Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
2000-12-21
2003-11-25
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...
C424S484000, C424S486000
Reexamination Certificate
active
06652876
ABSTRACT:
The invention relates to a drug patch system based on synthetic rubbers for delivering at least one nonsteroidal antirheumatic for absorption through the skin over a period of up to 24 h, and to a process for producing it.
Transdermal therapeutic systems (TTS) for delivering active substances through the skin have been known for a long time. The topical application of drugs by way of active substance patch systems offers two main advantages. Firstly, this form of administration produces first order release kinetics of the active substance, thereby enabling a constant level of active substance to be maintained in the body over a very long period. Secondly, the path of uptake through the skin avoids the gastrointestinal tract and also the first liver passage. As a result, selected drugs may be effectively administered in a low dose. This is particularly advantageous when the drug is desired to act locally while avoiding a systemic effect. This is the case, for example, with the treatment of rheumatic joint complaints or muscular inflammation.
One embodiment of such transdermal systems which has been well described in the technical literature is that of matrix systems or monolithic systems in which the drug is incorporated directly into the pressure sensitive adhesive. In the ready-to-apply product, a pressure sensitively adhesive matrix of this kind, comprising active substance, is equipped on one side with a backing impermeable to the active substance, while on the opposite side there is a backing film equipped with a release layer, which is removed prior to application to the skin (kleben&dichten, No. 42, 1998, p. 26 to 30).
A fundamental requirement of a TTS is very good adhesion to skin, which must be maintained over the entire duration of the intended dosing of active substance. A frequently observed side effect, however, is the appearance of skin irritations, which occur in particular when a TTS is applied for a relatively long period, or repeatedly, to the same body region. The principal cause of these irritations are the ingredients of the pressure sensitively adhesive matrix. Painful redetachment of the active substance patch following a prolonged period of wear is a further observation.
Repeated and long-lasting applications of pressure sensitively adhesive systems to the same regions of the human body are encountered above all in the area of ostomy care. In this utility, hydrocolloids have long been used with great success as pressure sensitive adhesives. They consist in principle of a hydrophobic, pressure sensitively adhesive polymer matrix based on synthetic rubbers, dispersed in which matrix there are insoluble hydrophilic fillers based on, for example, alginates, cellulose or pectins. In the development of hydrocolloids for ostomy care, however, the primary requirements are the adhesion properties to wet skin and the ability to absorb liquid.
As long ago as 1967, U.S. Pat. No. 3,339,546 described a hydrocolloid based on polyisobutylenes for use in the oral cavity. A great disadvantage of the early systems was the deficient integrity of the matrices, i.e., the dissolution and breakup of the pressure sensitively adhesive matrix on absorption of relatively large amounts of liquid.
Later developments therefore aimed to solve this problem, and a number of proposed solutions are described in the literature. U.S. Pat. No. 4,393,080, for example, describes a hydrocolloid system based on elastomers, which uses high molecular mass hydrophilic fillers which promote the cohesion of the system even when swollen.
Further patents describe solutions by way of the crosslinking of the elastomer matrix, which may take place either physically or chemically.
Physical crosslinking, for example, may be effected by using phase separating block polymers based on poly(styrene-b-isoprene-b-styrene) (SIS), poly(styrene-b-isoprene-b-styrene) (SBS) or poly[styrene-b-(ethylene-stat.-butylene)-b-styrene] (SEBS). One of the first such systems is described, for example, in DE 28 22 535.
Chemical crosslinking may be effective, for example, by electron beam treatment or &ggr; irradiation of the hydrocolloid matrix. A prerequisite for this is the presence in the pressure sensitively adhesive matrix of a sufficient number of reactive structural elements. This can be achieved, for example, as described in U.S. Pat. No. 4,477,325, by compounding with an ethylene-vinyl acetate copolymer.
Within the abovementioned inventions, although the technical problem of the cohesiveness of swollen hydrocolloids is described and solved, the problem of skin irritation as a result of repeated application is not addressed.
In contrast, WO 98/01167 does deal with skin irritations that may occur. In this case, aloe vera extract is used in order to prevent inflammatory skin changes and infection in the context of ostomy care. The system described, however, merely comprises a low molecular mass polyisobutylene as the polymer framework, and so the above-described problem of the cohesiveness of the hydrocolloid matrix continues to exist. Moreover, the composition described uses tackifier resins, whose allergenic potential is known.
Information regarding the suitability of such a system for the controlled delivery of drugs is present neither in this nor in any other of the abovementioned documents.
Transdermal therapeutic systems are generally applied to healthy, intact skin. In this case in particular it is especially important that the intact skin is not irritated, let alone damaged, by a drug. Furthermore, sufficient cohesiveness is necessary in order to be able to remove the active substance patch without residue after the period of wear is at an end.
Polyisobutylenes have long been used as a framework substance in the compounding of pressure sensitive adhesives. Relative to other known elastomers, synthetic polymers based on isobutylene offer a number of advantages. Owing to their synthetic production, they are free from unwanted ingredients; owing to their complete saturation they are highly stable to oxidation; and their inherent tack can be adjusted depending on molecular weight.
For application to skin in particular, therefore, they are preferred over other elastomers. For example, the allergenic potential of natural rubber, deriving from its natural impurities, is well known. Other synthetic rubbers based on styrene and isoprene and/or butadiene are very oxidation sensitive, necessitating the complicated addition of additives. Their hydrogenated derivatives based on poly[styrene-b-(ethylene-stat-propylene)-b-styrene] (SEPS) or poly[styrene-b-(ethylene-stat-butylene)-b-styrene] (SEBS), although more stable to oxidation, nevertheless lack inherent tack. Because of this, they additionally require compounding with tackifier resins in order to be used as pressure sensitive adhesives, as is described, for example, in EP 0 651 635 B1. These resins are generally very poorly defined mixtures of substances, frequently based on rosin. Consequently, here again an allergenic potential can not be ruled out.
The use of polyisobutylenes for transdermal therapeutic systems was described back in 1983 in DE 33 47 278 and DE 33 47 277. There, however, their use was always described in combination with either olefinic diene rubbers or tackifier resins, which again have the disadvantages described above. The use of amorphous poly-a-olefins as additives is also described, but without elucidating their effect on the overall system. The use of fillers is not mentioned in this description.
The use of PIB for transdermal systems without the addition of tackifier resins is described in U.S. Pat. No. 4,559,222. In that case, however, it is necessary to use very large amounts of mineral oil, the ratio of mineral oil to PIB in accordance with that invention being at least 1. Moreover, the system is restricted to active substances which are of moderate solubility in mineral oil. As a result, there is a further softening effect on the matrix. Fillers used comprise at least 6% by weight of colloidal silica. Regarding t
Radloff Detlev
Wasner Matthias
Beiersdorf AG
Norris & McLaughlin & Marcus
Page Thurman K.
Young Micah Paul
LandOfFree
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