Topically administered, skin-penetrating glycosaminoglycan formulations suitable for use in cosmetic and pharmaceutical applications

Abstract

The present invention relates to topical glycosaminoglycan compositions, particularly hyaluronan compositions, that facilitate the penetration of modified glycosaminoglycans through the skin barrier into the epidermal and dermal layers of the skin, thereby allowing for the dermal administration of a glycosaminoglycan, such as hyaluronan, without requiring an injection. Through their ability to deliver hyaluronan to the epidermal and dermal layers, the present formulations are therefore suitable for use in dermal rejuvenation, enhancement, hyaluronan replenishment and protection therapy. The glycosaminoglycan compositions are also useful as delivery devices to facilitate the dermal and transdermal delivery of cosmetically and pharmaceutically active substances, including pharmaceuticals, polypeptides, proteins and similarly sized biomacromolecules, through the skin barrier.

Description

FIELD OF THE INVENTION[0001]The present invention relates to topical glycosaminoglycan formulations that facilitate the penetration of glycosaminoglycans modified through the covalent linkage of lipid moieties to 1 to 10% of the disaccharide monomer units through the skin barrier into the epidermal and dermal layers of the skin, thereby allowing for the dermal administration of the glycosaminoglycan without requiring an injection. In particular, through their ability to deliver hyaluronan to the epidermal and dermal layers, which is retained in the skin for greater periods of time than topically delivered hyaluronan, the present formulations are therefore suitable for use in dermal rejuvenation, enhancement, hyaluronan replenishment, and protection therapy. The compositions may also be used as delivery devices for therapeutic compounds, including polypeptides, proteins and other similarly sized biomacromolecules, facilitating their passage through the skin barrier. Also provided is ...

AI Technical Summary

Benefits of technology

This invention provides a way to apply modified hyaluronan through the skin barrier, allowing for the replenishment of hyaluronan throughout the depleted areas of the skin. This results in a rejuvenating effect, reducing wrinkles without the need for injections. Additionally, this invention provides a method for making, reviving, or supplementing the microenvironment around cells associated with youthfulness, enhancing a youthful appearance in aged or repairing the damage done to traumatized skin.

Problems solved by technology

Loss of elastic tone in the skin results in flaccid, sagging facial tissue.

A number of temporary tissue fillers, such as collagen, hyaluronan and hydroxyapatite are currently available, however, these fillers are administered through a series of injections, and provide only a temporary effect, often failing to extend beyond 12 months in the case of collagen and hyaluronan.

Additionally, the treatments require skilled application through multiple injections, and carry a risk of infection at injection sites.

Thus, they are necessary for maintaining skin hydration and are particularly susceptible to the aging effects of environmental factors such as UV radiation since they are more constantly exposed to these factors than other skin cell types.

Since keratinocytes produce paracrine factors that affect the health / functioning of fibroblasts and other dermal cells, factors that are detrimental to keratinocyte functions are therefore also detrimental to dermal cell functions.6

As skin ages, the ability of dermal fibroblasts and keratinocytes to maintain their hyaluronan capsules diminishes, resulting in the dehydrated and sagging appearance of aging skin.5,7 Additionally, when skin is traumatized, e.g., through exposure to excessive UV radiation (sunburned), hyaluronan production by cells in the dermis is decreased, leading to an increase in hyaluronan degradation and the increased presence of hyaluronan degradation products in the skin.

While cross-linking of hyaluronan does enhance its retention at the injection site, these injections are not permanent and must be repeated on a regular (6-12 months) basis if the rejuvenating effect is to be preserved.

However, the cross-linking of hyaluronan with itself is believed to reduce its ability to bind to cell-surface receptor proteins, a key property necessary for the encasement of cells by coats of hyaluronan.

A further difficulty encountered include the difficultly to localize or “smooth” injected hyaluronan evenly under the skin.

Thus, while the use of injectable hyaluronan may act as an effective temporary filler, it is not able to act in the same manner as natural hyaluronan to provide a cell-coating effect.

While degradation of cross-linked injectable hyaluronan fillers could conceivably serve as a source of hyaluronan, retention of the hyaluronan is not expected owing to the known depletion of hyaluronan receptors on dermal cell surfaces and the high rate of hyaluronan degradation within the skin.

Since injectable fillers containing cross-linked hyaluronan are only administered at the site of the wrinkle or nasolabial fold, these treatments do not serve to “rejuvenate” the skin by replenishing the depleted hyaluronan levels in adjacent areas; rather, injectable treatments provide an appearance of rejuvenation by filling the depressed area.

As a result, treatment with injectable dermal fillers do not aid in preventing or delaying the appearance of new wrinkles in adjacent, untreated areas, nor do they address the underlying issues of hyaluronan deficiency, and the consequent decreases in skin hydration.

However, since hyaluronan is a polyanion, it is not expected efficiently to cross the skin's keratinocyte layer.

Therefore, merely enabling the passage of hyaluronan through the skin barrier will not necessarily provide a useful effect; for many uses it may also be necessary for the hyaluronan to have a prolonged residence time in order to observe an effect.

In addition, the requirement for a transdermal carrier, the most effective of which is DMSO, is generally not compatible with prolonged use.

However, as noted by the selected range of hyaluronan preferred 7 to 25 monosaccharide units (approximately 1,300-4,700 Da) owing to the difficulty in delivering hyaluronan through the skin barrier, these formulations are unsuitable to enable the passage of higher molecular weight hyaluronan through the skin barrier.

Epithelial delivery techniques, including transdermal delivery, for peptides and proteins was recently reviewed by Antosava et al.,17 who noted that although transdermal delivery is an attractive approach for development owing to its high bioavailability, long duration of action and painless application, it is hindered by the effectiveness of the skin barrier in preventing penetration and local irritation which preclude long-term application.

Although there are reports describing the use of phospholipid-based liposomes to transfer hyaluronan across the skin barrier, a number of problems are associated with their use, most notably, a lack of stability on storage.

In addition, phospholipid-based liposomes are expensive to prepare and purify on the scale required for use in cosmetic preparations.

Despite the numerous reports in the patent literature of topically-applied cosmetic compositions containing hyaluronan that are stated to facilitate the passage of hyaluronan through the skin barrier into the epidermal and dermal layers, it remains that there are no commercially available cosmetic products fulfilling these promises.

In particular, there are currently no viable methods with which effectively to deliver sufficient quantities of higher molecular weight hyaluronan (e.g., >250,000 Da) to the epidermal and dermal layers of the skin using topical cosmetic formulations that allow for retention of the hyaluronan within the skin.

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