Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-10-10
2002-10-08
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...
C424S443000, C424S448000, C514S946000, C514S947000
Reexamination Certificate
active
06461636
ABSTRACT:
This application is a 371 of PCT/EP 99/03278 filed May 12, 1999
DESCRIPTION
The present invention relates to a transdermal therapeutic system (TTS) for the transcutaneous administration of pergolide over several days and to a method for its manufacture without using solvents.
The bioavailability of orally administered active substances is often unsatisfactory. Hepatic metabolism of many active substances can lead on first passage through the liver to undesirable concentration ratios, toxic by-products and to reduced effect or even to loss of effect. Transdermal administration of active substances has various advantages over oral administration. The delivery of active substances can be better controlled over a longer period of time, as a result of which high fluctuations in blood levels are avoided. In addition, the required therapeutically effective dose can usually be significantly reduced. Also a plaster is often preferred by the patient to tablets, which have to be taken once or several times daily.
In the past, consideration has been given to overcoming the above disadvantages of non-transdermal administration of active substances by means of a multitude of transdermal therapeutic systems (TTSs) with different structures for different active substances treating different diseases.
The technical documents specified below therefore describe, in respect of a great variety of systemically or topically reacting active substances, their parenteral administration either on the basis of dose-controlled or generally releasing systems. By way of 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 originally theoretically presumed that any active substance with a short half-life but high efficacy and good skin-penetrating ability was suitable for reliable and effective administration by means of a TTS. However, these initial expectations with regard to the possibilities for the transdermal administration of active substances by means of TTSs were not fulfilled. The reasons for this were mainly that the skin is, by its very nature, endowed with an immense variety of properties to maintain its function as an intact barrier against penetration into the body of non-endogenous substances. (See in this connection: 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 only available for those few active substances, which have an appropriate combination of many favourable characteristics. However, these required characteristics, which should ensure reliable and effective transdermal administration, cannot be predicted for a specific active substance.
The demands to be made on an active substance to make it suitable for transdermal administration are as follows:
Ability to pass through the skin,
No impairment of the adhesive power of the plaster by the active substance,
Avoidance of skin irritations,
Avoidance of allergic reactions,
Favourable pharmacokinetic properties,
Favourable pharmacodynamic properties,
A relatively wide therapeutic window,
Metabolism properties, which are consistent with therapeutic application with continuous administration.
Certainly, the above list of requirements is not exhaustive. The “correct” combination of all these requirements is desirable if an active substance is to be suitable for transdermal administration.
The above specifications in respect of the active substances similarly apply to the composition of the TTS, which contains the respective active substance, and its structure.
Normally, transdermal therapeutic systems (TTSs) involve plasters, which are provided with an impermeable covering layer, a removable protective layer and a matrix containing the active substance or a reservoir containing the active substance with a semipermeable membrane. In the first case, they are known as matrix plasters, in the second case as membrane systems.
For the covering layer, polyester, polypropylene, polyethylene, polyurethane etc. are usually used, which can also be metallized or pigmented. For the removable protective layer, polyester, polypropylene or even paper with a silicon and/or polyethylene coating can also be considered among other things.
Materials based on polyacrylate, silicon, polyisobutylene, butyl rubber, styrene/butadiene copolymer or styrene/isoprene copolymer, are used for the standard pharmaceutical or medical matrices containing the active substances.
The membranes used in membrane systems can be microporous or semipermeable and are usually formed on a basis of an inert polymer, in particular polypropylene, polyvinyl acetate or silicon.
Whilst the matrix structures containing the active substance can be self-adhesive, matrices containing active substance are also produced, depending on the active substance used, which are not self-adhesive, so that the plaster or TTS must consequently be designed with an overtape.
For ensuring the required flux rate of the active substance, skin-penetration enhancers, such as aliphatic, cycloaliphatic and/or aromatic-aliphatic alcohols, in each case monohydric or polyhydric and each including up to 8 C-atoms, an alcohol/water mixture, a saturated and/or unsaturated fatty alcohol each having 8 to 18 carbon atoms, a saturated and/or unsaturated fatty acid each having 8 to 18 carbon atoms and/or its esters as well as vitamins are often necessary as additives.
Furthermore, stabilizers, such as polyvinyl pyrrolidone, &agr;-tocopherol succinate, propyl gallate, methionine, cysteine and/or cysteine-hydrochloride, are frequently added to the matrix containing the active substance.
As the above list shows, numerous TTS constructions and the materials used for these are known. Of course many interacting prerequisites are to be taken into account if a medicament in the form of a TTS should satisfy the medical needs.
The following problems are to be considered when developing TTSs containing active substances:
1. A high loading of the polymer matrix with the active substance is usually necessary to achieve the therapeutically necessary rates of penetration of the active substance through the skin. Active substance remaining in the TTS after administration is complete is therapeutically unused and is disposed of with the plaster. However, for environmental reasons and for reasons of cost, this is undesirable with highly effective and expensive active substances.
2. The polymer matrix, laden with active substance and if necessary also with skin-penetration enhancers, is not physically stable when stored for long periods of time. In particular, a crystallisation of the active substance may occur, which leads to an uncontrollable reduction in the TTS's capacity to release the active substance.
3. A high loading of the polymeric carrier material with active substance and/or skin-penetration enhancers hinders the standardization of the optimum adhesive properties of the transdermal system in the case of self-adhesive polymer films.
4. With applications over several days, the resorption rate of the active substance drops in an unacceptable way, so that additional control layers and/or control constituents are necessary.
5. Should layers, laden with active substance, be made of organic solutions, the problem arises of solvent residues remaining in the layer containing the active substance after the drying process. In addition, there is the risk of an undesirable evaporation of volatile auxiliary agents during manufacture. Since, for reasons of physical stability and skin compatibility of the system, complete freedom from solvent is generally desirable, the reservoir must if necessary be built up in several layers. This again leads to an increase in production costs.
Therefore, the problems as specified above call for a
Arth Christoph
Kollmeyer-Seeger Andreas
Rimpler Stephan
Wolff Hans-Michael
Marshall Gerstein & Borun
Page Thurman K.
Schwarz Pharma AG
Sheikh Humera N.
LandOfFree
Transdermal therapeutic system containing pergolide does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Transdermal therapeutic system containing pergolide, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Transdermal therapeutic system containing pergolide will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2956611