Transdermal delivery systems for active agents

Abstract

A delivery vehicle for topical pharmaceutical formulations that include a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether of diethylene glycol present in relative amounts sufficient to provide permeation enhancement of an active agent through mammalian dermal or mucosal surfaces. Preferably, the delivery vehicle as well as the formulations that contain it are substantially free of long-chain fatty alcohols, long-chain fatty acids and long-chain fatty esters in order to avoid potential undesirable odor and irritation effects caused by such compounds during use of the formulation. Without these additives, use of the formulations is facilitated and patient compliance is greater

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of application Ser. No. 12 / 614,216 filed Nov. 6, 2009, which is a continuation-in-part of application Ser. No. 10 / 798,111 filed Mar. 10, 2004, which claims the benefit of each of application Nos. 60 / 453,604 filed Mar. 11, 2003 and 60 / 510,613 filed Oct. 10, 2003. Application Ser. No. 12 / 614,216 is also a continuation-in-part of application Ser. No. 11 / 755,923 filed May 31, 2007, which is a continuation-in-part of U.S. patent application Ser. No. 11 / 371,042 filed Mar. 7, 2006, now U.S. Pat. No. 7,335,379, which is a continuation of International application no. PCT / EP2004 / 011175 filed Oct. 6, 2004, which claims the benefit of U.S. provisional patent application No. 60 / 510,613, filed Oct. 10, 2003. Application Ser. No. 11 / 755,923 is also a continuation-in-part of U.S. patent application Ser. No. 11 / 634,005 filed Dec. 4, 2006, now U.S. Pat. No. 7,404,965, which is a continuation of application Ser. No. 10 / 34...

AI Technical Summary

Benefits of technology

[0033]The present invention relates to a delivery vehicle for topical pharmaceutical formulations. The delivery vehicle comprises a C2 to C4 alkanol, a polyalcohol, and a monoalkyl ether of diethylene glycol present in relative amounts sufficient to provide permeation enhancement of an active agent through mammalian dermal or mucosal surfaces. Preferably, the delivery vehicle as well as the formulations that contain it are substantially free of long-chain fatty alcohols, long-chain fatty acids and long-chain fatty esters in order to avoid potential undesirable odor and irritation effects caused by such compounds during use of the formulation. These preferred formulations advantageously do not include the undesirable odor-causing and irritation-causing permeation enhancers that were once thought to be necessary for such transdermal or transmucosal formulations. Without these additives, use of the formulations is facilitated and patient compliance is greater.

[0034]Certain advantageous delivery system components and amounts are disclosed herein. The alkanol may be selected from the group consisting of ethanol, isopropanol, n-propanol, and mixtures thereof; the polyalcohol from the group consisting of propylene glycol and dipropylene glycol and mixtures thereof; and the monoalkyl ether of diethylene glycol is selected from the group consisting of monomethyl ether of diethylene glycol, monoethyl ether of diethylene glycol, and mixtures thereof. The alkanol is typically present in an amount between about 5 to 80% by weight, the polyalcohol in an amount between about 1% to 30% by weight, and the monoalkyl ether of diethylene glycol in an amount between about 0.2 to 30% by weight so that the delivery vehicle facilitates absorption of the active agent by the dermal or mucosal surfaces so that transfer or removal of the formulation from such surfaces is minimized.

[0035]The invention also relates to a non-occlusive formulation comprising a delivery vehicle as disclosed herein along with an active agent or a pharmaceutically acceptable salt thereof present in an amount of between about 1 to 20% by weight of the formulation. Like the deliver system, the formulation is substantially free of long-chain fatty alcohols, long-chain fatty acids, and long-chain fatty esters in order to avoid undesirable odor and irritation effects caused by such compounds during use. As disclosed herein, a wide range of active agents can be delivered by the formulations of the invention.

Problems solved by technology

In the area of hormones, for example, reduced levels of endogenous steroid hormones in humans often leads to a variety of undesirable clinical symptoms.

For example, men with low testosterone levels (hypogonadism) may result in clinical symptoms including impotence, lack of sex drive, muscle weakness, and osteoporosis.

Similarly, in women, reduced levels of testosterone and / or estrogen may result in female sexual disorder, which include clinical symptoms such as lack of sex drive, lack of arousal or pleasure, low energy, reduced sense of well-being, and osteoporosis.

Moreover, reduced levels of estrogen and / or progesterone in women, such as that due to menopause, often result in clinical symptoms including hot flashes, night sweats, vaginal atrophy, decreased libido, and osteoporosis.

For example, orally administered testosterone is largely degraded in the liver, and is therefore not a viable option for hormone replacement since it does not allow testosterone to reach systemic circulation.

Further, analogues of testosterone modified to reduce degradation (e.g., methyltestosterone and methandrostenolone) have been associated with abnormalities to liver function, such as elevation of liver enzymes and conjugated bilirubin.

Injected testosterone produces wide peak-to-trough variations in testosterone concentrations that do not mimic the normal fluctuations of testosterone making maintenance of physiological levels in the plasma difficult.

Injections require large needles for intramuscular delivery, which leads to diminished patient compliance due to discomfort.

This route of administration has been also associated with complications related to hormone metabolism, resulting in inadequate levels of circulating hormone.

Further, side-effects seen with the use of oral estrogen include gallstones and blood clots.

More specifically, one common problem associated with the oral delivery of drugs is the occurrence of peaks in serum levels of the drug, which is followed by a drop in serum levels of the drug due to its elimination and possible metabolism.

These highs and lows in serum level concentrations of drug often lead to undesirable side effects.

Although the transdermal and / or transmucosal delivery of active agents overcome some of the problems associated with oral administration of the same agents, this route of administration is not free of its own drawbacks.

Transdermal patches very often cause allergic reactions and skin irritations due to their occlusive nature, or due to their composition (incompatibility reactions with the polymers or adhesives that are used).

In addition to skin irritation and tolerance considerations, another issue of transdermal drug delivery systems is that these systems are typically restricted to low-molecular weight drugs and those with structures having the proper lipophilic / hydrophilic balance.

High molecular weight drugs, or drugs with too high or too low hydrophilic balance, often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum.

The most common penetration enhancers, however, are toxic, irritating, oily, odiferous, or allergenic.

Such formulations are not appealing to the user nor to anyone else in close proximity to the user.

Also, TESTIM® is not desirable because it contains undesirable amounts of glycerin which are not well tolerated by the skin.

Some of these permeation enhancers also present odor or even taste disadvantages.

In addition, transdermal drug delivery systems are typically restricted to low-molecular weight drugs and those with structures having the proper lipophilic / hydrophilic balance.

High molecular weight drugs, or drugs with too high or low hydrophilic balance, often cannot be incorporated into current transdermal systems in concentrations high enough to overcome their impermeability through the stratum corneum.

Specifically, polar drugs tend to penetrate the skin too slowly, and since most drugs are of a polar nature, this limitation is significant.

Further, transdermal delivery from semi-solid formulations faces antinomic requirements.

Conversely, for a volatile vehicle which begins evaporating from the moment of application, the surface concentration of the chemical increases with time up to the point at which the solvent has disappeared; one is now left with a solid film of the chemical from which continued uptake into the stratum corneum may be very slow and dissolution-limited.

Images