Patent Application
20070065496
2-(3-Benzophenyl)propionic acid, as a substance, was patented as early as 1968. Since then, it has been found to be highly advantageous in the therapy of acute forms of arthritis, including gout attack, chronic forms of arthritis, especially rheumatoid arthritis (chronic polyarthritis), and also ankylosing spondylitis (Bechterew's disease) and other inflammatory rheumatic conditioris of the spine, irritation conditions in the case of degenerative joint and spine diseases (arthroses and spondylarthroses), soft tissue rheumatism, painful swellings or inflammations after injuries or operations and also other non-rheumatic pain conditions and dysmenorrhoea. Because gastric and intestinal ulcers, gastrointestinal complaints such as nausea, vomiting, heartburn, stomach pain, sensation of bloatedness, constipation or diarrhoea frequently occur as side-effects when this class of substance and also, therefore, 2-(3-benzophenyl)propionic acid are administered perorally and because a large proportion of the indications are also amenable to treatment topically, especially in the case of irritation conditions in degenerative joint and spine diseases (arthroses and spondylarthroses), soft tissue rheumatism, painful swellings or inflammations after injuries and operations, the substance is also employed in topical formulations such as creams, ointments, gels, sprays etc. For that purpose, the 2-(3-benzophenyl)propionic acid released from the formulation penetrates the skin barrier and, by virtue of the acidic environment caused by the inflammation, accumulates in the inflamed soft tissue, where it produces a topical effect in the painful and inflamed region of that part of the body.
The penetration of pharmaceutical substances through the skin is largely governed by the physicochemical properties of the substance—the octanol/water partition coefficient and molecule size basically playing a role therein (Potts R O, Guy R H in: Gurny R, Teubner A; Dermal and transdermal drug delivery, Wiss. Verlagsges. Stuttgart (1993)). Because those parameters cannot be influenced without making modifications to the molecule, there are basically only two possibilities for increasing the penetration rate:
1. facilitating diffusion by means of the addition of penetration accelerators or employing electric potential (iontophoresis)
2. increasing the concentration of pharmaceutical substance in the base, even to beyond the limit of solubility (supersaturation).
As penetration accelerators there are used, inter alia, fatty acids, fatty alcohols, simple and polyhydric alcohols, laurocapram and surfactants. However, many of those substances act by disrupting the barrier function of the skin and consequently have to be categorised as being more or less irritating to the skin. Nevertheless, many such systems are described in patent specifications (cf. DE 19830649, WO 96229988 etc.).
Tolerability is better when systems are used in which the active ingredient is present in supersaturated form. Usually the maximum flux of a substance through the skin is limited by its solubility in the horny layer (stratum corneum), which constitutes the main penetration barrier. The said saturation concentration will be achieved when the active ingredient is present in the vehicle, for example in the matrix of the transdermal system, in a concentration that also corresponds to its solubility in that vehicle. A possibility for further increasing that so-called maximum thermodynamic activity consists in incorporating the pharmaceutical substance in a concentration exceeding its solubility in the vehicle. That is possible, for example, by incorporating 2-(3-benzophenyl)propionic acid in acrylate copolymers (DE 19843027). However, it is necessary for supersaturation to be sensitively adjusted so that the supersaturations are as high as possible but are also as stable as is necessary, because supersaturated systems are known to be metastable and recrystallisation during storage causes them to change to the saturated state. It is then disadvantageous that, because of the crystallisation, such systems lead to product complaints, resulting from shortcomings in appearance and also from a lack of adhesive strength. It is likewise necessary for there to be close contact between a dermal system and the skin in order to obtain an effective amount of 2-(3-benzophenyl)propionic acid in the target region of the inflamed soft tissue.
It has now been found that incorporating 2-(3-benzophenyl)propionic acid in a very specific acrylate copolymer achieves supersaturation that is so stable that an effective product is obtained without having to add penetration accelerators, as well as optimum adhesion to the skin such that, even with close contact between the dermal system and the outer barrier of the skin for several days up to a maximum of one week, the system can be removed at any time, without resulting in painful sensations or skin irritations. Consequently, the adhesive strength of the dermal system according to the invention makes possible a significantly longer period of wear than, for example, products that are on the market which comprise water-containing preparations of the cataplasm or poultice kind, as well as substantially longer contact than conventional topical formulations such as creams, gels or a spray, which can be removed as a result of contact with water or with clothing.
A number of solvent-based acrylate copolymers, as are made available, for example, by the company National Starch & Chemical, BV, Zutphen, Netherlands under the trade-name Durotak, have been tested with regard to their adhesion properties. The table that follows indicates the copolymer composition:
As can be seen, the properties for wear are achieved only by using an adhesive based on 2-ethylhexyl acrylate, methyl methacrylate and acrylic acid, for example by Durotak 2852, which is surprising. The company National Starch & Chemical makes available slight modifications of that adhesive (Durotak 387-2287, 387-2353), although the above-mentioned adhesive Durotak 87-2852 leads to the best result, with specific, unknown interactions taking place between the active ingredient and acrylate copolymer.
In addition, the support or cover layer of the matrix plays an important part in the properties for wear. Because the dermal system has to be applied to joints, a high degree of flexibility is necessary. Various materials, encompassing non-wovens, foams, films and wovens, have undergone testing. It was important, inter alia for tolerability, that the support used should have good permeability to water vapour. A longitudinally and transversally resilient woven polyester which is available in white or skin colours (company Karl Otto Braun, Germany) was found to be optimal.
As protective film there can be used a siliconised polyester film known to the person skilled in the art, for example Hostaphan RN 100 from Diafoil, Hoechst, Germany, easy/easy, which must not be too thin (a layer at least 36 μm thick, preferably 100 μm thick) so that a system of a large size such as from 70 to 140 cm2, preferably of 90 cm2, can still be handled well by the patient.
The dermal therapeutic systems according to the invention are preferably so arranged that they consist of a cover layer impermeable to the active ingredient, an active-ingredient-containing adhesive layer adhering to the cover layer, and a removable protective layer.
This most simple form of a TDS can be produced in a manner well known to the person skilled in the art, by mixing a solution of the adhesive in a low-boiling solvent with the active ingredient, applying the mixture evenly to a removable protective layer, removing the solvent by heating, and covering the resulting product with a support. The active-ingredient-containing adhesive layer applied has a thickness of from 20 to 500 μm.
The following exemplary embodiments serve to illustrate the invention in greater detail:
To 30.83 g of a 36% (w/w) solution of an acrylate adhesive (Durotak 87-2852, National Starch & Chemical B.V., NL-Zutphen) there is added a solution of 2.78 g of 2-(3-benzo-phenyl)propionic acid in 5.6 g of 2-propanol. The solution is homogenised by stirring for one hour and is then spread out, using a doctor blade, onto a siliconised, 100 μm-thick polyester film (FL 2000 100μ 1-S, Rexam Release B.V., NL-Apeldoom) in a wet-layer thickness of 260 μm. After drying (1 h at 40° C. and 50 min at 80° C.), the clear and homogenous laminate is lined with a woven polyester (M02/97, white, K. O. Braun, D-Wolfstein) without stretching. A patch 90 cm2 in size, at a matrix weight of 55.6 g/m2, contains 100 mg of 2-(3-benzo-phenyl)propionic acid.
To 17.46 g of a 35% (w/w) solution of an acrylate adhesive (Durotak 87-2852, National Starch & Chemical B.V., NL-Zutphen) there is added a solution of 2.08 g of 2-(3-benzo-phenyl)propionic acid and 0.21 g of neohesperidine DC in 4.17 g of isopropanol. The solution is homogenised by stirring for one hour and is then spread out, using a doctor blade, onto a siliconised, 100 μm-thick polyester film (FL 2000 100μ 1 -S, Rexam Release B.V., NL-Apeldoorn) in a wet-layer thickness of 270 μm. After drying (1 h at 40° C.), the slightly cloudy laminate is lined with a longitudinally and transversely resilient woven polyester (K. O. Braun, D-Wolfstein). A patch 90 cm2 in size, at a matrix weight of 55.6 g/m2, contains 125 mg of 2-(3-benzophenyl)propionic acid.
As Table 2 shows, the Example comprising neohesperidine DC does not have modified adhesive properties compared to the corresponding formulations without neohesperidine DC.
| Number | Date | Country | Kind |
|---|---|---|---|
| DE 100 32 537.8 | Jul 2000 | DE | national |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 10332221 | Apr 2003 | US |
| Child | 11603852 | Nov 2006 | US |
