Membrane delivery system

Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice

Reexamination Certificate

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Details

C424S427000, C424S078050, C424S451000, C604S020000

Reexamination Certificate

active

06497887

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a delivery system for application to the skin. In particular, the invention relates to a membrane-based system useful in delivering biologically active materials to the skin.
BACKGROUND OF THE INVENTION
The problem of effective delivery of active ingredients to the desired target site is one which continues to be problematic for both the cosmetic and pharmaceutical industries. Topical delivery of active agents is particularly difficult because, unlike parenteral or oral delivery, while the skin is certainly readily accessible, the exposure of the site at which the product is delivered can work against the goal of fully efficient receipt of the active by the target area. Typical vehicles for topical applications have normally been lotions, creams and gels, relatively viscous fluids that are rubbed into the skin, providing immediate contact with the target region. These vehicles are frequently very successfully used for active delivery, both of cosmetic and pharmaceutical delivery. They are, however, without more, not capable of delivering the active therein over long periods of time, which is sometimes required for the greatest efficacy of the active. In addition, from a strictly practical point of view, they are not frequently very portable, so that the user is frequently required to carry a bulky jar or bottle if the product is to be used outside the home.
Dermal patches represent an alternative to the liquid forms of application. These devices can come in a variety of forms, all having the capability of adhering to the skin, and thereby permitting prolonged contact between the active-containing composition and the target area, They also have the advantage of being relatively compact and portable, and permitting very precise delivery of product to the area to be treated. These patches come in a variety of forms, some containing fluid reservoirs for the active component, others containing dry ingredients that are released upon contact with moisture in the skin. Many require some form of adhesive to retain them in connection with the skin for an adequate period. A different type of patch is applied dry, with water applied to wet the patch to form a sticky film that is retained on the skin. Such films normally need to be washed or peeled off the skin, and can be very visible; for this reason they can be aesthetically unpleasant.
There thus continues to be a need for a topical delivery system which will be more convenient to use and more elegant than previous delivery forms and devices, while at the same time retaining the efficiency of providing the desired actives to the target location. The present invention now provides such a system.
SUMMARY OF THE INVENTION
The invention provides a delivery system for topical application to the skin comprising a freeze-dried, partially cross-inked polymeric gel membrane which can be reversibly returned to a dissolvable gel form upon the application of a wetting agent. In a preferred embodiment, the membrane also incorporates biologically active agents for delivery to the skin. Unlike previous “patches” or similar spot treatments, that need to washed or peeled off, the membrane of the present invention, when wet, assumes its previous gel form, which can be readily rubbed into the skin, thereby delivering the active agents and leaving substantially no residue to be removed from the application area. An additional benefit is that the membrane also stabilizes the actives contained therein, thereby allowing for prolonged storage and shelf-life of otherwise potentially unstable active materials.
DETAILED DESCRIPTION OF THE INVENTION
The membranes of the invention are based on a partially cross-linked gel network of polymeric material having sufficient structure to permit the suspension of one or more actives and to survive a freeze-drying process, but the structure of which is also reversible, so as to subsequently allow the return of the membrane to the gel condition when water or other wetting agent is applied. The reversibility of the structure allows the user to then rub the gel film into the skin, thereby avoiding the necessity of rinsing or peeling off a dried film, as is required with other types of skin patches.
A number of different types of polymers can be used as the base of the membrane. The polymers employed must of course be sufficiently water soluble to respond to the aqueous wetting agent that will eventually be applied. Preferred polymers are those which produce a fibrous type of gel network when cross-linked, the strength of the fibers being adequate to withstand the freeze-drying process, but as noted, adequately water-soluble to permit rewetting. Particularly preferred are gels based on alginic acid, for example, i.e., sodium or calcium alginate gels. However, other types of cross-linkable gel-forming polymers can also be used; examples of alternate bases for the gel include collagen, particularly partially hydrolyzed collagen, or cross-linkable starches.
The membrane is formed by standard methods of crosslinking of the chosen gel-forming polymer. For example, if the chosen gel is an alginate, this is normally achieved by the addition of a solution containing metal ions to a slurry of the alginate and water. Examples of useful sources of such metal ions include, but are not limited to, strongly electrolytic cosmetically or pharmaceutically acceptable acid salts of mono-, or more preferably, di- or trivalent metals, such as K
+
, Ca
+2
, Al
+2
, Fe
+2
, Fe
+3
, Cu
+2
, or Mn
+2
. The relative proportions of the components in the slurry are not very critical; however, for the wet gel, the polymer will normally constitute from about 0.5 to about 10% by weight; and the metal salts normally will be added in an amount of about 0.5 to about 3%. The amount of the polymer relative to the remaining dry ingredients to be included in the membrane will normally be from about 30 to about 70% by weight, preferably from about 45 to about 55% by weight of the dried composition. Gels based on other polymers are similarly prepared in accordance with known techniques. For example, if collagen is the chosen base for the gel, the cross-linking agent is normally an aldehyde, and with starch, a large number of crosslinking agents, such as phosphorus oxychloride, or epichlorohydrin, are also useful. In all cases, to this point, the procedure of gel formation is a routine preparation of the chosen type of gel.
However, for the purposes of the present membrane, it is desirable to interfere somewhat with the cross-linking, but only partially, so as to form an adequately supportive network, but to also permit reversal of the structure of the matrix back to its original gel state on contact with water. To achieve this, a cross-linking disrupter is added to the slurry of metal ions and polymer. In general terms, the disrupter is a hygroscopic material, and preferably of a fairly high molecular weight. The size of the molecule aids in the interference with cross-linking, while the hygroscopic property aids in the ultimate rewetting of the membrane at the appropriate time. Examples of materials of this type include breakdown products and derivatives of chitin and mucopolysaccharides, for example, chitosan, hyaluronic acid, glucuronic acid, and oligosaccharides(natural or synthetic) comprising glucosamine, galactosamine, and/or mannosamine monomeric units; hygroscopic, water soluble amino acids or peptides composed thereof, for example, glycine or lysine, or glycerin and glycerin derivatives. A particularly preferred cross-linking disrupter is hyaluronic acid . The disrupter is used in an amount sufficient to constitute from about 0.01 to about 10%, preferably about 1 to about 8%, by weight of the dried membrane.
Although the gel formed by the crosslinked polymer forms an adequate film to retain the product on the skin at the time of wetting, it may also be desirable to add small amounts of additional film-forming agents to the membrane mixture. Such film-forming agents

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