CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Patent Application No.

63/048,516, filed July 6, 2020, which is incorporated herein by reference in its entirety.

SUMMARY

This disclosure describes, in one aspect, a drug delivery device. Generally, the drug delivery device includes a substrate that includes a film cured under an atmospheric-pressure nitrogen dielectric barrier discharge, a reservoir disposed on at least a portion of the substrate, and a release liner disposed on at least a portion of the reservoir. The reservoir generally includes an adhesive composition and clobetasol propionate.

In some embodiments, the reservoir includes clobetasol propionate at a concentration of 0.005 wt% to 1.0 wt%.

In some embodiments, the film includes provides an occlusive backing. In some of these embodiments, the occlusive backing can include polyurethane, polyethylene, polyethylene terephthalate (PET), or a PET polyolefin laminate.

In some embodiments, the adhesive composition can include a silicone adhesive composition. In some of these embodiments, the silicone adhesive composition includes a blend of silicate resin and silicone polymer.

In some embodiments, the silicone adhesive composition includes two or more silicone polymers. In some of these embodiments, at least one silicone polymer includes trimethylsilyl end groups.

In some embodiments, the reservoir can further include an antioxidant. In some of these embodiments, the antioxidant can include propyl gallate.

In another aspect, this disclosure described a drug delivery device that generally includes a substrate, a reservoir disposed on at least a portion of the substrate, and a release liner disposed on at least a portion of the reservoir. In this aspect, the reservoir includes clobetasol propionate and an adhesive composition that includes a blend of silicate resin and silicone polymer provided in a silicate resin: silicone polymer ratio of from 57:43 to 59:41.

In some embodiments, the reservoir includes clobetasol propionate at a concentration of 0.005 wt% to 1.0 wt%.

In some embodiments, the film can provide an occlusive backing. In some of these embodiments, the occlusive backing can include polyurethane, polyethylene, polyethylene terephthalate (PET), or a PET polyolefin laminate.

In some embodiments, the silicate resimsilicone polymer ratio is from 58:42 to 59:41.

In some embodiments, the reservoir can further include an antioxidant. In some of these embodiments, the antioxidant can include propyl gallate.

In another aspect, this disclosure describes a drug delivery device that generally includes a substrate, a reservoir disposed on at least a portion of the substrate, and a release liner disposed on at least a portion of the reservoir. In this aspect, the reservoir includes clobetasol propionate and an adhesive composition comprising at least one silicone polymer having trimethyl silyl end groups.

In some embodiments, the reservoir includes clobetasol propionate at a concentration of 0.005 wt% to 1.0 wt%.

In some embodiments, the film can provide an occlusive backing. In some of these embodiments, the occlusive backing can include polyurethane, polyethylene, polyethylene terephthalate (PET), or a PET polyolefin laminate.

In some embodiments, the reservoir can further include an antioxidant. In some of these embodiments, the antioxidant can include propyl gallate.

The above summary is not intended to describe each disclosed embodiment or every implementation of the present invention. The description that follows more particularly exemplifies illustrative embodiments. In several places throughout the application, guidance is provided through lists of examples, which examples can be used in various combinations. In each instance, the recited list serves only as a representative group and should not be interpreted as an exclusive list.

BRIEF DESCRIPTION OF THE FIGURES FIG. 1. Cross section view of an occlusive drug delivery device. FIG. 2. In vitro cadaver skin permeation from 0.05% clobetasol propionate adhesive formulations compared to 0.05% ointment.

FIG. 3. In vitro cadaver skin permeation from 0.05% clobetasol propionate adhesive formulations compared to 0.05% ointment.

FIG. 4. In vitro cadaver skin permeation from 0.05% clobetasol propionate silicone adhesive formulations - effect of trimethyl silyl end capping (4202) versus silanol end capping (4502).

FIG. 5. Peel adhesion from HDPE, initial and delayed testing with silicone blend formulations.

FIG. 6. Shear creep compliance testing with silicone blend formulations.

FIG. 7. Effect of backing film on clobetasol propionate human cadaver skin permeation.

FIG. 8. Effect of backing film occlusion on clobetasol propionate human cadaver skin permeation.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

This disclosure describes a formulation for delivery of clobetasol propionate. Clobetasol propionate is a potent corticosteroid used, for example, in topical drug formulations for treating atopic dermatitis, psoriasis, and several other skin conditions. Clobetasol propionate is currently available by prescription in a variety of topical dosage forms, including ointments, lotions, creams, and foams, but is not available in a formulation suitable for delivery via an occlusive delivery device.

A formulation of clobetasol propionate designed for delivery via an occlusive delivery device can provide occlusion of the dosing site, which can hydrate the skin. Maintaining skin hydration can increase penetration of drug into the skin. Delivery of clobetasol propionate via an occlusive delivery device also can provide more precise dosing relative to other topical dosage forms, protect the dosing site from itching and scratching, and/or reduce mess during and after application, thereby reducing the likelihood and/or extent to which clobetasol propionate may be undesirably transferred to clothing, skin that is not in the treatment area, other surfaces, or other persons. Finally, the clobetasol propionate formulation described herein can deliver clobetasol propionate locally at a rate that is sufficient to provide therapeutic effect, but does not exceed the amount delivered from ointment or lotion formulations. FIG. 1 illustrates an exemplary embodiment of the drug delivery device 10 in cross- section. The drug delivery device 10 generally includes a substrate 11 that includes a film cured under an atmospheric-pressure nitrogen dielectric barrier discharge. A reservoir 20 is disposed on at least a portion of the substrate 11. The reservoir 20 includes an adhesive composition and clobetasol propionate. A release liner 12 is disposed on at least a portion of the reservoir 20.

The substrate 11 can be formed from any suitable material. Suitable materials include materials flexible enough that the substrate 11, and therefore the drug delivery device 10, can conform to the contours of the skin to which the drug delivery device 10 is applied. Suitable materials include conventional flexible backing materials used for pressure sensitive adhesive tapes, including, for example, polyethylene (particularly low density polyethylene, linear low density polyethylene, metallocene polyethylene, or high density polyethylene), polypropylene, polyesters such as polyethylene terephthalate, randomly oriented nylon fibers, ethylene-vinyl acetate copolymer, polyurethane, natural fibers such as rayon, and the like. Suitable materials also include materials that are layered including, but not limited to, polyethylene terephthalate- aluminum-polyethylene composites. The substrate material should be substantially inert to the components of the reservoir 20.

In some embodiments, the substrate 11 can provide an occlusive backing, which can promote hydration of the skin in the treatment area covered by the drug delivery device 10. A drug delivery device having an occlusive backing is referred to herein as an occlusive drug delivery device.

In some embodiments, the substrate 11 may be formed from low density polyethylene (LDPE) film, which is a low modulus film relative to other polymer backing materials. One exemplary low density polyethylene film is a 1.7 mil LDPE film (COTRAN, 3M Corp., St. Paul, MN). Several other lower modulus three-layer composite films were also evaluated and found to provide adequate adhesion to the knee and elbow joints. The exemplary 1.7 mil LDPE substrate film is occlusive, so that the skin hydrates and the clobetasol propionate more easily permeates the skin. Non-occlusive substrate films can reduce delivery to the skin. Preferably, the substrate is inert to, and resistant to uptake of, clobetasol propionate so that the clobetasol propionate remains available for delivery to the skin from the reservoir 20.

The substrate film is cured under an atmospheric-pressure nitrogen dielectric barrier discharge. The process for curing the substrate film in this manner is described in, for example, U.S. Patent No. 7,442,442. Curing the substrate film under an atmospheric-pressure nitrogen dielectric barrier discharge provides an unexpected benefit in product stability. Subjecting the substrate film to air corona-treatment resulted in a cl obetasol -related impurity being formed in the reservoir 20. Untreated substrate films resulted in impurities forming in the reservoir 20 after six months at accelerated conditions, simulating approximately two years of storage at room temperature. In contrast, the substrate film cured under an atmospheric-pressure nitrogen dielectric-barrier discharge did not form impurities in the reservoir 20. In comparison to films prepared by air corona-treatment, the atmospheric-pressure nitrogen dielectric barrier discharge curing treatment used to prepare the films described herein significantly reduces — and in some cases can eliminate — oxygenated species on the film surface that can cause impurities. The effect of curing the film under an atmospheric-pressure nitrogen dielectric barrier discharge therefore provides a cleaner film surface compared to an untreated substrate film. Alternatively, the atmospheric-pressure nitrogen dielectric barrier discharge curing process may crosslink a thin layer of the LDPE creating a greater barrier to migration of low level residual reactive species from the substrate film and into the clobetasol propionate-containing reservoir 20.

The reservoir 20 includes clobetasol propionate and an adhesive composition. In some embodiments, the clobetasol propionate can be provided at a minimum concentration of at least 0.005 wt% such as, for example, at least 0.010 wt%, at least 0.015 wt%, at least 0.02 wt%, at least 0.025 wt%, at least 0.03 wt%, at least 0.04 wt%, at least 0.05 wt%, at least 0.06 wt%, at least 0.07 wt%, at least 0.08 wt%, at least 0.09 wt%, or at least 0.10 wt%. In some embodiments, the clobetasol propionate can be provided at a maximum concentration of no more than 1.0 wt% such as, for example, no more than 0.90 wt%, no more than 0.80 wt%, no more than 0.70 wt%, no more than 0.60 wt%, no more than 0.50 wt%, no more than 0.40 wt%, no more than 0.30 wt%, no more than 0.20 wt%, no more than 0.10 wt%, or no more than 0.05 wt%. In some embodiments, the clobetasol propionate can be provided in a concentration expressed as a range having endpoints defined by any minimum concentration listed above and any maximum concentration listed above that is greater than the minimum concentration. Thus, for example, the clobetasol propionate can be provided at a concentration of from 0.005 wt% to 1.0 wt% such as, for example, from 0.025 wt% to 0.10 wt%. In certain embodiments, the clobetasol propionate can be provided in at a concentration equal to any minimum concentration or any maximum concentration. Thus, in some embodiments, clobetasol propionate can be provided at a concentration of 0.025 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, or 0.10 wt%.

The adhesive composition can include any polymer, or combination of polymers, that provides a desirable combination of adhesion to the skin and delivery of clobetasol propionate. Exemplary suitable polymers include, but are not limited to, acrylates, silicones, polyisobutylenes, and mixtures thereof.

In some embodiments, the adhesive composition can include a silicone adhesive composition. Many common silicone polymers have silanol end groups that can cause compatibility issues with certain amine containing drugs or excipients. In some embodiments, the adhesive composition includes condensation polymers of poly dimethyl siloxane and a silicate resin. In one particular exemplary embodiment, the adhesive composition includes one or more “amine compatible” adhesives that have trimethyl silyl end groups rather than silanol end groups. Formulations using adhesives with the trimethyl silyl groups provide superior delivery to and through the skin compared to equivalent formulations utilizing silanol-containing silicones. This observation was unexpected since clobetasol propionate is not an amine-containing compound and was not expected to interact with silanols. The improved delivery using amine compatible adhesives may be a solubility effect - the silanol groups enable a higher solubility of clobetasol propionate within the adhesive matrix, which reduces the thermodynamic activity of the clobetasol propionate in the adhesive composition and lowers the driving force for delivery to and through the skin. Likewise, acrylate adhesives that have much higher solubility than either variety of silicone adhesive provide reduced delivery of clobetasol propionate into and through skin. Polyisobutylene (PIB) adhesives provided adequate delivery but were not as durable as the silicone adhesives, which may be acceptable for applications in which durability is less of a concern.

In embodiments in which clobetasol propionate is provided in the reservoir 20 at low concentrations (e.g., 0.05 wt%), components of the adhesive composition may be selected to reduce solubility and thereby drive drug delivery. The trimethyl silyl end-capped silicones had the lowest clobetasol propionate solubility (approximately 0.1 wt.%) of any of the tested adhesives.

In one exemplary embodiment, the adhesive composition includes 70/30 blend of two siloxane polymers with trimethyl silyl groups (DC4202 and DC4302, Dow Corning Corp., Midland, MI). The difference between the two adhesives lies in the ratio of silicate resin to polydimethylsiloxane (PDMS) polymer. The DC4302 adhesive contains a 60/40 blend of resin to polymer, while the DC4202 contains a 55/45 blend. Thus, a 70/30 blend contains 70 parts 4302 to 30 parts 4202, which results in an overall resin to polymer ratio of approximately 58:42.

In other embodiments, the adhesive composition can include a blend of DC4202 and DC4302 that ranges from about 40/60 to about 80/20. A 40/60 blend provides a silicate resin to PDMS polymer ratio of 57:43. An 80/20 blend provides a silicate resin to PDMS polymer ratio of 59:41. Compositions within this range balance tack and cold flow properties of the component adhesive blends.

In some embodiments, the drug delivery device described herein delivers clobetasol propionate to and/or through skin at a slower rate than commercially available lotion and/or ointment formulations. Reducing clobetasol propionate systemic exposure is considered desirable, and the reduced delivery rate from the drug delivery device can result in reduced systemic exposure in vivo compared to lotion and/or ointment formulations.

The drug delivery device 10 also includes a release liner 12. The devices can include a release liner that covers and protects the skin-contacting surface, e.g., the adhesive composition, prior to application to a subject. Suitable release liners include, but are not limited to, conventional release liners that include a known sheet material, such as a polyester web, a polyethylene web, a polypropylene web, or a polyethylene-coated paper coated web with a suitable fluoropolymer or silicone-based coating. The devices can be packaged individually (e.g., in a foil-lined pouch) for storage or, alternatively, be provided in a rolled or stacked form suitable for use with a dispensing apparatus.

In some embodiments, over-formulation of clobetasol propionate may be desirable to compensate for losses of clobetasol propionate during the manufacturing process and/or to the release liner. For example, certain release liner materials may take up as much as 15% of the loaded clobetasol propionate.

The reservoir also can include one or more excipients. Certain excipients modulate the solubility of the clobetasol propionate within the formulation, enhance skin penetration of clobetasol propionate, modify adhesive properties, and/or minimize drug degradation. Exemplary excipient materials include C8-C36 fatty acids such as isostearic acid, octanoic acid, and oleic acid; C8-C36 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8- C36 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate, and methyl laurate; di(lower) alkyl esters of C6-C8 diacids such as diisopropyl adipate; monoglycerides of C8-C36 fatty acids such as glyceryl monolaurate; tetraglycol (tetrahydrofurfuryl alcohol polyethylene glycol ether); tetraethylene glycol (ethanol, 2, 2'-(oxybis(ethylenoxy))diglycol); C6-C36 alkyl pyrrolidone carboxylates; polyethylene glycol; propylene glycol; 2-(2-ethoxyethoxy)ethanol; diethylene glycol monomethyl ether; N,N-dimethyldodecylamine-N-oxide; lauryl lactate; levulinic acid; and combinations of the foregoing. Alkylaryl ethers of polyethylene oxide, polyethylene oxide monomethyl ethers, and polyethylene oxide dimethyl ethers are also suitable, as are solubilizers such as glycerol, triacetin, N-methyl pyrrolidone. Terpenes are another useful class of softeners, including pinene, d-limonene, carene, terpineol, terpinen-4-ol, carved, carvone, pulegone, piperitone, menthone, menthol, neomenthol, thymol, camphor, homed, citral, ionone, and cineole, alone or in any combination.

While many of the excipients enumerated above are known to affect skin penetration rate, certain excipients affect aspects of performance other than and/or in addition to skin penetration rate. For example, certain excipients may be useful in softening or increasing the compliance value and/or lowering the glass transition temperature of polymers, such that the resulting composition is more suitable for use as a pressure sensitive adhesive.

The excipient or excipients can be dispersed, preferably substantially uniformly, and more preferably dissolved in the composition. Where the excipient is a penetration enhancer, it can be present in an amount that enhances drug permeation through the skin compared to a like composition that does not contain the penetration enhancer when this phenomenon is measured using a standard skin penetration model, such as in U.S. Pat. No. 5,585,111, the disclosure of which is herein incorporated by reference. The total amount of excipient will generally be about 0.1% to about 40% by weight based on the total weight of the composition.

In some embodiments, the reservoir can include an antioxidant as an excipient.

Exemplary suitable antioxidants include, but are not limited to, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), tertiary butyl hydroquinone (TBHQ), propyl gallate, ascorbic acid and esters thereof (e.g., ascorbyl palmitate), tocopherol and esters thereof (e.g., tocopherol acetate and including isomers thereof), polyphenolic antioxidants, flavinoids, isoflavinoids, neoflavinoids, quercetin, rutin, epicatechins, resveratrol, thioglycerol, thioglycolic acid, thiourea, acetylcysteine, sodium bisulfite, sodium sulfite, sodium metabi sulfite, cyclodextrins (to cover site of active pharmaceutical compound subjected to oxidation), and carotenoids.

The drug delivery device 10 may be prepared by combining the clobetasol propionate, the selected components of the adhesive composition, and any additional excipients with an organic solvent (e.g., ethyl acetate, isopropanol, methanol, acetone, 2-butanone, ethanol, toluene, alkanes, or a mixture thereof) to provide a coating composition. The mixture is shaken or stirred until a homogeneous coating composition is obtained. The resulting composition is then applied to a release liner using conventional coating methods (e.g., knife coating or extrusion die coating) to provide a predetermined uniform thickness of coating composition.

The drug delivery device can be in the form of an article such as a tape, a patch, a sheet, a dressing, or any other form known to those skilled in the art. In some embodiments, the device will be in the form of a patch of a size suitable to deliver a preselected amount of clobetasol propionate through the skin. Generally, the device will have a surface area of about 5 cm ² to about 500 cm ² . In some cases, it may be useful to use multiple patches to provide the most effective treatment to patients with multiple sites or larger surface areas affected by atopic dermatitis or psoriatic lesions. In some embodiments, the device may take the form of a patch having a plurality of sections separated by perforations. Co-pending U.S. provisional patent application number 63/048,487, filed July 6, 2020, includes description of suitable patch designs.

While described below in the context of an exemplary embodiment in which the drug delivery device is in the form of a patch, and the clobetasol propionate formulation may therefore be referred to as a patch formulation, the described formulation can be used in the context of any delivery device having a backing material for handling and/or occlusion purposes. Thus, while the clobetasol propionate formulation is referred to herein as a “patch” formulation, the formulation may be used in the context of, for example, a bandage, a wrap, a plaster, a dressing, etc.

Human cadaver skin permeation studies were performed to evaluate the extent of clobetasol absorption from patch formulations made with different adhesive materials. These studies identified silicone, and to a lesser extent, polyisobutylene (PIB) as adhesives that promote permeation of clobetasol propionate into the skin. FIG. 2 shows better absorption from silicone (BIO-PSA 7-4302) relative to a selection of acrylates and acrylate/ silicone blends. FIG.

3 shows a similar study with polyisobutylene and a silicone polyoxamide (SPOX) adhesive compared to DC4302 (Dow Coming Corp., Midland, MI). In both studies, the silicone formulation provided permeation into the skin and the receptor solution that more closely matched the performance of the ointment formulation used as a positive control. Further study evaluated the effect of end-capping the siloxane polymer with trimethyl silyl groups (DC4202 and DC4302, Dow Corning Corp., Midland, MI) versus using a silanol end groups (DC4502, Dow Corning Corp., Midland, MI). The results are shown in FIG. 4, and show that the formulation with trimethyl silyl-end-capped siloxane polymer (DC4202) provided greater permeation of clobetasol propionate into and through the skin than the adhesive with the siloxane polymer having silanol groups (DC4502).

Blends of the “high tack” DC4302 and “medium tack” DC4202 adhesives were evaluated for in vitro adhesion to high density polyethylene (HDPE) test plates (FIG. 5) and for their compliance (FIG. 6). Despite relatively small differences in the composition of these adhesives based on slightly different ratios of silicone polymer to silicate resin, the adhesive performance is quite sensitive to these changes, with large swings in the both the peel adhesion and the compliance values. Adhesives richer in 4302 had higher compliance and better initial adhesion. Adhesives with more 4202 had lower compliance and higher adhesion after 30 minutes of dwell time. Thus, one can design a patch formulation according to desired adhesion properties. A 70/30 blend of 4302/4202 provides a shear creep compliance value of approximately 2 ^c 10 ⁵ cm ² /dyne, which is line with the compliance value of other transdermal delivery adhesive formulations designed for 24-hour wear. A clinical adhesion panel confirmed the acceptability of both 70/30 and 50/50 blends in adhesion to sites on the knee and elbow.

In the preceding description and following claims, the term “and/or” means one or all of the listed elements or a combination of any two or more of the listed elements; the terms “comprises,” “comprising,” and variations thereof are to be construed as open ended — i.e., additional elements or steps are optional and may or may not be present; unless otherwise specified, “a,” “an,” “the,” and “at least one” are used interchangeably and mean one or more than one; and the recitations of numerical ranges by endpoints include all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

The words “preferred” and “preferably” refer to embodiments of the invention that may afford certain benefits, under certain circumstances. However, other embodiments may also be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful and is not intended to exclude other embodiments from the scope of the invention.

Reference throughout this specification to “one embodiment,” “an embodiment,” “certain embodiments,” or “some embodiments,” etc., means that a particular feature, configuration, composition, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of such phrases in various places throughout this specification are not necessarily referring to the same embodiment of the disclosure. Furthermore, the particular features, configurations, compositions, or characteristics may be combined in any suitable manner in one or more embodiments. Further, features described in the context of one embodiment may be combined with features described in the context of a different embodiment except where the features are necessarily mutually exclusive.

In the preceding description, particular embodiments may be described in isolation for clarity. Unless otherwise expressly specified that the features of a particular embodiment are incompatible with the features of another embodiment, certain embodiments can include a combination of compatible features described herein in connection with one or more embodiments.

For any method disclosed herein that includes discrete steps, the steps may be conducted in any feasible order. And, as appropriate, any combination of two or more steps may be conducted simultaneously.

The present invention is illustrated by the following examples. It is to be understood that the particular examples, materials, amounts, and procedures are to be interpreted broadly in accordance with the scope and spirit of the invention as set forth herein.

EXAMPLES

General Instructions for Preparation of the Clobetasol Propionate Formulations

Clobetasol propionate and solvated adhesive polymer composition are weighed and added in the desired proportions to an appropriately sized vessel. Optionally, the clobetasol propionate may be pre-dissolved in ethyl acetate, NF at approximately 5-8 wt.% before adding to the adhesive. Any excipients are added to the vessel in the desired proportion, and the contents of the vessel are mixed until a uniform solution is obtained. The drug-in-adhesive solution is then coated on a release liner at the desired dry coating weight (e.g., 5 mg/cm ² ) using a suitable coating method (such as a knife coater) to obtain a uniform coating on the liner. The coated liner is then placed in an oven for a period of time (e.g., a Despatch convection oven at 43°C for 10 minutes) to remove the solvent and obtain a dried drug-in-adhesive coating on the release liner. The coated liner is then laminated to the desired backing film by bringing them together through a nip where pressure is applied to adhere the drug-in-adhesive coating to the backing (such as with a Laminex laminator). The liner was Scotchpak 9744 (3M Co., St. Paul, MN) and the backing was CoTran 9719 (3M Co., St. Paul, MN) unless stated otherwise. A punch, steel-rule die or other suitable tooling is then used to punch through the laminated material and create patches of the desired size.

Backing corona treatment:

Backing films were treated with a corona discharge using a corona treatment process as disclosed in U.S. Patent No. 7,442,442, the disclosure of which is incorporated by reference herein. For nitrogen treatment, the internal atmosphere within the corona treater was filled with nitrogen gas — i.e., a maximum of 100 ppm oxygen. The backing film is conveyed through the corona treater and is exposed to the corona discharge. A range of energy levels may be used (for example, 0.1 - 2.5 Joules/cm ² ), but the most preferable level for treatment of CoTran 9719 backing film is approximately 0.5 Joules/cm ² . Optionally, the backing film may be treated on both sides by running the film through the corona treater a second time, or by using a dual electrode corona treater.

In vitro skin permeation testing

Each study used dermatomed partial thickness human cadaver skin (full epidermis, partial dermis), which was cryopreserved and stored at -60°C until prepared for the study. The frozen skin was prepared for use by thawing and equilibrating in an antimicrobial solution on the day prior to the study (total preparation time is typically between 16-24 hours). After preparation, the skin was carefully and thoroughly patted dry and cut into appropriately sized sections for the respective sample/cell size. Any damaged skin was screened out prior to use. Skin samples are randomly selected during sample application. The studies used static modified Franz diffusion cells. The cells used have a 5 mL receptor solution volume for tape samples or a 25 mL volume for the ointment. The receptor solution was continually circulated via a stir bar. The environmental chamber that contains the Franz cells was maintained at 32°C. The receptor solution was a pH 7.4 phosphate buffered saline solution with 20% (v/v) PEG-400 and an antimicrobial.

Patch samples were 1 cm ² and the target coating weight was 5 mg/cm ² unless noted otherwise. The ointment was applied over a ~1 cm ² area with a target dose of between 4-6 mg to match the tape samples.

Each study used four replicates for each test sample unless otherwise noted.

The study run time was 24 hours with a single pull point at the end of the study.

The receptor solution was sampled at the end of the study. Approximately 1.5 ml of the receptor solution was filtered through a 0.45-micron filter, placed in an HPLC vial and capped. HPLC vials were refrigerated until analysis by HPLC. Patches were carefully removed from the skin after study completion and placed in a vial for extraction followed by analysis by HPLC. Any residual adhesive after removal was gently rolled off and added to the sample vial. Residual ointment was wiped from the skin using one cleaning swab soaked in ethanol followed by one dry swab. The swabs were placed in vials for extraction followed by HPLC analysis. The skin samples were placed in a vial for extraction followed by HPLC analysis. The assayed values were used to calculate the amount and the percentage of the applied dose found in each compartment (patch or ointment, skin, and receptor).

Example 1

Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with a selection of different adhesive polymers. The samples were coated at a target coating weight of 10 mg/cm ² and the backing film was CoTran 9720 (3M Co., St. Paul, MN). In vitro human cadaver skin permeation results with each adhesive polymer along with a 0.05 wt.% ointment control is shown in Table 1 and FIG. 2.

Table 1 - 24-hour in vitro cadaver skin permeation

Example 2

Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with two different adhesive polymers. In vitro human cadaver skin permeation results with each adhesive polymer along with a 0.05 wt.% ointment control is shown in Table 2 and FIG. 3.

Table 2 - 24-hour in vitro cadaver skin permeation Example 3

Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with two different silicone adhesive polymers, one with silanol end groups (BIO- PSA 4502 and one with trimethyl silyl end groups (BIO-PSA 4202). In vitro human cadaver skin permeation results with each adhesive polymer along with a 0.05 wt.% ointment control is shown in Table 3 and FIG. 4.

Table 3 - 24-hour in vitro cadaver skin permeation

Example 4

Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with binary silicone adhesive mixtures of BIO-PSA 7-4302 (medium tack) and BIO-PSA 7-4202 (low tack) polymers. The 180-degree peel strength to high density polyethylene test plates was measured using a Texture Analyzer tensile tester approximately one minute after application to the plate and 30 minutes after application to the plate. The average peel strength was obtained from a minimum of six replicate samples. The shear creep compliance was measured using a custom tester designed to measure the displacement of two 5 cm ² patches when placed under a 500 g shear force. The results are shown in Table 4, FIG. 5, and FIG. 6.

Table 4 - Average adhesive 180-degree peel strength to high density polyethylene Example 5 Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with BIO-PSA 7-4302 adhesive polymer. This single formulation was coated, dried, and laminated to a range of different backing materials. The in vitro permeation results are shown in Table 5 and FIG. 7.

Table 5 - 24-hour in vitro cadaver skin permeation

Example 6

Patch samples containing 0.05 wt.% clobetasol propionate were prepared according to the method above with a 70:30 blend of BIO-PSA 7-4302 and BIO-PSA 7-4202 adhesive polymers. This single formulation was coated, dried, and laminated to three different lots of CoTran 9719 backing, each with a different surface treatment. One of the backings was untreated, another was corona treated in ambient air, and the third was corona treated in a nitrogen atmosphere. Samples were packaged in a foil pouch and stored at 40°C/75%RH. The impurity profile was monitored over time via an HPLC method. The results are shown in Table 6.

Table 6 - Patch stability with various backing surface treatments

*IMP is an abbreviation for Impurity and RRT is an abbreviation for Relative Retention Time

Example 7 Patch samples containing 0.05 wt.% clobetasol propionate and 0.5 wt.% of an antioxidant in a 70:30 blend of BIO-PSA 7-4302 and BIO-PSA 7-4202 adhesive polymers were prepared by the general method described above. Samples were packaged in a foil pouch and stored at 40°C/75%RH. The generation of clobetasone propionate (an oxidative degradant of clobetasol propionate) was monitored over time via an HPLC method. The results are shown in Table 7.

Table 7 - Clobetasone propionate impurity formation at 40°C/75%RH

Example 8

Patch samples containing 0.05 wt.% clobetasol propionate in a 70:30 blend of BIO-PSA 7-4302 and BIO-PSA 7-4202 adhesive polymers were prepared by coating on each of five different release liners. The coatings were dried at 150°F for 10 minutes, then laminated to Scotchpak 9744 (3M Co., St. Paul, MN) release liner. The three layers of the resulting laminate (coating liner, adhesive matrix, and cover liner) were assayed individually for clobetasol propionate content via HPLC within hours of the coating process. The results of the content analysis are shown in Table 8.

Table 8 - Clobetasol propionate migration into coating liners and cover liners

The complete disclosure of all patents, patent applications, and publications, and electronically available material cited herein are incorporated by reference in their entirety. In the event that any inconsistency exists between the disclosure of the present application and the disclosure(s) of any document incorporated herein by reference, the disclosure of the present application shall govern. The foregoing detailed description and examples have been given for clarity of understanding only. No unnecessary limitations are to be understood therefrom. The invention is not limited to the exact details shown and described, for variations obvious to one skilled in the art will be included within the invention defined by the claims.

Unless otherwise indicated, all numbers expressing quantities of components, molecular weights, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless otherwise indicated to the contrary, the numerical parameters set forth in the specification and claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the doctrine of equivalents to the scope of the claims, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. All numerical values, however, inherently contain a range necessarily resulting from the standard deviation found in their respective testing measurements.

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