Liquid topical pharmaceutical nano-emulsion formulations

Abstract

Aspects of the present invention are directed to compositions that are useful for delivery of an active ingredient to a subject. Some embodiments are formulated with an active ingredient, including, for example, a non-steroidal anti-inflammatory drug (NSAID), such as aspirin, ibuprofen, ketoprofen, or naproxen, acetaminophen, or a polypeptide or protein, such as insulin, wherein the active ingredient is stabilized and greater than 90% of the particles of the active ingredient have a particle size that is less than or equal to or any number in between 100, 90, 80, 70, 60, 50, 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, or 4 nanometers, or smaller, as determined by Dynamic Light Scattering (DLS), using a volume-weighted particle size distribution calculation method.

Description

RELATED APPLICATIONS[0001]The present application claims priority to U.S. provisional application Ser. No. 61 / 748,036, filed Dec. 31, 2012, which is hereby expressly incorporated by reference in its entirety, and the present application also claims priority to U.S. provisional application Ser. No. 61 / 758,726, filed Jan. 30, 2013, which is hereby expressly incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]Aspects of the present invention are directed to preparations that are useful for delivery of an active ingredient. Some embodiments of these preparations include transdermal and / or dermal compositions, which are formulated with an active ingredient, including, for example, a non-steroidal anti-inflammatory drug (NSAID), such as aspirin, ibuprofen, ketoprofen, or naproxen, acetaminophen, or a polypeptide or protein, such as insulin, wherein the active ingredient is stabilized and greater than 90% of the particles of the active ingredient have a particle size that...

AI Technical Summary

Benefits of technology

[0011]Aspects of the present invention concern the discovery of compositions and methods that reduce the particle size of active ingredients, including non-steroidal anti-inflammatory drugs (NSAID)s, acetaminophen, and / or polypeptides or proteins such as, insulin and thereby stabilize these active ingredients in an emulsion (a nano-emulsion), which, in turn, improves the delivery of the active ingredients and / or extends the shelf-life of these products. For example, when the transdermal and / or dermal formulations are prepared as described herein, it was found that the particle size of the active ingredient (e.g., NSAIDS, such as aspirin, ibuprofen, ketoprofen, and naproxen, and acetaminophen, as well as polypeptides or proteins such as, insulin) was reduced (e.g., after formulation as described herein, greater than 90% of the particles have a particle size of less than or equal to 100 nanometers, such as 4-20 nanometers, as determined by Dynamic Light Scattering (DLS), preferably using a volume-weighted particle size distribution calculation method). Accordingly, when the transdermal and / or dermal formulations are prepared, as described herein, it is contemplated that greater than or equal to or any number in between 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of the particles of the active ingredient in the transdermal and / or dermal liquid, e.g., NSAIDS such as, aspirin, ibuprofen, ketoprofen, naproxen, and / or acetaminophen, and / or polypeptides or proteins such as, insulin, are reduced to an average particle size of less than or equal to any number in between 100, 90, 80, 70, 60, 50, 40, 30, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, or 3 nanometers, as determined by DLS, preferably using a volume-weighted particle size distribution calculation method.

[0012]The reduced particle size of the active ingredient is contemplated to increase the stability of the active ingredient within the composition (e.g., a transdermal and / or dermal preparation). It is contemplated that formulations prepared by an alternative method, wherein water is allowed to contact the active ingredient prior to mixing the active ingredient with an alcohol or ethoxylated oil or both will have considerably larger particle size of active ingredient, with greater heterogeneity in size of particles and the active ingredient in these formulations will be less stable and will have a shorter shelf-life than formulations prepared in accordance with the teachings provided herein.

[0013]It is contemplated that the reduced particle size and the increased stability of the active ingredient in the transdermal and / or dermal formulations described herein are the result of the particular amounts of the components in the formulations (e.g., the amount of ethoxylated oil, such as ethoxylated macadamia nut oil, ethoxylated meadow foam oil, or ethoxylated emu oil or mixtures thereof, having 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 ethoxylations per molecule relative to the amount of water, alcohol (e.g., 100% ethanol), and any additional ingredients, such as fragrance), as well as, the order of the addition of the active ingredient(s) to the components of the liquid (e.g., the alcohol, ethoxylated oil, and water) during the mixing phase. For example, a process for making the transdermal and / or dermal compositions (e.g., liquids) described herein can be practiced by mixing an alcohol (e.g., 200 proof ethyl alcohol) and / or an ethoxylated oil (e.g., macadamia nut oil that has been ethoxylated to 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 ethoxylations per molecule) with an active ingredient (e.g., an NSAID, such as aspirin, acetaminophen, or a protein such as, insulin) and subsequently adding water. By this approach, in particular adding the water after the active ingredient has mixed with the alcohol and / or ethoxylated oil, it is thought that the active ingredient reduces its particle size and the active ingredient is protected from destabilizing forces, such as hydrolysis mediated by the water in the formulation. In addition to increasing the stability of the active ingredient, it is contemplated that the reduced particle size of the active ingredient achieved by the methodologies described herein also allows for the active ingredient to remain in a liquid form for extended periods of time, which will facilitate and / or improve transdermal and / or dermal delivery of the active ingredient.

[0014]Nanoemulsion delivery system technology has been reviewed in the past, see e.g., “Edible nanoemulsions: fabrication, properties, and functional performance” (review) by David Julian McClements, Soft Matter, (2011) 7: 2297-2316. Nanoemulsions are typically characterized by extremely low interfacial tension. Accordingly, the system not only forms with minimal shear, but also spreads very easily after application to the surface of the skin or tissue (e.g., when applied topically or when introduced internally by injection or oral consumption). In the context of a transdermal and / or dermal composition, this property allows the formulation to immediately spread across the surface of the skin, penetrating all of the macroscopic openings in the dermis (e.g., pores and hair follicles) well in advance of the transfer of an active ingredient. The low interfacial tension can also be exploited in conjunction with micro-abrasion and injection or oral administration methodologies.

[0019]Since the active ingredient is confined to a region of the nano-emulsion, which does not favor hydrolysis or allow for contact with enzymes, proteases, hydrolases, and other degradative components of the body, e.g. the digestive track, the active ingredient is protected, stabilized, and the shelf-life of the active ingredient is extended. Because the primary surfactants used in the formulations described herein are chosen such that the hydrophobic portion of the surfactants (e.g., ethoxylated macadamia nut oil) matches the lipid makeup of the cell membranes of the target organ, the lamellar phase of the nano-emulsion containing the active ingredient is readily incorporated into the target cell membrane.

Problems solved by technology

NSAIDs taken orally may cause an increased risk of serious cardiovascular thrombotic events, myocardial infarction, and stroke, which can be fatal.

This risk may increase with duration of systemic use.

Taking oral NSAIDs, including aspirin, can also increase the risk of serious gastrointestinal adverse events including bleeding, ulceration, and perforation of the stomach or intestines, which can be fatal.

Elderly patients are at greater risk for serious gastrointestinal events.

However, there are many obstacles to achieving a useful topical formulation containing an NSAID and / or acetaminophen, including safety, stability of the active ingredient over time, and efficacy.

Topical pain reliever formulations in the form of a liquid have been introduced in the past, but such topical pain relievers have traditionally lacked the ability to maintain the active ingredient in a suspension within the liquid of the topical pain reliever formulation.

Further, topical pain reliever formulations may have significant lag time between application to the skin and reducing pain / inflammation.

For example, the topical pain reliever formulations may not quickly or effectively permeate the skin.

As a consequence, it may take longer, if at all, for a user to experience any pain relief due to slow penetration of active ingredient of penetration of only an insignificant dose of active ingredient.

Additionally, current NSAID and / or acetaminophen-containing topical pain reliever formulations have not adequately stabilized the active ingredient in liquid.

That is, current NSAID and / or acetaminophen-containing topical pain formulations generally have a short shelf life since the active ingredient degrades, for example, by hydrolysis, glycolysis and / or transesterification.

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