Transdermal therapeutic systems have been established on the market for numerous active substances for a number of years. Administration forms of this kind allow the cutting of skin-permeable active pharmaceutical substances through the healthy human skin for the purpose of obtaining systemic therapeutic effects. In general, pharmaceutical active-substance patches of this kind are based on what are known as matrix patches or reservoir/membrane patches which comprise the active substance embedded in dissolved or crystalline form in a predominantly lipophilic polymer. Numerous technologies are also based on the addition of predominantly lipid-soluble excipients which in some cases are intended to produce enhanced bond strength or diffusiveness of the active substance and on the other hand are also aimed at boosting the absorption effect of the skin itself.
The delivery of predominantly hydrophilic active substances to the human skin that are of limited solubility in lipophilic media has to date been less of a subject of intense research. It is true that there are hydrogel systems known whose adhesive matrix facing the skin is composed predominantly of water and thus allows the use of highly water-soluble active substances. A disadvantage of such systems, however, is that pharmaceutical active substances, especially those of high molecular mass, are greatly hindered in their diffusion before they reach the skin, as a result of the polymeric gel framework that is present.
U.S. Pat. No. 5,707,641 describes a pharmaceutical formulation, composed of an aqueous emulsion or dispersion, intended more particularly for transdermal administration, which further to the aqueous phase comprises as active substance a pharmaceutically active protein or polypeptide, an emulsifier, and an oily phase. The patent specification further discloses a matrix for the transdermal administration of the stated formulation, composed of a porous, absorbent, and monolaminar solid material that comprises said formulation in absorbed form. The matrix may further be provided with a flexible, breathable (i.e., nonocclusive) backing layer.
EP 0 412 869 B1 proposes a composite film for local treatment of the skin surface, comprising an occlusive layer and a reservoir layer. The latter is formed from a matrix consisting of a silicone polymer and, within internal inclusions, comprises an aqueous gel layer with an active pharmaceutical substance. For the purpose of reinforcement, the reservoir layer may include an inlay of perforated fiber nonwoven, but this inlay is not in contact with the active substance gel. From the description and the claims it is clear that this composite film is suitable only for local treatment of the skin, since there are no measures indicated that ensure the controlled release of the active substance that is necessary for systemically transdermal administration.
The last-mentioned defect is also present in proposals for the administration of aqueous active substance formulations, as per Indian patent specification IN 187032 and also DE 42 23 004 A1, which describe the administration of undosed aqueous formulations to the skin. Neither of these publications discloses a solution for a really precise application to the human skin or for unhindered diffusion of water-soluble active substances. The prior art, furthermore, does not specify any solution for the problem of protection from evaporation. Complex pharmaceutical preparations which comprise volatile ingredients, especially water, suffer on the skin from unanticipable changes in the formulation as a result of evaporation of the volatile fraction. The problem is therefore not removed by simple application to the skin or possibly the application of pure foils, since the liquid active substance formulations spread uncontrolledly on the skin and so increase the area of action, and since, moreover, no fixing of the active substance on the skin is ensured.
For some considerable time it was considered to be a fact set in stone that the presence of an impermeable (occlusive) backing layer in transdermal therapeutic systems generally increases the skin permeation of active substances (Ann. Red. Med., Vol. 33, 18 (1982); p. 475, 476, U.S. Pat. No. 4,597,961 (1986), column 2, lines 61-65). More recent publications, however, have shown that under occlusive conditions, penetration or permeation of the human skin is increased only by lipophilic active substances, whereas that by hydrophilic and low-lipophilicity active substances remains unchanged (Bucks, D. A. et al, J. Invest Dermatol 1988 July; 91(1): 29-33; Treffel P.; Skin Pharmacol. 1992, 5(2), 108-113).
Surprisingly it has now been found that the transdermal therapeutic system of the invention, comprising a continuous, concentrically disposed, water-insoluble adhesive-layer margin, an occlusive backing layer impermeable for the active substance, a device facing the skin and intended for the delivery of a hydrophilic active substance from an aqueous phase, and a detachable protective foil permits the controlled release of the active substance from the delivery device and permits increased permeation through the skin.
The transdermal therapeutic system of the invention can be described in detail as follows:
The central device for delivering the active substance is composed of two phases, the stationary solid phase being formed from a solid, which may be flexible and which has a fibrous or open-pore fleece- or spongelike structure, and the liquid phase being composed of an aqueous solution, emulsion or suspension that comprises the pharmaceutically active substance.
The two-phase delivery device is concentrically surrounded by an adhesive-layer margin consisting of a customary adhesive polymer. In one preferred embodiment of the invention this margin is reinforced in thickness by a layer of nonadhesive polymers, which may also be present in the form of closed-pore foams. Through the thickness of this layer, which is in a range of 200-5000 μm, preferably of 500-2000, it is also possible to regulate the space for the central delivery device.
The delivery device may be circular or may represent a square or rectangle whose angles may be rounded or beveled (
The present invention is elucidated further by the figures,
1 represents the central delivery device, 2 a layer of at least one nonadhesive polymer, 3 an adhesive layer, 4 a release liner, and 5 an occlusive backing layer.
The stationary phase of the central delivery device is a solid phase which may be rigid or flexible and which has a fibrous, open-pore, fleece- or spongelike structure. Materials contemplated for this solid phase include substances from the group of synthetic or natural fiber materials, e.g., cellulose, viscose, polyester fibers, polyurethane fibers, silicone fibers, etc. Preference is given to materials referred to as nonwovens.
As the liquid phase of the central delivery device, use is made of aqueous solutions of active pharmaceutical substances which are hydrophilic—that is, readily water-soluble; this aqueous solution may also be part of an emulsion or suspension.
In addition to the excipients that are needed to form an emulsion or suspension, the liquid phase may comprise further excipients which permit, for example, the formation of liposomes.
Hydrophilic active substances in the context of the invention are meant those which have a higher solubility in water than in organic media. This group includes numerous drugs whose transdermal use was hitherto possible either not at all or only to a limited degree. They include, for example, adrenalin, heparin, methoclopramide hydrochloride, salbutamol hydrochloride, and also peptides or polypeptides, such as vasopressin, insulin, somatotropin or calcitonin, for example.
For the occlusive backing layer, olefinic foils are contemplated, such as, for example, those of polyethylene, polypropylenes or polyurethanes, but preferably a polyethylene terephthalate foil. The adhesive-layer margin may be composed of polymers of the polyisoprene group, polyisobutylene group or polyacrylic ester group or else of polysiloxane copolymers.
The layer of nonadhesive polymer which serves to reinforce the adhesive-layer margin is composed of polyolefins, preferably of a foam of at least one of these materials.
The following examples of semisolid or liquid active substance formulations are intended to elucidate the invention without restricting it.
Number | Date | Country | Kind |
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10 2007 006 244.5 | Feb 2007 | DE | national |
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/EP2008/000392 | 1/19/2008 | WO | 8/5/2009 |
Publishing Document | Publishing Date | Country | Kind |
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WO2008/095597 | 8/14/2008 | WO | A |
Number | Name | Date | Kind |
---|---|---|---|
4597961 | Etscorn | Jul 1986 | A |
4719239 | Muller | Jan 1988 | A |
4784857 | Berry | Nov 1988 | A |
4994049 | Latzke et al. | Feb 1991 | A |
5100672 | Gueret et al. | Mar 1992 | A |
5244677 | Kreckel et al. | Sep 1993 | A |
5462743 | Turner | Oct 1995 | A |
5686112 | Liedtke | Nov 1997 | A |
5707641 | Gertner et al. | Jan 1998 | A |
5807570 | Chen | Sep 1998 | A |
6328992 | Brooke et al. | Dec 2001 | B1 |
20010038862 | Luo | Nov 2001 | A1 |
20030133970 | Bracht et al. | Jul 2003 | A1 |
20030147943 | Luo et al. | Aug 2003 | A1 |
20040247657 | Susilo | Dec 2004 | A1 |
20050074487 | Hsu et al. | Apr 2005 | A1 |
20050244484 | Hsu et al. | Nov 2005 | A1 |
20060093659 | Luo et al. | May 2006 | A1 |
20080175891 | Stover | Jul 2008 | A1 |
Number | Date | Country |
---|---|---|
2341643 | Mar 2000 | CA |
4223004 | Jul 1992 | DE |
19849823 | May 2000 | DE |
10027258 | Oct 2001 | DE |
0412869 | Apr 1994 | EP |
187032 | Dec 2001 | IN |
01-224312 | Sep 1989 | JP |
07-277961 | Oct 1995 | JP |
8-509200 | Oct 1996 | JP |
WO 9007328 | Jul 1990 | WO |
WO 2004060447 | Jul 2004 | WO |
WO 2005037157 | Apr 2005 | WO |
Entry |
---|
Online dictionary, definition of transcutaneous. |
Webster's II dictionary, definition of transcutaneous. |
Online dictionary, definition of transdermal. |
Treffel et al., Effect of Occlusion on vitro Percutaneous Absorption of Two Compounds with Different Physicochemical Properties, Skin Pharmacol, 1992, 5, 108-113. |
Bucks et al., Bioavailability of Topically Administered Steroids: A “Mass Balance” Technique, J.Investigative Dermatology, Jul. 1988, 91, 29-33. |
Zelis et al., “Calcium Blocking Drugs for Angina Pectoris,” Ann. Rev. Med. (1982) vol. 33, pp. 475-476. |
Number | Date | Country | |
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20100028412 A1 | Feb 2010 | US |