Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2001-11-19
2004-06-29
Azpuru, Carlos A. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S447000, C424S449000, C514S947000
Reexamination Certificate
active
06756052
ABSTRACT:
The invention relates to a device for and to a method of increasing the dermal and/or transdermal permeation of drugs.
The transdermal administration of pharmaceutical active substances has been known from the time of the first commercial use of a scopolamine transdermal therapeutic system (Scopoderm TTS). Other active substances (nitroglycerine, estradiol, clonidine, isosorbide dinitrate, fentanyl, nicotine, norethisterone etc.) as well are now offered in the form of such a TTS. These active substance patches are adhered to the skin of a patient. The active substance is then released in a controlled manner from the TTS to the skin of the patient, travels through the various layers of the skin, and, finally, enters the circulation.
A problem with this mode of administration of a substance having a systemic action is very frequently that the path taken by the active substance through the differently constructed layers of the skin is very long and the transport of the active substance until it enters the circulation is time-consuming. There are a number of reasons for this. First, the skin possesses a natural barrier function against the penetration of foreign substances into the body.
Secondly, substances having a very large molecular radius possess only a low diffusion coefficient. The latter is a measure of the ability of a substance to travel within a medium; in the case in hand, therefore, the permeation behavior within the skin layers. And, finally, physico-chemical interactions (for example, polar interactions, dipole-dipole interactions, etc.) between the active substance and the various constituents of the different skin layers may lower the rate of diffusion of an active substance in the skin.
All of these phenomena may result in the percutaneous and subsequent absorption of the active substance taking place so slowly that a pharmacological effect occurs only with considerable time delay. This period between the application of a TTS to the skin of the patient and the onset of the pharmacological effect is referred to by the skilled worker as the lag time.
Almost logically, therefore, enhancing the percutaneous permeation of a transdermally administerable active substance has been the subject of extensive research work, especially by the pharmaceutical industry. It has led to the use of a very wide variety of substances which improve skin penetration (known as enhancers) and to the development of specific substances, e.g., Azone®. Enhancers include alcohols, amides, amino acids, derivatives of Azone®, essential oils, fatty acids and fatty acid derivatives such as fatty acid esters, macrocyclic compounds, phospholipids, pyrrolidones, sulfoxides, and others.
When such enhancers are given, the increase in skin penetration (or, more precisely, the acceleration of an active substance's entry into and travel through the various skin layers and thus, ultimately, the raising of the transdermal absorption rate as well) is essentially achieved by virtue of the fact that these enhancers penetrate the uppermost layers of the skin, where they alter the structure of the skin in such a way that its barrier function is no longer fully effective. This mode of action is explained at the molecular level as follows: the enhancers incorporate themselves into biological membranes and alter the natural structure of lipids and proteins—causing them, for example, to swell. The active substance applied to the skin is then able to travel more easily, i.e., more quickly, through the different layers of the skin.
The use of the prior art enhancers, however, also possesses many disadvantages. First of all, the enhancer must not be toxic and must not cause any physiological side effects. Further, there must be no chemical or physical incompatibilities between enhancer and both the active substance and the other materials constituting the TTS. Finally, the enhancer must be present in the TTS in an amount such that the permeation-intensifying effect is retained over the entire period of its application (generally from 16 to 24 hours, although there are also 3-day plasters already available). An inevitable result of this, however, is often that said enhancer is administered to the patient likewise in amounts such as to cause a systemic effect.
It is an object of the present invention to accelerate the penetration of an active substance into the skin and/or the travel of this active substance through the different layers of the skin and/or the transport of this active substance through the blood capillary system of the dermis and/or the blood vessels of the hypodermis in such a way that absorption through the skin takes place more rapidly and thus a reduction in the lag time is achieved. In particular, practical transdermal application should be made accessible to active substances which by their nature exhibit a long lag time for absorption through the skin.
This object is achieved by a device which comprises a component which brings about a local temperature increase in the skin and/or increases the circulation. The device of the invention can be, for example, an ointment, a solution, a suspension, an emulsion, a foam, a paste, a gel or a patch, a patch of this kind being a preferred embodiment.
The invention further provides a method which comprises achieving an increase in the rate of penetration of an active substance into the skin and/or of travel of this active substance through the different layers of the skin and/or of transport of this active substance through the blood capillary system of the dermis and/or the blood vessels of the hypodermis by means of a local temperature increase and/or an increase in the circulation of the skin. In this way, ultimately, the transdermal absorption rate of said active substance is increased and the lag time to the onset of a pharmacological effect of said active substance is reduced.
The use of substances which bring about a local temperature increase in the skin for the purpose of increasing the rate of penetration of an active substance into the skin and/or of travel of this active substance through the different layers of the skin and/or of transport of this active substance through the blood capillary system of the dermis and/or the blood vessels of the hypodermis is likewise provided by the present invention. It is possible to achieve either a short-term effect (that is, up to the onset of the pharmacological effect) or a long-term effect (that is, throughout the duration of transdermal administration of the active substance in question).
Further elucidation of the invention is aided by the following definitions:
Skin refers to the uninjured, i.e., undamaged, unshaved skin of a mammal, especially that of a human, said skin having its normal hair cover. For the purposes of this invention, the term skin does not include mucous membrane. Normal skin consists essentially of three layers: the epidermis (situated externally), the dermis, and the hypodermis (which is situated below). The hypodermis is also referred to as the subcutis. The epidermis in turn is composed of the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum and stratum germativum. The dermis contains, inter alia, the blood capillary system. The hypodermis houses the blood vessels.
Penetration refers to the penetration of an active substance into the outer layers of the skin, especially into those of the epidermis. Permeation refers to the travel of the active substance through the skin, especially through the epidermis (including the stratum corneum) and the dermis.
The term dermal administration as used in the present description means that an active substance is applied to the skin and develops a local or regional (i.e., topical) action in the epidermis and/or dermis. Transdermal administration in the present description means that an active substance is applied to the skin, passes through the epidermis and/or dermis into the blood stream or into the lymph system, is distributed from there throughout the body, and develops a systemic action at the target site. Trans
Adam Bernd
Koch Andreas
Matusch Rudolf
von Falkenhausen Christian
Azpuru Carlos A.
Frommer & Lawrence & Haug LLP
LTS Lohmann Therapie-Systeme AG
Young Micah-Paul
LandOfFree
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