Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-03-09
2003-04-29
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S484000, C424S487000, C424S448000, C424S443000
Reexamination Certificate
active
06555131
ABSTRACT:
The present invention concerns a Transdermal Therapeutic System (TTS) for the administration of levonorgestrel alone or with other steroid sex hormones through the skin over a longer period of time, as well as a method for its production without the use of solvents, the method being especially protective for the active ingredient.
The bioavailability of orally administered active ingredients is frequently unsatisfactory. Metabolization of many active ingredients in the liver can lead during the first passage through the liver to undesirable concentration relationships, toxic by-products and to the reduction of the activity and even to loss of activity. In comparison to oral administration, transdermal administration of active ingredients has various advantages. The introduction of the active ingredient can be controlled better over a longer period of time as a result of which high fluctuations in blood level are avoided. In addition, the required therapeutic effective dose can mostly be reduced significantly. In addition, patients frequently prefer a plaster to tablets, which must be taken once or several times daily.
In the past, in order to overcome the disadvantages of nontransdermal administration of active ingredients mentioned above, a number of transdermal therapeutic systems (TTS) with different structure were proposed for various active ingredients for the therapy of different diseases.
Thus, the technical documents given below describe a broad variety of systemically or locally reacting active ingredients, their parenteral administration either based on dose-controlled or generally releasing systems. For example, these are: U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,559,222; 4,568,343; 4,573,995; 4,588,580; 4,645,502; 4,702,282; 4,788,062; 4,816,258; 4,849,226; 4,908,027; 4,943,435 and 5,004,610.
In the late sixties of this century, it was assumed originally theoretically that all active ingredients with short half-life but high activity and good penetration of the skin would be suitable for safe and effective administration via a TTS. These early expectations regarding the possibilities of transdermal administration of active ingredients by TTS could, however, not be fulfilled. The reason for this is mainly that the skin is equipped naturally with an inassessable variety of properties in order to maintain its function as an intact barrier to the penetration of substances that are foreign to the body. (See in this regard: Transdermal Drug Delivery: Problems and Possibilities, B. M. Knepp et al., CRC Critical Review and Therapeutic Drug Carrier Systems, Vol. 4, Issue 1 (1987).)
Therefore, transdermal administration is available only for those few active ingredients which have a suitable combination of many favorable characteristics. For a given active ingredient, all other required characteristics that permit safe and effective transdermal administration cannot be predicted, either theoretically or practically.
The requirements for an active ingredient suitable for transdermal administration are the following:
permeability through the skin,
no adverse influence on the adhesiveness of the plaster by the active ingredient,
avoidance of skin irritations,
avoidance of allergic reactions,
favorable pharmacokinetic properties,
favorable pharmacodynamic properties,
relatively broad therapeutic window,
metabolic properties which are consistent with the therapeutic application with continuous administration.
Undoubtedly, the above list of requirements is not exhaustive. In order for having an active ingredient available for transdermal application, the “correct” combination of all these requirements is desirable. What was said above for active ingredient applies similarly to the TTS composition containing the particular ingredient and to its structure.
Usually, transdermal therapeutic systems (TTS) are plasters which are equipped with an impermeable cover layer, a removable protective layer and a matrix which contains the active ingredient or a reservoir. With semipermeable membrane, which contains the active ingredient. In the first case, they are called matrix plasters and in the second case, they are called membrane systems.
For the cover layer, usually films made of polyester, polypropylene, polyethylene, polyurethane, etc., are used which can also be metallized or pigmented.
For the removable protective layer, among others, films made of polyester, polypropylene or even paper with silicone and/or polyethylene coating come into consideration.
For the active-ingredient-containing matrices which are usually used pharmaceutically or medically, polymer materials based on polyacrylate, silicone, polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer are used.
The membranes used in the membrane systems can be microporous or semipermeable and are usually based on an inert polymer, especially polypropylene, polyvinyl acetate or silicone.
While the active-ingredient matrix compositions can be self-adhesive, depending on the active ingredient used, one can also have active-ingredient containing matrices, which are not self-adhesive, so that, as a consequence of this, the plaster or TTS must have an overtape in its structure.
In order to ensure the required flux rate of the active ingredient, frequently skin penetration enhancers are necessary as additives, such as aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, which can be monovalent or polyvalent and may have up to 8 C-atoms, including an alcohol/water mixture, a saturated and/or unsaturated fatty alcohol with 8 to 18 carbon atoms, a saturated and/or unsaturated fatty acid with 8 to 18 carbon atoms and/or their esters, as well as vitamins.
Furthermore, frequently stabilizers such as polyvinylpyrrolidone, &agr;-tocopherol succinate, propyl gallate, methionine, cysteine and/or cysteine-hydrochloride are added to the active-ingredient-containing matrix.
As the above discussion shows, numerous TTS structures and the materials used for them are known. In any case, there are many interacting requirements to be considered when a drug is to satisfy medical requirements in the form of a TTS.
The following problems are to be considered fundamentally in the development of active-ingredient-containing TTS:
1. In order to achieve the therapeutically necessary penetration rates of the active ingredient through the skin, mostly it is required to have a high load of active ingredient in the polymer matrix. After the end of application, the active ingredient remaining in the TTS is not used therapeutically and is disposed with the plaster. However, this is undesirable, especially in the case of highly active and expensive active ingredients for reasons of environmental protection and costs.
2. The polymer matrix which is loaded with the active ingredient and optionally additionally with skin penetration enhancers is not stable physically upon long storage. Especially, recrystallization of the active ingredient may occur, which leads to an uncontrollable decrease of the release capacity of the TTS for the active ingredient.
3. High load of the polymer carrier with active ingredient and/or skin penetration enhancers makes the adjustment of optimum adhesive properties of the transdermal system difficult in the case of self-adhesive polymer films.
4. The resorption rate of the active ingredient decreases during application over several days in an unacceptable manner, so that additional control layers and/or components are necessary.
5. If the active-ingredient-loaded layers are made of organic solutions, the problem of remaining solvent residues in the active-ingredient-containing layer occurs after the drying process. Additionally, there is a danger of undesirable evaporation of volatile additives during manufacture. Since, for reasons of physical stability and skin compatibility of the system, as a rule, an attempt is made to have our system completely free from solvent, and, optionally, the reservoir therefore must be
Arth Christoph
Wolff Hans-Michael
Azpuru Carlos
Ghali Isis
Marshall Gerstein & Borun
Schwarz Pharma AG
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