Patent Application
20130211351
The invention relates to a pharmaceutical patch for transdermal administration of the pharmacologically active ingredient (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof, the patch comprising a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.
The pharmacologically active ingredient according to the invention is known from the prior art to exhibit analgesic properties and is particularly suitable for the treatment of acute, visceral, neuropathic or chronic pain (cf., e.g., WO 2004/043967 and WO 2008/040481).
While the pharmacologically active ingredient according to the invention has a sufficient bioavailability so that it can be administered orally, it is desirable to provide an alternative route of systemic administration. It is known that transdermal administration of a pharmacologically active ingredient can be advantageous compared to its oral administration, e.g. with respect to patient compliance.
The working principle of a pharmaceutical patch for transdermal administration relies on the release of the pharmacologically active ingredient from the patch, its penetration into and through the skin barrier, and its entry into the systemic circulation through the perfused subcutaneous tissue, where it then develops its pharmacological effect at the targeted receptors. The penetration of a pharmacologically active ingredient through the skin is largely determined by its physicochemical properties and so far, there are only relatively few preparations of pharmacologically active ingredients that are suitable for transdermal administration.
In general, besides the desired pharmacological effect of pain relief, a pharmaceutical patch for transdermal administration of an analgesic should satisfy the following requirements:
Only a very few pharmacologically active ingredients may be administered transdermally. Typically, the transdermal administrability of a given drug can be assessed in view of some of its characteristic features (cf. T. K. Ghosh et al., Transdermal and topical drug delivery systems; Interpharm Press (Buffalo Grove, Ill., 2002)), particularly
High water solubilities, low melting points as well as partition coefficients between 1 and 3.5 (log P, max. 4.0) have been reported in the literature as being generally desirable for transdermal administration.
The water solubility of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclo-hexane-1,1-pyrano[3,4-b]indol]-4-amine (free base as well as hemicitrate) is very poor (less than 0.3 μg/ml), its melting point is very high (˜300° C.) and its partition coefficient substantially outside the desirable range (log P 5.3).
Therefore, one would typically expect that this pharmacologically active ingredient cannot be administered transdermally.
It is an object of the invention to provide an advantageous pharmaceutical preparation of (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine or a physiologically acceptable salt thereof.
This object has been achieved by the subject-matter of the patent claims.
It has been surprisingly found that (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine, in form of the free base or in form of its physiologically acceptable salts, can be administered transdermally, i.e. that pharmaceutical formulations can be found which release the pharmacologically active ingredient in a form that is capable of penetrating into the skin barrier and entering into the systemic circulation through the perfused subcutaneous tissue in a sufficient quantity and rate to develop its desired analgesic effect.
The pharmaceutical patch according to the invention comprises a surface layer, an adhesive layer, and a removable protective layer, wherein the adhesive layer is located between the surface layer and the removable protective layer.
The adhesive layer is located between the surface layer and the removable protective layer. Preferably, the surface layer forms the outer surface of the pharmaceutical patch, i.e. when the pharmaceutical patch is applied to the skin the surface layer is the visible layer of the pharmaceutical patch.
Preferably, one of the two opposing surfaces of the adhesive layer is in intimate contact with, i.e. adjacent to the removable protective layer.
In a preferred embodiment, the other of the two opposing surfaces of the adhesive layer is in intimate contact with the surface layer, which in turn preferably forms on its outer surface the outer surface of the pharmaceutical patch. According to this embodiment of the invention, the pharmaceutical patch preferably consists of surface layer, adhesive layer and removable protective layer, so that the adhesive layer contains the pharmacologically active ingredient (drug-in-adhesive).
In another preferred embodiment, the other of the two opposing surfaces of the adhesive layer is not in intimate contact with the surface layer, which in turn preferably forms on its outer surface the outer surface of the pharmaceutical patch. Thus, according to this embodiment, at least one additional layer is present between the surface layer and the adhesive layer. According to this embodiment of the invention, the pharmaceutical patch preferably comprises the surface layer, the adhesive layer, the removable protective layer and one, two, three or more additional layers between the adhesive layer and the surface layer, so that the pharmacologically active ingredient can be present in the adhesive layer and/or in any one of said additional layers.
The total thickness of the pharmaceutical patch is not particularly limited. Preferably, the total thickness of the pharmaceutical patch is within the range of from more preferably 20 to 1000 μm, still more preferably 40 to 800 μm, yet more preferably 60 to 650 μm, even more preferably 80 to 550 μm, most preferably 100 to 450 μm, and in particular 150 to 400 μm. In a preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 100±75 μm (i.e. from 25 μm to 175 μm), preferably 100±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 150±100 μm, preferably 150±75 μm, more preferably 150±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 200±150 μm, preferably 200±100 μm, more preferably 200±50 μm. In another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 300±250 μm, preferably 300±200 μm, more preferably 300±150 μm, still more preferably 300±100 μm, and yet more preferably 300±50 μm. In still another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 400±350 μm, preferably 400±300 μm, more preferably 400±250 μm, still more preferably 400±200 μm, yet more preferably 400±150 μm, even more preferably 400±100 μm, and most preferably 400±50 μm. In yet another preferred embodiment, the total thickness of the pharmaceutical patch is within the range of 500±400 μm, preferably 500±350 μm, more preferably 500±300 μm, still more preferably 500±250 μm, yet more preferably 500±200 μm, even more preferably 500±150 μm, most preferably 500±100 μm, and in particular 500±50 μm. In preferred embodiments, the aforementioned values include the removable protective layer. In another preferred embodiment, the aforementioned values exclude the removable protective layer.
In a preferred embodiment, the adhesive layer comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.
In a preferred embodiment, the adhesive layer is adjacent to the removable protective layer and/or to the surface layer. Preferably, the adhesive layer is adjacent to the removable protective layer and to the surface layer. In a particularly preferred embodiment, the pharmaceutical patch is composed of the surface layer, the adhesive layer, and the removable protective layer and does not contain any additional layer.
In another preferred embodiment, the pharmaceutical patch further comprises at least one drug layer, which comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.
Preferably, the drug layer comprises at least 10 wt.-%, more preferably at least 25 wt.-%, still more preferably at least 50 wt.-%, yet more preferably at least 75 wt.-%, even more preferably at least 85 wt.-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-% of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. In an especially preferred embodiment, the drug layer comprises the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. A skilled person recognizes that when the drug layer is not identical with the adhesive layer, a certain amount of the pharmacologically active ingredient migrates from the drug layer into the adjacent drug permeable layer(s) for thermodynamic reasons until an equilibrium has been reached. Thus, even if the material forming the adhesive layer did not contain any pharmacologically active ingredient when the pharmaceutical patch was manufactured, the final product typically does contain pharmacologically active ingredient not only in the drug layer but also in the adhesive layer.
In a preferred embodiment, the drug layer is located between the adhesive layer and the surface layer. The drug layer may be separated from the adhesive layer by a membrane or may be in intimate contact with, i.e. adjacent to the adhesive layer.
In a preferred embodiment, the drug layer comprises a portion of the total amount of the pharmacologically active ingredient and the adhesive layer comprises another portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.
In another preferred embodiment, the adhesive layer does not comprise any pharmacologically active ingredient upon manufacture of the pharmaceutical patch, whereas typically there is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium between the drug permeable layers has been reached. Preferably, when the pharmaceutical patch comprises a drug layer that is separate from the adhesive layer, the drug layer is located between the adhesive layer and the surface layer, in particular adjacent to the adhesive layer. In another preferred embodiment, the drug layer and at least a part of the adhesive layer are both in contact with the same side of the removable protective layer, wherein the area of the drug layer is preferably smaller than the area of the removable protective layer. The adhesive layer may either overlap with the drug layer or be only present in that part of the removable protective layer that is not in contact with the drug layer, for example by forming a ring or a frame around the drug layer.
In a preferred embodiment, the material of the adhesive layer only covers a portion of the adjacent layer(s), e.g. assumes the form of a grid or any other suitable pattern.
The drug layer may be present in form of a liquid, a semisolid, or a solid polymer matrix.
In a preferred embodiment, the drug layer comprises a liquid containing the pharmacologically active ingredient in form of a solution or suspension.
In another preferred embodiment, the drug layer is a semisolid, such as a gel, or a solid polymer matrix wherein the pharmacologically active ingredient is dispersed.
In a preferred embodiment, the total amount of the pharmacologically active ingredient is present in molecular dispersed form.
In another preferred embodiment, only a portion of the pharmacologically active ingredient is present in molecular dispersed form, while the remainder of the pharmacologically active ingredient is present is non-molecular dispersed form (e.g. in form of droplets, crystals and the like) serving the purpose of a depot, also called “microreservoir”.
The pharmacologically active ingredient according to the invention, i.e. (1r,4r)-6′-fluoro-N,N-dimethyl-4-phenyl-4′,9′-dihydro-3′H-spiro[cyclohexane-1,1′-pyrano[3,4-b]indol]-4-amine (free base), has the following structural formula (I):
The pharmacologically active ingredient (free base) can alternatively be referred to as “1,1-(3-dimethylamino-3-phenylpentamethylene)-6-fluoro-1,3,4,9-tetrahydropyrano[3,4-b]indole (trans)”. Unless expressly stated otherwise, all quantities refer to the weight of the free base.
The pharmacologically active ingredient can be present in the pharmaceutical patch according to the invention in form of the free base or as derivative thereof in any possible form, thereby particularly including solvates and polymorphs, salts, in particular acid addition salts and corresponding solvates and polymorphs. The hemicitrate is a preferred example of an acid addition salt.
The pharmacologically active ingredient can be present in the pharmaceutical patch according to the invention in form of the free base or in form of an acid addition salt, whereby any suitable acid capable of forming such an addition salt may be used. The conversion of the pharmacologically active ingredient into a corresponding addition salt, for example, via reaction with a suitable acid may be effected in a manner well known to those skilled in the art. Suitable acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid and/or aspartic acid. Salt formation is preferably effected in a solvent, for example, diethyl ether, diisopropyl ether, alkyl acetates, acetone and/or 2-butanone. Moreover, trimethylchlorosilane in aqueous solution is also suitable for the preparation of hydrochlorides.
Preferably, however, the pharmacologically active ingredient is present in form of the free base. It has been found that the transdermal bioavailability of the pharmacologically active ingredient in form of the free base is substantially higher (about 2-3 times higher) than the bioavailability of its hemicitrate.
Preferably, the pharmacologically active ingredient is contained in the adhesive layer, while a certain portion of the pharmacologically active ingredient may be contained in the adjacent layers e.g. due to migration and/or diffusion. Preferably, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 0.10 wt.-%, more preferably at least 0.20 wt.-%, still more preferably at least 0.30 wt.-%, yet more preferably at least 0.40 wt.-%, even more preferably at least 0.50 wt.-%, most preferably at least 0.60 wt.-% and in particular at least 0.70 wt.-%, relative to the total weight of the adhesive layer.
For the purpose of the specification, unless expressly stated otherwise, all weight percentages relate to the total weight of the pharmaceutical patch or to the total weight of a specific layer thereof in terms of total per dry unit. In this regard, “dry unit” shall encompass all constituents, irrespective of whether they are present in solid, semisolid or liquid form, but shall not encompass volatile solvents that are evaporated in course of the preparation of the pharmaceutical patch such as ethanol, heptane, ethyl acetate and the like. Thus, “dry unit” shall merely encompass the residual content of volatile solvent(s), if any.
In a preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 1.00 wt.-%, more preferably at least 1.25 wt.-%, still more preferably at least 1.50 wt.-%, yet more preferably at least 1.75 wt.-%, even more preferably at least 2.00 wt.-%, most preferably at least 2.25 wt.-% and in particular at least 2.50 wt.-%, relative to the total weight of the adhesive layer. In another preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 2.75 wt.-%, more preferably at least 3.00 wt.-%, still more preferably at least 3.25 wt.-%, yet more preferably at least 3.50 wt.-%, even more preferably at least 3.75 wt.-%, most preferably at least 4.00 wt.-% and in particular at least 4.25 wt.-%, relative to the total weight of the adhesive layer. In still another preferred embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer is at least 4.50 wt.-%, more preferably at least 4.75 wt.-%, still more preferably at least 5.00 wt.-%, yet more preferably at least 5.25 wt.-%, even more preferably at least 5.50 wt.-%, most preferably at least 5.75 wt.-% and in particular at least 6.00 wt.-%, relative to the total weight of the adhesive layer.
It is principally desirable to provide the pharmacologically active ingredient in the adhesive layer at comparatively high concentrations, as this may positively influence the flux rate. As there is evidence, however, that the pharmacologically active ingredient tends to recrystallize at high concentrations, the concentration of the pharmacologically active ingredient in the adhesive layer is preferably at most 7.50 wt.-%, more preferably at most 5.00 wt.-%, still more preferably at most 2.50 wt.-%, yet more preferably at most 2.00 wt.-%, even more preferably at most 1.50 wt.-%, most preferably at most 1.00 wt.-%, and in particular at most 0.80 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).
The total dose of the pharmacologically active ingredient that is contained in the pharmaceutical patch is not particularly limited and may depend upon various factors such as body weight of the subject to be treated and duration of application on the skin. The pharmacologically active ingredient is contained in the pharmaceutical patch in a therapeutically effective amount. The amount that constitutes a therapeutically effective amount varies according to the form of the pharmacologically active ingredient being present, the condition being treated, the severity of said condition, the patient being treated, and the prescribed duration of application of the pharmaceutical patch to the skin.
In a preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 20±15 μg (i.e. from 5 μg to 35 μg), more preferably 20±12.5 μg, still more preferably 20±10 μg, most preferably 20±7.5 μg, and in particular 20±5 μg is systemically administered per day.
In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 40±35 μg, more preferably 40±30 μg, still more preferably 40±25 μg, yet more preferably 40±20 μg, even more preferably 40±15 μg, most preferably 40±10 μg, and in particular 40±5 μg is systemically administered per day.
In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 60±45 μg, more preferably 60±35 μg, still more preferably 60±25 μg, yet more preferably 60±20 μg, even more preferably 60±15 μg, most preferably 60±10 μg, and in particular 60±5 μg is systemically administered per day.
In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 80±70 μg, more preferably 80±60 μg, still more preferably 80±50 μg, yet more preferably 80±40 μg, even more preferably 80±30 μg, most preferably 80±20 μg, and in particular 80±10 μg is systemically administered per day.
In still another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 160±140 μg, more preferably 160±120 μg, still more preferably 160±100 μg, yet more preferably 160±80 μg, even more preferably 160±60 μg, most preferably 160±40 μg, and in particular 160±20 μg is systemically administered per day.
In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 280±250 μg, more preferably 280±200 μg, still more preferably 280±150 μg, yet more preferably 280±100 μg, even more preferably 280±75 μg, most preferably 280±50 μg, and in particular 280±25 μg is systemically administered per day.
In yet another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 400±350 μg, more preferably 400±300 μg, still more preferably 400±250 μg, yet more preferably 400±200 μg, even more preferably 400±150 μg, most preferably 400±100 μg, and in particular 400±50 μg is systemically administered per day.
In another preferred embodiment, the pharmaceutical patch contains the pharmacologically active ingredient in a quantity so that during 12 hours or during 24 hours or during 48 hours or during 72 hours or during 96 hours or even during 168 hours of consecutive application of a series of pharmaceutical patches to the skin, i.e. under steady state conditions taking into account the depot effect of the skin, an amount of 600±400 μg, more preferably 600±300 μg, still more preferably 600±200 μg, yet more preferably 600±150 μg, even more preferably 600±100 μg, most preferably 600±75 μg, and in particular 600±50 μg is systemically administered per day.
Preferably, the total dose of the pharmacologically active ingredient that is contained in the pharmaceutical patch satisfies the following requirement:
In a preferred embodiment, the desired daily dose amounts to 20±15 μg (i.e. from 5 μg to 35 μg), more preferably 20±10 μg; or 40±20 μg, more preferably 40±10 μg; or 80±40 μg, more preferably 80±20 μg; or 160±80 μg, more preferably 160±40 μg; or 400±200 μg, more preferably 400±100 μg. The intended duration of application is preferably 1, 2, 3, 4, 5, 6, or 7 days. The bioavailability is preferably as high as possible and can be determined for a given pharmaceutical patch by routine experimentation.
Preferably, the transdermal bioavailability is within the range of 2.0±1.8% (i.e. from 0.2% to 3.8%), more preferably 2.0±1.6%, still more preferably 2.0±1.4%, yet more preferably 2.0±1.2%, even more preferably 2.0±1.0%, most preferably 2.0±0.8%, and in particular 2.0±0.6%. In a preferred embodiment, the transdermal bioavailability is within the range of 5.0±4.5%, more preferably 5.0±4.0%, still more preferably 5.0±3.5%, yet more preferably 5.0±3.0%, even more preferably 5.0±2.5%, most preferably 5.0±2.0%, and in particular 5.0±1.5%. In another preferred embodiment, the transdermal bioavailability is within the range of 10±8.0%, more preferably 10±7.0%, still more preferably 10±6.0%, yet more preferably 10±5.0%, even more preferably 10±4.0%, most preferably 10±3.0%, and in particular 10±2.0%. In still another preferred embodiment, the transdermal bioavailability is within the range of 15±13%, more preferably 15±11%, still more preferably 15±9.0%, yet more preferably 15±7.0%, even more preferably 15±6.0%, most preferably 15±5.0%, and in particular 15±4.0%. In yet another preferred embodiment, the transdermal bioavailability is within the range of 20±18%, more preferably 20±16%, still more preferably 20±14%, yet more preferably 20±12%, even more preferably 20±10%, most preferably 20±8.0%, and in particular 20±6.0%.
Preferably, the area concentration of the pharmacologically active ingredient in the adhesive layer and the drug layer, respectively, is within the range of from 0.01 to 10 g/m2.
In a preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 0.20±0.18 g/m2 (i.e. from 0.02 g/m2 to 0.38 g/m2), more preferably 0.20±0.15 g/m2, still more preferably 0.20±0.13 g/m2, yet more preferably 0.20±0.10 g/m2, even more preferably 0.20±0.08 g/m2, most preferably 0.20±0.05 g/m2, and in particular 0.20±0.03 g/m2.
In another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 0.40±0.35 g/m2, more preferably 0.40±0.30 g/m2, still more preferably 0.40±0.25 g/m2, yet more preferably 0.40±0.20 g/m2, even more preferably 0.40±0.15 g/m2, most preferably 0.40±0.10 g/m2, and in particular 0.40±0.05 g/m2. In still another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 1.00±0.85 g/m2, more preferably 1.00±0.80 g/m2, still more preferably 1.00±0.75 g/m2, yet more preferably 1.00±0.70 g/m2, even more preferably 1.00±0.65 g/m2, most preferably 1.00±0.60 g/m2, and in particular 1.00±0.55 g/m2. In yet another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 3.00±2.50 g/m2, more preferably 3.00±2.25 g/m2, still more preferably 3.00±2.00 g/m2, yet more preferably 3.00±1.75 g/m2, even more preferably 3.00±1.50 g/m2, most preferably 3.00±1.25 g/m2, and in particular 3.00±1.00 g/m2. In another preferred embodiment, the area concentration of the pharmacologically active ingredient is within the range of 6.00±5.00 g/m2, more preferably 6.00±4.50 g/m2, still more preferably 6.00±4.00 g/m2, yet more preferably 6.00±3.50 g/m2, even more preferably 6.00±3.00 g/m2, most preferably 6.00±2.50 g/m2, and in particular 6.00±2.00 g/m2.
In a preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of at least 1.0 ng·cm−2·h−1 or at least 2.5 ng·cm−2·h−1 or at least 5.0 ng·cm−2·h−1; still more preferably at least 7.5 ng·ng·h−1 or at least 10 ng·cm−2 2·h−1 or at least 15 ng·cm−2·h−1; still more preferably at least 25 ng·cm−2·h−1 or at least 50 ng·cm−2·h−1 or at least 75 ng·cm−2·h−1; yet more preferably at least 100 ng·cm−2·h−1 or at least 150 ng·cm−2·h−1 or at least 200 ng·cm−2·h−1; even more preferably at least 250 ng·cm−2·h−1 or at least 300 ng·cm−2·h−1 or at least 350 ng·cm−2·h−1; most preferably at least 400 ng·cm−2·h−1 or at least 450 ng·cm−2·h−1 or at least 500 ng·h−1; and in particular at least 550 ng·cm−2·h−1 or at least 600 ng·cm−2·h−1 or at least 650 ng·cm−2·h−1.
In a preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 5.0±4.6 ng·cm−2·h−1 (i.e. from 0.4 ng·cm−2·h−1 to 9.6 ng·cm−2·h−1), more preferably 5.0±4.2 ng·cm−2·h−1, still more preferably 5.0±3.8 ng·cm−2·h−1, yet more preferably 5.0±3.4 ng·cm−2·h−1, even more preferably 5.0±3.0 ng·cm−2·h−1, most preferably 5.0±2.6 ng·cm−2·h−1 and oin particular 5.0±2.2 ng·cm−2·h−1.
In another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 50±46 ng·cm−2·h−1, more preferably 50±42 ng·cm−2·h−1, still more preferably 50±38 ng·cm−2·h−1, yet more preferably 50±34 ng·cm−2·h−1, even more preferably 50±30 ng·cm−2·h−1, most preferably 50±26 ng·cm−2·h−1 and in particular 50±22 ng·cm−2·h−1.
In still another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 500±460 ng·cm−2·h−1, more preferably 500±420 ng·cm−2·h−1, still more preferably 500±380 ng·cm−2·h−1, yet more preferably 500±340 ng·cm−2·h−1, even more preferably 500±300 ng·cm−2·h−1, most preferably 500±260 ng·cm−2·h−1 and in particular 500±220 ng·cm−2·h−1.
In yet another preferred embodiment, the pharmaceutical patch upon application to the human skin provides over a period of at least 6 hours, more preferably at least 12 hours, release of the pharmacologically active ingredient at a rate of 5000±4600 ng·cm−2·h−1, more preferably 5000±4200 ng·cm−2·h−1, still more preferably 5000±3800 ng·cm−2·h−1, yet more preferably 5000±3400 ng·cm−2·h−1, even more preferably 5000±3000 ng·cm−2·h−1, most preferably 5000±2600 ng·cm−2·h−1 and in particular 5000±2200
In a preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of at least 10 pg·ml−1, at least 25 pg·ml−1 or at least 50 pg·ml−1; more preferably at least 75 pg·ml−1, at least 100 pg·ml−1 or at least 150 pg·ml−1; still more preferably at least 200 pg·ml−1, at least 250 pg·ml−1 or at least 300 pg·ml−1; yet more preferably at least 350 pg·ml−1, at least 400 pg·ml−1 or at least 450 pg·ml−1; even more preferably at least 500 pg·ml−1, at least 550 pg·ml−1 or at least 600 pg·ml−1; most preferably at least 650 pg·ml−1, at least 700 pg·ml−1 or at least 750 pg·ml−1; and in particular at least 800 pg·ml−1, at least 850 pg·ml−1 or at least 900 pg·ml−1.
In a preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 10±8.0 pg·ml−1, more preferably 10±7.0 pg·ml−1, still more preferably 10±6.0 pg·ml−1, yet more preferably 10±5.0 pg·ml−1, even more preferably 10±4.0 pg·ml−1, most preferably 10±3.0 pg·ml−1, and in particular 10±2.0 pg·ml−1.
In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 20±16 pg·ml−1, more preferably 20±14 pg·ml−1, still more preferably 20±12 pg−ml−1, yet more preferably 20±10 pg−ml−1, even more preferably 20±8.0 pg−ml−1, most preferably 20±6.0 pg·ml−1, and in particular 20±4.0 pg·ml−1.
In still another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 40±32 pg·ml−1, more preferably 40±28 pg·ml−1, still more preferably 40±24 pg·ml−1, yet more preferably 40±20 pg·ml−1, even more preferably 40±16 pg·ml−1, most preferably 40±12 pg·ml−1, and in particular 40±8.0 pg·ml−1.
In yet another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 75±64 pg·ml−1, more preferably 75±56 pg·ml−1, still more preferably 75±48 pg·ml−1, yet more preferably 75±40 pg·ml−1, even more preferably 75±32 pg·ml−1, most preferably 75±24 pg·ml−1, and in particular 75±16 pg·ml−1.
In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 150±128 pg·ml−1, more preferably 150±112 pg·ml−1, still more preferably 150±96 pg·ml−1, yet more preferably 150±80 pg·ml−1, even more preferably 150±64 pg·ml−1, most preferably 150±48 pg·ml−1, and in particular 150±32 pg·ml−1.
In still another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 300±256 pg·ml−1, more preferably 300±224 pg·ml−1, still more preferably 300±192 pg·ml−1, yet more preferably 300±160 pg·ml−1, even more preferably 300±128 pg·ml−1, most preferably 300±96 pg·ml−1, and in particular 300±64 pg·ml−1.
In yet another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of 600±512 pg·ml−1, more preferably 600±448 pg·ml−1, still more preferably 600±384 pg·ml−1, yet more preferably 600±320 pg·ml−1, even more preferably 600±256 pg·ml−1, most preferably 600±192 pg·ml−1, and in particular 600±128 pg·ml−1.
In another preferred embodiment, the pharmaceutical patch according to the invention provides plasma concentrations of the pharmacologically active ingredient over a period of at least 6 hours, more preferably at least 12 hours upon repeated application to the human skin, i.e. under steady state conditions taking into account the depot effect of the skin, of at least 1.0 ng·ml−1, at least 2.5 ng·ml−1 or at least 5.0 ng·ml−1; more preferably at least 7.5 ng·ml−1, at least 10.0 ng·ml−1 or at least 15.0 ng·ml−1; still more preferably at least 20.0 ng·ml−1, at least 25.0 ng·ml−1 or at least 30.0 ng·ml−1; yet more preferably at least 35.0 ng·ml−1, at least 40.0 ng·ml−1 or at least 45.0 ng·ml−1; even more preferably at least 50.0 ng·ml−1, at least 55.0 ng·ml−1 or at least 60.0 ng·ml−1; most preferably at least 65.0 ng·ml−1, at least 70.0 ng·ml−1 or at least 75.0 ng·ml−1; and in particular at least 80.0 ng·ml−1, at least 85.0 ng·ml−1 or at least 90.0 ng·ml−1.
The pharmaceutical patch according to the invention preferably contains a crystallization inhibitor which inhibits the crystallization of the pharmacologically active ingredient within the adhesive layer and drug layer, respectively. Thus, the crystallization inhibitor is preferably contained in the same layer as the pharmacologically active ingredient. Preferably, the content of the crystallization inhibitor within said layer is within the range of from 1.0 to 20 wt.-%, more preferably 2.5 to 17.5 wt.-%, still more preferably 5.0 to 15 wt.-%, yet more preferably 6.0 to 14 wt.-%, even more preferably 7.0 to 13 wt.-%, most preferably 8.0 to 12 wt.-%, and in particular 9.0 to 11 wt.-%, relative to the total weight of said layer. Preferred crystallization inhibitors include but are not limited to polyvinylpyrrolidones (povidone, polyvidone) (e.g. Kollidon 25), N-vinyl-1-aza-cycloheptan-2-one homopolymers, N-vinylpiperidin-2-one homopolymers, polyethylene glycol, poloxamer (e.g. Lutrol F127), and copovidone (e.g. Kollidon VA64).
Preferably, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of from 1000:1 to 1:1000, more preferably 250:1 to 1:250, still more preferably 100:1 to 1:100, yet more preferably 50:1 to 1:50, even more preferably 25:1 to 1:25, most preferably 10:1 to 1:10, and in particular 5:1 to 1:5.
In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:10±7 (i.e. from 1:3 to 1:17), more preferably 1:10±6, still more preferably 1:10±5, yet more preferably 1:10±4, even more preferably 1:10±3, most preferably 1:10±2, and in particular 1:10±1. In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:20±14, more preferably 1:20±12, still more preferably 1:20±10, yet more preferably 1:20±8, even more preferably 1:20±6, most preferably 1:20±4, and in particular 1:20±2. In another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:45±37, more preferably 1:45±35, still more preferably 1:45±33, yet more preferably 1:45±31, even more preferably 1:45±29, most preferably 1:45±27, and in particular 1:45±25. In still another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:70±42, more preferably 1:70±36, still more preferably 1:70±30, yet more preferably 1:70±24, even more preferably 1:70±18, most preferably 1:70±12, and in particular 1:70±6. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:90±70, more preferably 1:90±60, still more preferably 1:90±50, yet more preferably 1:90±40, even more preferably 1:90±30, most preferably 1:90±20, and in particular 1:90±10. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the crystallization inhibitor is within the range of 1:110±70, more preferably 1:110±60, still more preferably 1:110±50, yet more preferably 1:110±40, even more preferably 1:110±30, most preferably 1:110±20, and in particular 1:110±10.
The pharmaceutical patch according to the invention preferably contains a permeation component which enhances percutaneous penetration and permeation of the pharmacologically active ingredient through human skin, i.e. one or more percutaneous penetration enhancers. Percutaneous penetration enhancers are known to the skilled person (cf., e.g., Smith et al., Percutaneous Penetration Enhancers, CRC Press, 1995).
Preferably, the layer of the pharmaceutical patch which contains the pharmacologically active ingredient, i.e. the adhesive layer and/or the drug layer, contains at least one percutaneous penetration enhancer.
Preferably, the relative weight ratio of the pharmacologically active ingredient to the permeation component is within the range of from 25:1 to 1:1000, more preferably 10:1 to 1:250, still more preferably 5:1 to 1:100, yet more preferably 1:1 to 1:50, even more preferably 1:2 to 1:25, most preferably 1:6 to 1:20, and in particular 1:9 to 1:17.
Preferably, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of from 1000:1 to 1:1000, more preferably 250:1 to 1:250, still more preferably 100:1 to 1:100, yet more preferably 50:1 to 1:50, even more preferably 25:1 to 1:25, most preferably 10:1 to 1:10, and in particular 5:1 to 1:5.
In a preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:20±14 (i.e. from 1:6 to 1:34), more preferably 1:20±12, still more preferably 1:20±10, yet more preferably 1:20±8, even more preferably 1:20±6, most preferably 1:20±4, and in particular 1:20±2. In another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:45±37, more preferably 1:45±35, still more preferably 1:45±33, yet more preferably 1:45±31, even more preferably 1:45±29, most preferably 1:45±27, and in particular 1:45±25. In still another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:70±42, more preferably 1:70±36, still more preferably 1:70±30, yet more preferably 1:70±24, even more preferably 1:70±18, most preferably 1:70±12, and in particular 1:70±6. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:90±70, more preferably 1:90±60, still more preferably 1:90±50, yet more preferably 1:90±40, even more preferably 1:90±30, most preferably 1:90±20, and in particular 1:90±10. In yet another preferred embodiment, the molar ratio of the pharmacologically active ingredient to the permeation component is within the range of 1:110±70, more preferably 1:110±60, still more preferably 1:110±50, yet more preferably 1:110±40, even more preferably 1:110±30, most preferably 1:110±20, and in particular 1:110±10.
Preferably, the permeation component is contained in the same layer of the pharmaceutical patch that also contains the pharmacologically active ingredient or at least a portion thereof. Preferably, the content of the permeation component within said layer is within the range of from 1.0 to 20 wt.-%, more preferably 2.5 to 17.5 wt.-%, still more preferably 5.0 to 15 wt.-%, yet more preferably 6.0 to 14 wt.-%, even more preferably 7.0 to 13 wt.-%, most preferably 8.0 to 12 wt.-%, and in particular 9.0 to 11 wt.-%, relative to the total weight of said layer.
In a preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 4.0±3.5 (i.e. from 0.5 to 7.5), more preferably 4.0±3.0, still more preferably 4.0±2.5, yet more preferably 4.0±2.0, even more preferably 4.0±1.5, most preferably 4.0±1.0, and in particular 4.0±0.5. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 8±7, more preferably 8±6, still more preferably 8±5, yet more preferably 8±4, even more preferably 8±3, most preferably 8±2, and in particular 8±1. In still another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 12±7, more preferably 12±6, still more preferably 12±5, yet more preferably 12±4, even more preferably 12±3, most preferably 12±2, and in particular 12±1. In yet another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 16±7, more preferably 16±6, still more preferably 16±5, yet more preferably 16±4, even more preferably 16±3, most preferably 16±2, and in particular 16±1. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 20±7, more preferably 20±6, still more preferably 20±5, yet more preferably 20±4, even more preferably 20±3, most preferably 20±2, and in particular 20±1. In another preferred embodiment, the permeation component comprises at least one percutaneous penetration enhancer having a HLB value (hydrophilic-lipophilic balance) within the range of 24±7, more preferably 24±6, still more preferably 24±5, yet more preferably 24±4, even more preferably 24±3, most preferably 24±2, and in particular 24±1.
Preferred percutaneous penetration enhancers include but are not limited to:
Preferably, the permeation component comprises as percutaneous penetration enhancer a non-cyclic compound of formula C2nH4n+2On, where index n is 2, 3 or 4; preferably diethylene glycol monomethylether, dipropylene glycol or a mixture thereof.
Preferably, the permeation component comprises one or more percutaneous penetration enhancers selected from transcutol (diethylene glycol monoethylether), oleyl alcohol, dipropylene glycol, levulinic acid and mixtures thereof.
Preferably, the pharmaceutical patch has an area of at least 5 cm2, more preferably at least 7.5 cm2, still more preferably at least 10 cm2, and most preferably at least 15 cm2.
In a preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 200±150 cm2 (i.e. from 50 cm2 to 350 cm2), more preferably 200±125 cm2, still more preferably 200±100 cm2, yet more preferably 200±75 cm2, even more preferably 150±50 cm2, most preferably 150±25 cm2, and in particular 150±10 cm2. In another preferred embodiment, the pharmaceutical patch has an area within the range of 300±150 cm2, more preferably 300±125 cm2, still more preferably 300±100 cm2, yet more preferably 300±75 cm2, even more preferably 300±50 cm2, most preferably 300±25 cm2, and in particular 300±10 cm2. In still another preferred embodiment, the pharmaceutical patch has an area within the range of 400±150 cm2, more preferably 400±125 cm2, still more preferably 400±100 cm2, yet more preferably 400±75 cm2, even more preferably 400±50 cm2, most preferably 400±25 cm2, and in particular 400±10 cm2.
In a preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 25±20 cm2, more preferably 25±15 cm2, still more preferably 25±10 cm2. In another preferred embodiment, the pharmaceutical patch has an area, i.e. total surface area when being applied to the skin, within the range of 50±40 cm2, more preferably 50±35 cm2, still more preferably 50±30 cm2, yet more preferably 50±25 cm2, even more preferably 50±20 cm2, most preferably 50±15 cm2, and in particular 50±10 cm2. In still another preferred embodiment, the pharmaceutical patch has an area within the range of 75±40 cm2, more preferably 75±35 cm2, still more preferably 75±30 cm2, yet more preferably 75±25 cm2, even more preferably 75±20 cm2, most preferably 75±15 cm2, and in particular 75±10 cm2. In yet another preferred embodiment, the pharmaceutical patch has an area within the range of 100±80 cm2, more preferably 100±60 cm2, still more preferably 100±50 cm2, yet more preferably 100±40 cm2, even more preferably 100±30 cm2, most preferably 100±20 cm2, and in particular 100±10 cm2. In another preferred embodiment, the pharmaceutical patch has an area within the range of 150±80 cm2, more preferably 150±60 cm2, still more preferably 150±50 cm2, yet more preferably 150±40 cm2, even more preferably 150±30 cm2, most preferably 150±20 cm2, and in particular 150±10 cm2. In another preferred embodiment, the pharmaceutical patch has an area within the range of 200±80 cm2, more preferably 200±60 cm2, still more preferably 200±50 cm2, yet more preferably 200±40 cm2, even more preferably 200±30 cm2, most preferably 200±20 cm2, and in particular 200±10 cm2. In another preferred embodiment, the pharmaceutical patch has an area within the range of 250±80 cm2, more preferably 250±60 cm2, still more preferably 250±50 cm2, yet more preferably 250±40 cm2, even more preferably 250±30 cm2, most preferably 250±20 cm2, and in particular 250±10 cm2.
The pharmaceutical patch according to the invention comprises a surface layer.
The term “surface layer” as used herein refers to any layer that represents the surface layer after the application of the pharmaceutical patch. This definition includes permanent backing layer commonly used for pharmaceutical patches as well as thin non-removable films that are typically used in thin flexible patches.
In a preferred embodiment, the surface layer comprises one or more polymers selected from the group consisting of polyurethanes, polyester elastomers, polyether block amides, polyacrylates, ethylene vinyl acetates, ethylene acrylate copolymers, ionomer resins, polyvinyl chloride, polyvinylidene chloride, polyesters and polyolefins, such as polyethylene; polyolefins, in particular polyethylene, polyesters, ethylene vinylacetate copolymers and polyurethanes are particularly preferred.
The surface layer may be a laminate, preferably comprising a polymer film, such as a polyester film, and aluminum foil and/or heat seal layer.
In a preferred embodiment, the surface layer consists of a polyester film and an ethylene vinylacetate copolymer heat seal layer.
The thickness of the surface layer is not particularly limited. Preferably, the surface layer has a thickness within the range of from 0.1 to 5000 μm. In a preferred embodiment, the surface layer has a thickness within the range of from 0.5 to 1000 μm, more preferably from 1 to 750 μm, still more preferably from 5 to 500 μm, most preferably from 10 to 250 μm, and in particular from 20 to 150 μm or from 40 to 100 μm.
In a preferred embodiment, the surface layer has a thickness within the range of 25±20 μm (i.e. from 5 μm to 45 μm), more preferably 25±15 μm, still more preferably 25±10 μm, and yet more preferably 25±5 μm.
The pharmaceutical patch according to the invention comprises a removable protective layer (release liner).
Preferably, the removable protective layer comprises a polymer film and a silicone coating or fluoropolymer coating. Preferably, the polymer film is a polyolefin, in particular polyethylene or polypropylene film or polyester, in particular polyethylene terephthalate film.
In a preferred embodiment, the removable protective layer is a silicone coated polyolefin or silicone coated polyester film, such as a silicone coated polyethylene terephthalate, polypropylene or polyethylene film.
In another preferred embodiment, the removable protective layer is a fluoropolymer coated polyolefin or polyester film, such as a fluoropolymer coated polyethylene terephthalate, polypropylene or polyethylene film.
The thickness of the removable protective layer is not particularly limited. Preferably, the removable protective layer has a thickness within the range of from 0.1 to 500 μm. In a preferred embodiment, the removable protective layer has a thickness within the range of from 0.5 to 400 μm, more preferably from 1 to 300 μm, still more preferably from 5 to 250 μm, most preferably from 10 to 200 μm, and in particular from 20 to 150 μm or from 40 to 100 μm.
In a preferred embodiment, the removable protective layer has a thickness within the range of 75±70 μm (i.e. from 5 μm to 145 μm), more preferably 75±60 μm, still more preferably 75±50 μm, yet more preferably 75±40 μm, even more preferably 75±30 μm, most preferably 75±20 μm, and in particular 75±10 μm. In another preferred embodiment, the removable protective layer has a thickness within the range of 100±70 μm, more preferably 100±60 μm, still more preferably 100±50 μm, yet more preferably 100±40 μm, even more preferably 100±30 μm, most preferably 100±20 μm, and in particular 100±10 μm.
The pharmaceutical patch according to the invention comprises an adhesive layer.
In a preferred embodiment, the adhesive layer comprises at least a portion of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch. Preferably, the adhesive layer comprises at least 10 wt.-%, more preferably at least 25 wt.-%, still more preferably at least 50 wt.-%, yet more preferably at least 75 wt.-%, most preferably at least 90 wt.-%, and in particular at least 95 wt.-% of the total amount of the pharmacologically active ingredient that is contained in the pharmaceutical patch.
In another preferred embodiment, the adhesive layer does not contain the pharmacologically active ingredient. According to this embodiment, the pharmaceutical patch comprises an additional drug layer that in turn contains the total amount or at least a portion of the pharmacologically active ingredient, taking into account that after manufacture there typically is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium has been reached.
Preferably, the adhesive layer comprises a polymer that forms a matrix in which the pharmacologically active ingredient is dispersed (drug-in-adhesive).
Preferably, the adhesive layer comprises a pressure sensitive adhesive selected from the group consisting of polysilicone based pressure sensitive adhesives, polyacrylate based pressure sensitive adhesives, polyisobutylene based pressure sensitive adhesives, and styrenic rubber based pressure sensitive adhesives.
The thickness of the adhesive layer is not particularly limited and may depend upon a number of factors such as function within the patch (e.g. drug-in-adhesive), content of pharmacologically active ingredient and excipients, prescribed duration of application of pharmaceutical patch on the skin, and the like.
Preferably, the adhesive layer has a thickness within the range of from 1.0 to 1000 μm.
In a preferred embodiment, the adhesive layer has a thickness within the range of from 50±35 μm (i.e. from 15 μm to 85 μm), more preferably 50±30 μm, still more preferably 50±25 μm, yet more preferably 50±20 μm, even more preferably 50±15 μm, most preferably 50±10 μm, and in particular 50±5 μm. In another preferred embodiment, the adhesive layer has a thickness within the range of from 75±70 μm, more preferably 75±60 μm, still more preferably 75±50 μm, yet more preferably 75±40 μm, even more preferably 75±30 μm, most preferably 75±20 μm, and in particular 75±10 μm. In still another preferred embodiment, the adhesive layer has a thickness within the range of from 100±70 μm, more preferably 100±60 μm, still more preferably 100±50 μm, yet more preferably 100±40 μm, even more preferably 100±30 μm, most preferably 100±20 μm, and in particular 100±10 μm. In yet another preferred embodiment, the adhesive layer has a thickness within the range of from 200±175 μm, more preferably 200±150 μm, still more preferably 200±125 μm, yet more preferably 200±100 μm, even more preferably 200±75 μm, most preferably 200±50 μm, and in particular 200±25 μm. In another preferred embodiment, the adhesive layer has a thickness within the range of from 300±175 μm, more preferably 300±150 μm, still more preferably 300±125 μm, yet more preferably 300±100 μm, even more preferably 300±75 μm, most preferably 300±50 μm, and in particular 300±25 μm. In still another preferred embodiment, the adhesive layer has a thickness within the range of from 400±175 μm, more preferably 400±150 μm, still more preferably 400±125 μm, yet more preferably 400±100 μm, even more preferably 400±75 μm, most preferably 400±50 μm, and in particular 400±25 μm. In yet another preferred embodiment, the adhesive layer has a thickness within the range of from 500±175 μm, more preferably 500±150 μm, still more preferably 500±125 μm, yet more preferably 500±100 μm, even more preferably 500±75 μm, most preferably 500±50 μm, and in particular 500±25 μm.
Preferably, particularly when the adhesive layer contains the pharmacologically active ingredient or a portion thereof, the area weight of the adhesive layer is within the range of from 1.0 to 160 g/m2, more preferably 5.0 to 125 g/m2 or 45 to 155 g/m2, still more preferably 10 to 100 g/m2 or 55 to 145 g/m2, yet more preferably 20 to 90 g/m2 or 65 to 135 g/m2, even more preferably 30 to 80 g/m2 or 75 to 125 g/m2, most preferably 40 to 70 g/m2 or 85 to 115 g/m2, and in particular 50 to 60 g/m2 or 95 to 105 g/m2.
In preferred embodiments a comparatively low area weight may positively influence the shelf-life of the pharmaceutical patch.
The ratio of the thickness of the surface layer to the thickness of the adhesive layer is not particularly limited. In a preferred embodiment, the thickness of the surface layer is greater than the thickness of the adhesive layer. In another preferred embodiment, the thickness of the adhesive layer is greater than the thickness of the surface layer.
In a preferred embodiment, the adhesive layer provides a peel strength of 5.5±5.0 N/25 mm, more preferably 5.5±4.5 N/25 mm, still more preferably 5.5±4.0 N/25 mm, yet more preferably 5.5±3.5 N/25 mm, even more preferably 5.5±3.0 N/25 mm, most preferably 5.5±2.5 N/25 mm, and in particular 5.5±2.0 N/25 mm.
In another preferred embodiment, the adhesive layer provides a peel strength of 2.0±1.8 N/25 mm, more preferably 2.0±1.6 N/25 mm, still more preferably 2.0±1.4 N/25 mm, yet more preferably 2.0±1.2 N/25 mm, even more preferably 2.0±1.0 N/25 mm, most preferably 2.0±0.8 N/25 mm, and in particular 2.0±0.6 N/25 mm.
Preferably, the peel test is performed as further specified in the experimental section.
In a preferred embodiment, the pressure sensitive adhesive is a polysilicone based pressure sensitive adhesive. Preferably, said polysilicone based pressure sensitive adhesive forms a matrix in which the pharmacologically active ingredient is embedded. Polysilicone based pressure sensitive adhesives are commercially available, e.g. under the trademarks BIO-PSA 7-4301, BIO-PSA 7-4302, BIO-PSA 7-4302/3, BIO-PSA 7-4201, BIO-PSA 7-4202, BIO-PSA 7-4101, BIO-PSA 7-4102, BIO-PSA 7-4601, BIO-PSA 7-4602, BIO-PSA 7-4602/3, BIO-PSA 7-4501, BIO-PSA 7-4502, BIO-PSA 7-4503, BIO-PSA 7-4401 and BIO-PSA 7-4402 by Dow Corning Corporation. The polysilicone based pressure sensitive adhesive preferably contains a solvent such as ethyl acetate or heptane and has a solids content of approx. 55-65 wt.-% solids before being dried during the preparation of the plaster. Especially preferred polysilicone based adhesives are commercially available by Dow Corning Corporation under the trademarks BIO PSA 7-4501 (solvent: heptane); BIO PSA 7-4502 (solvent: ethyl acetate); and BIO PSA 7-4503 (solvent: toluene).
In a preferred embodiment, the pressure sensitive adhesive is a polysilicone based pressure sensitive adhesive that is supplied in heptane or ethyl acetate. These solvents are typically removed during the manufacture of the pharmaceutical patch, though residual traces of solvent may be analytically detectable.
Preferably, the silicone polymers contained in the polysilicone based pressure sensitive adhesives are produced through a condensation reaction of a silanol endblocked polydimethylsiloxane (PDMS) with a silicate resin.
Preferably, the polysilicone based pressure sensitive adhesive provides a peel adhesion, preferably measured in accordance with Dow Corning Corp. corporate test method 0964A, of 300±200 g/cm (i.e. from 100 g/cm to 500 g/cm), more preferably 300±100 g/cm, still more preferably 300±50 g/cm; or 400±200 g/cm, more preferably 400±100 g/cm, still more preferably 400±50 g/cm; or 500±200 g/cm, more preferably 500±100 g/cm, still more preferably 500±50 g/cm; or 600±200 g/cm, more preferably 600±100 g/cm, still more preferably 600±50 g/cm; or 700±200 g/cm, more preferably 700±100 g/cm, still more preferably 700±50 g/cm; or 800±200 g/cm, more preferably 800±100 g/cm, still more preferably 800±50 g/cm; or 900±200 g/cm, more preferably 900±100 g/cm, still more preferably 900±50 g/cm.
In preferred embodiments polysilicone based pressure sensitive adhesives stabilize the pharmacologically active ingredient with respect to the formation of undesired degradation products. Formation of said degradation products can be suppressed especially when the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polysilicone based pressure sensitive adhesive is comparatively low.
According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polysilicone based pressure sensitive adhesive is preferably at most 1.00 wt.-%, more preferably at most 0.80 wt.-%, still more preferably at most 0.70 wt.-%, yet more preferably at most 0.60 wt.-%, even more preferably at most 0.50 wt.-%, most preferably at most 0.40 wt.-%, and in particular at most 0.30 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).
According to this embodiment, the adhesive layer preferably contains the pharmacologically active ingredient, the polysilicone based pressure sensitive adhesive and optional auxiliary substances (excipients) such as one or more percutaneous penetration enhancers, antioxidants, and the like.
According to this embodiment, the adhesive layer comprises the polysilicone based pressure sensitive adhesive preferably in combination with a permeation component, preferably comprising transcutol (diethylene glycol monoethylether), optionally in combination with dipropylene glycol. Preferably, the content of the transcutol and the optionally present dipropylene glycol is in each case independently of one another within the range of from 0.1 to 20 wt.-%, more preferably 0.2 to 15 wt.-%, still more preferably 0.5 to 10 wt.-%, yet more preferably 1.0 to 9.0 wt.-%, even more preferably 2.0 to 8.0 wt.-%, most preferably 3.0 to 7.0 wt.-%, and in particular 4.0 to 6.0 wt.-%, relative to the total weight of the adhesive layer. When dipropylene glycol is present as additional percutaneous penetration enhancer besides transcutol, the relative weight ratio of dipropylene glycol to transcutol is preferably within the range of from 10:1 to 1:10, more preferably 7.5:1 to 1:7.5, still more preferably 5:1 to 1:5, yet more preferably 4:1 to 1:4, even more preferably 3:1 to 1:3, most preferably 2:1 to 1:2, and in particular 1.5:1 to 1:1.5.
Preferred compositions of adhesive layers that comprise polysilicone based pressure sensitive adhesives are summarized as embodiments A1 to A12 in the table here below (all values as percentages relative to the total weight of the adhesive layer, total per dry unit):
It has been unexpectedly found that at concentrations within the range of from 0.20 to 0.30 wt.-%, relative to the total weight of the adhesive layer containing a silicone polymer (total per dry unit), the pharmacologically active ingredient can be formulated in dispersed form that exhibits a satisfactory shelf-life, i.e. that does not tend to recrystallize, and provides acceptable flux rates.
In another preferred embodiment, the pressure sensitive adhesive is an polyacrylate based pressure sensitive adhesive. Preferably, said polyacrylate based pressure sensitive adhesive forms a matrix in which the pharmacologically active ingredient is embedded. Polyacrylate based pressure sensitive adhesives are commercially available, e.g. under the trademark DuroTAK®, especially the 87 series, e.g. Duro-Tak® 87-202A; Duro-Tak® 87-208A; Duro-Tak® 87-502A; Duro-Tak® 87-503A; Duro-Tak® 87-2051; Duro-Tak® 87-2054; Duro-Tak® 87-2287; Duro-Tak® 87-2353; Duro-Tak® 87-2510; Duro-Tak® 87-2516; Duro-Tak® 87-4098; Duro-Tak® 87-4287; Duro-Tak® 87-9088; and Duro-Tak® 87-9301; or Duro-Tak® 387-2516.
When the pressure sensitive adhesive is an polyacrylate based pressure sensitive adhesive, e.g. Duro-Tak® 87-4287, it can contain a cationic copolymer based on dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate, e.g. EUDRAGIT® E PO. According to this embodiment, the weight amount of EUDRAGIT® E PO is preferably 0.01 to 70 wt.-%, more preferably 10±9 wt.-%, or 20±10 wt.-%, or 30±10 wt.-%, or 40±10 wt.-%, or 50±10 wt.-% relative to the total combined weight of the acrylate pressure sensitive adhesive and the EUDRAGIT® E PO.
The polyacrylate based pressure sensitive adhesive may contain one or more acrylate homopolymers or one or more acrylate copolymers or mixtures thereof.
For the purpose of the specification, “(meth)acryl” shall refer to both, methacryl as well as acryl.
In a preferred embodiment, the adhesive layer comprises an acrylate copolymer comprising monomer units originating from monomers A which are selected from C1-18-alkyl(meth)acrylates and monomers B which are copolymerizable with monomers A. Thus, the acrylate copolymer is derived from at least one monomer of the type of monomers A and at least one monomer of the type of monomers B.
In a preferred embodiment, the acrylate copolymer is derived from two different monomers (bipolymer), three different monomers (terpolymer) or four different monomers (quaterpolymer). Terpolymers are particularly preferred.
Preferred monomers A are selected from the group consisting of methyl (meth)acrylate, ethyl(meth)acrylate, propyl(meth)acrylate, butyl (meth)acrylate, pentyl(meth)acrylate, hexyl(meth)acrylate, cyclohexyl(meth)acrylate, octyl(meth)acrylate, isobornyl(meth)acrylate, and mixtures thereof. 2-Ethylhexyl(meth)acrylate is a preferred representative of an octyl(meth)acrylate.
Preferred monomers B are selected from the group consisting of 2-hydroxyethyl(meth)-acrylate, glyceryl mono(meth)acrylate, glycidyl(meth)acrylate, acrylamide, N,N-diethyl-(meth)acrylamide, 2-ethoxyethyl(meth)acrylate, 2-ethoxyethoxyethyl(meth)acrylate, tetra-hydrofuryl(meth)acrylate, vinyl acetate, N-vinyl pyrrolidone and mixtures thereof.
In a preferred embodiment, the acrylate copolymer is derived from a monomer composition comprising monomer units having at least one hydroxyl functional group, preferably selected from 2-hydroxyethyl(meth)acrylate and glyceryl mono(meth)acrylate.
In a particularly preferred embodiment, the acrylate copolymer is derived from a monomer composition comprising vinyl acetate, 2-ethylhexyl acrylate and 2-hydroxyethyl acrylate (terpolymer), optionally also comprising glycidyl methacrylate (quaterpolymer).
In another preferred embodiment, the acrylate copolymer that is contained in the adhesive layer does not comprise any monomer units having free hydroxyl functional groups.
Preferred embodiments B1 to B8 of acrylate copolymers that are preferably contained in the adhesive layer are summarized in the table here below:
It has been found that different acrylate copolymers, i.e. acrylate copolymers originating from different comonomers and/or different relative amounts of comonomers, have a different influence on the chemical stability of the pharmacologically active ingredient, its maximal concentration in dispersed form at a sufficient shelf-life as well as its flux rate.
According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polyacrylate based pressure sensitive adhesive is preferably at most 1.10 wt.-%, more preferably at most 1.05 wt.-%, still more preferably at most 1.00 wt.-%, yet more preferably at most 0.95 wt.-%, even more preferably at most 0.90 wt.-%, most preferably at most 0.85 wt.-%, and in particular at most 0.80 wt.-%, relative to the total weight of the adhesive layer (total per dry unit). According to this embodiment, the concentration of the pharmacologically active ingredient in the adhesive layer that comprises the polyacrylate based pressure sensitive adhesive is preferably at least 0.35 wt.-%, more preferably at least 0.40 wt.-%, still more preferably at least 0.45 wt.-%, yet more preferably at least 0.55 wt.-%, even more preferably at least 0.60 wt.-%, most preferably at least 0.65 wt.-%, and in particular at least 0.70 wt.-%, relative to the total weight of the adhesive layer (total per dry unit).
According to this embodiment, the adhesive layer preferably contains the pharmacologically active ingredient, the polyacrylate based pressure sensitive adhesive and optional auxiliary substances (excipients) such as one or more percutaneous penetration enhancers, antioxidants, and the like.
According to this embodiment, the adhesive layer comprises the polyacrylate based pressure sensitive adhesive preferably in combination with a crystallization inhibitor, preferably comprising polyvinylpyrrolidone (e.g. Kollidon 25), and/or in combination with a permeation component, preferably comprising dipropylene glycol, optionally in combination with or oleyl alcohol. The combination of dipropylene glycol (permeation enhancer) with polyvinylpyrrolidone (crystallization inhibitor) is most preferred. Preferably, the content of the dipropylene glycol and the optionally present polyvinylpyrrolidone and oleyl alcohol, respectively, is in each case independently of one another within the range of from 0.1 to 20 wt.-%, more preferably 0.2 to 15 wt.-%, still more preferably 0.5 to 10 wt.-%, yet more preferably 1.0 to 9.0 wt.-%, even more preferably 2.0 to 8.0 wt.-%, most preferably 3.0 to 7.0 wt.-%, and in particular 4.0 to 6.0 wt.-%, relative to the total weight of the adhesive layer. When polyvinylpyrrolidone is present as crystallization inhibitor and/or oleyl alcohol is present as additional percutaneous penetration enhancer besides dipropylene glycol, the relative weight ratio of dipropylene glycol to polyvinylpyrrolidone and oleyl alcohol, respectively, is preferably within the range of from 10:1 to 1:10, more preferably 7.5:1 to 1:7.5, still more preferably 5:1 to 1:5, yet more preferably 4:1 to 1:4, even more preferably 3:1 to 1:3, most preferably 2:1 to 1:2, and in particular 1.5:1 to 1:1.5.
It has been surprisingly found that the combination of dipropylene glycol as permeation enhancer and polyvinyl pyrrolidone (Kollidon 25) as crystallization inhibitor provides particularly beneficial permeation performance of the pharmacologically active ingredient through the skin, particularly in adhesive layers containing polyacrylate based pressure sensitive adhesives.
Preferred compositions of adhesive layers that comprise polyacrylate based pressure sensitive adhesives are summarized as embodiments C1 to C12 in the table here below (all values as percentages relative to the total weight of the adhesive layer, total per dry unit):
It has been unexpectedly found that at concentrations within the range of from 0.50 to 1.00 wt.-%, relative to the total weight of the adhesive layer containing an acrylate polymer (total per dry unit), the pharmacologically active ingredient can be formulated in molecular dispersed form that exhibits a satisfactory shelf-life, i.e. that does not tend to recrystallize, and excellent flux rates. In this regard, the acrylate polymer is superior over the silicone polymer, particularly when it contains one or more percutaneous permeation enhancers selected from dipropylene glycol and oleyl alcohol and/or a crystallization inhibitor such as polyvinylpyrrolidone.
Preferably, the preferred acrylate copolymers according to any of embodiments B1 to B8 can be contained in any of the preferred compositions of adhesive layers according to any of embodiments C1 to C12, i.e.: B1C1, B1C2, B1C3, B1C4, B1C5, B1C6, B1C7, B1C8, B1C9, B1C10, B1C11, and B1C12; B2C1, B2C2, B2C3, B2C4, B2C5, B2C6, B2C7, B2C8, B2C9, B2C10, B2C11, and B2C12; B3C1, B3C2, B3C3, B3C4, B3C5, B3C6, B3C7, B3C8, B3C9, B3C10, B3C11, and B3C12, B4C1, B4C2, B4C3, B4C4, B4C5, B4C6, B4C7, B4C8, B4C9, B4C10, B4C11, and B4C12, B5C1, B5C2, B5C3, B5C4, B5C5, B5C6, B5C7, B5C8, B5C9, B5C10, B5C11, and B5C12, B6C1, B6C2, B6C3, B6C4, B6C5, B6C6, B6C7, B6C8, B6C9, B6C10, B6C11, and B6C12; and B7C1, B7C2, B7C3, B7C4, B7C6, B7C6, B7C7, B7C8, B7C9, B7C10, B7C11, and B7C12; B8C1, B8C2, B8C4, B8C5, C8C6, B8C7, B8C8, B8C9, B8C10, B8C11, and B8C12.
In another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a polyisobutylene based pressure sensitive adhesive (e.g. Duro-Tak® 87-6908).
In still another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a styrenic rubber based pressure sensitive adhesive (polystyrene based pressure sensitive adhesive) (e.g.Duro-Tak® 87-6911).
In yet another preferred embodiment, the pressure sensitive adhesive contained in the adhesive layer comprises a mixture of two or more different pressure sensitive adhesives, e.g. a combination of two different polyacrylate based pressure sensitive adhesives, or a combination of an polyacrylate based pressure sensitive adhesive with a polysilicone based pressure sensitive adhesive; or a combination of an polyacrylate based pressure sensitive adhesive with a polyisobutylene based pressure sensitive adhesive or styrenic rubber based pressure sensitive adhesive; or a combination of a polysilicone based pressure sensitive adhesive with a polyisobutylene based pressure sensitive adhesive or styrenic rubber based pressure sensitive adhesive.
The layer of the pharmaceutical patch that contains the pharmacologically active ingredient or a portion thereof, i.e. the adhesive layer and the drug layer, respectively, may contain other pharmaceutical excipients that are conventionally contained in pharmaceutical patches.
Preferably, the adhesive layer comprises an antioxidant. Suitable antioxidants include but are not limited to alpha-tocopherol, butyl hydroxytoluene or n-propylgalat.
Preferably, the content of the antioxidant is within the range of from 0.01 to 10 wt.-%, more preferably 0.05 to 7.5 wt.-%, still more preferably 0.1 to 2.5 wt.-%, yet more preferably 0.5 to 1.5 wt.-%, even more preferably 0.7 to 1.3 wt.-%, most preferably 0.8 to 1.2 wt.-%, and in particular 0.9 to 1.1 wt.-%, relative to the total weight of the adhesive layer.
In a preferred embodiment, particularly when the adhesive layer does not contain the pharmacologically active ingredient (taking into account that after manufacture there typically is an exchange of the pharmacologically active ingredient between adjacent layers until an equilibrium has been reached), the area of the adhesive layer corresponds to the area of the pharmaceutical patch.
In another preferred embodiment, particularly when the adhesive layer contains the pharmacologically active ingredient, the total area of the adhesive layer can be divided into at least two portions of different composition: an inner area containing the pharmacologically active ingredient and an outer rim surrounding said inner area like a frame, said outer rim preferably not containing pharmacologically active ingredient. The area of said outer rim is not particularly limited but preferably amounts to e.g. about 5% of the total area of the adhesive layer.
In preferred embodiments, the pharmaceutical patch according to the invention exhibits satisfactory storage stability and shelf-life.
Preferably, after storage of the pharmaceutical patch for 3 month at 40° C. and 75% relative humidity in a sealed glass container, the degradation of the pharmacologically active ingredient does not exceed 5%, more preferably 4%, still more preferably 3%, yet more preferably 2%, and most preferably 1.5%.
Preferably, after storage of the pharmaceutical patch for 3 month at 5±3° C. in a sealed glass container, the degradation of the pharmacologically active ingredient does not exceed 4%, more preferably 3%, still more preferably 2%, yet more preferably 1.5%, most preferably 1%, and in particular 0.75%.
In a preferred embodiment of the pharmaceutical patch according to the invention
In another preferred embodiment of the pharmaceutical patch according to the invention
The pharmaceutical patch according to the invention may be prepared by standard techniques for the manufacture of pharmaceutical patches. Such standard techniques are known to the skilled person (cf., e.g., H. A. E. Benson et al., Topical and Transdermal Drug Delivery: Principles and Practice, John Wiley & Sons; 2011; A. K. Banga, Transdermal and Intradermal Delivery of Therapeutic Agents: Application of Physical Technologies, CRC Press Inc; 2011).
Another aspect of the invention relates to a pharmaceutical patch as described above for use in the treatment of pain, preferably moderate to severe pain. The pain may be acute or chronic, central or peripheral, visceral or neuropathic.
The pharmaceutical patch according to the invention is suitable for use in the treatment of neuropathic pain, preferably chronic neuropathic pain such as painful diabetic neuropathy. Preferably, the pain is moderate, severe, or moderate to severe.
For the purpose of the specification, neuropathic pain is pain that originates from nerve damage or nerve malfunction. Preferably, the neuropathic pain is selected from acute neuropathic pain and chronic neuropathic pain. Neuropathic pain may be caused by damage or disease affecting the central or peripheral portions of the nervous system involved in bodily feelings (the somatosensory system). Preferably, the pharmaceutical patch according to the invention is for use in the treatment of chronic neuropathic pain or acute neuropathic pain, peripheral neuropathic pain or central neuropathic pain, mononeuropathic pain or polyneuropathic pain. When the neuropathic pain is chronic, it may be chronic peripheral neuropathic pain or chronic central neuropathic pain, in a preferred embodiment chronic peripheral mononeuropathic pain or chronic central mononeuropathic pain, in another preferred embodiment chronic peripheral polyneuropathic pain or chronic central polyneuropathic pain. When the neuropathic pain is acute, it may be acute peripheral neuropathic pain or acute central neuropathic pain, in a preferred embodiment acute peripheral mononeuropathic pain or acute central mononeuropathic pain, in another preferred embodiment acute peripheral polyneuropathic pain or acute central polyneuropathic pain. The invention also relates to the pharmacologically active ingredient according to the invention a physiologically acceptable salt thereof for use in the treatment of neuropathic pain as described above.
Central neuropathic pain is found in spinal cord injury, multiple sclerosis, and some strokes. Fibromyalgia is potentially a central pain disorder and is responsive to medications that are effective for neuropathic pain. Accordingly, the pharmaceutical patch according to the invention is also suitable for the treatment of fibromyalgia. Aside from diabetic neuropathy and other metabolic conditions, the common causes of painful peripheral neuropathies are herpes zoster infection, HIV-related neuropathies, nutritional deficiencies, toxins, remote manifestations of malignancies, genetic, and immune mediated disorders or physical trauma to a nerve trunk. Neuropathic pain is common in cancer as a direct result of cancer on peripheral nerves (e.g., compression by a tumor), or as a side effect of chemotherapy, radiation injury or surgery.
The pharmaceutical patch according to the invention is also suitable for use in the treatment of nociceptive pain, preferably acute or chronic nociceptive pain. Preferably, the pain is moderate, severe, or moderate to severe.
Nociceptive pain refers to the discomfort that results when a stimulus causes tissue damage to the muscles, bones, skin or internal organs. For the purpose of the specification, nociceptive pain is caused by stimulation of peripheral nerve fibers that respond only to stimuli approaching or exceeding harmful intensity (nociceptors), and may be classified according to the mode of noxious stimulation; the most common categories being “thermal” (heat or cold), “mechanical” (crushing, tearing, etc.) and “chemical” (iodine in a cut, chili powder in the eyes). Nociceptive pain may also be divided into “visceral,” “deep somatic” and “superficial somatic” pain.
Visceral pain describes a type of nociceptive pain originating in the body's internal organs or their surrounding tissues. This form of pain usually results from the infiltration of harmful cells, as well as the compression or extension of healthy cells. Patients suffering from visceral pain tend to feel generally achy, as this pain tends to not be localized to a specific area. Cancer is a common source of visceral pain.
Somatic pain is nociceptive pain that results from some injury to the body. It's generally localized to the affected area and abates when the body repairs the damage to that area. Deep somatic pain is initiated by stimulation of nociceptors in ligaments, tendons, bones, blood vessels, fasciae and muscles, and is dull, aching, poorly-localized pain. Examples include sprains and broken bones. Superficial pain is initiated by activation of nociceptors in the skin or superficial tissues, and is sharp, well-defined and clearly located.
According to the invention, nociceptive pain is preferably classified chronic if it has occurred for at least 3 months. Preferably, the chronic nociceptive pain is selected from chronic visceral pain, chronic deep somatic pain and chronic superficial somatic pain.
Preferred causes of nociceptive pain according to the invention include broken or fractured bones, bruises, burns, cuts, inflammation (from infection or arthritis), and sprains. Thus, nociceptive pain includes post-operative pain, cancer pain, low back pain, and inflammatory pain.
In preferred embodiments, the pain to be treated is selected from the group consisting of pain being or being associated with panic disorder [episodic paroxysmal anxiety] [F41.0]; dissociative [conversion] disorders [F44]; persistent somatoform pain disorder [F45.4]; pain disorders exclusively related to psychological factors [F45.41]; nonorganic dyspareunia [F52.6]; other enduring personality changes [F62.8]; sadomasochism [F65.5]; elaboration of physical symptoms for psychological reasons [F68.0]; migraine [G43]; other headache syndromes [G44]; trigeminal neuralgia [G50.0]; atypical facial pain [G50.1]; phantom limb syndrome with pain [G54.6]; phantom limb syndrome without pain [G54.7]; acute and chronic pain, not elsewhere classified [G89]; ocular pain [H57.1]; otalgia [H92.0]; angina pectoris, unspecified [120.9]; other specified disorders of nose and nasal sinuses [J34.8]; other diseases of pharynx [J39.2]; temporomandibular joint disorders [K07.6]; other specified disorders of teeth and supporting structures [K08.8]; other specified diseases of jaws [K10.8]; other and unspecified lesions of oral mucosa [K13.7]; glossodynia [K14.6]; other specified diseases of anus and rectum [K62.8]; pain in joint [M25.5]; shoulder pain [M25.51]; sacrococcygeal disorders, not elsewhere classified [M53.3]; spine pain [M54.]; radiculopathy [M54.1]; cervicalgia [M54.2]; sciatica [M54.3]; low back pain [M54.5]; pain in thoracic spine [M54.6]; other dorsalgia [M54.8]; dorsalgia, unspecified [M54.9]; other shoulder lesions [M75.8]; other soft tissue disorders, not elsewhere classified [M79]; myalgia [M79.1]; neuralgia and neuritis, unspecified [M79.2]; pain in limb [M79.6]; other specified disorders of bone [M89.8]; unspecified renal colic [N23]; other specified disorders of penis [N48.8]; other specified disorders of male genital organs [N50.8]; mastodynia [N64.4]; pain and other conditions associated with female genital organs and menstrual cycle [N94]; mittelschmerz [N94.0]; other specified conditions associated with female genital organs and menstrual cycle [N94.8]; pain in throat and chest [R07]; pain in throat [R07.0]; chest pain on breathing [R07.1]; pericardial pain [R07.2]; other chest pain [R07.3]; chest pain, unspecified [R07.4]; abdominal and pelvic pain [R10]; acute abdomen pain [R10.0]; pain localized to upper abdomen [R10.1]; pelvic and perineal pain [R10.2]; pain localized to other parts of lower abdomen [R10.3]; other and unspecified abdominal pain [R10.4]; flatulence and related conditions [R14]; abdominal rigidity [R19.3]; other and unspecified disturbances of skin sensation [R20.8]; pain associated with micturition [R30]; other and unspecified symptoms and signs involving the urinary system [R39.8]; headache [R51]; pain, not elsewhere classified [R52]; acute pain [R52.0]; chronic intractable pain [R52.1]; other chronic pain [R52.2]; pain, unspecified [R52.9]; other complications of cardiac and vascular prosthetic devices, implants and grafts [T82.8]; other complications of genitourinary prosthetic devices, implants and grafts [T83.8]; other complications of internal orthopedic prosthetic devices, implants and grafts [T84.8]; other complications of internal prosthetic devices, implants and grafts, not elsewhere classified [T85.8]; wherein the information in brackets refers to the classification according to ICD-10.
Preferably, the pharmaceutical patch is designed for application to the skin for a period of least 1 day, more preferably at least 2 days, most preferably at least 3 days or at least 3.5 days, and in particular 3 days, 3.5 days, 4 days or 7 days. Thus, according to this embodiment, continuous administration of the pharmacologically active ingredient can be achieved by removing a used pharmaceutical patch after the predetermined period has expired and replacing it by a fresh pharmaceutical patch.
In a preferred embodiment, the pharmaceutical patch is designed for application to the skin for an application period A, followed by a treatment period T during which no pharmaceutical patch is applied to the skin. Thus, according to this embodiment, continuous administration of the pharmacologically active ingredient can be achieved by removing a used pharmaceutical patch after the application period A has expired and replacing it by a fresh pharmaceutical patch after the treatment period has expired as well. It has been surprisingly found that the pharmacological half life t1/2 of the pharmacologically active ingredient is comparatively high so that its pharmacological effect lasts for a long time after administration has been interrupted or terminated. Preferred durations of application period A and treatment period T are summarized as embodiments D1 to D17 in the table here below:
The locations of the skin to which the pharmaceutical patch according to the invention is to be applied are not particularly limited. Preferably, the pharmaceutical patch according to the invention is applied to the skin of the breast or the skin of the back.
In a preferred embodiment, the pharmaceutical patches according to the invention are repeatedly applied to the same location on the skin, i.e. after a first pharmaceutical patch has been used and needs to be replaced by a second pharmaceutical patch in order to maintain the desired pharmacological effect, said second pharmaceutical patch is preferably applied to the same location on the skin to which said first pharmaceutical patch was applied before.
In another preferred embodiment, particularly when the patient has a sensitive skin, the pharmaceutical patches according to the invention are applied to the different locations on the skin, i.e. after a first pharmaceutical patch has been used and needs to be replaced by a second pharmaceutical patch in order to maintain the desired pharmacological effect, said second pharmaceutical patch is preferably applied to a location on the skin differing from the location on the skin to which said first pharmaceutical patch was applied before.
The pharmaceutical patch according to the invention is for administration to the skin of an mammal, preferably of a human (pediatrics or adults).
The following examples further illustrate the invention but are not to be construed as limiting its scope.
For the purpose of the specification, “API” refers to the pharmacologically active ingredient, unless expressly stated otherwise in form of its free base.
For the purpose of the specification, “DEGR1”, “DEGR2”, “DEGR3” and “DEGR4” are identified degradation products of the API. DEGR2 has been confirmed as being non-toxic.
The peel strength is the force, measured in Newton, that must be exerted to remove the patch with a defined velocity from a stainless steel test plate.
Tensile testing device (e.g. Zwick BT1-FR2.5TN.D14) including PC/application
Adequate load cell (e.g. 100 N)
Grips enabling measurement in 90° angle
Peeling apparatus (Sliding table), for measuring at 90° angle
Stainless steel test plate eg. V4A-AISI 316L
Separation aid: adhesive tape (e.g. tesafix 4963)
Cleaning agent: acetone
Die cut and die cut form (25 mm width)
25 mm wide stripes are die cut out of the patches, which are equilibrated to the climatic measuring conditions (23° C.±3° C./50%±10% r.h.) for at least 2 h prior to measurement.
The 100 N load cell and the sliding table including the stainless steel testing plate are installed. The test plate is cleaned with acetone.
After the separation aid is affixed to the patch, the release liner is removed completely from the patch and the patch is adhered to the stainless steel plate without pressure, air bubbles or wrinkles. The separation aid is then fixed into the clamp of the tensile testing device in such a way that the patch is peeled off of the test plate in a 90° angle running a test velocity of 300 mm/min. The measurement has to be carried out in a timeframe of 30 to 60 seconds after adhering the sample to the test plate.
Evaluation of the Data
The standard procedure comprises 6 samples. The average value among the mean forces occurred within the measurement range is reported as N/25 mm.
Patches with a layer sequence protective layer/adhesive layer/protective layer and differing in the formulation of the adhesive were prepared as follows:
Adhesive formulations of API at 1 wt.-% and 3 wt.-% in different adhesives were prepared in 20 mL vials and mixed on a jar roller. API at 1 wt.-% and 3 wt.-% in Duro-Tak 87-2287 (Ex. 1-3 and 1-4) were found to be insoluble. The other acrylate-based adhesive formulations were used to cast one sheet on a silicone coated polyester or polyethylene film (Loparex Primeliner® FLS release liner). Silicone-based adhesive formulations (Ex. 1-7 and 1-8) were cast onto a fluoropolymer coated polyester film (3M Scotchpak® 1022 release liner). A Gardco Automatic Drawdown machine was used to spread the adhesive at a thickness to target 100 g/m2. The sheet was dried for five minutes at room temperature, then for seven minutes at 92° C. It was laminated with another sheet of the respective protective layer. The sheets were visually examined to verify API solubility, and checked for crystallization. The sheets were cut into round patches (3.9 cm2), stored at room temperature in polypropylene ziplock bags and were checked for crystallization formation with time.
1)adhesive composition (5 g batch) after mixing;
2)composition of adhesive layer after drying
According to the procedure of Example 1, further patches containing transcutol, oleyl alcohol or dipropylene glycol as additives were prepared. The final adhesive formulations and results are summarized here below:
1)adhesive composition (5 g batch) after mixing;
2)composition of adhesive layer after drying
An in-vitro permeation study was performed with the adhesive formulations of the patches to show permeation of drug through synthetic membranes. The in-vitro experiments were conducted using Hanson Microette Franz Cell apparatus. The Franz-diffusion Cell consists of a donor compartment and a receiver compartment. A donut-shaped dosage wafer (inside diameter 15 mm) was fixated on top of each membrane and approximately 300 mg of the adhesive formulation were applied on top of the membrane to top the dosage wafer compartment. The membrane was sandwiched between the two compartments. A 40% aqueous PEG-400 solution (vol.-% PEG-400) was used as the receiving medium. The diffusion cells temperature was maintained at 32.5° C.±0.5° C. At predetermined times (2, 4, 6, 8, 12 and 24 hours) samples (aliquots of 500 μl) were withdrawn from the receiving compartment and immediately replaced by the same volume of fresh receiver medium. The permeation area (effective surface of sample well) was 1.76 cm2 and the volume of the individual Franz Cell was 7 mL.
The synthetic membranes selected were: Nylon μm, Polysulfone, 0.45 μm, Cellulose acetate, 0.45 μm and SilTech (non-porous, silicone).
Flux studies with all five adhesive formulations were conducted using a Nylon membrane. The permeability results expressed in terms of cumulative amount (Q; pg/cm2) and flux (μg/cm2×h) are summarized here below:
1)effective area of sample well: 1.76 cm2
Ex. 2-3 exhibits the best permeation through Nylon membranes.
Based on these results, a comparative flux study on the adhesive formulation of Ex. 2-3 using Nylon, Polysulfone, Cellulose acetate and SilTech (silicone) membranes was performed. The nylon membrane was run in duplicate to verify the reproducibility of permeation through this membrane. A summary of the results is presented in the table below:
1)effective area of sample well: 1.76 cm2
As a result, nylon and cellulose acetate produced the most controlled results, that is, membranes showing the lowest permeation which would potentially be indicative of an ex vivo model. These membranes represent opposite polarities cellulose acetate being highly polar and porous (0.45 μm) and silicone being non-polar and non-porous. The other 3 membranes exhibited a high initial permeation and significant tailing off which indicates the membrane is not rate-controlling, but merely a membrane that allows dissolution of the drug from the adhesive matrix.
Patches were prepared from the adhesive composition of the patch according to Ex. 2-3 (Ex. 3-1) and from six further adhesive compositions containing transcutol, oleyl alcohol and/or dipropylene glycol as additives.
The adhesive formulations were prepared in 20 mL vials and mixed on a jar roller. The formulations were used to cast one sheet on a silicone coated polyester or polyethylene film (Loparex Primeliner® FLS release liner). A Gardco Automatic Drawdown machine was used to spread the adhesive at a thickness to target 100 g/m2. The sheet was dried for five minutes at room temperature, then for seven minutes at 92° C. It was laminated with a polyester laminate (3M Scotchpak® 9754 Surface layer, polyester film with an ethylene vinylacetate copolymer heat seal layer). Some 3.9 cm2 round patches were cut from each sheet and packaged in heat sealed foil pouches.
The patches were visually examined to verify API solubility, and checked for crystallization. The sheets were stored at room temperature in polypropylene ziplock bags and were checked for crystallization formation with time.
The final adhesive formulations and results are summarized here below:
According to Example 2, a comparative flux study was conducted on the patches using cellulose acetate and silicone membranes.
The results are depicted in
1)effective area of sample well: 1.76 cm2
1)effective area of sample well: 1.76 cm2
The results above indicate that Examples 3-5 and 3-6 show the best flux profiles when using both polar (cellulose acetate) and non-polar (silicone) membranes although the flux is higher with the cellulose acetate membranes.
In accordance with Example 3, a patch was prepared from the adhesive composition according to the patch of Example 2-4, a fluoropolymer coated polyester film (3M Scotchpak® 1022) as protective layer and a polyester laminate (3M Scotchpak® 9754, polyester film with an ethylene vinylacetate copolymer heat seal layer) as surface layer.
A comparative study was conducted to evaluate the permeation behavior of API from the transdermal patches according to Examples 3-5, 3-6 and 4-1 through artificial skin constructs in comparison with two solutions (solution A: 300 μg/mL API in ethanol/DMSO/PEG 200=8:1:1; solution B: saturated solution of API in PEG 400).
Although the performance of the two solutions was better than the performance of the transdermal patches, these tests revealed that the pharmacologically active ingredient, when being contained in a pharmaceutical patch, can also penetrate into and through artificial skin. Furthermore, these tests indicate that pharmaceutical patches containing the pharmacologically active ingredient in an polyacrylate based pressure sensitive adhesive (drug-in-adhesive) are superior with respect to skin permeation performance over pharmaceutical patches containing the pharmacologically active ingredient in a polysilicone based pressure sensitive adhesive (drug-in-adhesive).
Chemical stability testing was conducted with the patches of Examples and 3-5, 3-6 and 4. The conditions and detected amounts of impurities DEGR1 and DEGR2 are summarized here below:
As DEGR2 itself exhibits pharmacological activity and is non-toxic, it can be concluded from the above data that formulation 4 is storage stable, while the storage stability of formulations 3-5 and 3-6 is not satisfactory.
The patches according to the previous Examples showed some re-crystallization of the matrices containing 1 wt.-% of API. In order to develop non-recrystallizing maximum API loads, variations of the patches according to Examples 3-5, 3-6 and 4-1 containing varying amounts of API were prepared according to the following procedure.
API in form of the free base is dissolved in isopropanol/toluene (1:1). The solution is sonicated, the other ingredients are added and the mixture is stirred overnight. A Gardco Automatic Drawdown machine is used to spread the adhesive composition at a thickness of 100 g/m2 (unless stated otherwise) on a protective layer. The laminate is dried for ten minutes at room temperature and for 10 minutes at 70° C. before it is laminated with a sheet of Surface layer and cut to the desired size (9 cm2 unit). The resulting patches were tested microscopically for recrystallization at 5 storing conditions after 1, 2 and 4 weeks.
It can be concluded from the above data that in polyacrylate based adhesive layers a substantially higher API load can be achieved than in polysilicone based adhesive layers. Further, it can be concluded from the above data that in the presence of polyvinylpyrrolidone (PVP) a substantially higher API load can be achieved than in the presence of oleyl alcohol.
Variations of the patch according to Ex. 6-14 (acrylic adhesive) were prepared according to the procedure of Example 6 using different antioxidants. The amount of impurity DEGR1 was determined:
It can be concluded from the above data that compared to formulation 3-6 of Example 5 (1.15%), the addition of antioxidants reduces the initial content of undesired degradation product DEGR1. In this regard, the stabilizing effect of different antioxidants is equivalent to one another.
Patches were prepared according to the procedure of Example 6, one based on acrylate adhesive Durotak 87-9301 and the others based on acrylate adhesive Durotak 87-4287. Further, the area weight of the adhesive was varied. The resulting patches were exposed to short term and stress stability testing and the amount of impurities DEGR1 and API was determined.
Durotak 87-4287 (40 wt.-% solids, copolymer of vinyl acetate (17-40%), 2-ethylhexylacrylate (55-75%) and hydroxyethyl acrylate (5.2%)).
It becomes evident from the above table that the change from acrylic adhesive Durotak 87-9301 to Durotak 87-4287 led to a significantly decreased level of DEGR1 after manufacturing. The amount of DEGR1 is further dependent on the area weight and thickness of the adhesive.
The patches according to Example 8-7 were chosen for further short term and accelerated stability studies:
It can be concluded from the above data that the formation of degradation product DEGR1 during manufacture and storage can be suppressed by
According to the procedure of Example 6, patches were prepared from the acrylic adhesive compositions given in the table here below. The resulting patches were tested microscopically for recrystallization after 4 weeks storing at 40° C./75% relative humidity, open to air.
It can be concluded from the above data that when replacing Durotak 87-9301 by Durotak 87-4287 the API load cannot be further increased.
According to the procedure of Example 6, patches were prepared from the silicone adhesive compositions given in the table here below. The resulting patches were tested microscopically for recrystallization after 4 weeks storing at 40° C./75% relative humidity, open to air.
The patches according to Examples 10-4 and 10-8 were exposed to short term and stress stability testing. The amount of impurities DEGR1 and API was determined at different times.
It can be concluded from the above data that this formulations exhibits excellent storage stability and shelf-life.
Patches containing acrylic adhesive and silicone adhesive were prepared according to the procedure of Example 6. The amount of impurity DEGR1 was detected and the resulting patches were tested microscopically for recrystallization at 5 different storing conditions.
Storing conditions: a) 2-8° C.
It can be concluded from the above data that two-component-formulation systems did neither provide advantages with regards to increased API load as compared to one-component silicone systems nor lower initial DEGR1 levels as compared to one-component-acrylate systems.
In accordance with Example 3, laminates were prepared from the following acrylate adhesive compositions:
Patches of different sizes (3, 5, 12, 12.5 and 25 cm2) were cut from the laminate.
The analgesic efficacy of the patches was investigated in comparison to the efficacy of a topically applied PEG 400 solution of API (600 μg/mL) in the burning ray (tail flick) test on the rat by the method of D'Amour and Smith (J. Pharm. Exp. Ther. 72, 74 79 (1941). Female hairless rats (OFA hr/hr, Charles River USA) weighing approx. 200 g were used. The animals were placed individually in special test cages and the base of the tail was exposed to a focused ray of heat from an electric lamp. The lamp intensity was adjusted such that the time from switching on the lamp to sudden jerking away of the tail (pain latency) was 3-5 seconds in untreated animals. Before topical administration of the drug-containing plaster or solution, the animals were pretested twice in the course of five minutes and the mean of these measurements was calculated as the pretest mean.
The pain measurement and the plasma concentrations were determined at different points in time after application of the plaster or solution (see table below).
The analgesic action was determined as the increase in the pain latency (% MPE) according to the following formula: [(T1−T0)/(T2−T0)]*100. In this, T0 is the latency time before and T1 the latency time after administration of the substance, T2 is the maximum exposure time (12 sec).
The compositions of the solutions that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in
A Body weight = 160 g/animal
B Body weight = 200 g/animal
Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal
It becomes evident from the above tables that the bioavailability of the API hemicitrate in Ethanol:DMSO:Lipoxol (8:1:1 v/v/v) was 100% after dermal application compared to intravenous administration. Further, a dose-proportional increase of AUC0-t was found.
The compositions of the solutions that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in
The composition of the patches and the solution that were applied to the different groups are summarized in the table here below. The results of the tail-flick test and the plasma concentration measurements are depicted in
1)body weight: approx. 200 g
Based on the pharmacological data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal
1)body weight: approx. 200 g/animal
2)reference: Sprague-Dawley rat, API free base intravenous
It becomes evident from the above tables that the bioavailability of the patches is approximately 1.8%. Further, a dose-proportional (area-proportional) increase of AUC0-t was found.
The composition of the patches and the solution that were applied to the different groups are summarized in the table here below.
The results of the tail-flick test and the plasma concentration measurements are depicted in
The absolute bioavailability of API free base and API hemicitrate is summarized in the table here below.
Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal
It becomes evident from the above table that the bioavailability of the API hemicitrate is approximately 2.5 fold lower compared to the API free base in PEG400. The bioavailability of API free base in human SEDDS is slightly higher compared to the PEG formulation (Finn chamber).
Further, a dose-proportional increase of AUC0-t for the API free base in PEG400 was observed.
The absolute bioavailability of API free base after application of Patch 12C (acrylate), Patch 12D (acrylate) and Patch 12E (silicone) is summarized in the table here below.
Based on the pharmacokinetic data, the bioavailability of API from the patches was calculated. The pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal
It becomes evident from the above table that the bioavailability of acrylate Patch 12C is approximately 1.8%. The bioavailability of API free base in Patch 12D is slightly higher compared to the silicone Patch 12E (8.5% vs. 6.4%).
Further, a dose-proportional (area-proportional) increase of AUC0-t was observed.
The absolute bioavailability and flux of API free base for different topical vehicles is summarized in the table here below.
A) based on total patch load or load in solution
Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal×100%.
It becomes evident from the above table that highest flux rates were derived from highly dosed PEG400 solution and from patch 12D (acrylate).
Patches with vehicles 13-1 to 13-12 were prepared and tested as described above in Example 12:
The absolute bioavailability of API free base and API hemicitrate is summarized in the table here below.
A) based on total patch load or load in solution
B)AUC0-24h
Based on the pharmacokinetic data, bioavailability F and flux rate of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference.
F=AUC
dermal
/AUC
intravenous×doseintravenous/dosedermal×100%
Flux(ng/cm2/h)=(AUCdermal×dosedermal)/(AUCintravenous×sizedermal×duration)
It becomes evident from the above table that the flux of the styrene patch (13-9) was slightly higher but still comparable to the acrylate prototype (13-1). The silicone formulations 13-7 and 13-8 showed significantly reduced plasma levels.
None of the combinations of adhesives with enhancers demonstrate increased flux in comparison to the acrylate prototype (13-1). In contrast, levels were significantly reduced in some cases.
According to Example 6, laminates were prepared from the following adhesive compositions:
Patches of 100 cm2 size were cut from the two laminates.
An animal study was conducted using eight male mini-pigs. In two periods, four different formulations of API free base were administered to the animals:
Plasma concentrations of API free base were determined at different times after application of the formulations.
The resulting mean pharmacokinetic data are summarized in the table here below and in
1)data of one animal only
2)n = 3
Based on the pharmacokinetic data, bioavailability F and flux rate of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference.
F=AUC
dermal
/AUC
intravenous×doseintravenous/dosedermal×100%
Flux(ng/cm2/h)=(AUCdermal×dosedermal)/(AUCintravenous×sizedermal×duration)
1)reference: intravenous dose of API free base: 40 μg/kg to 4 male pigs (3 were evaluated, mean body weight: 14.1 kg)
2)duration = 72 h
Patches were prepared as described above. An overview on the study is provided by the table below:
The plasma concentrations of API free base after application of Patch 12D (acrylate) and Patch 12E (silicone) and PEG to male minipigs (Study no. 1) are displayed in
The resulting mean pharmacokinetic data of Study no. 1 (male) are summarized in the table here below:
Aone out of four animals showed concentrations >LLOQ (lower limit of quantification)
Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal×100%.
It becomes evident from the above table that the bioavailability of API free base in acrylate Patch 12D is 7-fold higher compared to the silicone patch (1.7% vs. 0.24%). Without wanting to be limited by theory, this could be a consequence of the insufficient adherence of the silicone patch to the skin compared to the acrylate patch.
Only one out of four animals showed concentrations>LLOQ after PEG400 in Finn chambers.
The plasma concentrations of API free base after application of Patch 12D (acrylate) and Patch 12E (silicone) and PEG to female minipigs (Study no. 2) are displayed in
The resulting mean pharmacokinetic data of Study no. 2 (female) are summarized in the table here below:
Aone out of four animals showed concentrations >LLOQ
Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal×100%.
It becomes evident from the above table that with the silicone patch, due to the very low plasma concentrations in three out of four animals no PK parameters were calculated. Without wanting to be limited by theory, this may be an effect of the low adhesiveness.
The bioavailability of API free base in female animals was 2-3 times lower compared to the study in male animals which might be a consequence of the skin lesions in male minipigs.
The absolute bioavailability and flux of API free base for different topical vehicles is summarized in the table below:
Aone out of four animals showed concentrations >LLOQ
B) based on total patch load or load in solution
Based on the pharmacokinetic data, bioavailability F of API from the different formulations was calculated. For the calculation, the corresponding pharmacokinetic data of an intravenous application of API free base was used as reference: F=AUCdermal/AUCintravenous×doseintravenous/dosedermal×100%.
It becomes evident from above table that in the minipig, penetration of API free base was not found for all tested formulations (reliable plasma concentration was measured only for the “painted” PEG400, Acrylate patch and Silicone patch in males only).
The females showed 2-3 fold lower plasma concentrations compared to the males, which might be a consequence of the skin lesions in male minipigs.
Plasma concentrations increased within the first 2 days after dermal application and thereafter a concentration plateau was observed until removal of the foil (solutions) or patch at 72 h/96 h.
The absolute bioavailability was low for all tested formulations (PEG400=3.6% male/1.2% female and Acrylate patch=1.7% male/0.9% female).
The face-to-face comparison of the patch types showed significantly lower performances of the Silicone patch, which might be a consequence of the insufficient adherence of the Silicone Patch to the skin compared to the Acrylate Patch.
The permeation of API free base across dermatomized pig skin (incl. stratum corneum) from the following patches has been investigated:
The results of ex vivo testing of patches P1 to P6 across dermatomized pig skin are summarized in the table below and in
It becomes evident from
In a series of experiments under comparable conditions, the permeation of the API from various patches across a synthetic EVA membrane was tested.
Patch 16-1 corresponds to 12E (silicone prototype). Patches 16-2 to 16-4 correspond to 12E (acrylate prototype).
The results are summarized in
Summarizing, both EVA-membrane permeation systems showed a permeation kinetic which could not be obtained by using human skin, however, data achieved from the two patch prototypes are in a comparable order and ratio as observed in hairless rats. Both buffer systems yielded a similar permeation performance of patches containing API free base. The data obtained with the ammonium acetate buffer were more sophisticated compared to the system with a PEG 400 solution as acceptor medium. Accordingly, the EVA-membrane permeation system using ammonium acetate buffer is suitable to compare patch formulations containing API free base.
In a series of experiments under comparable conditions, patches of identical basic compositions but of different polymers were tested in terms of compatibility with the API free base. All patches contained 0.75 wt.-% of API free base.
The different polymers which were tested are summarized in the table below:
All polyacrylate based adhesives showed no re-crystallisation of the API at start and after 6 days at 60° C. The styrenic rubber (17-9) as well as the isobutylene prototype (17-8) showed after the manufacturing and after 6 days at 60° C. re-crystallisation of the API.
The results of a stress stability testing of API free base containing wet polymer matrices at room temperature (RT) over 6 days are summarized in the table below:
The results of a stress stability testing of API free base containing patch samples at 60° C. over 6 days are summarized in the table below:
The styrenic rubber DuroTak 87-6911 as well as the polyisobutylene prototypes DuroTak 87-6908 yielded formulations with very low amounts of impurities. The acrylate adhesives DuroTak 87-2051, as well as DuroTak 87-2353 showed the lowest degradation profiles of the acrylate formulations.
In a series of experiments under comparable conditions, patches made of silicone adhesives and various solubilizers were tested in terms of compatibility with the API free base and the recrystallization tendency for the API free base.
An overview of the different batches which were prepared is given in the table below:
Re-crystallization was tested at the start and after 6 days at room temperature (RT). Square-shaped and needle-shaped crystals could be detected. The results are summarized in the table below:
Two silicone adhesives (BioPSA 7-4503 and BioPSA 7-4603) in combination with either PVP or PVA showed promising results.
The results of a stress stability testing of API free base containing patch samples at 60° C. over 6 days are summarized in the table below:
All formulations containing 1.5% API free base and 13.5% hydrophilic polymer showed an acceptable degradation profile.
In a series of experiments under comparable conditions, patches of identical basic compositions but of different polymers were tested in terms of recrystallization of the API free base and permeation across a synthetic EVA membrane.
An overview of the different batches which were prepared is given in the table below:
Re-crystallization was tested at the start and after 4 weeks at 25° C./60% r.h. (relative humidity) as well as 40° C./75% r.h. The results are summarized in the table below:
Re-crystallization occurred in the isobutylene as well as in the styrenic rubber adhesive at higher concentrations. Both acrylate adhesives showed no recrystallization events.
API free base containing patch samples were tested on assay and purity after manufacturing. The results are summarized in the table below:
The permeation through an EVA membrane was tested.
The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:
It becomes evident from the above table that the styrenic rubber polymer DuroTak 87-6911 shows increased permeation rate while being lower concentrated in comparison to an acrylate reference patch 12D.
Following silicone patches were tested:
The permeation through an EVA membrane was tested.
The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:
It becomes evident from the above table that both, the silicone/PVA and the silicone/PVP formulation with 1.5% API free base shows increased permeation rate in comparison to an acrylate reference patch 12D.
In a series of experiments under comparable conditions, patches of identical basic compositions of two acrylate adhesives were tested in terms of saturation solubility of the API free base and permeation across a synthetic EVA membrane.
An overview of the different batches which were prepared is given in the table below:
Re-crystallization was not observed at the start, and neither after 7 days at 25° C./60% r.h. (relative humidity) or 40° C./75% r.h. Even with 4% API free base in the polymers, the patch samples showed no re-crystallization over a time period of 7 days.
API free base containing patch samples were tested on assay and purity after manufacturing. The results are summarized in the table below:
The permeation through an EVA membrane was tested.
The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:
Both acrylate adhesive have acidic functional groups. It is likely that an interaction with API free base occurs so that a saturation of the polymer with the API free base could not reached even at a high concentration of 4% API free base. The low flux rate observed is a consequence of the non-saturated system.
In a series of experiments under comparable conditions, patches made of acrylate DuroTak 87-4287 and Eudragit EPO were tested in terms of adhesiveness.
An overview of the different batches which were prepared is given in the table below:
The in vitro peel strength of Duro Tak® 87-4287 prototypes containing different amounts of Eudragit® EPO was determined. The results are summarized in the table below:
A decrease of peel strength with increasing methacrylate amount could be detected. No differences in vivo between formulations III to VI could be seen (data not shown).
In a series of experiments under comparable conditions, patches made of various acrylate adhesives were tested in terms of saturation solubility and stability of API free base and permeation across a synthetic EVA membrane.
The saturation concentrations of API free base in the coating masses were determined. An overview of the different batches which were prepared is given in the table below:
Over a time period of four weeks at 25° C./65% r.h. and 40° C./75% r.h. there was no re-crystallization of any of patch systems 23-1 to 23-4, neither with nor without seeding crystals.
The assay under stress stability conditions at 60° C. over a period of 6 days was determined. The results are summarized in the table below:
The purity under stress stability conditions at 60° C. for 6 days was determined. The results are summarized in the table below:
The EVA membrane permeation testing of API free base containing prototypes vs. an acrylate reference patch (19-13) is also summarized in the table below:
It becomes evident from the above tables that a combination of DuroTak 87-4287 and Eudragit EPO lead to reduced degradation of the API free base. Furthermore, this formulation shows increased permeation increased rate in comparison to an acrylate reference patch 12D.
The solubility of API free base in different liquid permeation enhancer substances was determined. The results are summarized in the table below:
Out of the substances mentioned in the table above, the following enhancers were selected to be tested further.
The permeation of API free base across dermatomized pig skin (incl. stratum corneum) from saturated solutions in enhancers E1 to E8 has been investigated, results are shown in
It becomes evident from
In a series of experiments under comparable conditions, patches made of acrylate adhesive DuroTak 87-4287 or styrenic rubber adhesive DuroTak 87-6911 in combination with Eudragit EPO were tested in terms of saturation solubility and stability of the API free base and permeation across a synthetic EVA membrane.
The saturation concentration of API free base in Eudragit® EPO containing polymer systems was determined. The results are summarized in the table below:
By adding more Eudragit® EPO to the formulation no or only a low increase of the saturation concentration of API free base in the patch could be obtained.
Over a time period of four weeks at 25° C./60% r.h. and 40° C./75% r.h. there was no re-crystallization of any of patch systems 25-1 to 25-5 and 23-4, neither with nor without seeding crystals. The patches were stored in Surlyn® pouches.
Stress stability was tested at 60° C. over a period of 6 days in Surlyn® pouches. The results are summarized in the table below:
It becomes evident from above table that by increasing the Eudragit® EPO amount in the formulation the amount of degradation products could be decreased.
The EVA membrane permeation data and calculation of flux rate across the membrane is summarized in the table below:
It becomes evident from the above tables that Eudragit EPO lead to reduced degradation of the API free base. In addition, an increased permeation rate in comparison to an acrylate reference patch 12D could be observed in combination with acrylate adhesive DuroTak 87-4287 but not in combination with the styrenic rubber adhesive DuroTak 87-6911.
| Number | Date | Country | Kind |
|---|---|---|---|
| 12 002 356.9 | Mar 2012 | EP | regional |
| Number | Date | Country | |
|---|---|---|---|
| 61592850 | Jan 2012 | US |
