Adhesives

Details Adhesives Adhesives

2001-10-15

2003-10-14

Harlan, Robert (Department: 1713)

Synthetic resins or natural rubbers -- part of the class 520 ser

Synthetic resins

Polymers from only ethylenic monomers or processes of...

C526S319000, C526S347000, C524S282000

Reexamination Certificate

active

06632906

ABSTRACT:

The present invention relates to adhesives suitable for use as bioadhesives and which comprise both adhesive polymer and plasticiser.
Various applications for bioadhesives exist, including medical tape and transdermal patches, for example. Methods of manufacture of these products are well advanced, but the nature of the adhesive remains a problem.
If the adhesive on medical tape is too strong, then removal can be painful, and will also serve to exfoliate the skin, which can cause irritation and may even lead to sensitisation to any drugs that the patient might be taking.
If the bioadhesive is too weak, then the patch or tape will tend to come away from the skin before it should. This has led to bioadhesives being developed which have merely been adapted so as not to be too strong to be painful, and not so weak as to be relatively useless.
More recently, it has been established that strong adhesives can be tempered with plasticisers. These generally take the form of oil substances introduced into the adhesive polymer. The effect of the introduction of such oily substances is to soften the physical structure of the adhesive whilst, at the same time, acting at the interface between the adhesive and the skin, thereby helping to somewhat weaken the adhesive, and to prevent exfoliation. Such a beneficial type of adhesive was first noted in certain types of electrical insulating tape.
The problem with such softened, or plasticised, adhesives is that, once they are weak enough to be medically acceptable, their cohesive strength is poor. Thus, such adhesives, when used in transdermal patches or surgical tape, for example, have insufficient integrity, and tend to tear, leaving bits of adhesive behind on the skin.
EP-A-450986 discloses an acrylic adhesive plasticised with isopropyl myristate (IPM) and which also contains nitroglycerine, which can further serve as a plasticiser. In order to improve cohesion of this adhesive, cross-linking was effected with aerosil silica. The problem with such cross-linking is the technical difficulty involved in sufficiently finely dividing the aerosil silica and incorporating it uniformly throughout the adhesive. Such cross-linking would not be generally practical.
U.S. Pat. No. 5,298,258 more generally seeks to solve the problems noted above, and discloses acrylic adhesives containing substantial amounts of plasticisers. Various methods for cross-linking the adhesive are mentioned, including irradiation and exposure to UV, but chemical cross-linking with a metal alcoholate, metal chelate or trifunctional isocyanate is preferred. The cross-linking of such an adhesive requires the presence of active hydrogen, generally in the form of a carboxyl or hydroxyl group, typically provided by a co-monomer having the required functionality.
The problem with such a system is with regard to the nature of the cross-linking, where there is necessarily involved an active chemical reagent, either on the adhesive (carboxyl groups, for example) or in the cross-linker (such as aluminium in aluminium alcoholate). Many drugs can react or interact with such groups, which can lead to problems, such as breakdown of the drug, or simple blocking of the cross-linking. For example, where a drug is weakly basic, then this can interact with the carboxyl groups present on the adhesive, thereby competing with the cross-linker.
WO 99/02141 discloses block copolymers wherein the soft segments are cross-linked, these copolymers being suitable for use as drug-retaining bioadhesives in transdermal patches. These adhesives suffer a loss of cohesion, however, when a plasticiser is incorporated.
It has now, surprisingly, been found that it is possible to provide a satisfactory medical adhesive with good cohesion and adhesion properties and low irritation which comprises an adhesive polymer and a plasticiser, wherein the polymer is cross-linked by a polyamine reacting with ketone groups present in the adhesive. Such adhesives are also useful in other non-medical applications where it is desired to apply an area of material, such as a patch or tape, for what may be only a limited period of time.
Thus, in a first aspect, the present invention provides an adhesive material suitable for use as a bioadhesive and comprising an adhesive polymer and a plasticiser therefor, wherein the adhesive is cross-linked, characterised in that the adhesive comprises ketone groups cross-linked by a polyamine cross-linking agent.
For the avoidance of doubt, the present invention encompasses novel adhesive materials, as disclosed herein, wherein the polymer and/or copolymer constituents thereof are cross-linked, wherein at least a portion of the cross links comprise a moiety
>C═N—(X)—N═C<
in which the carbon atoms are each a part of the respective polymer and/or copolymer constituents and each X is the same or different, preferably the same, and is directly equivalent to any group that would serve to carry the necessary amine groups of a polyamine cross-linking agent of the present invention.
Accordingly, it will be appreciated that X need not necessarily exist, in the instance of hydrazine, for example. It will also be appreciated that more than two suitable amine groups may be attached to X, although X may often be of the form X
1
—N<, or of the form X
2
(NA—)
2
, wherein X
1
and X
2
represent the kernel of X, and the groups —N< and NA represent the links with —N═C< groups, with each A representing a hydrogen or a direct bond with X
2
.
Bioadhesive materials of the present invention have been found to possess good water vapour permeabilities, which allows the skin to breathe when the tape or patch is in place. In addition, the lack of any necessary reactive groups is useful for drug stability, and also in providing certain sorts of patch that could not previously be made, as the bioadhesives of the invention are generally susceptible to very little interaction with other materials.
It will be appreciated that the adhesive polymers of the present invention are not restricted to the nature of the application, and that any reference to a specific embodiment, such as tape, or a patch, should be construed as incorporating reference to any other possible embodiment incorporating an adhesive of the invention, mutatis mutandis, where appropriate.
The nature of the adhesive polymer is not critical to the present invention. Indeed, the term “polymer” is used generically herein to relate to polymers, copolymers and mixtures thereof.
In general, it is preferred that the polymer should be a synthetic polymer, in order to be able to provide adequate quality control and predictability of results. It is also advantageous to use synthetic polymers, as they can be controlled to contain desired side-groups, as necessary. In the present invention, the adhesive polymer, or a substantial component thereof, has at least one ketone group which is able to react with a polyamine.
Ketone groups are capable of tautomerisation, where there is an equilibrium between the ketone and the corresponding enol compound. This equilibrium is generally in favour of the ketone. In the present invention, it is strongly preferred that the ketone-containing polymer should have at least one ketone group with little or substantially no tendency to enolisation. Hence, it is preferred that the ketone group should not be part of a larger functionality, and it is particularly the case that the ketone group should not be part of a carboxyl group or any derivative thereof, such as an esteric linkage or amide group, although it may be linked to or adjacent such a group. It is also strongly preferred that the ketone group should not be part of an aldehyde group.
It appears that, in the present invention, the cross-linking reaction takes place between the keto form of the carbonyl group and the amine group of the cross-linking agent. It has been found that, if the ketone group is not stable in the keto form, then it reacts only poorly, if at all, with the cross-linking agent. Preferred compounds are those in which the keto form is at l

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