxacin had limited success in treating otitis media in chinchillas (see Ref. 33).
  • this poor efficacy is likely to the presence of SDS, which inhibits both the gelation and hydrogel homogeneity (see Refs. 8, 13, 14, 63).
  • cytotoxicity testing indicates that methyl laurate has much lower cytotoxicity than SDS or 3CPE(ML) based on in vitro studies conducted using primary human adult fibroblast cells and PC 12, which is a pheochromocytoma cell line used in neurotoxicity testing. While P407 had minimal cytotoxicity, ciprofloxacin showed evident cytotoxicity at 4% concentration.
  • these hydrogel compositions only induced slight inflammation of the TM, likely due to the exfoliating effect of the surfactant and pseudo-surfactant.
  • Example 6 DSC and Rheology of ML- and SDS-Containing Compositions
  • micellization transition was observed using differential scanning calorimetry (DSC), with polypropylene oxide) dehydration and micellization corresponding to a broad endothermic peak in the heat flow trace (see Refs. 32, 46, 51-54). Consistent with prior reports (see Refs. 55, 56), increases in temperature resulted in a many-order-of-magnitude increase in the dynamic moduli as the compositions underwent the solution-to-gel transition.
  • DSC differential scanning calorimetry
  • R m ic The radius of the micelles, was estimated as half of the nearest-neighbor distance between micelles on the FCC lattice.
  • R m ic is 109 A at 35 °C.
  • Rh This micelle size closely matched the hydrodynamic radius, Rh, of micelles in a 1% (w/v) P407 solution at 37 °C measured via dynamic light scattering (DLS) and is consistent with P407 micelle sizes reported previously (see Refs. 32, 48, 58).
  • SAXS Synchrotron small-angle X-ray scattering
  • Measurements were conducted using a wavelength of 0.793 A, allowing for an accessible q- range from 0.002 to 4.4 A-l across three detectors. Data were truncated to highlight features of interest between 0.02 and 0.1 A’ 1 . Samples were loaded into 1.5-mm quartz capillaries within a custom multi-capillary temperature stage and scanned every 5 °C from 5 °C to 50 °C following a 10-minute equilibration period at each temperature. Select samples containing ML and ciprofloxacin hydrochloride were scanned at 37 °C. Each scan used a 1 second exposure time and every sample was scanned in three positions vertically along the capillary. The 2D patterns were visualized using DataSqueeze80 and azimuthally integrated to yield ID traces. Ordered phases were identified based on the position of Bragg peaks within the ID traces.
  • R m ic is plotted as a function of the ML concentration in formulations containing 18% w/v P407 and 4% w/v ciprofloxacin, where R m ic was determined via SAXS. Dashed line indicates a 1:1 molar ratio of CIP:ML.
  • Example 8 Dynamic Light Scattering & Optical Characterization of P407 /ML P407/SDS Compositions
  • Multi-angle DLS was performed on a Brookhaven BL200SM instrument with a 637 nm laser. Throughout the measurements, samples were submerged in a circulating decalin bath maintained at 37 °C. Autocorrelation functions were collected for 5 minutes over a range of 0.5 ps to 10 ms at 60°, 75°, 90°, 105°, and 120°. Regularized positive exponential sum (REPES) analysis was used to determine that all data could be described by a single relaxation mode. Hydrodynamic radii were determined by fitting the data at each angle to a second cumulant expansion. For each sample, there was a strong linear relationship between the first cumulant versus scattering angle squared, indicating a diffusive process. The slope of this line corresponds to the mutual diffusion coefficient (Dm), which in these dilute solutions is equivalent to the tracer diffusion coefficient (Dt). The tracer diffusion coefficient can be related to the hydrodynamic radius using the Stokes-Einstein relation.
  • DLS revealed a highly dispersed population of aggregates with an average hydrodynamic radius, Rh of 47 A. This measured hydrodynamic radius is consistent with that of an SDS micelle stabilized by a single P407 chain.
  • P407 micellization is a critical precursor to gelation
  • SDS incorporation prevents the solution-to-gel transition of the P407 formulation by disrupting P407 micellization.
  • Optical microscopy was used to visualize the size of ML droplets within hydrogels containing 18% P407 with 2% ML. Measurements were conducted on an Olympus BX53 microscope. Samples were preheated to 37 °C before being transferred to a glass microscope slide. Samples were then placed into a Linkam T95 temperature controller and imaged at 37 °C.
  • Cytotoxicity was also assessed in vitro using primary human adult fibroblast cells and PC 12 (a pheochromocytoma cell line used in neurotoxicity testing).
  • Adult primary dermal fibroblast cells hFbs, ATCC PCS-201-012
  • ATCC PCS-201-030 fibroblast basal medium
  • penicillin/streptomycin Gabco 15-140-122
  • PC-12 cells isolated from pheochromocytoma, were maintained in F-12K medium (Gibco 21-127-022) supplemented with 2.5% fetal bovine serum (Gibco 16-000-044), 15% horse serum (Gibco 26-050-088) and 1% penicillin/streptomycin (Gibco 15-140-122). All cell cultures were maintained in an incubator kept at 37°C and 5% CO2.
  • hFbs and PC- 12 cells were seeded into 12- well plates at a cell density of 80,000 cells/well and incubated overnight prior to being treated with the various formulations.
  • Small molecule compounds and CPEs (without P407) were directly dissolved in media, or dissolved in media with 1% v/v dimethyl sulfoxide (DMSO, Coming®) in the case of ML to improve its solubility. After one day of culture, cell media were replaced with 1 mL fresh media containing the tested compounds.
  • DOI 10.1021/la304836e Alexandridis, P.; Athanassiou, V.; Fukuda, S.; Hatton, T. A., Langmuir 1994, 10 (8), 2604-2612. DOI 10.1021/la00020a019. Cabana, A.; Ait-Kadi, A.; Juhasz, J., J Colloid Interface Sci 1997, 190 (2), 307-12. DOI 10.1006/jcis.1997.4880. Alexandridis, P.; Hatton, T. A., Colloids Surf A Physicochem Eng Asp 1995, 96 (1-2), 1- 46. DOI 10.1016/0927-7757(94)03028-X.
  • PubChem Ciprofloxacin (Compound). https://pubchem.ncbi.nlm.nih.gov/compound/Ciprofloxacin. Edmunds, A. L practice P T 2017, 42 (5), 307-311. PubChem Ammonium Chloride. https://pubchem.ncbi.nlm.nih.gov/compound/Ammonium-Chloride. Miro, N.; The Spanish ENT study group, Otolaryngol Head Neck Surg 2000, 123 (5), 617-23. DOI 10.1067/mhn.2000.107888.
  • cfm?setid 242759ef-cb6d-4e3e-9f8d- 5e31efalf289.
  • cfm?setid e58a5328-fdd9-40cb-al9f- 8ed798989b9c. Heiney, P. A., Int. Union Crystallogr 2005, 32, 9-11.

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Abstract

La présente invention concerne des compositions appropriées pour l'administration transdermique, transmembranaire, transmuqueuse et/ou transtympanique d'une quantité thérapeutiquement efficace d'un composé thérapeutique tel qu'un antibiotique pour le traitement d'un sujet, l'administration du composé thérapeutique étant améliorée par formation d'un ensemble pseudo-tensioactif avec un premier composé comprenant un amplificateur de pénétration chimique.
PCT/US2024/028845 2023-05-10 2024-05-10 Compositions pour l'administration transtympanique d'antibiotiques et leurs procédés d'utilisation Pending WO2024233921A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150374685A1 (en) * 2008-05-15 2015-12-31 Jeffry Weers Pulmonary delivery of a fluoroquinolone
US20160000948A1 (en) * 2014-07-03 2016-01-07 Otonomy, Inc. Sterilization of ciprofloxacin composition
WO2021195319A1 (fr) * 2020-03-26 2021-09-30 Plx Opco Inc. Supports pharmaceutiques aptes à la reconstitution dépendante du ph et leurs procédés de fabrication et d'utilisation
US20220040309A1 (en) * 2015-08-05 2022-02-10 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150374685A1 (en) * 2008-05-15 2015-12-31 Jeffry Weers Pulmonary delivery of a fluoroquinolone
US20160000948A1 (en) * 2014-07-03 2016-01-07 Otonomy, Inc. Sterilization of ciprofloxacin composition
US20220040309A1 (en) * 2015-08-05 2022-02-10 Children's Medical Center Corporation Compositions with permeation enhancers for drug delivery
WO2021195319A1 (fr) * 2020-03-26 2021-09-30 Plx Opco Inc. Supports pharmaceutiques aptes à la reconstitution dépendante du ph et leurs procédés de fabrication et d'utilisation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YOUSSEF AHMED ADEL, CAI CHUNTIAN, DUDHIPALA NARENDAR, MAJUMDAR SOUMYAJIT: "Design of Topical Ocular Ciprofloxacin Nanoemulsion for the Management of Bacterial Keratitis", PHARMACEUTICALS, vol. 14, no. 3, CH , pages 210 - 210-19, XP093239111, ISSN: 1424-8247, DOI: 10.3390/ph14030210 *

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