Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1996-11-08
2001-07-24
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S448000, C424S447000, C424S450000
Reexamination Certificate
active
06264979
ABSTRACT:
FIELD OF THE INVENTION
BACKGROUND OF THE INVENTION
The invention relates to a device for delivery of a pharmaceutical to the systemic circulation of a human or animal body via the skin, and in particular, via skin from which the epidermis has been removed.
The administration of pharmaceuticals through the skin is a concept which is now well-established. Transdermal administration has several advantages over more conventional forms of drug delivery such as injection or oral ingestion. Transdermal devices can provide sustained and controlled release of the active agent over a prolonged period so that the resulting blood levels remain constant. This is in contrast to administration, by injection, for example where surges of the agent occur in the bloodstream immediately after administration and then drop away rapidly until the next dose is given. In the case of oral administration the blood level is further influenced by the contents of the intestines and is therefore difficult to control. Transdermal administration permits direct access to the bloodstream without first passage through the gastro-intestinal tract and liver. In addition, transdermal administration is more convenient and comfortable for patients because a small device or plaster can remain attached to the skin for a prolonged period without patient intervention. The inconvenience of administering drugs at regular intervals orally or by injection is therefore avoided.
Despite the aforementioned advantages, the number and type of pharmaceutically active agents which have been successfully given transdermally is limited. This is because the epidermis provides a natural barrier against the ingress of foreign substances into the body and there are few drugs which are able to adequately permeate this barrier of their own accord. One approach to this problem has been to include in transdermal devices so-called permeation enhancers, molecules which are able to increase the uptake of an active agent through the skin. A particular example is diethyltoluamide although many others are known to the skilled man in this field. The use of permeation enhancers has increased the number of drugs which may be given transdermally and because of the lipophilic nature of the epidermis there has been reasonable success with drugs which are relatively hydrophobic molecules. The steroid hormones are a particular example. In addition to the use of permeation enhancers, electrochemical means have also been used to promote drug transport across the epidermis with some success.
However, notwithstanding these methods the epidermis is a very effective barrier against hydrophilic substances which has hitherto rendered transdermal administration of drugs falling in this category very difficult, if not impossible. Thus the increasing number of potent pharmaceuticals which are proteins and polypeptides cannot generally be administered transdermally.
SUMMARY OF THE INVENTION
To overcome the aforementioned problems the present inventor has developed a technique for circumventing the epidermal barrier by administering a drug transdermally through a patch of skin which is de-epithelialized i.e. has a portion of the epidermis absent, whether or not deliberately removed.
A standardized de-epithelialized lesion of pre-determined size can be made using a device such as that described in the Applicants' co-pending International Application WO92/11879. This device when attached to the skin applies suction to delaminate the epidermis from the dermis and so form a blister containing a clear blister fluid. The roof of the blister comprises the epidermis and can easily be removed leaving a standard-sized de-epithelialized lesion where the dermis is exposed. Typical lesions are about 4 to 6 mm in diameter and about 200 &mgr;m to about 1000 &mgr;m deep when made on the lower forearm for example. Where the epidermis is thicker e.g. sole of the foot a lesion of 2 mm to 4 mm would be expected. The lesions are suitable for the application of a drug-loaded transdermal device.
The passage of pharmaceutically active agents through the skin to the bloodstream has been demonstrated to be much improved where the skin is de-epithelialized. Further, it has been shown by the present inventor that de-epithelialized skin allows transdermal administration of hydrophilic drugs such as proteins, polypeptides and polysaccharides. In a paper by the inventor in the Lancet Vol 337 June 1991, successful transdermal delivery of the vasopressin analogue 1-deamino-8-D-arginine vasopressin through a de-epithelialized skin lesion is described. The inventor has also achieved successful administration of the polypeptide human growth hormone and the polysaccharide anti-thrombotic agent, Fragmin. Once treatment is complete and the device removed, the de-epithelialized lesion heals without scarring and accordingly it is not substantially more inconvenient than applying a transdermal device directly to the epidermis.
While there are clearly advantages to transdermal administration of pharmaceutically active agents through de-epithelialized skin, i.e. a lesion of about 200 &mgr;m to about 1000 &mgr;m in depth with the dermis exposed, certain problems are encountered when applying a transdermal device to an open wound which do not arise when applying a device to intact skin. Firstly the device will be susceptible to the ingress of exudate from the wound. The suction injury elicits acute inflammation within 24 hours which brings polymorphs and macrophages to the wound site. The exudate will include bacteria, whole cells, cellular debris and enzymes, in particular proteolytic enzymes which will interfere with the proper functioning of the device. Proteolytic enzymes will of course be particularly damaging when the drug being delivered is a protein or polypeptide. The present invention is thus concerned with improved transdermal devices which are suitable for use on de-epithelialized skin which include features to overcome the aforementioned problem and with methods of using them for transdermal administration.
Secondly, in a method of administering an active agent transdermally through a de-epithelialized skin lesion it is desirable to ensure that substantially all of the active agent is taken up by the lesion and not lost to portions of intact epidermis and/or in adhesive layers of the device. The present invention is thus also concerned with transdermal devices which ensure efficient delivery of the active agent within the area of the lesion and with methods of using such devices for transdermal administration.
In accordance with a first aspect of the invention there is provided a transdermal device suitable for administration of an active agent to the systemic circulation through a de-epithelialized skin lesion which device is provided with means to prevent the attack of any protein or polypeptide active agent included therein by proteolytic enzymes which exude from said de-epithelialized lesion.
In accordance with a second aspect of the invention there is provided a transdermal device suitable for administration of at least one pharmaceutically active agent to the systemic circulation through a de-epithelialized skin lesion wherein said device is provided with means to de-activate bacteria entering the device from the lesion and/or to prevent the ingress of said bacteria and other cellular debris.
In accordance with a third aspect of the invention there is provided a transdermal device suitable for administration of at least one pharmaceutically active agent to the systemic circulation through a de-epithelialized skin lesion wherein said device is provided with means to ensure that substantially all said active agent is directed to the de-epithelialized area within the boundaries of said lesion.
In accordance with a fourth aspect of the invention there is provided a method of administering a pharmaceutically active agent to the systemic circulation of a human or animal body comprising:
(a) for an area of skin of pre-determined size, delaminating the epidermis from the dermis,
(b) removing said
Flehr Hohbach Test Albritton & Herbert LLP
Page Thurman K.
Seidleck Brian K.
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