Tympanic membrane permeating ear drops and uses thereof
The present invention provides compositions and methods for noninvasive delivery of therapeutic agents across an intact tympanic membrane. For example, the compositions include a penetration enhancer which increases the flux of a therapeutic agent (e.g., antibiotic) across the tympanic membrane. Such compositions are particularly useful in the treatment of otitis media. Additionally, the composition may include a sustained release agents that, in some embodiments form sustained release reservoirs, in situ, once administered to a patient.
1. A composition for treating otitis media comprising:
a. a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of ciprofloxacin, cefuroxime, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
b. a penetration enhancer, wherein the penetration enhancer is a combination of bupivacaine, limonene, and sodium dodecyl sulfate; and
c. a sustained release drug delivery agent, wherein the sustained release drug delivery agent is a matrix forming agent.
2. The composition of claim 1 further comprising another therapeutic agent.
3. The composition of claim 1 wherein the matrix forming agent is selected from the group consisting of polyelectrolyte complexes, thermo-responsive gelling agents, pre-polymers, alginates, un-crosslinked polymers, and monomers.
4. The composition of claim 1 wherein the matrix forming agent is a polyelectrolyte complex comprising chitosan, as a cationic component, and one of chondroitin sulfate, dextran sulfate, hyaluronic acid, alginic acid, or carboxymethyl cellulose, as an anionic component.
5. The composition of claim 1 wherein the matrix forming agent is selected from the group consisting of chitosan-chondroitin sulfate, chitosan-dextran sulfate, chitosan-hyaluronic acid, chitosan-alginic acid, and chitosan-carboxymethylcellulose.
6. The composition of claim 1 wherein the matrix forming agent is selected from a group consisting of poloxamer 407, poloxamer 188, poloxamines, methylcellulose, hydroxypropyl methylcellulose, ethyl (hydroxy ethyl) cellulose, xyloglucan, celluose acetate phthalate latex, poly (acrylic acid), and gellan gum.
7. The composition of claim 1 , wherein the matrix forming agent is biocompatible.
8. The composition of claim 1 , wherein the matrix forming agent is biodegradable.
9. The composition of claim 1 , wherein the penetration enhancer is about 0.1 to about 10 percent of the composition.
10. The composition of claim 1 , comprising 0.5% bupivacaine, about 2% limonene, and about 1% sodium dodecyl sulfate.
11. A method of treating a subject with otitis media comprising administering to the subject a composition comprising:
a. a therapeutic agent, wherein the therapeutic agent is selected from the group consisting of ciprofloxacin, cefuroxime, cefadroxil, cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftobiprole, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, trovafloxacin, bacitracin, colistin, polymyxin B, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, spectinomycin, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, meticillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, mafenide, sulfacetamide, sulfamethizole, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole;
b. a penetration enhancer, wherein the penetration enhancer is a combination of bupivacaine, limonene, and sodium dodecyl sulfate; and
c. a sustained release drug delivery agent, wherein the sustained release drug delivery agent is a matrix forming agent.