Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1998-09-15
2001-05-15
Clardy, S. Mark (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Web, sheet or filament bases; compositions of bandages; or...
C424S449000, C602S041000, C602S060000, C604S290000, C604S304000, C604S307000
Reexamination Certificate
active
06231885
ABSTRACT:
This application claims priority of Italian Application Serial No. MI97A 002106, filed Sept. 17, 1997.
FIELD OF THE INVENTION
The present invention relates to a novel composition for controlled and sustained drug transdermal administration, comprising a combination of two or more fatty acids or alcohols of different chain length as permeation enhancers.
The invention reveals a monolithic formulation with good adhesive properties and low irritation potential, useful for administering active agent(s) by transdermal route, during long periods of time. A formulation that administers active agent(s) or a combination thereof, at a permeation rate that would ensure therapeutically effective systemic concentration. This formulation contains defined amounts of chemicals that minimize the barrier characteristics of the uppermost layer of the epidermis and provide sustained and controlled permeation rate. Said chemicals are: fatty acids such as oleic acid, palmitoleic acid, palmitic acid, myristic acid, lauric acid, etc. and fatty alcohols such as oleyl alcohol, palmityl alcohol, myristyl alcohol, lauryl alcohol, n-decanol, etc. This formulation contains defined amounts of chemicals that assure good adhesive properties and low irritation potencial during long periods of time.
BACKGROUND OF THE INVENTION
While there are many patents and publications available which relate to the transdermal administration of drugs, and the use of penetration enhancers, the applicant is unaware of any prior art which relates to the penetration enhancer composition of a monolithic transdermal device with adequate adhesive properties disclosed herein and to use such composition in the transdermal administration of drug(s).
The present invention relates to a novel composition based on enhancers combination, specifically fatty acids and fatty alcohols with different chain length in an adhesive matrix containing defined amount of chemicals as cellulose derivatives (ethylcellulose) to avoid cohesive failure. This formulation is suitable for transdermal administration of drug(s) alone or mixture thereof, and would provide therapeutically useful concentrations of drug for long periods of time, up to 7 (seven) days.
Using skin as the port for the drug entry offers unique potential, because transdermal delivery permits close control over drug absorption. For example, it avoids factors that can cause unpredictable absorption from the gastrointestinal tract, including: changes in acidity, motility, and food content. It also avoids initial metabolism of the drug by the liver. Thus, controlled drug entry through skin can achieve a high degree of control over blood concentrations of drug.
Transdermal delivery particularly benefits patients with chronic diseases. Many of such patients have difficulties following regimen requiring several daily doses of medications that repeatedly cause unpleasant symptoms. They find the same drugs much more acceptable when administered in transdermal systems that require, application infrequently, in some cases, only once or twice a week and that reduce adverse events.
Monolithic transdermal drug delivery systems involve incorporation of an active agent into the pressure sensitive adhesive formulation. The pressure sensitive adhesive must adhere effectively to the skin and then permit migration of the drug from the pressure sensitive adhesive through the skin and into the blood stream of the patient. Transdermal administration of drugs offers several therapeutic and compliance advantages over the more traditional routes of administration. A major drawback of this therapy however, is the limitation of the amount of drug that can be transported across the skin. This limitation is due to several factors. Since the skin is a protective barrier by nature, the rates of transport of most compounds through the skin is quite slow.
The rate of percutaneous absorption can be affected by the oil/water partition coefficient, the polarity of the drug and its degree of ionization, its solubility characteristic, molecular weight, volatility, concentration and the nature of the drug vehicle.
In order to overcome the barrier properties of the stratum corneum and facilitate the percutaneous absorption of the active agent, many compounds are described as penetration enhancers, such as, azone, glycol, pyrrolidone, fatty alcohol, fatty acid and ester thereof, etc., mentioned by Møllgaard in “Pharmaceutical Skin Penetration Enhancement”, Marcel Dekker, New York 1993, pages 229-242.
The behavior of an enhancer depends on the penetrant drug and the transdermal device design. That is, a given enhancer does not necessarily increase the absorption of all drugs, as it is quoted by Hori, Satoh and Maibach in “Percutaneous Absorption”, Marcel Dekker, New York 1989, pages 197-211.
It is possible to excerpt from the scientific literature many examples in which two or more permeation enhancers in mixture have been shown to act synergically in percutaneous absorption enhancement.
A true synergically effect is achieved when the combination of permeation enhancers elicit a greater effect than the addition of the individual responses of each component used alone. However, for practical reasons the definition is expanded to comprise all examples for which two or more permeation enhancers in a mixture have worked well together in increasing the transport of drugs into and through the skin.
Cooper (1984) showed that the combination of propylene glycol and oleic acid increased the penetration of salicylic acid compared with each penetration enhancer alone. Aungst et al (1986) showed that the effects of permeation enhancer on absorption of naloxone in in vitro studies are vehicle dependent, showing that the combination of vehicles promotes the absorption better than one vehicle alone.
Green, Guy and Hadgraft (1988) reported that oleic and lauric acid can be employed to increase the permeability of human skin to a number of charged and uncharged molecules. The authors suggest that improved permeation is due to disruption of the stratum corneum structure.
Fatty acids are described as effective penetration enhancers for the transdermal delivery of several drugs. Golden et al. (1987) postulated that the likely enhancement mechanism of the fatty acids is mediated by the disruption of the stratum corneum lipid packed and hence decrease the diffusional resistance to permeants.
On the contrary Kadir et al. in “Pharmaceutical Skin Penetration Enhancement”, Marcel Dekker, New York 1993, pages 215-227, assert that the mode of action of some enhancers is still unclear since, in most studies, no efforts have been made to distinguish between their direct effect on the skin barrier properties on the one hand, and their effects on the thermodynamic activity of the penetrating species in the vehicle on the other. It is quite likely that incorporating permeation enhancer in transdermal formulations will change the thermodynamic activity of the drug in the matrix, and thereby lead to a positive or negative “push” effect. In addition, some permeation enhancers may conceivable penetrate into the highly ordered intercellular lipid structure of the stratum corneum and reduce its resistance by increasing lipid acyl chain mobility, thus providing a “pull” effect.
It is now well accepted that the mechanism by which fatty acids and alcohols increase the skin permeability involves an interaction with the intercellular lipids in the stratum corneum. Alteration of the lipid bilayers has been assessed using differential scanning calorimetry (DSC) and fourier infrared spectroscopy (FTIR). These methods indicate that the enhancer system may cause a disruption of the ordered lamellar structure of the biolayers in the stratum corneum, leading to an increased fluidization of intercellular medium. As it is stated by Møllgaard in “Pharmaceutical Skin Penetration Enhancement”, Marcel Dekker, New York 1993, pages 229-242 it is likely that in a binary composition comprising oleic acid and propylene glycol, the propylene glycol enhances the oleic acid penetration, and ol
Clardy S. Mark
Hedman & Costigan PC
Permatec Technologie AG
Williamson Michael A.
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