TOPICAL FILM-FORMING SPRAY
A polymeric bio-adhesive film forming topical spray formulation providing a modified, pulsatile (e.g., biphasic) release of the active agent(s) once the solvent evaporates and the film sets, e.g., on human skin is disclosed. In certain embodiments, the active agent is bupivacaine hydrochloride.
1 . A method of treating pain, comprising spraying onto the skin of a human a unit dose of a topical spray pharmaceutical formulation comprising a polymeric solution, emulsion or suspension of a hydrophilic polymer, a drug crystal precipitation inhibiting agent, an effective amount of an active agent suitable for treating pain, and a pharmaceutically acceptable permeation enhancer dispersed in a pharmaceutically acceptable hydroalcoholic solvent, the unit dose comprising a plurality of spray droplets, wherein 10% of the spray droplets in the unit dose have a mean diameter of about 26 μm±20 μm, about 50% of the spray droplets in the unit dose have a mean diameter of about 55 μm±20 μm, and about 90% of the spray droplets in the unit dose have a mean diameter of about 116 μm±40 μm, such that the unit dose topical spray provides a film surface area from about 1 cm 2 to about 40 cm 2 per spray and sets as a microporous, breathable and bioadhesive film when the hydroalcoholic solvent evaporates and provides a biphasic release of the active agent.
2 . The method of claim 1 , wherein the active agent is selected from the group consisting of bupivacaine base, bupivacaine hydrochloride, and a combination thereof in an amount from about 0.5 to about 40 mg, based on bupivacaine hydrochloride.
3 . The method of claim 1 , wherein the active agent is selected from the group consisting of an anesthetic, steroid, an opioid, a non-steroidal anti-inflammatory agent (NSAID), a central nervous system stimulant, an anti-bacterial, and combinations of any of the foregoing.
4 . The method of claim 1 , which provides (i) an in-vitro cumulative drug permeation from about 10 ug/cm 2 to about 500 ug/cm 2 after 2 hours, and a cumulative drug permeation from 10 μg/cm 2 to 6500 μg/cm 2 after 24 hours and/or (ii) an in-vivo cumulative drug permeation on human skin from about 10 ng/cm 2 to about 500 ng/cm 2 after 2 hours, and a cumulative drug permeation from about 10 ng/cm 2 cm2 to about 6500 ng/cm 2 after 24 hours.
5 . The method of claim 1 , wherein the biphasic release provides a first peak concentration of the active agent at from about 0.5 to about 3 hours and the second peak concentration of the active agent at from about 3 to about 15 hours after application of the unit dose on human skin.
6 . The method of claim 1 , wherein the biphasic release provides a first peak at from about 0.5 to about 3 hours and a second peak at from about 3 to about 7 hours after application of the unit dose on human skin.
7 . The method of claim 2 , wherein the hydrophilic polymer comprises from about 2 to about 50% of the formulation, and the drug crystal precipitation inhibiting agent comprises from about 2.5 to about 10% of the formulation, by weight and wherein the bupivacaine concentration in the formulation is supersaturated.
8 . The method of claim 7 , wherein the supersaturated drug concentration lasts for a time period from about 1 to about 24 hours in vivo to achieve increased bioavailability.
9 . The method of claim 1 wherein the human is treated for neuropathic pain.
10 . The method of claim 1 , wherein the human has a disease selected from the group consisting of general pain, neuropathic pain neuropathic pain, postoperative pain, sports pain, osteoporosis pain, pain resulting from cosmetic procedures, dental pain, wound pain and burn pain.
11 . The method of claim 1 , wherein the human is treated for pain arising from post-herpetic neuralgia.
12 . A method of treating pain, comprising spraying onto the skin of a human in proximity to an affected area a unit dose of a topical spray pharmaceutical formulation comprising a polymeric solution, emulsion or suspension of a hydrophilic polymer, a drug crystal precipitation inhibiting agent, an effective amount of an active agent comprising a local anesthetic or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable permeation enhancer dispersed in a pharmaceutically acceptable hydroalcoholic solvent, the unit dose comprising a plurality of spray droplets, wherein 10% of the spray droplets in the unit dose have a mean diameter of about 26 μm±20 μm, about 50% of the spray droplets in the unit dose have a mean diameter of about 55 μm±20 μm, and about 90% of the spray droplets in the unit dose have a mean diameter of about 116 μm±40 μm, such that the unit dose topical spray sets as a microporous, breathable and bioadhesive film having a film surface area from about 1 cm 2 to about 40 cm 2 per spray and when the hydroalcoholic solvent evaporates and provides a biphasic release of the active agent.
13 . The method of claim 12 , further comprising using a metered pump delivering, e.g., from about 40 μl to about 350 μl volume per spray to deliver the active agent onto the skin of the human.
14 . The method of claim 12 , wherein the unit dose comprises from about 1 to about 20 sprays of the topical spray pharmaceutical formulation.
15 . The method of claim 13 , wherein the local anesthetic is bupivacaine hydrochloride in an amount from about 0.5 to about 40 mg.
16 . The method of claim 15 , wherein the biphasic release provides a first and second phase of bupivacaine release, wherein the first phase of bupivacaine release reaches a peak at from about 0.25 to about 1.5 hours and the second phase of bupivacaine release reaches a peak plasma concentration at from about 4 to about 12 hours after application of the unit dose on human skin.
17 . The method of claim 15 , wherein the bupivacaine is supersaturated in the topical spray formulation.
18 . The method of claim 12 , further comprising topically spraying additional unit doses of the topical spray pharmaceutical formulation as needed to treat pain in the human.
19 . The method of claim 12 , wherein the human is suffering from neuropathic pain.
20 . The method of claim 18 , wherein the neuropathic pain is selected from the group consisting of erythromelalgia, post-herpetic neuralgia (PHN), fibromyalgia and complex regional pain syndrome (CRPS).
21 . The method of claim 16 , wherein 10% of the spray droplets in the unit dose have a mean diameter of about 26 μm±1.82 μm, about 50% of the spray droplets in the unit dose have a mean diameter of about 55 μm±2.39 μm, and about 90% of the spray droplets in the unit dose have a mean diameter of about 116 μm±4.9 μm.
22 . The method of claim 15 , wherein the biphasic release provides a first peak concentration which occurs at from about 0.17 to about 0.67 hours after the unit dose is sprayed onto the human subject, and provides a second peak concentration which occurs at from about 4 to about 24 hours after the unit dose is sprayed onto the human subject.
23 . The method of unit dose of claim 22 , wherein the unit dose provides a first peak plasma concentration from about 29 pg/ml to about 380 pg/ml bupivacaine, and a second peak plasma concentration from about 864 pg/ml to about 3463 pg/ml bupivacaine.