Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Web – sheet or filament bases; compositions of bandages; or...
Reexamination Certificate
1999-07-15
2001-10-09
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...
C424S449000, C424S486000, C424S484000, C424S485000, C424S487000
Reexamination Certificate
active
06299899
ABSTRACT:
The present invention relates to an extremely flexible patch having a dermal or transdermal action for controlled release of active compounds to human or animal skin, which comprises an adhesive matrix layer which contains the active compound or compounds and has been freed from its adhesive properties on the side facing away from the skin, and to a process for its production.
Patches for controlled release of active compounds to human or animal skin are adequately known and described as transdermal therapeutic systems (TTS) or “transdermal delivery systems” (TDS). A distinction is generally made in these systems between so-called pouch or reservoir patches and so-called matrix patches, depending on the structure and the nature of the release of active compound. In the first case, such patches comprise a flat pouch or sachet which contains the active compound and of which the side facing away from the skin is impermeable and the side facing the skin is constructed as a control membrane coated with an adhesive for the purpose of adhesion to the skin. Because of their complicated structure, the production of such patches is very expensive, since the individual components have to be prepared separately and then brought together into one system.
Furthermore, because of the necessary thickness of the patch, the wearing properties are impaired. Moreover, with the pouch system there is the risk of so-called “drug dumping”, that is to say sudden complete release of the active compound to the skin owing to destruction of the membrane or of the pouch. EP 0 235 563 describes, for example, a transdermal therapeutic system or patch of this type for combined administration of oestrogens and gestagens.
Systems or therapeutic patches which comprise the active compound in microencapsulated form in the reservoir are known from U.S. Pat. No. 4,624,665. The reservoir is embedded between a backing layer and a membrane. The peripheral edge of the patch is provided with a contact adhesive. The structure and the production of such patches are very complicated, since the active compound has to be microencapsulated and distributed homogeneously, to then be embedded between the backing layer and membrane. Furthermore, the patch must be provided with an edge which sticks to skin and covered with a protective layer. Matrix systems or patches generally comprise a backing layer which faces away from the skin and is impermeable to the active compound and an adhesive layer in which the active compound is distributed. To protect the adhesive layer, this is provided with a protective film which has been given an abhesive treatment and must be removed before application. DE-OS 20 06 969, for example, describes such a system in which contraceptive substances are incorporated into the adhesive components or the adhesive film. This specification shows that the adhesive film can be an acrylate.
A disadvantage of known pouch, reservoir or matrix systems or patches is the necessary thickness caused by the production process, which impairs the flexibility in an undesirable manner. The flexibility of the system or patch in fact has a direct effect on its wearing properties, since the wearing comfort required increases with decreasing thickness and decreases with increasing thickness.
The present invention is based on the object of providing a process for the production of an extremely flexible patch which has a dermal or transdermal action, is provided with preferred wearing comfort, dispenses entirely with a separate backing layer and consequently is thinner and more flexible and, as a result of reduced expenditure during production, results in a less expensive alternative to the systems to date.
This object is achieved by a process according to the features of the main claim.
Surprisingly, it has been found that as a result of their greater suppleness, such patches also adhere to skin more reliably and for a longer time.
Because of the-comparatively lower thickness and higher flexibility, in contrast to conventional systems or patches the patch according to the invention is also suitable for permanent application to difficult areas of the body, e.g. in the region of the ear, in the genital region or on toenails and fingernails.
A preferred embodiment of a patch according to the invention, given by way of example, is constructed as follows: it comprises a supporting layer, an adhesive part with a non-adhesive surface of a matrix containing the active compound and a detachable protective layer.
To apply the patch according to the invention, the protective layer is removed and the patch is applied to the application area with the aid of the supporting layer such that the adhesive side is facing the skin, and the supporting layer is then peeled off from the side which has been given a non-adhesive treatment.
To cancel the adhesive strength on the surface of adhesive layers, suitable methods are all those which modify the surface structure
a) by changing the molecular bond of the adhesive system in the surface itself
1. by changing the state of aggregation—liquid/crystalline (influence of heat)
liquid=adhesive
crystalline=non-adhesive,
2. by crosslinking, chemically by crosslinking agents or by radiation, the parts of the polymer molecules which determine the adhesive strength,
b) by changing the surface structure by means of additives which provide a new interface on the outside, are available, additives which can be used being:
1. solid particles with a particle size in the range of 0.5-20 &mgr;m, which are either spherical or platelet-like in structure. Starch flours or laminar silicates, such as bentonite or mica, may be mentioned as an example. The pulverulent nature of these particles, which allow a uniform application, is decisive.
2. liquid media which, after application,
a) form a liquid, semi-solid or solid film physically by themselves —(for example silicone oil, fats, aqueous acrylate dispersions or polymer solutions),
b) form a new interface by chemical cross-linking.
The adhesive matrix layer can comprise polymers, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, vinylpyrrolidone/vinyl acetate copolymer 60:40, ethylcellulose, acrylic and methacrylic acid ester copolymers with trimethylammoniummethyl acrylate, copolymers of dimethylaminomethacrylic acid and neutral methacrylic acid esters, shellac, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polymers of methacrylic acid and methacrylic acid esters, ethyl acrylate/methyl methacrylate copolymer 70:30, methacrylic acid/methyl acrylate copolymer 50:50, gelatin, polyvinyl acetate, methacrylate, acrylate dispersions, polyether/polyamide block copolymers, polyethylene/methyl methacrylate block copolymers, polyurethanes, polyester block copolymers, polyisobutylene/styrene/styrene copolymer, styrene/butadiene/styrene/isoprene copolymer, ethylene/vinyl acetate copolymer, polyamide, nitrocellulose and further coat- or film-forming agents which are known to the expert and have at least one reactive polymer end group. The addition of plasticizers results automatically in accordance with the proviso of the required flexibility of the film.
Further substances which may be added or applied to complete a film to be crosslinked are: acrylic- and/or methacrylic-modified polysiloxanes which have a high content of non-polar methyl groups and contain at least one reactive terminal acrylic and/or methacrylic acid group, and furthermore mono-, bi- and trifunctional acrylic and methacrylic acid esters. Vinyl or epoxide compounds containing perfluoroalkyl or perfluoroalkenyl groups or epoxypropylsiloxanes are moreover possible.
Suitable pulverulent substances are additives, in particular, of SiO
2
, zinc stearate, mica, bismuth oxychloride, titanium dioxide, magnesium oxide, talc, magnesium stearate and other metal salts of fatty acids, and furthermore triglycerides and the colored pigments used in particular in decorative cosmetics. In this connection, it should be noted that the surface of the adhesive matrix
Ghali Isis
Hochberg D. Peter
Holt William H.
LTS Lohmann Therapie-Systeme AG
Page Thurman K.
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