WO2017153441A1

WO2017153441A1 - Topical composition

Info

Publication number: WO2017153441A1
Application number: PCT/EP2017/055376
Authority: WO
Inventors: Armin Breitenbach; Thomas Reintjes
Original assignee: Tesa Labtec Gmbh
Priority date: 2016-03-09
Filing date: 2017-03-08
Publication date: 2017-09-14

Abstract

The present invention relates to a topical composition for delivering API. In at least one embodiment, the composition comprises the pharmaceutically active ingredient, in particular ropivacaine, and/or a salt thereof; at least one adhesive material; and at least one backing material; and wherein, after application of the topical composition to keratinous materials of a subject, a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for greater than 12 hours while the topical composition remains adhesive to the keratinous material. A method of making the topical composition, and a method of continuous treatment of pain using the topical composition are also disclosed. Furthermore, a topical composition delivering at least one pharmaceutically active ingredient or salts thereof comprising the at least one pharmaceutically active ingredient or salts thereof; at least one adhesive material; at least one backing material; and at least one hydrophilic polymer in an amount ranging from 5% (w/w)-10% (w/w); wherein, after application of the topical composition to keratin material of a subject, the adhesivity of the topical composition is reduced while wearing, such that after 24 hours an external force no greater than 2.4 N is required to remove the topical composition from the keratin material.

Description

TOPICAL COMPOSITION

FIELD OF THE INVENTION

[001 ] The invention relates to the field of topical compositions, in particular self- adhesive patches, its production and its use in therapy.

BACKGROUND OF THE INVENTION

[002] Ropivacaine is a long-acting, amide-type local anesthetic with both anesthetic and analgesic effects.

[003] The S-enantiomer of ropivacaine has the following structure:

and the lUPAC name, (S)-/V-(2,6-dimethylphenyl)-1 -propylpiperidine-2-carboxamide.

[004] Ropivacaine hydrochloride is marketed by AstraZeneca under the trade name NAROPIN®, which is a sterile isotonic solution comprising ropivacaine HCI, sodium chloride for isotonicity, and water. [005] NAROPIN® is indicated for the production of local or regional anesthesia for surgery (epidural block for surgery including cesarean section; major nerve block; local infiltration) and for acute pain management (epidural continuous infusion or intermittent bolus, e.g., postoperative or labor; local infiltration).

[006] However, systemic over-exposure to ropivacaine can result in central nervous system (CNS) and cardiovascular effects. CNS effects usually occur at lower blood plasma concentrations and cardiovascular effects occur at higher concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures) followed by depression (drowsiness, loss of consciousness, respiratory depression and apnea). Cardiovascular effects can include hypotension, bradycardia, arrhythmias, and/or cardiac arrest - some of which may be due to hypoxemia secondary to respiratory depression.

[007] It may be possible to avoid at least one of the foregoing side-effects by administering ropivacaine via a non-systemic route, for instance, via a topical, e.g., dermal and transdermal system.

[008] A topical system for administering local anasthetic has been developed before. For instance, LIDODERM® (Versatis®) is a skin patch comprising 5% of lidocaine (acetamide, 2-(diethylamino)-/V-(2,6-dimethylphenyl)). One of the flaws with LIDODERM® is the adverse reactions on the application site. The FDA-approved label provides that "the skin may develop blisters, bruising, burning sensation, depigmentation, dermatitis, discoloration, edema, erythema, exfoliation, irritation, papules, petechia, pruritus, vesicles, or may be the locus of abnormal sensation. These reactions are generally mild and transient, resolving spontaneously within a few minutes to hours." Another flaw with LIDODERM® is that, according to the label, LIDODERM® is to be applied "only once for up to 12 hours within a 24 hour-period." This 12- hour wearing limit is due in part to the fact that a lidocaine metabolite will trigger a systemic reaction. Therefore, there is a need for a new topical composition for improved pain treatment that allows for at least one of: longer continuous use, minimal systemic reaction, and minimal skin damage. Skin damage may include, for example, stripping, itching, irritation, swelling, inflammation, redness, blistering, bruising, or change in skin color.

[009] Ropivacaine has a lower water solubility than lidocaine (5.8 mg/mL vs. 21 .7 mg/mL), and a higher melting point than lidocaine (145 vs. 68.5 °C). Both factors, water solubility and melting point, would be expected to have a negative impact on the ability of ropivacaine to penetrate and permeate the skin because the thermodynamic activity is decreased. Thus the LIDODERM® formulation would not be expected to make a suitable topical composition containing ropivacaine.

[010] In addition, there exist several challenges in formulating a topical composition containing ropivacaine or other pharmaceutically active ingredients (also known as active pharmaceutical ingredients or API's). For example, the formulation should be stable enough, such that the ropivacaine (or other API) undergo minimal degradation during storage and wearing. The formulation should allow sufficient solubility of ropivacaine (or other API) and yet avoid precipitation or crystallization during storage and wearing. Further for example, the topical composition should provide satisfactory flux rate or skin permeability, such that a pharmaceutically effective amount of ropivacaine (or other API) may be absorbed through the skin.

[01 1 ] Another challenge in preparing a suitable topical composition formulation can be the adhesivity. The adhesivity should be enough so that the topical composition can remain on keratinous material for a period of time long enough for the ease of administration without the need to reapply frequently. On the other hand, the adhesivity of the topical composition should not be too strong at the end of wearing period such that removal of the topical composition causes damage. SUMMARY OF THE INVENTION

[012] Accordingly, the present disclosure relates to topical compositions which can deliver a sufficient amount of ropivacaine (or other API) into a subject's skin over a period of time longer than 12 hours, such as 18 hours, 24 hours, or 36 hours, while removal of such topical composition from the keratin material of the subject can avoid skin damage at the application site, and may allow a subsequent application of topical composition on the same location immediately thereafter.

[013] The most pronounced effect is obtained when there is a need for repeated application of topical compositions on same locations of the skin and where application of known topical compositions results in skin damage. Hence, in preferred embodiments of the invention, the API is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), such as, in particular, ketorolac, diclofenac, ibuprofen or naproxen, local anesthetics, medications for skin conditions, for example for treating atopic dermatitis, antipruritics, in particular antihistamines, medications for local pain, medications for neuropathic pain.

[014] The present disclosure also relates to a topical composition containing ropivacaine (or other API), which adheres to keratinous material for a period of time greater than 12 hours, such as 18 hours, 24 hours, or 36 hours, and may be removed easily after wearing, without causing severe skin damage, such as skin stripping.

[015] Thus, the present disclosure relates to suitable topical composition which comprises suitable adhesive(s), backing material(s), and with optionally added enhancer(s), hydrophilic polymer(s), and other appropriate additives.

[016] Disclosed herein is a topical composition for delivering a pharmaceutically active ingredient, in particular ropivacaine, comprising:

ropivacaine and/or a salt thereof;

at least one adhesive material; and at least one backing material,

[017] wherein, after application of the topical composition to keratinous material of a subject, a pharmaceutically effective amount of a pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for a desired period of time, while the topical composition remains adhesive to the keratinous material. The desired period of time for pain treatment is typically greater than 12 hours, for example, at least 18 hours, 24 hours, or 36 hours.

[018] In at least one embodiment of the present disclosure, the adhesivity of the topical composition is reduced by at least 20% after 12 hours while the topical composition remains adhesive to the keratinous material. In at least one embodiment, after applying the topical composition to the keratinous material, the adhesivity of the topical composition is reduced, such that after 12 hours an external force no greater 2.5 N is required to remove the topical composition from the keratinous material. For example, no greater than 2.4 N, no greater than 2.3 N, no greater than 2.2 N, no greater than 2.1 N, no greater than 2.0 N, no greater than 1 .9 N , no greater than 1 .8 N , no greater than 1 .7 N , no greater than 1 .6 N, no greater than 1.5 N , no greater than 1 .4 N, no greater than 1.3 N , no greater than 1.2 N, no greater than 1 .1 N , no greater than 1 .0 N, no greater than 0.9 N , no greater than 0.8 N, no greater than 0.7 N , no greater than 0.6 N, no greater than 0.5 N , no greater than 0.4 N, no greater than 0.3 N , no greater than 0.2 N, no greater than 0.1 N, or no greater than 0 N, is required to remove the topical composition from the keratinous material.

[019] In at least one embodiment, the average in vitro flux rate of ropivacaine (or other API) ranges from 1 to 10 g/(cm^2*h) during the first 24 hours after application, such as from 2 to 8 g/(cm^2*h), from 3 to 6 g/(cm^2*h), from 4 to 5 g/(cm^2*h), or 4.5 g/(cm^2*h).

[020] In at least one embodiment, the topical composition leaves the skin visibly intact.

[021 ] In at least one embodiment, ropivacaine (or other API) is present in an amount ranging from 1 to 10% (w/w) , such as from 2 to 5% (w/w), or from 3 to 4% (w/w), or for instance, ranging from 3.0% (w/w), 3.1% (w/w), 3.2% (w/w), 3.3% (w/w), 3.4% (w/w), 3.5% (w/w), 3.6% (w/w), 3.7% (w/w), 3.8% (w/w), 3.9% (w/w) and 4.0% (w/w), relative to composition without solvent or backing material. In at least one embodiment, the pharmaceutically active ingredient, in particular ropivacaine, is present in an amount ranging from 3.6 to 3.7% (w/w). In at least one embodiment, the pharmaceutically active ingredient, in particular ropivacaine, is present in amorphous state.

[022] In at least one embodiment, the at least one adhesive material is chosen from acrylate polymer, styrene polymer, silicone, Ethylene vinyl acetate (EVA), and polyisobutene (PIB). In at least one embodiment, the at least one adhesive material is acrylate polymer. In at least one embodiment, at least one adhesive material is chosen from DURO-TAK® 87-9301 (Durotak 9301 , acrylate copolymer), DURO-TAK® 87-2510 (Durotak 2510, acrylate polymer), DURO-TAK® 87-2516 (Durotak 2516, acrylate vinylacetate copolymer), PIB 618A (poly isobutylene), and BIO PSA 7-4302 (silicone).

[023] In at least one embodiment, the topical composition may further comprise at least one hydrophilic polymer. In at least one embodiment, the at least one hydrophilic polymer is present in an amount ranging from 1 to 20 % (w/w), for example, from 2.5 to 10% (w/w), or about 5% (w/w), relative to composition without solvent or backing material.

[024] In at least one embodiment, the at least one hydrophilic polymer is a product of at least one monomer comprising vinylpyrrolidone monomer, such as polyvinylpyrrolidone (PVP). In at least one embodiment, the at least one hydrophilic polymer is a product of at least one monomer comprising vinyl acetate monomer, such as PVP-VA (copovidone).

[025] In at least one embodiment, the at least one hydrophilic polymer is chosen from PVP, and copovidone. In at least one embodiment, the at least one hydrophilic polymer is a mixture of PVP and copovidone in a ratio ranging from 1 :0.1 to 1 :10, for example, in a ratio of 1 :1 , or in a ratio of 1 :3. [026] In at least one embodiment, the at least one hydrophilic polymer can be chosen from Soluplus®, PVP (Kollidon 30), copovidone (Kollidon VA64), Eudragit E and Kollicoat MAE.

[027] The at least one hydrophilic polymer can be present in an amount ranging from 1 to 20% (w/w), for example, 2.5% (w/w) to 10% (w/w), or about 5% (w/w), relative to composition without solvent or backing material.

[028] In at least one embodiment, the at least one hydrophilic polymer is cross-linked, for example, a cross-linked PVP. In at least one embodiment, the at least one hydrophilic polymer is insoluble in solvents, for example, water, ethanol, isopropyl alcohol, heptane, ethyl acetate.

[029] In at least one embodiment, the topical composition may further comprise at least one enhancer. The at least one enhancer can be chosen from, for example, oleic acid, caprylic acid, lactic acid, oleyl alcohol, dodecanol, triacetin, isoprolyl myriastate (IPM), levulinic acid, polysorbate 60 (polyoxyethylene sorbitan monostearate), lauryl lactate, dimethyl isosorbide (DMI), azone ( 1 -dodecylazacycloheptan-2-one), and poloxamer 188 (poly ethylene oxide-poly propylene oxide copolymer).

[030] The at least one enhancer may comprise an acid functionality, for example, oleic acid, caprylic acid, lactic acid, and levulinic acid; or the at least one enhancer may comprise an alcohol functionality, such oleyl alcohol, dodecanol, and polysorbates, such as polysorbate 60. In at least one embodiment, the at least one enhancer is chosen from oleic acid and oleyl alcohol.

[031 ] In at least one embodiment, the at least one enhancer may be present in an amount ranging from 1 to 20% (w/w), relative to composition without solvent or backing material. For example, the topical composition can contain at least one enhancer comprising, for example, 5% (w/w) oleic acid and 5% (w/w) caprylic acid, relative to composition without solvent or backing material. By way of further example, the topical composition can contain at least one enhancer comprising 2.5% (w/w) oleic acid and 5% (w/w) oleyl alcohol, relative to composition without solvent or backing material. In at least one embodiment, the topical composition may contain at least one enhancer comprising 2.5% (w/w) oleic acid, relative to composition without solvent or backing material.

[032] The backing material of the topical composition may be chosen from a variety of materials, for example, PE, PET, PU, non-woven, and acrylonitrile-methyl acrylate copolymer (Barex). The at least one backing material can be chosen from occlusive materials, such as PET; semi-occlusive materials, such as PE; and non-occlusive materials, such as PU. In at least one embodiment, the backing material is a PET.

[033] The thickness of the at least one backing material can range from 10 m to 10 mm, for example, 20 μηη to 1 mm, or 40 to 100 μηη.

[034] The topical composition may further comprise at least one antioxidant. The at least one antioxidant can be chosen from, for example, a-tocopherol, butylhydroxy toluene (BHT), and sodium-EDTA. The amount of the at least one antioxidant in the topical composition can range from 0.01% (w/w) to 10% (w/w), for example, from 0.1% (w/w) to 5% (w/w), or about 1 % (w/w, relative to composition without solvent or backing material).

[035] In at least one embodiment, the topical composition comprises:

at least one backing material comprising PE (CoTran™ 9719);

at least one adhesive material comprising an acrylate polymer (Durotak 9301 );

the pharmaceutically active ingredient, in particular ropivacaine, in an amount ranging from 3-5% (w/w);

1 :3 mixture of PVP: copovidone in an amount of 5% (w/w), relative to composition without solvent or backing;

at least one enhancer comprising 2.5% (w/w) oleic acid, and optionally 5% (w/w) oleyl alcohol,

BHT in an amount of 1 % (w/w),

wherein, all (w/w) % is relative to composition without solvent or backing material, and further wherein after application of the topical composition to the keratinous material of a subject, a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for at least 12 hours while the patch remains adhesive to the keratin material.

[036] Further disclosed herein is a method of making a topical composition for keratin material, comprising

providing a liner;

preparing a solution of an adhesive mixture comprising:

the pharmaceutically active ingredient, in particular ropivacaine, in a pharmaceutically sufficient amount;

at least one adhesive material;

at least one solvent; and

at least one hydrophilic polymer;

casting the solution to the liner;

allowing the solution to dry on the liner; and

attaching a backing material on the exposed surface of the dried adhesive mixture.

[037] Also disclosed herein is a method of making a topical composition for keratin material, comprising

providing a backing material;

preparing a solution of an adhesive mixture comprising:

at least one adhesive material;

at least one solvent; and

at least one hydrophilic polymer;

casting the solution to the backing material; allowing the solution to dry on the backing material; and

attaching a liner on the exposed surface of the dried adhesive mixture.

[038] In at least one embodiment, the topical composition is cut into suitable size such that a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into a subject continuously for at least 12 hours.

[039] The present disclosure also relates to a method for continuous treatment of pain for at least 12 hours, comprising:

applying a topical composition to keratinous material of a subject in need, wherein the topical composition comprises:

the pharmaceutically active ingredient, in particular ropivacaine, and/or a salt thereof;

at least one adhesive;

at least one backing material,

optionally at least one hydrophilic polymer; and

optionally at least one enhancer, and

wherein a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for at least 12 hours while the patch remains adhesive to the keratinous material.

[040] The present disclosure also relates to a topical composition wherein, after application of the topical composition to keratinous materials of the subject in need, the adhesivity of the topical composition is reduced during a wearing time of greater than 12 hours, such that an external force no greater than 2.5 N is required to remove the topical composition from the keratinous material. For example, an external force no greater than 2.4 N, no greater than 2.3 N, no greater than 2.2 N, no greater than 2.1 N, no greater than 2.0 N, no greater than 1 .9 N , no greater than 1 .8 N , no greater than 1.7 N , no greater than 1.6 N, no greater than 1 .5 N , no greater than 1.4 N, no greater than 1 .3 N , no greater than 1 .2 N, no greater than 1 .1 N , no greater than 1 .0 N, no greater than 0.9 N , no greater than 0.8 N, no greater than 0.7 N , no greater than 0.6 N, no greater than 0.5 N , no greater than 0.4 N, no greater than 0.3 N , no greater than 0.2 N, no greater than 0.1 N, or no greater than 0 N, is required to remove the topical composition from the keratinous material. The external force is measured using standard international testing machine, modified for measurement of transdermal system. For example, the adhesivity of the topical composition may be reduced by at least 20% after more than 12 hours while the topical composition remains adhesive to the keratinous material.

[041 ] In at least one embodiment, removal of the topical composition from the subject comprises:

pulling a portion of the topical composition away from the subject; and

exposing the interface between the subject and the pulled portion of the topical composition to water. In at least one embodiment, the topical composition falls off on its own.

[042] In at least one embodiment, after the topical composition is removed after more than 12 hours, application of a second topical composition can be placed on the same location on the subject.

[043] Also disclosed herein is a topical composition for delivering at least one pharmaceutically active ingredient or salts thereof, comprising:

the at least one pharmaceutically active ingredient and/or salts thereof;

at least one adhesive material;

at least one backing material; and

at least one hydrophilic polymer in an amount ranging from 5% (w/w)-10% (w/w), relative to composition without solvent or backing material;

wherein, after application of the topical composition to keratin material of a subject, the adhesivity of the topical composition is reduced by at least 20% after more than 12 hours while the topical composition remains adhesive to the keratinous material. [044] In at least one embodiment, the at least one hydrophilic polymer comprises PVP and optionally PVP-VA. In at least one embodiment, the at least one hydrophilic polymer comprises PVP and PVP-VA, for example, in a ratio of 1 :3. For example, a mixture

of:PVP:copovidone (Kollidon 30:Kollidon VA64) in a ratio of 1 :3. In at least one embodiment, the PVP is cross-linked.

[045] In at least one embodiment, after application of the topical composition to keratin material of a subject, the adhesivity of the topical composition is reduced while wearing, such that an external force no greater than 2.5 N is required to remove the topical composition from the keratin material. For example, an external force no greater than 2.4 N, no greater than 2.3 N, no greater than 2.2 N, no greater than 2.1 N, no greater than 2.0 N, no greater than 1.9 N , no greater than 1 .8 N , no greater than 1 .7 N , no greater than 1.6 N, no greater than 1 .5 N , no greater than 1 .4 N, no greater than 1.3 N , no greater than 1.2 N, no greater than 1 .1 N , no greater than 1 .0 N, no greater than 0.9 N , no greater than 0.8 N, no greater than 0.7 N , no greater than 0.6 N, no greater than 0.5 N , no greater than 0.4 N, no greater than 0.3 N , no greater than 0.2 N, no greater than 0.1 N, or no greater than 0 N, is required to remove the topical composition from the keratin material.

[046] Also disclosed herein is a self-adhesive patch comprising:

at least one pharmaceutically active ingredient for treatment of pain, and/or a salt thereof;

at least one adhesive material; and

means for reducing adhesivity of the patch, over a time period of more than 12 hours after application of the self-adhesive matrix patch to skin of a subject, such that an external force no greater than 2.5 N is required to remove the matrix patch from the skin after the 24 hours, for example, no greater than 2.4 N, no greater than 2.3 N, no greater than 2.2 N, no greater than 2.1 N, no greater than 2.0 N, no greater than 1 .9 N , no greater than 1.8 N , no greater than 1 .7 N , no greater than 1 .6 N, no greater than 1.5 N , no greater than 1 .4 N, no greater than 1 .3 N , no greater than 1 .2 N, no greater than 1.1 N , no greater than 1 .0 N, no greater than 0.9 N , no greater than 0.8 N, no greater than 0.7 N , no greater than 0.6 N, no greater than 0.5 N , no greater than 0.4 N, no greater than 0.3 N , no greater than 0.2 N, no greater than 0.1 N, or no greater than 0 N. In at least one embodiment, the pharmaceutically active ingredient is ropivacaine.

[047] Additional objects and advantages of the present disclosure, as disclosed herein, will be clear from the description, or may be learned by practice of the disclosure. It is to be understood that both the general description and detailed description found herein are exemplary and explanatory only and are not restrictive of the disclosure, as claimed.

[048] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate one (several) embodiment(s) of the disclosure and together with the description, serve to explain the principles of the disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

[049] Figure 1 A illustrates a graph from which in vitro flux rates can be calculated, as well as a table showing the calculated value.

[050] Figure 1 B illustrates comparison of relative in vitro flux rates from enhancer formulations with varying concentrations.

[051 ] Figure 2 illustrates changes of adhesiveness over 48 hours in formulations with different amounts of a soluble Kollidon mixture.

[052] Figure 3 illustrates changes of adhesiveness over 48 hours in formulations with different amounts of an insoluble cross-linked PVP

[053] Figure 4 illustrates changes of water content and weight over 24 hours in patch formulations with different hydrophilic polymers.

[054] Figure 5 illustrates change of in-vivo adhesiveness during a wearing experiment with five volunteers over 24 hours. [055] Figure 6 illustrates influence of polymer content on in-vivo adhesiveness volunteer.

DETAILED DESCRIPTION OF THE INVENTION

[056] As used herein:

[057] The singular forms "a," "an," and "the" include plural reference unless the context indicates otherwise. Any term ending with "(s)" encompasses the term in both singular and plural form.

[058] The terms "approximately" and "about" mean to be nearly the same as a referenced number or value. As used herein, the terms "approximately" and "about" should be generally understood to encompass ±10% of a specified amount, frequency or value. Further, all numbers expressing the quantities used in the specification and claims, for example, concentration, reaction conditions, time, temperature and yield, are modified by the term "about," unless otherwise indicated. As used herein, when a numerical range is given, both ends of the range are included.

[059] In at least one embodiment, the at least one hydrophilic polymer in the topical composition reduces the force required to peel off the composition from the keratinous material, over a period of wearing time of greater than 12 hours, for example, 18 hours, 24 hours, or 36 hours, by at least about 20% compared to a topical composition containing no such hydrophilic composition, for example, by at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[060] The topical composition in this disclosure can be in the form of a patch, such as a reservoir-type patch or a matrix patch. A reservoir type patch may include a membrane which controls the rate of drug release. A matrix type patch may have at least one pharmaceutically active ingredient dispersed or dissolved in a matrix, such as an adhesive material.

[061 ] Keratinous material makes up the outer layer of skin, hair and nails. [062] If not otherwise specified, the concentrations defined herein are based on weight percentage relative to the combined weight of the all pharmaceutically active ingredient(s), all excipient(s) such as adhesive material, enhancers, hydrophilic polymers, antioxidants, excluding any solvents, backing material or release layer.

[063] A pharmaceutically active ingredient, or an active pharmaceutical ingredient (API), is a substance used in a finished pharmaceutical product intended to furnish

pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings. For example, a pharmaceutically active ingredient can be an anesthetic or an analgesic. The topical composition, as used herein, may contain a pharmaceutically active ingredient, an anesthetic or an analgesic, for example, ropivacaine.

[064] In preferred embodiments of the invention, the API is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as, in particular, ketorolac, diclofenac, ibuprofen or naproxen, local anesthetics, medications for skin conditions, for example for treating atopic dermatitis, antipruritics, in particular antihistamines, medications for local pain and medications for neuropathic pain.

[065] The effective amount for treatment of a given API will vary with many factors, for example, the efficacy of the API, the formulation, skin type, age of the subject receiving the treatment, location and area of the topical treatment.

[066] Many factors may affect the flux rate of a topical composition, for example, API(s), concentration of the pharmaceutically active ingredient(s), choices of backing material and adhesive material. Flux may also be affected by addition of enhancer(s) and/or hydrophilic polymers in the topical composition and choice thereof.

[067] Measurement of in vitro flux rate or skin permeation can be done by, for example, a Franz-Cell experiment using human donor skin as a membrane. In the setup that was used for all experiments, the skin sample was placed in horizontal orientation. A patch sample is directly placed on the skin and samples were drawn from the acceptor side at predefined sampling times. A marketed patch formulation, such as a lidocaine patch (Versatis®), may be used as a reference to calculate relative flux rates.

[068] The in vitro flux was calculated from the linear part of the graphs (see, e.g., Figure 1 A), when the system was in the "steady-state." This was for most formulations typically from 6 to 32 hours. For Versatis® the steady state was usually even longer, due to its higher drug load. Here, the flux was typically calculated between 8 and 48 hours. The linearity was evaluated by the correlation coefficient. Five to six replicates were used for the calculation of a mean flux rate. If a sample showed a strong variation from the other samples, or within its linearity, it was excluded from the calculation. The values calculated from the different experiments showed that a comparison of the absolute flux among different experiments is not practical, since the skin samples vary between each experiment. For example, the absolute in vitro flux for Versatis® for different skin samples may vary from 5 to 25 g/(cm^2*h). However, the relative flux rates, e.g., relative to Versatis®, have shown to be consistent among different experiments. Therefore, an assessment of a relative flux was deemed an appropriate parameter to rely on for comparison of different formulations.

[069] Measurement of adhesivity can be achieved by a static material testing machine (e.g. Zwick Roell), which measures the force that is needed to pull off a patch sample from a surface. In some embodiments, the adhesivity of the topical composition is reduced by at least 20% after more than 12 hours. For example, the adhesivity over a period of wearing time of more than 12 hours, for example, 18 hours, 24 hours, or 36 hours, may be reduced by at least 25%, 30%, 35%, 40%, 45, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, while the topical composition remains adhesive to the keratinous material.

[070] It was unexpectedly discovered that the addition of at least one hydrophilic polymer, which increases flux rate of ropivacaine or other API in a topical composition, may also reduce the adhesivity of the topical composition. The topical composition disclosed herein may be worn by a subject for more than 12 hours, such as at least 18 hours, 24 hours, or 36 hours without at least one untoward side effect such as skin damage (e.g., stripping, itching, irritation, swelling, inflammation, redness, blistering, bruising, or change in skin color). In at least one embodiment, removal of the topical composition leaves the skin visibly intact. As a non-limiting example, removal of the topical composition would not cause any discomfort to the subject, or only cause minimal discomfort.

[071 ] In preferred embodiments of the invention, the pharmaceutically active ingredient is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), such as, in particular, ketorolac, diclofenac, ibuprofen or naproxen, local anesthetics, medications for skin conditions, for example for treating atopic dermatitis, antipruritics, in particular

antihistamines, medications for local pain and medications for neuropathic pain.

[072] The pharmaceutically active ingredient, in particular ropivacaine, as used herein, may be a free base, or a salt, such an acid addition salt. In at least one embodiment, the free base of the pharmaceutically active ingredient, in particular ropivacaine, is used. In at least one embodiment, the pharmaceutically active ingredient, in particular ropivacaine, is in a

concentration in the topical composition such that very little or no recrystallization or

precipitation occurs during storage or wearing.

[073] As used herein, "polymer" encompasses homopolymers (polymerization products of one single monomer), and copolymers (polymerization products of more than one

monomers).

[074] A hydrophilic polymer, as used herein, is a polymer which contains polar or charged functional groups. Non-limiting examples of hydrophilic polymers include

polyacrylamides, poly(2-oxazoline), polyethylenimine (PEI), polyacrylates, polyethyleneglycol, poly(ethylene oxide), polyvinyl alcohol) and copolymers, poly(vinylpyrrolidinone) (PVP), and polyelectrolytes, and copolymers thereof. Non-limiting examples of commercially available hydrophilic polymers include Soluplus®, Eudrafit E PO, Kollidon VA 64, Kollidon 30, and Kollicoat MAE.

[075] For example, PVP's are sold under brand names such as Kollidon®, for instance, Kollidon® 30. Examples of copolymers of PVP include, but not limited to copolymer of 1 -vinyl-2- pyrrolidone and vinyl acetate, also known as PVP-VA or VP-VA copolymer, such as

copovidone, which contains 1 -vinyl-2-pyrrolidone and vinyl acetate in mass ratio of 3:2.

Examples of commercial products of copovidone include, but not limited to those sold under brand name, Kollidone® VA 64, sold by BASF.

[076] The at least one hydrophilic polymer may be present in an amount ranging from 1 to 20% (w/w), relative to composition without solvent or backing material, for example, from 2% (w/w) to 10% (w/w), such as 5% (w/w). As used herein, more than one hydrophilic polymer may be used in the topical composition. In at least one embodiment, the hydrophilic polymers include PVP and copovidone. In at least one embodiment, two hydrophilic polymers are mixed in a ratio ranging from 1 :0.1 to 1 :10, such as 1 :0.2, 1 :0.5, 1 :1 , 1 :3, 1 :5, and 1 :8. In at least one embodiment, PVP and copovidone are used in a ratio of 1 :3. In at least one embodiment, Kollidon 30 and Kollidon VA64 are used in a ratio of 1 :3. In at least one embodiment, the topical composition contains 5% (w/w) of hydrophilic polymers including Kollidon 30 and Kollidon VA64 in a ratio of 1 :3.

[077] One of the potential concerns during the development of any topical composition containing an API is that the API may re-crystallize in the topical composition upon long-term storage. Thus, in at least one embodiment, the topical compositions may further comprise at least one precipitation inhibitor to prevent crystallization of ropivacaine, or other API, or salts thereof.

[078] A cross-linked polymer is a polymer in which chemical bonds link one polymer chain to another. It is formed when substances are subject to a cross-linking method. For instance, PVP (povidone) can become insoluble as a result of crosslinking, frequently at higher temperatures, if it is combined with strongly alkaline substances such as lithium carbonate or sodium hydroxide. For example, crospovidone, available commercially under the name

Kollidon® CL, is a physically cross-linked insoluble polyvinylpyrrolidone. Many cross-linked polymers are insoluble in solvents such as water, ethanol, isopropyl alcohol, heptane or ethyl acetate.

[079] An adhesive material enables the topical composition to attach to the keratinous material for a period of time. The amount of adhesive may constitute an amount in the range of 1 % (w/w) to 99% (w/w), relative to composition without solvent or backing material, for example, about 2% (w/w) to 90% (w/w), or 30% (w/w) to 90% (w/w), or 60% (w/w) to 85% (w/w).

[080] The at least one adhesive material suitable for the topical composition in this disclosure may be chosen from acrylate polymers, styrene polymer, polysiloxanes,

polyisobutene (PIB), polystyrene-isoprene block copolymers, amine-compatible and standard silicones, and polyurethane. In at least one embodiment, the at least one adhesive may be a hydrogel.

[081 ] In at least one embodiment, the at least one adhesive material is an acrylate polymer. Acrylate monomers generally used include acrylic acid, methacrylic acid, butyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2- ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2- ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, and tridecyl methacrylate. Functional monomers,

copolymerizable with the above alkyl acrylates or methacrylates, which are generally used include acrylic acid, methacrylic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate and methoxyethyl methacrylate. [082] Acrylate polymers include but are not limited to acrylate copolymers without any functional groups such as -OH or -COOH, for instance, DURO-TAK® 87-9301 .

[083] The adhesive material may be a pressure-sensitive adhesive (PSA) which adheres when pressure is applied to attach the adhesive with a surface, such as keratinous material, and the degree of adhesiveness is affected by the amount of pressure used for the adhesion. Non-limiting examples of PSA are adhesives sold under brand names such as DURO-TAK®.

[084] Non-limiting examples of commercially available acrylate polymers are Durotak 87-9301 , Durotak 2510, Durotak 2516.

[085] The at least one adhesive material can be combined with at least one substance suitable for topical application, for example, at least one API, such as ropivacaine, enhancers, hydrophilic polymer(s), antioxidant(s) to provide a mixture as a solution, which can then be cast on a surface, such as a liner. After the solution is dried, a backing material can be attached to the exposed surface to provide a patch.

[086] The solubility of the API can be affected by several factors, for example, the type of adhesive material and backing material, the addition of enhancers added into the

pharmaceutical composition, and the addition of any hydrophilic polymers, as disclosed herein.

[087] Crystallization may be investigated after manufacturing of topical formulations. For example, the saturation solubility may be determined by placing some crystals of a pharmaceutically active ingredient in the topical formulation and storing it at 60 °C for several days to observe if crystallization takes place on the formulation. Alternatively, an excess of a API may be added to initiate crystallization right after the topical formulation is prepared. With the latter method, only fully saturated formulations would be studied in the skin permeation experiments. The appearance of crystals may be monitored by microscopic investigation.

[088] Crystallization in a topical formulation, such as a patch, may be an issue when supersaturated formulations are used. The supersaturated formulations are instable and temporarily provide higher flux rates, but there is a possibility of re-crystallization over time, which reduces performance. This phenomenon is discussed, for example, in the article (Jasti, B. R. et al., "A novel method for determination of drug solubility in polymeric matrices." Journal of Pharmaceutical Sciences 2004: 2135-2141 ). Therefore, if crystallization is to be avoided, the amount of API in a formulation should be at or below saturation.

[089] In some embodiments, the topical composition may further comprise at least one enhancer. The at least one enhancer may contain an acid functionality or an alcohol functionality. An enhancer with acid functionality may improve the solubility of an API containing a basic functionality. For example, the solubility of the pharmaceutically active ingredient, in particular ropivacaine, can be increased from 3% in oleyl alcohol to about 20% in oleic acid and caprylic acid. Non-limiting examples of the at least one enhancer include oleic acid, caprylic acid, lactic acid, oleyl alcohol, dodecanol, triacetin, isoprolyl myriastate (IPM), levulinic acid, polysorbate 60, lauryl lactate, dimethyl isosorbide (DMI), azone, and poloxamer 188. In some embodiments, a combination of more than one enhancer may help improve flux rate of an API. For example, oleic acid and oleyl alcohol may improve the flux rate of ropivicaine. The at least one enhancer may be present in the composition in an amount ranging from 1 to 20% (w/w), relative to composition without solvent or backing material, such as 1 % (w/w), 2.5% (w/w), 5% (w/w), 7.5% (w/w), 10% (w/w), 12.5% (w/w), 15% (w/w), or 17.5% (w/w).

[090] In at least one embodiment, the topical composition further comprises at least one backing material. The backing layer described herein may be adhered directly the adhesive material by adding an adhesive solution comprising an adhesive material onto a backing material. The backing material may serve as the upper layer of the topical composition, such as a patch, during administration and may function as the primary structural element of the patch. The backing material may also be attached to a release liner that contains the adhesive matrix. In at least one embodiment, the backing material is attached to a pre-formed liner with adhesive and API. [091 ] It may be desired that a backing material exhibit good flexibility and ductility in order to not affect a subject's movement if the topical composition is to be applied universally to any body part. However, it may also be desired that the backing material prevent some movement, for example, if it is desired that the subject not move the area being treated for pain. It is worth noting that the characteristics of the backing material may also affect the flux rate. For example, a PET backing foil is considered fully occlusive, which may provide higher flux rate but the PET material lacks flexibility. In another example, PE backing material is semi- occlusive, which may lower the flux rate of pharmaceutically active ingredient(s), such as 20- 30% lower, but provides a lower tensile strength which can be beneficial for larger-size patch. A commercial example of a stretchable PE backing is CoTran™.

[092] The backing material can be a monolithic (single layer) or a multi-layer

(multilaminate) having a thickness ranging from 0.1 mm to 50 mm, such as from 0.5 mm to 30 mm, and further such as from 1 mm to 25 mm.

[093] In at least one embodiment, the backing material may comprise at least one polymeric material chosen from polyethylene (PE), polypropylene (PP), polyesters,

polyurethanes (PU), polyethylene vinyl acetate, polyvinylidene chloride (PVC), block copolymers such as PEBAX, polyvinyl acetate (PVA), ethylene vinyl acetate, polyethylene terephthalate (PET), polybutylene terephthalate, acrylonitrile-methyl acrylate copolymer such as Barex, non- woven fabric, coated paper products, and metal or metalized sheets.

[094] As a non-limiting example, the backing material may comprise at least one flexible elastomeric material that would allow the patch to follow the contours of the skin such that the patch can be worn comfortably on any skin area including joints or other areas of flexure.

[095] Also as a non-limiting example, the backing material may be occlusive to the diffusion of the pharmaceutically active ingredient, in particular ropivacaine,, i.e., rather impermeable to an API. For instance, the backing material may comprise PET. [096] Further as a non-limiting example, the backing material may comprise at least one material that is semi-occlusive to the diffusion of an API. For instance, the backing material may comprise PE.

[097] Even further as a non-limiting example, the backing material may comprise at least one material that has no occlusive effect to the diffusion of a pharmaceutically active ingredient. For instance, the backing material may comprise PU.

[098] Also further as an additional non-limiting example, the backing material may comprise a breathable or occlusive material comprising woven or non-woven fabric. For example, the backing layer may further comprise a non-woven polyester fabric (e.g., DuPont's SONTARA® or SOFTESSE® fabric, Style 8005).

[099] In other embodiments, the topical composition may further comprise a liner or a release layer. The liner may be added on top of the adhesive layer, which is formed by casting the backing layer with adhesive solution comprising an adhesive material, and allowing the solution to dry. The liner serves as a protective outer surface to the adhesive layer, for example, during storage, and is removed prior to application to the keratinous material.

[0100] The topical composition can be manufactured into appropriate sizes in order to have sufficient amount of API permeate through the skin barrier to trigger a pharmaceutical effect. For example, a patch can be manufactured in a size ranging from about 10 cm² to about 200 cm², such as about 140 cm².

[0101 ] The topical composition as disclosed herein may also be cutable for providing therapeutic effects to areas of different sizes, configurations, curvatures and movement. For instance, a patch according to the present disclosure may be cut into a dimension suitable for applying to irregularly shaped body parts such as toes and fingers. The topical composition disclosed herein may also be cut into a dimension suitable for applying to the chest, back, legs, arms, and other larger areas, and possibly the face. The dosage of each topical composition application may be adjusted by cutting a patch into appropriate size. [0102] The topical composition can be stable, with minimal or no degradation during storage and wearing. Stability of the topical composition may be affected by pH value of the composition, the choices of adhesive material, backing material, enhancer(s) and hydrophilic polymers, as well as by the environment, such as temperature and relative humidity.

EXAMPLES

Example 1. Preparation of a Topical Matrix Patch Containing Ropivacaine

[0103] As set forth in Table 1 below, the adhesive material, enhancer(s), hydrophilic polymer(s), and antioxidant(s) were weighed in and diluted with ethyl acetate to get final solutions with a solid content of 30% (w/w), relative to the total weight of the composition. See Table 1 below. Ropivacaine was added to this solution and stirred for at least one hour with a magnetic stirrer, until the API was completely dissolved. This solution was then cast with a casting knife (400 μηη slit, Erichsen) onto a surface coated release liner and dried in an oven at 70^qC for 20 min. After drying, the adhesive was laminated with a backing film. Patches were then punched out from the laminate using a cutting die.

[0104] Table 1. Topical composition containing ropivacaine

As disclosed herein, all percentage is w/w relative to combined weight of the composition components, excluding any solvent(s), backing material, and release liner. Ethyl acetate was used during preparation of both topical matrix patches. Example 2. Saturation Solubility in Adhesive Materials

[0105] The adhesives that were successfully tested for compatibility with ropivacaine were also used to determine the saturation solubility of ropivacaine in these polymers.

Therefore a defined amount API was dissolved in the adhesive solution, as described in Example 1 . The solution was dried and investigated for crystals and recrystallization upon storage at 60 °C for several days. If no crystals appeared in the dried solution, the amount of API was increased until crystals were detected. Alternatively, if crystals were already found in the dried solution, the amount of API was reduced, until the crystals disappeared.

[0106] Ropivacaine showed high solubility in acrylate adhesives such as Durotak 2516 and Durotak 2510 (1 -3%), such as in Durotak 87-9301 (about 3.0%), which is an acrylate copolymer without any functional groups, like -OH or -COOH. The solubility in alternative adhesives, like silicone 4302 or PIB 618A, was lower, for instance, about 0.2 to 0.4% could be dissolved.

Example 3. Effects of Adhesive Material on Flux Rate

[0107] Five baseline formulations with different adhesives were split up into two sets, each containing the Versatis® patch as reference. The first set contained the different acrylates, from which the Durotak 9301 achieved the highest flux rate (Table 2). This flux rate was at about 22% of the Versatis® flux rate that was achieved with the Versatis® formulation.

Table 2. First set of formulations with different adhesives

[0109] The second set contained the baseline formulations with a silicone adhesive and a PIB adhesive. Here, the calculated relative flux rates were lower than for the acrylate adhesives, at about 12% for the silicone formulation, and at about 4% for the PIB formulations. See Table 3.

Table 3. Second set of formulations with different adhesives

Example 4. Microreservoir Formulation Based on a Silicone Adhesive

[01 1 1 ] A formulation based on the silicone adhesive was prepared. Poly vinyl pyrrolidone (PVP) was used to manufacture a bi-phase system with API loaded PVP droplets in an inner phase, to obtain a so-called "microreservoir" system. Another microreservoir system based on the silicone adhesive was prepared with the addition of PVP and oleic acid. This formulation had a drug load of 1 % (w/w), five times higher than in the pure silicone matrix. However, in a skin permeation experiment it did not show an increased relative flux rate. As shown in Table 4, the relative flux rate is about 6% relative to Versatis®.

[01 12] Table 4. Silicone based microreservoir

Example 5. Effects of Single Enhancers on Flux rate

[01 13] As shown in the following Tables 5 and 6, all tested enhancers had a positive influence on the relative flux rate of ropivacaine. For instance: the oleic acid formulation had a relative flux rate of 40.1 %. The relative flux rates achieved with addition of caprylic acid and dodecanol were at comparable levels of about 32%. The backing foil was a fully occlusive PET material.

Table 5. Single enhancers

Table 6. Single enhancers (continued)

Example 6. Adjustment of Enhancer Concentration

[01 16] In Figure 1 B, the fluxes for formulations with different enhancer and API concentrations are shown, relative to Versatis® An increase of the enhancer concentration did not lead to an increase of the ropivacaine flux rate, in the case of oleic acid, and oleyl alcohol. Moreover, the relative flux rates seemed to be reduced a little, although the standard deviations did not show a significant effect.

[01 17] For the oleyl alcohol formulation, a reduction of the enhancer concentration to 2.5% (w/w) also had a negative effect on the relative flux rate, while for the oleic acid formulation the relative flux rate remained at a consistently higher level. The results of these studies indicated that a concentration of 2.5% (w/w) was sufficient for oleic acid to perform with a maximum effectiveness. For oleyl alcohol a concentration at about 5% (w/w), seemed to be result in the highest relative flux rate. Due to the fact that the flux rate could not be increased with varying concentrations, combinations of the potential enhancers were tested as well.

Example 7. Use of a Hydrophilic Polymer as Precipitation Inhibitor

[01 18] The addition of 10% (w/w) Soluplus® showed a surprisingly high relative flux rate in skin permeation. See Table 7. With increased relative flux rate, a reduction in API could be possible, which could reduce the chances of re-crystallization. [01 19] Table 7. First set of alternative enhancer formulations

Example 8. Combinations of Different Enhancers and Alternative Backing

[0120] The combination of oleic acid and caprylic acid as well as the combination of oleic acid and oleyl alcohol showed an increase in the relative flux rate of ropivacaine from patch formulations.

[0121 ] The permeation experiment for the oleic acid/caprylic acid combination showed a relative flux rate in the range of 67-89%, which was higher than for the oleic acid/oleyl alcohol combination, as shown in Table 8.

[0122] The influence of a semi-occlusive PE backing was also studied in the same experiment. It was observed that changing from an occlusive PET backing to a semi-occlusive backing could decrease the relative flux-rate the range of 20-30%. However, this decrease could be acceptable because the aforementioned enhancer combinations resulted in achieving more than the targeted flux rate.

[0123] Table 8. Ropivacaine permeation from formulations with a caprylic acid/oleic acid combination and two different backing materials

[0124] In case of the oleic acid/oleyl alcohol combination, as shown in Table 9, a relative flux rate of 61 .1 % was achieved. The combination of dodecanol and oleyl alcohol, however, did not show synergistic effects, since the relative flux rate (40.0%) was only at a level that was comparable to the flux rate from a formulation with oleyl alcohol alone.

Table 9. Formulations with enhancer combinations

Example 9. Hydrophilic Polymers as Alternative to Soluplus®

[0126] The screening for alternative polymers showed that polymers that formed a turbid solution with the adhesive were able to increase the relative flux rate as it was observed with Soluplus®. Only Eudragit E PO, which was perfectly miscible with the adhesive, did not show a positive effect on the flux rate. A turbid bi-phase system was observed in the formulations in which the flux rate was increased. The highest potential was seen in Kollidon VA 64. Although the sample set contained two underperforming samples that caused high standard deviations, the overall increase of the relative flux rate seemed to be highest with Kollidon VA 64. Additionally, the polymer was completely soluble in ethyl acetate, the solvent of the used adhesive, which was not the case for Kollidon 30 or for Kollicoat MAE (Table 10).

Table 10. Overview of results from hydrophilic polymer screening

[0128] The formulation with Kollidon VA 64 showed a relative slow onset of drug release, which was much faster with the Kollidon 30 formulation. Therefore a combination of the two polymers, with a higher percentage of Kollidon VA 64, seemed to be a good alternative. A 1 :3 (Kollidon 30: Kollidon VA 64) combination of the two polymers was tested in different concentrations.

[0129] Four formulations with 6% API (w/w) and different concentrations (2.5% (w/w)- 15% (w/w)) of the Kollidon mixture and 5% (w/w) of oleic acid were studied in skin permeation. The results of these tests showed that the concentration of the Kollidon mixture had no influence on the flux rate, as all formulations performed equally well (Table 1 1 ). [0130] Table 11. Formulations with different concentrations of a hydrophilic polymer mixture

[0131 ] Furthermore, the onset of drug release from all formulations was fast and comparable to the Versatis® formulation. Because of the semi-occlusive PE backing that was used for all formulations in Table 1 1 , the calculated relative flux rates were all in the range of 40- 45%. This flux rate would already be sufficient, and it is believed that it could be further increased in combination with an enhancer.

Example 10. Influence of Hydrophilic Polymers Without Additional Enhancers

[0132] For a baseline formulation containing no enhancer, addition of a Kollidon-mixture increased the flux rate by about 4%, as shown in Table 12.

[0133] Table 12. Comparison of two baseline formulations with and without addition of a Kollidon-mixture

Example 11. Enhancers

[0134] In the first set of alternative enhancer formulations, isopropyl myristate (IPM) and triacetin showed a trend of higher flux rates than achieved with levulinic acid or polysorbate 60. The observed trend was clear enough to rank the different enhancers according to their relative flux rates. Furthermore, the relative flux rates of IPM and triacetin formulations were comparable to the relative flux rate that was achieved with oleic acid in a comparable formulation. The data are shown in Table 13.

[0135] Table 13. First set of alternative enhancer formulations

[0136] In a second set of comparison experiments, absolute flux rate of reference Versatis® was much higher than other set of experiments (24.8 vs. 7.7 g (cm^2*h)). Therefore, absolute flux rates, rather than the relative flux rates, of formulations containing different enhancers were compared. In this set, two formulations showed a trend towards higher flux rates: lauryl lactate and dimethyl isosorbide (DM I) showed higher enhancer potential than azone or poloxamer 188. The data are shown in Table 14.

[0137] Table 14. Second set of alternative enhancer formulations

[0138] In a further investigation of suitable enhancers, six combinations of enhancers were tested. In the first set, the combination of triacetin and lauryl lactate achieved a positive effect, while all other combinations showed a comparable but lower flux rate (Table 15). It might also be possible that some of the tested enhancers are not effective in lower concentrations as the test formulations contained only 2.5% (w/w) of each enhancer.

[0139] Table 15. First set of enhancer combination formulations

[0140] In the second set of combination tests, the oleic acid formulation was used as additional reference. See Table 16. The highest relative flux rate in this experiment was achieved with a combination of DMI and lauryl lactate. This combination also seemed to suggest some synergistic effects.

Table 16. Second set of enhancer combination formulations

Example 12. Reduction of Adhesivity Upon Open storage

[0142] Although the average adhesivity of patches with addition of a water-soluble Kollidon mixture decreased with increasing amounts of hydrophilic polymer, the adhesiveness did not change significantly upon storage at higher humidity. Comparison of adhesiveness [N] among patches containing 2.5% (w/w), 5.0% (w/w), 10.0% (w/w), and 15.0% (w/w) of soluble Kollidon as a hydrophilic polymer at 5, 25, and 48 hours are shown in Figure 2.

[0143] In the case of the addition of cross-linked (insoluble) PVP, the adhesiveness not only decreased with increase of the concentration, but showed also a significant decrease upon storage at high humidity. This effect was more pronounced for patches that contained 5% (w/w) or more of the hydrophilic polymer. For the patches with addition of 15% (w/w) cross- linked PVP the adhesiveness was reduced from about 10 N to about 3 N over a storage time of 48 hours. Here, the reduction of the adhesiveness was high within the first 2-4 hours and did not really decrease much further after 24 hours, as illustrated in Figure 3. [0144] Figure 4 shows that the water uptake over 24 hours increased with increasing polymer content but comparable for the two tested hydrophilic polymers. Furthermore, the investigation of the weight increase confirmed the results from the KF-titration.

[0145] The different behavior of the two formulations might be due to the insoluble cross-linked PVP which segregates during the manufacturing of the patches, and is therefore found in higher ratios at the surface of the patch, while the soluble Kollidon mixture is distributed homogenously in the patch. Since the patch with 15% (w/w) cross-linked PVP showed the most considerable effect of adhesiveness reduction in vitro, it was decided to investigate this formulation in an in vivo wearing test as well.

Example 13. In-vivo Wearing Test for Patches Containing Hydrophilic Polymer(s)

[0146] It was found that the values for adhesiveness in-vivo were substantially lower and showed values for the initial adhesiveness of around 1 N for most volunteers only.

Although, the absolute values for the adhesiveness on human skin did not correlate with the adhesiveness on steel, it was still possible to observe a reduction of the adhesiveness after a wearing time of greater than 12 hours - specifically, in this test, the target was 24 hours. In two volunteers it was not really possible to quantify this reduction, since the adhesiveness was too low and the volunteers lost their patches after ~20 hours. In two other volunteers the deviation was high and no statistical significance of the reduction in the range of 20-30% was given. The last volunteer showed a statistical significant reduction of the adhesiveness of around 70%. See Figure 5.

[0147] In general it could be shown that it is possible to reduce the adhesiveness over a wearing time of greater than 12 hours, such as around 24 hours. In some cases the initial adhesiveness was already low and the decrease of the adhesiveness was in some cases too strong and too fast to obtain a sufficient adhesion over 24 hours. Therefore, there was an additional experiment to see if a reduction of the amount of cross-linked PVP could increase the initial adhesiveness of the patch. However, the adhesiveness remained at the observed low level also for patches with 10% (w/w) or 5% (w/w) of cross-linked PVP, only. See Figure 6. A patch with higher adhesivity may be formed by addition of enhancers. A patch with a different backing material, such as a softer material, or with a different shapes may also be produced.

Example 14. In-vitro Skin Permeation Test

Preparation of skin samples

[0148] Dermal absorption through human skin was assessed applying abdominal or breast skin. Skin from female donors was supplied from plastic surgery. After arrival, skin was visually inspected whether it was without any scars and stretch marks. The skin used ranged from 300 to 500 μηη thick and prepared by a dermatome. The skin can be stored for half a year -20 °C storage, or directly used for permeation. The skin was punched to pieces of 1 .5 cm² to allow a permeation area of 0.82 cm² in the Franz-type diffusion cell.

Preparation of patch

[0148] Round shaped patch samples of 0.82 cm² were punched out of the topical compositions prepared according to the above-described methods. The patch samples then were tested in in-vitro skin permeation experiments (horizontal orientation of sample in Franz cell, human skin).

Franz-type Diffusion Cell

[0149] Franz-type diffusion cell, used in the examples discussed herein, includes a donor compartment and a receptor compartment. The skin is placed between the two compartments, and the permeation area of the cell is 0.82 cm². The static cell is made of glass and may be used in either a horizontal or vertical orientation.

In Vitro Skin Permeation

[0150] The skin sample was prepared and dermatomed as described above. The patch was then placed on the skin sample and was pressed against it for a short time, such as 10 seconds. The skin with adhered patch was added to the donor compartment of a horizontal Franz-type diffusion cell which was filled with acceptor medium. The Franz-type diffusion cell which was later placed in a water bath with temperature controlled at 32 °C ± 2°C for the permeation with a stirring speed of 350 rpm. The testing usually lasted over a period of 72 hours.

[0151 ] At each sampling time, 4.5 ml_ of the acceptor medium was withdrawn manually, and analyzed by HPLC. The amount of withdrawn medium was replaced afterwards. The content of ropivacaine was determined by HPLC. Samples not used that day were stored at 2- 8^<C until the time of HPLC analysis.

Evaluation and Calculation of in vitro flux rate

[0152] The cumulative API amount per permeation area of each cell was plotted against the corresponding sampling time. Flux rate was calculated from the linear part of the graphs, when the system was in the "steady-state." The time required for a particular API to reach steady state varies. For example, the time for ropivacaine formulations to reach steady state is usually from 6 to 32 hours. For Versatis®, the time required to reach steady state can be longer, due to its higher drug load. In the examples discussed herein, the flux was typically calculated between 8 and 48 hours.

[0153] The linearity was evaluated by the correlation coefficient. Five to six sampling data were used for the calculation of a mean flux rate. If a sampling data showed a large variation from the others (or from their linearity), it was excluded from the calculation.

[0154] From the linear part of the resulting curve the slope and correlation coefficient was calculated. A correlation coefficient >0.995 was usually regarded as a good linearity. The slope of the curve is equal to the flux rate expressed in g (cm^2*h). For each testing with Franz- type diffusion cell, usually n (number of sampling data points) being 6, a mean flux rate and standard deviation was calculated.

[0155] As previously discussed herein, comparison of the absolute flux value from different experiments had some difficulty, possibly because a flux value highly depends on the skin sample used in each experiment. For example, the flux for Versatis® could vary from 5 to 25 g/(cm^2*h) among different experiments. The relative flux rates, however, were shown to be rather consistent across different skin samples. Therefore, relative flux was used in most examples for comparison.

Example 15. In vitro Test for Patch Adhesion ("Peel Strength")

[0156] Laminate strips of known width or patches were stored over 24 hours under controlled condition at 23°C ± 2°C temperature.

[0157] Adhesion strength is the force required to strip off a sample with a defined angle and defined speed from a plate with a defined surface.

[0158] Test samples are adhered with defined force onto a testing surface. Using a suitable test system (e.g. Zwick Roell machine BT1 -FR2.5TN.D14, as used for the data discussed herein, including PC/application (100N)) the sample was stripped off from the test surface under continuous measurement of the force needed to maintain the stripping speed at the defined angle. The testing method was according to the directions of the European standard test DIN EN 1939.

[0159] The test was performed according the written operating manual of the test system. The specified plain test surface (polished stainless steel plate or plexiglass) was cleaned carefully. The release liner of the test sample was removed and the sample was placed immediately (within 15 seconds) onto the horizontally adjusted testing surface without applying any pressure.

[0160] The sample was then pressed onto the surface by defined procedure, which uses 1 ) a stainless steel barrel providing the mass of 2kg sample width or 2) a 2kg weight on a glass plate placed onto the sample surface, for the time of 60 ± 6 seconds.

[0161 ] The sample is allowed to stay at least 60 seconds on the test surface before the stripping off procedure.

[0162] The test plate with the sample was inserted into the test machine according to the desired test direction (90° or 180° peel angle). A connecting aid (e.g. piece of double sided adhesive tape) was attached to one end to the sample. The peel off test using the specified instrument settings was conducted on the other end of the sample, with continuous force measurement and with a speed of 300 ± 50 mm/min.

Evaluation

[0163] The evaluation was only performed in the steady state section of the test, and the starting "crack" section, usually no less than 5 mm sample length, is discarded.

[0164] The adhesive strength of the test sample, measured by the force values of the adhesive strength, was evaluated using software. Based on the actual sample size, the results were also converted for the standard sample width of 25mm.

[0165] Unless otherwise stated, six parallel samples are measured and evaluated and the F_mit mean of the six determinations is reported.

F_mit: mean force in measuring range

F_min: minimum force in measuring range

F_max: maximum force in measuring range

Example 16. Wearing Test with Different Enhancers

[0166] Two topical formulations, (1 ) the 5% (w/w) oleic acid/5% (w/w) caprylic acid combination in and (2) the 10% (w/w) Soluplus®/10% (w/w) oleic acid combination, were chosen to be manufactured into patches using Durotak 9301 as adhesive, with a size of about 136 cm². The backing material used in this experiment was a flexible PE foil with a thickness of 74 μηη. One of each patch was given to every volunteer of a group with 13 volunteers. The volunteers were asked to wear both patches on upper arm or breast simultaneously over a period of 24 hours and rate them for their wearing comfort, adhesiveness and cold flow.

Table 17. Results of wearing tests

Standard Standard

Average Average

deviation deviation after

1.0% 2.6% 0.0% 0.0%

Loose areas % application

Day 1 1 1.8% 13.1% 0.2% 0.3%

Comfort (0-5) Day 1 2.9 1 .6 3.6 0.8 after

3.8 0.9 3.2 1 .3

Adhesion (0-5) application

Day 1 3.1 1 .4 2.0 1 .6

Cold flow (0-5) Day 1 1 .4 1 .0 1 .3 0.8

Skin redness

Day 1 2.6 1 .5 1 .6 0.8 (1 -10)

itching (1 -10) Day 1 2.3 0.4 3.6 1 .6

[0168] The patch that contained an enhancer combination of oleic acid and caprylic acid, 5% (w/w) each, was rated, on average, slightly better with regard to adhesiveness than the patch containing 10% (w/w) oleic acid and 10% (w/w) Soluplus®. However, less adhesiveness can be useful, when thinking of a repeated application, where the stripping effect and therefore also the skin irritation/damage would be reduced. Other results also showed that the amount of hydrophilic polymer as well as oleic acid can be reduced to adjust the adhesiveness to a desired level.

[0169] Cold-flow describes the moving of the patch on the skin, which often causes the formation of a dirty, adhesive area around the patch. This phenomenon was not observed for any of the tested patches, which confirmed Durotak 9301 as a suitable choice as the adhesive material. Example 17. Stability Evaluation

[0170] Informal stability evaluations were performed on the two formulations shown in Table 18. The storage conditions were at

- 25^<€/60% relative humidity (r.H). and

- 40^<€/75% r.H.

The stability data at different time point are shown in Table 3. The results of the informal stability were all within acceptable limits. At accelerated conditions the API content seems to decrease. The sum of impurities remains marginally lower for the prototype without oleyl alcohol.

Table 18. Stability data of Formulations 1 and 2.

[0172] After a storage time of two months the content of ropivacaine continued to decrease. This became more noticeable at accelerated conditions of 40^qC/ 75% r.H. A loss of active ingredient of up to 7 % was observed after two months storage at 40 °C/ 75% r.H. for both prototypes. However, the trend was not as clear for storage at 25^qC/60%r.H, in which only Formulation B showed a higher loss of active ingredient of up to 3% ropivacaine after two months. The ropivacaine content of Formulation A seemed to be stable. No high loss of active ingredient was observed. [0173] The situation was different for the impurities. Formulation A showed a higher amount of impurities than Formulation B. Both formulations showed no increase of the amount of impurities. After a storage time of two months the impurity level stayed the same for all storage conditions.

[0174] Both formulations were stored in PE pouches. It is possible the packaging material (pouch) may affect the amount of lost active ingredient in the formulations. For example, the loss of active may be reduced, if a different packaging material, such as Barex- coated material, is used. Furthermore, a decreased concentration of the active ingredient may also slow down the loss over time.

[0175] Preferred embodiments of the invention are described in the following:

[0176] Embodiment 1 . A topical composition for delivering a pharmaceutically active ingredient, in particular ropivacaine, comprising: the pharmaceutically active ingredient, in particular ropivacaine, and/or a salt thereof; at least one adhesive material; and at least one backing material, wherein, after application of the topical composition to keratinous material of a subject, a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for a wearing period greater than 12 hours, while the topical composition remains adhesive to the keratinous material.

[0177] Embodiment 2. The topical composition of embodiment 1 , wherein the wearing period of the topical composition is at least 18 hours.

[0178] Embodiment 3. The topical composition of embodiment 1 or 2, wherein the wearing period of the topical composition is at least 24 hours.

[0179] Embodiment 4. The topical composition of any one of the preceding

embodiments, wherein the wearing period of the topical composition is at least 36 hours.

[0180] Embodiment 5. The topical composition of any one of the preceding

embodiments, wherein the adhesivity of the topical composition is reduced by at least 20% after 24 hours while the topical composition remains adhesive to the keratinous material. [0181 ] Embodiment 6. The topical composition of any one of the preceding embodiments, wherein, after applying the topical composition to the keratinous material, the adhesivity of the topical composition is reduced, such that after 24 hours an external force no greater than 2.4 N is required to remove the topical composition from the keratinous material.

[0182] Embodiment 7. The topical composition of any one of the preceding embodiments, wherein the average flux rate of the pharmaceutically active ingredient, in particular ropivacaine, ranges from 1 -10 g/(cm2^*h) during the first 24 hours after application

[0183] Embodiment 8. The topical composition of any one of the preceding embodiments, wherein the keratinous material includes skin, and the removal leaves the skin visibly intact.

[0184] Embodiment 9. The topical composition of any one of the preceding embodiments, wherein the pharmaceutically active ingredient, in particular ropivacaine, is present in an amount ranging from 1 to 10% (w/w), relative to the weight of the composition excluding the backing material.

[0185] Embodiment 10. The topical composition of any one of the preceding embodiments, wherein the pharmaceutically active ingredient, in particular ropivacaine, is present in an amount ranging from 3 to 4% (w/w), relative to weight of the composition excluding the backing material.

[0186] Embodiment 1 1 . The topical composition of any one of the preceding embodiments, wherein the at least one adhesive material is chosen from acrylate polymer, styrene polymer, silicone, and polyisobutene.

[0187] Embodiment 12. The topical composition of any one of the preceding embodiments, wherein the at least one adhesive material is acrylate polymer.

[0188] Embodiment 13. The topical composition of any one of the preceding embodiments, wherein the at least one adhesive material is chosen from Durotak 87-9301 , Durotak 2510, Durotak 2516, PIB 618A, and BIO PSA 4302. [0189] Embodiment 14. The topical composition of any one of the preceding

embodiments, further comprising at least one hydrophilic polymer.

[0190] Embodiment 15. The topical composition of embodiment 14, wherein the at least one hydrophilic polymer is present in an amount ranging from 1 to 20% (w/w), relative to the weight of the composition excluding the backing material.

[0191 ] Embodiment 16. The topical composition of embodiment 14, wherein the at least one hydrophilic polymer is present in an amount ranging from 2.5% (w/w) to 10% (w/w), relative to the weight of the composition excluding the backing material.

[0192] Embodiment 17. The topical composition of embodiment 14, wherein the at least one hydrophilic polymer is present in an amount of 5% (w/w), relative to the weight of the composition excluding the backing material.

[0193] Embodiment 18. The topical composition of any one of the preceding

embodiments 14 to 17, wherein the at least one hydrophilic polymer is a product of at least one monomer comprising vinylpyrrolidone monomer.

[0194] Embodiment 19. The topical composition of any one of the preceding

embodiments 14 to 17, wherein the at least one hydrophilic polymer is a product of at least one monomer comprising vinyl acetate monomer.

[0195] Embodiment 20. The topical composition of any one of the preceding

embodiments 14 to 19, wherein the at least one hydrophilic polymer is chosen from PVP and copovidone.

[0196] Embodiment 21 . The topical composition of any one of the preceding

embodiments 14 to 20, wherein the at least one hydrophilic polymer is a mixture of PVP and copovidone in a ratio of 1 :3.

[0197] Embodiment 22. The topical composition of any one of the preceding

embodiments 14 to 21 , wherein the at least one hydrophilic polymer is chosen from Soluplus®, PVP (Kollidon 30), copovidone (Kollidon VA64), Eudragit E and Kollicoat MAE. [0198] Embodiment 23. The topical composition of any one of the preceding

embodiments 14 to 22, wherein the at least one hydrophilic polymer is cross-linked.

[0199] Embodiment 24. The topical composition of any one of the preceding

embodiments 14 to 23, wherein the at least one hydrophilic polymer is insoluble in water, ethanol, isopropyl alcohol, heptane, or ethyl acetate.

[0200] Embodiment 25. The topical composition of any one of the preceding embodiments 14 to 24, wherein the at least one hydrophilic polymer comprises cross-linked PVP and optionally PVP:VA.

[0201 ] Embodiment 26. The topical composition of any one of the preceding

embodiments, further comprising at least one enhancer.

[0202] Embodiment 27. The topical composition of embodiment 26, wherein the at least one enhancer comprises an acid functionality.

[0203] Embodiment 28. The topical composition of any one of the preceding

embodiments 26 to 27, wherein the at least one enhancer is chosen from oleic acid, caprylic acid, lactic acid, oleyl alcohol, dodecanol, triacetin, isopropyl myriastate (IPM), levulinic acid, polysorbate 60, lauryl lactate, dimethyl isosorbide (DMI), azone, and poloxamer 188.

[0204] Embodiment 29. The topical composition of embodiment 28, wherein the at least one enhancer is chosen from oleic acid and oleyl alcohol.

[0205] Embodiment 30. The topical composition of any one of the preceding

embodiments 26 to 29, wherein the at least one enhancer is present in an amount ranging from 1 to 20% (w/w), relative to the weight of the composition excluding the backing material.

[0206] Embodiment 31 . The topical composition of embodiment 28, wherein the at least one enhancer comprises 5% (w/w) oleic acid and 5% (w/w) caprylic acid, relative to the weight of the composition excluding the backing material. [0207] Embodiment 32. The topical composition of embodiment 29, wherein the at least one enhancer comprises 2.5% (w/w) oleic acid and 5% (w/w) oleyl alcohol, relative to the weight of the composition excluding the backing material.

[0208] Embodiment 33. The topical composition of embodiment 28, wherein the at least one enhancer comprises 2.5% (w/w) oleic acid, relative to the weight of the composition excluding the backing material.

[0209] Embodiment 34. The topical composition of any one of the preceding

embodiments, wherein the at least one backing material is chosen from PE, PET, PU, non- woven, and acrylonitrile-methyl acrylate copolymer (Barex).

[0210] Embodiment 35. The topical composition of any one of the preceding

embodiments, wherein the at least one backing material is occlusive, semi-occlusive, or non- occlusive.

[021 1 ] Embodiment 36. The topical composition of any one of the preceding

embodiments, wherein the backing material is PET.

[0212] Embodiment 37. The topical composition of any one of the preceding

embodiments, wherein the at least one backing material has a thickness ranging from 10 m to 10 mm.

[0213] Embodiment 38. The topical composition of any one of the preceding

embodiments, further comprising at least one antioxidant.

[0214] Embodiment 39. The topical composition of embodiment 38, wherein the at least one antioxidant is chosen from a-tocopherol, butylhydroxy toluene (BHT), and sodium-EDTA.

[0215] Embodiment 40. The topical composition of embodiment 38 or 39, wherein the at least one antioxidant is present in an amount ranging from 0.01 % (w/w) to 5% (w/w), relative to the weight of the composition excluding the backing material.

[0216] Embodiment 41 . A method of making a topical composition for keratin material, comprising providing a liner, preparing a solution of an adhesive mixture comprising: a pharmaceutically active ingredient, in particular ropivacaine, and/or a salt thereof; at least one adhesive material; at least one solvent; and at least one hydrophilic polymer; casting the solution to the liner; allowing the solution to dry on the liner; and attaching a backing material on the exposed surface of the dried adhesive mixture.

[0217] Embodiment 42. The method of embodiment 41 , wherein the topical composition is cut into suitable size such that a pharmaceutically effective amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into a subject continuously for a period of time greater than 12 hours.

[0218] Embodiment 43. A method for continuous treatment of pain for greater than 12 hours, comprising: applying a topical composition to keratinous material of a subject in need, wherein the topical composition comprises: a pharmaceutically active ingredient, in particular ropivacaine, and/or a salt thereof; at least one adhesive; at least one backing material, optionally at least one hydrophilic polymer; and optionally at least one enhancer, and wherein a pharmaceutically effect amount of the pharmaceutically active ingredient, in particular ropivacaine, permeates into the subject for a wearing period greater than 12 hours, while the topical composition remains adhesive to the keratinous material.

[0219] Embodiment 44. The method of embodiment 43, wherein, after application of the topical composition to the keratinous material, the adhesivity of the topical composition is reduced during wearing, such that an external force no greater than 2.4 N is required to remove the topical composition from the keratinous material.

[0220] Embodiment 45. The method of embodiment 43 or 44, wherein the wearing period is at least 24 hours, and wherein the adhesivity of the topical composition is reduced by at least 20% after 24 hours while the topical composition remains adhesive to the keratinous material.

[0221 ] Embodiment 46. The method of any one of the preceding embodiments 43 to 45, wherein removal of the topical composition from the subject comprises: pulling a portion of the topical composition away from the subject; and exposing the interface between the subject and the pulled portion of the topical composition to water.

[0222] Embodiment 47. The method of any one of the preceding embodiments 43 to 46, wherein, the topical composition is removed after the wearing period, and a second topical composition is applied on the same location of the subject as the previous composition.

[0223] Embodiment 48. A topical composition for delivering at least one

pharmaceutically active ingredient and/or salts thereof, comprising: the at least one

pharmaceutically active ingredient and/or salts thereof; at least one adhesive material; at least one backing material; and at least one hydrophilic polymer present in an amount ranging from 5% (w/w)-10% (w/w), relative to the weight of the composition excluding the backing material; wherein, after application to keratinous material of a subject, the adhesivity of the topical composition is reduced by at least 20% after 24 hours of wearing, while the topical composition remains adhesive to the keratinous material.

[0224] Embodiment 49. The topical composition of embodiment 48, wherein the at least one hydrophilic polymer comprises PVP and optionally PVP-VA.

[0225] Embodiment 50. The topical composition of embodiment 48, wherein the at least one hydrophilic polymer comprises PVP and PVP-VA.

[0226] Embodiment 51 . The topical composition of embodiment 50, wherein PVP and PVP-VA are in a ratio of 1 :3.

[0227] Embodiment 52. The topical composition of any one of the preceding

embodiments 49 to 51 , wherein PVP is cross-linked.

[0228] Embodiment 53. The topical composition of any one of the preceding

embodiments 49 to 52, wherein, after application of the topical composition to keratin material of a subject, the adhesivity of the topical composition is reduced while wearing, such that after 24 hours of wearing, an external force no greater than 2.4 N is required to remove the topical composition from the keratin material. [0229] Embodiment 54. The topical composition of any one of the preceding embodiments 49 to 53, wherein a pharmaceutically effective amount of the pharmaceutically active ingredient permeates into the subject for at least 24 hours while the topical composition remains adhesive to the keratin material.

[0230] Embodiment 55. The topical composition of any one of the preceding

embodiments 49 to 54, further comprising at least one enhancer.

[0231 ] Embodiment 56. A self-adhesive patch comprising: at least one pharmaceutically active ingredient for treatment of pain and/or salts thereof; at least one adhesive material; and means for reducing adhesivity of the matrix over a wearing period greater than 12 hours on the skin of a subject, such that an external force no greater than 2.4 N is required to remove the patch from the skin after the 24 hours.

[0232] Embodiment 57. The self-adhesive patch of embodiment 56, wherein the at least one pharmaceutically active ingredient is ropivacaine.

[0233] Other embodiments of the present disclosure will be apparent to those skilled in the art from consideration of the specification and practice as disclosed herein. It is intended that the specification and examples be considered as exemplary, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

1 . A topical composition for delivering at least one pharmaceutically active ingredient and/or salts thereof, comprising:

the at least one pharmaceutically active ingredient and/or salts thereof;

at least one adhesive material; and

at least one backing material;

wherein, after application to keratinous material of a subject, the adhesivity of the topical composition is reduced by at least 20% after 24 hours of wearing, while the topical composition remains adhesive to the keratinous material.

2. The topical composition of claim 1 further comprising at least one hydrophilic polymer.

3. The topical composition of any one of claim 2, wherein the at least one hydrophilic polymer comprises PVP and optionally PVP-VA, preferably PVP and PVP-VA in a ratio of 1 :3.

4. The topical composition of any one of the preceding claims, further comprising at least one enhancer.

5. The topical composition of any one of the preceding claims, wherein the at least one adhesive material is chosen from acrylate polymer, styrene polymer, silicone, and

polyisobutene, preferably acrylate polymer.

6. The topical composition of any one of the preceding claims, wherein the at least one hydrophilic polymer is selected from the group consisting of products of at least one monomer comprising vinylpyrrolidone monomer, products of at least one monomer comprising vinyl acetate monomer, in particular PVP, copovidone and a mixture of PVP and copovidone.

7. The topical composition of any one of the preceding claims, further comprising at least one enhancer, which preferably comprises at least an acid functionality.

8. The topical composition of any one of the preceding claims, wherein the at least one enhancer is chosen from oleic acid, caprylic acid, lactic acid, oleyl alcohol, dodecanol, triacetin, isopropyl myriastate (IPM), levulinic acid, polysorbate 60, lauryl lactate, dimethyl isosorbide (DMI), azone, and poloxamer 188, preferably oleic acid and oleyl alcohol.

9. The topical composition of any one of the preceding claims, wherein the at least one backing material is chosen from PE, PET, PU, non-woven, and acrylonitrile-methyl acrylate copolymer (Barex), preferably PET.

10. A self-adhesive patch comprising:

at least one pharmaceutically active ingredient for treatment of pain and/or salts thereof; at least one adhesive material; and

means for reducing adhesivity of the matrix over a wearing period greater than 12 hours on the skin of a subject, such that an external force no greater than 2.4 N is required to remove the patch from the skin after the 24 hours.

1 1. The topical composition of any one of the preceding claims 1 to 9 or the self- adhesive patch of claim 10, wherein the at least one pharmaceutically active ingredient is selected from the group consisting of nonsteroidal anti-inflammatory drugs (NSAIDs) such as, in particular, ketorolac, diclofenac, ibuprofen or naproxen, local anesthetics, medications for skin conditions, for example for treating atopic dermatitis, antipruritics, in particular antihistamines, medications for local pain and medications for neuropathic pain, preferably ropivacaine.

12. A topical composition as defined in any one of the preceding claims 1 to 9 or a self-adhesive patch as defined in claim 10 for use in therapy.

13. A topical composition as defined in any one of the preceding claims 1 to 9 or a self-adhesive patch as defined in claim 10 for use in the continuous treatment of pain for greater than 12 hours.

14. A method for continuous treatment of pain for greater than 12 hours, comprising: applying a topical composition to keratinous material of a subject in need, wherein the topical composition comprises:

at least one pharmaceutically active ingredient, in particular ropivacaine, and/or salt thereof;

at least one adhesive;

at least one backing material,

optionally at least one hydrophilic polymer; and

optionally at least one enhancer, and

wherein a pharmaceutically effect amount of ropivacaine permeates into the subject for wearing period greater than 12 hours, while the topical composition remains adhesive to the keratinous material.

15. A method of making a topical composition for keratin material, comprising providing a liner,

preparing a solution of an adhesive mixture comprising:

at least one adhesive material;

at least one solvent; and

at least one hydrophilic polymer;

casting the solution to the liner;

allowing the solution to dry on the liner; and