EP1959930A2 - Compositions de fluidification et procede pour administrer par voie cutanee des medicaments - Google Patents

Compositions de fluidification et procede pour administrer par voie cutanee des medicaments

Info

Publication number
EP1959930A2
EP1959930A2 EP06847684A EP06847684A EP1959930A2 EP 1959930 A2 EP1959930 A2 EP 1959930A2 EP 06847684 A EP06847684 A EP 06847684A EP 06847684 A EP06847684 A EP 06847684A EP 1959930 A2 EP1959930 A2 EP 1959930A2
Authority
EP
European Patent Office
Prior art keywords
formulation
volatile solvent
solvent system
skin
drug
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06847684A
Other languages
German (de)
English (en)
Inventor
Jie Zhang
Kevin S. Warner
Sanjay Sharma
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ZARS Pharma Inc
Original Assignee
Zars Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zars Inc filed Critical Zars Inc
Publication of EP1959930A2 publication Critical patent/EP1959930A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7015—Drug-containing film-forming compositions, e.g. spray-on
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A61K9/0017—Non-human animal skin, e.g. pour-on, spot-on

Definitions

  • the present invention relates generally to systems developed for dermal delivery of drugs. More particularly, the present invention relates to adhesive solidifying formulations having a viscosity suitable for application to a skin surface, and which form a sustained drug-delivering adhesive solidified layer.
  • Semisolid formulations are available in a few different forms, including ointments, creams, foams, pastes, gels, or lotions and are applied topically to the skin.
  • Dermal (including transdermal) patch dosage forms also are available in a few different forms, including matrix patch configurations and liquid reservoir patch configurations.
  • matrix patch the active drug is mixed in an adhesive that is coated on a backing film.
  • the drug-laced adhesive layer is typically directly applied onto the skin and serves both as means for affixing the patch to the skin and as a reservoir or vehicle for facilitating delivery of the drug.
  • the drug is typically incorporated into a solvent system which is held by a thin bag, which can be a thin flexible container.
  • the thin bag can include a permeable or semi-permeable membrane surface that is coated with an adhesive for affixing the membrane to the skin.
  • the membrane is often referred to as a rate limiting membrane (although it may not actually be rate limiting in the delivery process in all cases) and can control transport of the drug from within the thin bag to the skin for dermal delivery.
  • patches and semisolid formulations are widely used to deliver drugs into and through the skin, they both have significant limitations.
  • many semisolid formulations usually contain only volatile solvent(s), such as water and ethanol, which evaporate shortly after application. The evaporation of such solvents can cause a significant decrease or even termination of dermal drug delivery, which may not be desirable in many cases.
  • Some traditional semisolid formulations may also contain some non-volatile liquid substances that are chosen or formulated for spreading the formulation or improving the aesthetics of the formulation rather than delivering the drug with sufficient flux. Drug delivery from those formulations may not be sufficient or sustainable. Additionally, semisolid formulations are often "rubbed into" the skin, which does not necessarily mean the drug formulation is actually delivered into the skin.
  • this phrase often means that a very thin layer of the drug formulation is applied onto but still outside the surface of the skin.
  • Such thin layers of traditional semisolid formulations applied to the skin may not contain sufficient quantity of active drug to achieve sustained delivery over long periods of time.
  • traditional semisolid formulations are often subject to unintentional removal due to contact with objects such as clothing, which may compromise the sustained delivery and/or undesirably soil clothing.
  • Drugs present in a semisolid formulation may also be unintentionally delivered to persons who come in contact with a subject undergoing treatment with a topical semisolid formulation.
  • a drug in order to be delivered appropriately, a drug should have sufficient solubility in the adhesive, as primarily only dissolved drug contributes to the driving force required for skin permeation.
  • solubility in adhesives that is too low does not generate adequate skin permeation driving force over sustained period of time.
  • many ingredients e.g., liquid solvents and permeation enhancers, which could be used to help dissolve the drug or increase the skin permeability, may not be able to be incorporated into many adhesive matrix systems in sufficient quantities to be effective. For example, at functional levels, most of these materials may adversely alter the wear properties of the adhesive. As such, the selection and allowable quantities of additives, enhancers, excipients, or the like in adhesive-based matrix patches can be limited.
  • liquid reservoir patches even if a drug is compatible with a particular liquid or semisolid solvent system carried by the thin bag of the patch, the solvent system still has to be compatible to the adhesive layer coated on the permeable or semi-permeable membrane; otherwise the drug may be adversely affected by the adhesive layer or the drug/solvent system may reduce the tackiness of the adhesive layer.
  • reservoir patches are bulkier and usually are more expensive to manufacture than matrix patches.
  • dermal (including transdermal) patches is that they are usually neither stretchable nor flexible, as the backing film (in matrix patches) and the thin fluid bag (in reservoir patches) are typically made of polyethylene or polyester, both of which are relatively non-stretchable materials.
  • patches are not ideal dosage forms for skin areas subject to expansion, flexing and stretching during body movements.
  • the solvents used in such systems do not last very long on skin surface, and thus, are not optimal for sustained-release applications.
  • the inventors of the current invention recognized that the use of both volatile solvent as well as flux-enabling nonvolatile solvent in the formulation can improve or even optimize sustained drug delivery.
  • dermal delivery formulations, systems, and/or methods in the form of adhesive solidifying compositions or formulations having a viscosity suitable for application to the skin surface and which form a drug-delivering solidified layer on the skin that can be easily removed, such as by peeling or washing with a solvent.
  • the adhesive solidifying compositions or formulation, once solidified can be cohesive.
  • a solidifying formulation for dermal delivery of a drug can comprise a drug, a solvent vehicle, and a solidifying agent.
  • the solvent vehicle can comprise a volatile solvent system having one or more volatile solvent(s) and a non-volatile solvent system having one or more nonvolatile solvent(s), wherein the non-volatile solvent system comprises at least one flux-enabling non-volatile solvent for the drug such that the drug can be delivered in therapeutically effective amounts over a period of time, even after most of the volatile solvent(s) is (are) evaporated.
  • the formulation can have viscosity suitable for application to the skin surface prior to evaporation of at least one volatile solvent, and can further be configured such that when applied to the skin surface, the formulation forms a solidified layer after at least a portion of the volatile solvent(s) is (are) evaporated, but yet continues to deliver drug after substantially solidifying.
  • the solidified layer can be coherent so that it is peelable from the skin, or is washable from the skin using a solvent.
  • the drug can be a sex hormone, and in another particular embodiment, the drug can be an anti-wart drug, though many other drug types can be used, as described herein.
  • the solidifying agents are typically polymers that form rigid solids without plasticizing agent (plasticizer).
  • a method of dermally delivering a drug to, into, or through the skin can comprise applying a formulation to a skin surface of a subject, where the formulation comprises a drug; a solvent vehicle, and a solidifying agent.
  • the solvent vehicle comprises a volatile solvent system including one or more volatile solvent, and a non-volatile solvent system including one or more non-volatile solvent, wherein the non-volatile solvent system is flux-enabling for the drug.
  • the formulation can have a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and the formulation can be applied such that the skin surface forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • An additional step includes dermally delivering the drug from the solidified layer to the subject at therapeutically effective rates over a sustained period of time, wherein the drug continues to be delivered after the volatile solvent system is substantially evaporated.
  • the solidified layer can be a soft or flexible, coherent, continuous solid, and can be removed by peeling.
  • a method of preparing a formulation for dermal drug delivery can comprise steps of selecting a drug suitable for dermal delivery; selecting or formulating a non-volatile solvent or a mixture of nonvolatile solvents that is flux-enabling for the selected drug, selecting a solidifying agent that is compatible with the drug and the non-volatile solvent, selecting or formulating a volatile solvent system that is compatible with the drug, the nonvolatile solvent and the solidifying agent; and formulating all above ingredients into a formulation.
  • the formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, and can be applied to the skin surface where it forms a solidified layer after at least a portion of the volatile solvent system is evaporated.
  • the drug continues to be delivered at a therapeutically effective amount after the volatile solvent system is substantially evaporated.
  • a solidified layer for delivering a drug can comprise a drug, a non-volatile solvent system, and a solidifying agent.
  • the non-volatile solvent system can include at least one flux-enabling non-volatile solvent or a mixture of non-volatile solvents that is/are flux-enabling for the drug.
  • the solidified layer can be a soft, coherent solid that is adhered to a body surface, and while dermalJy delivering at least a portion of the drug therefrom, the solidified layer is at least substantially devoid of water and solvents more volatile than water, and wherein the solidified layer is also flux-enabling for the drug.
  • FIG. 1 is a graphical representation of the cumulative amount of diclofenac delivered transdermally across human cadaver skin over time from a formulation in accordance with embodiments of the present invention where steady-state delivery is shown over 28 hours.
  • FIG. 2 is a graphical representation of the cumulative amount of ropivacaine delivered transdermally across human cadaver skin over time from a formulation with similar composition in accordance with embodiments of the present invention, where steady-state delivery is shown over 30 hours.
  • FIG. 3 is a graphical representation of cumulative amount of testosterone delivered across a biological membrane in vitro over time from a solidified adhesive formulation in accordance with embodiments of the present invention, which is compared to the marketed product (AndroGel).
  • FIG. 4 is a graphical representation of the cumulative amount of acyclovir delivered transdermally over time from two separate formulations in accordance with embodiments of the present invention, which is compared to the marketed product Zovirax cream.
  • Skin is defined to include human skin (intact, diseased, ulcerous, or broken), finger and toe nail surfaces, and mucosal surfaces that are usually at least partially exposed to air such as lips, genital and anal mucosa, and nasal and oral mucosa.
  • drug(s) refers to any bioactive agent that is applied to, into, or through the skin which is applied for achieving a therapeutic affect. This includes compositions that are traditionally identified as drugs, as well other bioactive agents that are not always considered to be “drugs” in the classic sense, e.g., peroxides, humectants, emollients, etc., but which can provide a therapeutic effect for certain conditions.
  • drug it is understood that there are various forms of a given drug, and those various forms are expressly included. In accordance with this, various drug forms include polymorphs, salts, hydrates, solvates, and cocrystals.
  • one physical form of a drug may possess better physical-chemical properties making it more amenable for getting to, into, or through the skin, and this particular form is defined as the physical form favorable for dermal delivery.
  • this particular form is defined as the physical form favorable for dermal delivery.
  • the steady state flux of diclofenac sodium from flux enabling nonvolatile solvents is much higher than the steady state flux of diclofenac acid from the same flux enabling non-volatile solvents. It is therefore desirable to evaluate the flux of the physical forms of a drug from non-volatile solvents to select a desirable physical form/non-volatile solvent combination.
  • transdermal drug delivery or “dermal delivery of drug(s)” shall include both transdermal and topical drug delivery, and includes the delivery of drug(s) to, through, or into the skin.
  • Transdermal delivery of drug can be targeted to skin tissues just under the skin, regional tissues or organs under the skin, systemic circulation, and/or the central nervous system.
  • Topical delivery includes delivery of a drug to a skin tissue, and subsequent absorption into deeper tissues that may occur.
  • flux such as in the context of "dermal flux” or “transdermal flux,” respectively, refers to the quantity of the drug permeated into or across skin per unit area per unit time. A typical unit of flux is microgram per square centimeter per hour.
  • One way to measure flux is to place the formulation on a known skin area of a human volunteer and measure how much drug can permeate into or across skin within certain time constraints.
  • Various methods in vivo methods might be used for the measurements as well.
  • the method described in Example 1 or other similar method in vitro methods can also be used to measure flux.
  • a flux enabling non-volatile solvent system is defined as a non-volatile solvent system which, alone without the help of any other ingredients, is capable of delivering therapeutic sufficient levels of the drug across, onto or into the subject's skin when the non-volatile solvent system is saturated with the drug.
  • a flux enabling non-volatile solvent system is a non-volatile solvent system that can provide therapeutically sufficient daily doses over 24 hours when the nonvolatile solvent system is saturated with the drug and is in full contact with the subject's skin with no more than 500 cm 2 contact area.
  • the contact area for the non-volatile solvent system is no more than 100 cm 2 .
  • Testing using this saturated drug-in-solvent state can be used to measure the maximum flux- generating ability of a non-volatile solvent system.
  • the drug solvent mixture needs to be kept on the skin for a clinically sufficient amount of time. In reality, it may be difficult to keep a liquid solvent on the skin of a human volunteer for an extended period of time.
  • an alternative method to determine whether a solvent system is "flux-enabling" is to measure the in vitro drug permeation across the hairless mouse skin or human cadaver skin using the apparatus and method described in Example 1. This and similar methods are commonly used by those skilled in the art to evaluate permeability and feasibility of formulations.
  • whether a non-volatile solvent system is flux-enabling can be tested on the skin of a live human subject with means to maintain the non-volatile solvent system with saturated drug on the skin, and such means may not be practical for a product.
  • the non-volatile solvent system with saturated drug can be soaked into an absorbent fabric material which is then applied on the skin and covered with a protective membrane.
  • Such a system is not practical as a pharmaceutical product, but is appropriate for testing whether a non-volatile solvent system has the intrinsic ability to provide sufficient drug flux, or whether it is flux-enabling. It is also noted that once the formulation forms a solidified layer, the solidified layer can also be "flux enabling" for the drug while some of the non- volatile solvents remain in the solidified layer, even after the volatile solvents (including water) have been substantially evaporated.
  • an "effective amount,” “therapeutically effective amount,” “therapeutically effective rate(s),” or the like, as it relates to a drug refers to sufficient amounts or delivery rates of a drug which achieves any appreciable level of therapeutic results in treating a condition for which the drug is being delivered. It is understood that “appreciable level of therapeutic results” may or may not meet any government agencies' efficacy standards for approving the commercialization of a product. It is understood that various biological factors may affect the ability of a substance to perform its intended task. Therefore, an "effective amount,” “therapeutically effective amount,” or “therapeutically effective rate(s)” may be dependent in some instances on such biological factors to some degree.
  • “Therapeutically effective flux” is defined as the permeation flux of the selected drug that delivers sufficient amount of drug into or across the skin to be clinically beneficial in that some of the patient population can obtain some degree of benefit from the drug flux. It does not necessarily mean that most of the patient population can obtain some degree of benefit or the benefit is high enough to be deemed “effective” by relevant government agencies or the medical profession. More specifically, for drugs that target skin or regional tissues or organs close to the skin surface (such as joints, certain muscles, or tissues/organs that are at least partially within 5 cm of the skin surface),
  • therapeutically effective flux refers to the drug flux that can deliver a sufficient amount of the drug into the target tissues within a clinically reasonable amount of time.
  • therapeutically effective flux refers to drug flux that, via clinically reasonable skin contact area, can deliver sufficient amounts of the selected drug to generate clinically beneficial plasma or blood drug concentrations within a clinically reasonable time.
  • Clinically reasonable skin contact area is defined as a size of skin application area that most subjects would accept. Typically, a skin contact area of 400 cm 2 or less is considered reasonable.
  • the flux needs to be at least 4000 mcg/400cm 2 /10 hour, which equals 1 mcg/cm 2 /hr.
  • different drugs have different "therapeutically effective flux" and may be different in different subjects and or at different times for even the same subject.
  • the therapeutically effective flux values in Table A represent the steady state flux values of marketed products through hairless mouse or human epidermal membrane in an in vitro system described in Example 1. These values are meant only to be estimates and to provide a basis of comparison for formulation development and optimization.
  • the therapeutically effective flux for a selected drug could be very different for different diseases to be treated for, different stages of diseases, and different individual subjects. It should be noted that the flux listed may be more than therapeutically effective.
  • the in vitro steady state flux values in Table B from non-volatile solvents show surprising flux-enabling and non flux-enabling solvents. This information can be used to guide formulation development.
  • the term "plasticizing" in relation to flux-enabling non-volatile solvent(s) is defined as a flux-enabling non-volatile solvent that acts as a plasticizer for the solidifying agent.
  • a "plasticizer” is an agent which is capable of increasing the percentage elongation of the formulation after the volatile solvent system has at least substantially evaporated. Plasticizers also have the capability to reduce the brittleness of solidified formulation by making it more flexible and/or elastic.
  • propylene glycol is a "flux-enabling, plasticizing non-volatile solvent" for the drug ketoprofen with polyvinyl alcohol as the selected solidifying agent.
  • propylene glycol in a formulation of ketoprofen with Gantrez S- 97 or Avalure UR 405 as solidifying agents does not provide the same plasticizing effect.
  • the combination of propylene glycol and Gantrez S-97 or Avalure UR 405 is less compatible and results in less desirable formulation for topical applications. Therefore, whether a given non-volatile solvent is "plasticizing" depends on which solidifying agent(s) is selected.
  • flux-enabling non-volatile solvent can be a single chemical substance or a mixture of two or more chemical substances.
  • the steady state flux value for clobetasol propionate in Table C is a 9:1 for propylene glycoliisostearic acid mixture that generated much higher clobetasol flux than propylene glycol or ISA alone (see Table B). Therefore, the 9:1 propylene glycol :isostearic acid mixture is a "high flux- enabling non-volatile solvent” but propylene glycol or isostearic acid alone is not.
  • adheresion when referring to a solidified layer herein refers to sufficient adhesion between the solidified layer and the skin so that the layer does not fall off the skin during intended use on most subjects.
  • Adhesive when used to describe the solidified layer means the solidified layer is adhesive to the body surface to which the initial formulation layer was originally applied (before the evaporation of the volatile solvent(s)). In one embodiment, it does not mean the solidified layer is adhesive on the opposing side.
  • a solidified layer can adhere to a human body surface for the desired extended period of time partially depends on the condition of the body surface. For example, excessively sweating or oily skin, or oily substances on the skin surface may make the solidified layer less adhesive to the skin. Therefore, the adhesive solidified layer of the current invention may not be able to maintain perfect contact with the body surface and deliver the drug over a sustained period of time for every subject under any conditions on the body surface.
  • a standard is that it maintains good contact with most of the body surface, e.g. 70% of the total area, over the specified period of time for most subjects under normal conditions of the body surface and external environment.
  • a solidified layer that exhibits acceptably elasticity and adhesion to skin can be attached to human skin over a flexible skin location, e.g., elbow, finger, wrist, neck, lower back, lips, knee, etc., and will remain substantially intact on the skin upon stretching of the skin. It should be noted that the solidified layers of the present invention do not necessarily have to have any elasticity in some embodiments.
  • peelable when used to describe the solidified layer, means the solidified layer can be lifted from the skin surface in one large piece or several large pieces, as opposed to many small pieces or crumbs.
  • the term "sustained” relates to therapeutically effective rates of dermal drug delivery for a continuous period of time of at least 30 minutes, and in some embodiments, periods of time of at least about 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, or longer.
  • the use of the term “substantially” when referring to the evaporation of the volatile solvents means that a majority of the volatile solvents which were included in the initial formulation have evaporated.
  • a solidified layer is said to be “substantially devoid” of volatile solvents, including water, the solidified layer has less than 10 wt%, and preferably less than 5 wt%, of the volatile solvents in the solidified layer as a whole.
  • Volatile solvent system can be a single solvent or a mixture of solvents that are volatile, including water and solvents that are more volatile than water.
  • volatile solvents that can be used in the present invention include iso-amyl acetate, denatured alcohol, methanol, ethanol, isopropyl alcohol, water, propanol, C4-C6 hydrocarbons, butane, isobutene, pentane, hexane, acetone, chlorobutanol, ethyl acetate, fluro-chloro- hydrocarbons, turpentine, methyl ethyl ketone, methyl ether, hydrofluorocarbons, ethyl ether, 1,1,1,2 tetrafluorethane 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, or combinations thereof.
  • Non-volatile solvent system can be a single solvent or mixture of solvents that are less volatile than water. It can also contain substances that are solid or liquid at room temperatures, such as pH or ion-pairing agents. After evaporation of the volatite solvent system, most of the non-volatile solvent system should remain in the solidified layer for an amount of time sufficient to dermally delivery a given drug to, into, or through the skin of a subject at a sufficient flux for a period of time to provide a therapeutic effect. In some embodiments, in order to obtain desired permeability for an active drug and/or compatibility with solidifying agents or other ingredients of the formulation, a mixture of two or more non-volatile solvents can be used to form the non-volatile solvent system.
  • the combination of two or more non- volatile solvents to form a solvent system provides a higher transdermal flux for a drug than the flux provided for the drug by each of the non-volatile solvents individually.
  • the non-volatile solvent system may also serve as a plasticizer of the solidified layer, so that the solidified layer is elastic and flexible.
  • solvent vehicle describes compositions that include both a volatile solvent system and non-volatile solvent system.
  • the volatile solvent system is chosen so as to evaporate from the adhesive peelable formulation quickly to form a solidified layer, and the non-volatile solvent system is formulated or chosen to substantially remain as part of the solidified layer after volatile solvent system evaporation so as to provide continued delivery of the drug.
  • the drug can be partially or completely dissolved in the solvent vehicle or formulation as a whole.
  • the drug can also be partially or completely solubilizable in the non-volatile solvent system once the volatile solvent system is evaporated.
  • Formulations in which the drug is only partially dissolved in the non-volatile solvent system after the evaporation of the volatile solvent system have the potential to maintain longer duration of sustained delivery, as the undissolved drug can dissolve into the non-volatile solvent system as the dissolved drug is being depleted from the solidified layer during drug delivery.
  • adheresive in relation to the solidified layer means it is adhesive to the skin on which the original formulation was applied, and not necessarily, and preferably not, adhesive on the other side to other objects.
  • “Adhesive solidifying formulation,” “solidifying formulation” or “formulation” in some embodiments refers to a composition that has a viscosity suitable for application to a skin surface prior to evaporation of its volatile solvent(s), and which can become a solidified layer after evaporation of at least a portion of the volatile solvent(s).
  • the solidified layer once formed, can be very durable.
  • the formulation once solidified on a skin surface, the formulation can form a peel. Such a peel can be a soft, coherent solid that can be removed by peeling large pieces from the skin relative to the size of the applied formulation, and often, can be peeled from the skin as a single piece.
  • the application viscosity is typically more viscous than a water-like liquid, but less viscous than a soft solid.
  • preferred viscosities include materials that have consistencies similar to pastes, gels, ointments, and the like, e.g., viscous liquids that flow but are not subject to spilling.
  • a composition is said to have a viscosity "suitable for application" to a skin surface, this means the composition has a viscosity that is high enough so that the composition does not substantially run off the skin after being applied to skin, but also has a low enough viscosity so that it can be easily spread onto the skin.
  • a viscosity range that meets this definition can be from about 100 cP to about 3,000,000 cP (centipoises), and more preferably from about 1 ,000 cP to about 1 ,000,000 cP.
  • an additional agent or substance can be an additional non-volatile solvent or an additional solidifying agent.
  • Non-limiting examples of substances which might be used as additional adhesion enhancing agents include copolymers of methylvinyl ether and maleic anhydride (Gantrez polymers), polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, copolymer of acrylsan alkyl/octylacrylamido (Dermacry! 79), and various aliphatic resins and aromatic resins.
  • the terms "washable,” “washing” or “removed by washing” when used with respect to the adhesive formulations of the present invention refers to the ability of the adhesive formulation to be removed by the application of a washing solvent using a normal or medium amount of washing force.
  • washing solvents which can be used for removing by washing the formulations of the present invention are numerous, but preferably are chosen from commonly acceptable solvents including the volatile solvents listed herein. Preferred washing solvents do not significantly irritate human skin and are generally available to the average subject. Examples of washing solvents include but are not limited to water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, or combinations thereof.
  • the washing solvents can be selected from the group consisting of water, ethanol, isopropyl alcohol or combinations thereof.
  • Surfactants can also be used in some embodiments.
  • An acceptable length of time as it relates to "drying time” refers to the time it takes for the formulation to form a non-messy solidified surface after application on skin under standard skin and ambient conditions, and with standard testing procedure. It is noted that the word “drying time” in this application does not mean the time it takes to completely evaporate off the volatile solvent(s). Instead, it means the time it takes to form the non-messy solidified surface as described above.
  • Standard skin is defined as dry, healthy human skin with a surface temperature of between about 30 0 C to about 36 0 C.
  • Standard ambient conditions are defined by the temperature range of from 20 0 C to 25°C and a relative humidity range of from 20% to 80%.
  • the term "standard skin” in no way limits the types of skin or skin conditions on which the formulations of the present invention can be used.
  • the formulations of the present invention can be used to treat all types of "skin,” including undamaged (standard skin), diseased skin, or damaged skin.
  • skin conditions having different characteristics can be treated using the formulations of the present invention, the use of the term "standard skin” is used merely as a standard to test the compositions of the varying embodiments of the present invention.
  • formulations that perform well e.g., solidify, provide therapeutically effective flux, etc.
  • the "standard testing procedure” or “standard testing condition” is as follows: To standard skin at standard ambient conditions is applied an approximately 0.1 mm layer of the adhesive solidifying formulation and the drying time is measured. The drying time is defined as the time it takes for the formulation to form a non-messy surface such that the formulation does not lose mass by adhesion to a piece of 100% cotton cloth pressed onto the formulation surface with a pressure of between about 5 and about 10 g/cm 2 for 5 seconds. .
  • Solidified layer describes the solidified or dried layer of an adhesive solidifying formulation after at least a portion of the volatile solvent system has evaporated.
  • the solidified layer remains adhered to the skin, and is preferably capable of maintaining good contact with the subject's skin for substantially the entire duration of application under standard skin and ambient conditions.
  • the solidified layer also preferably exhibits sufficient tensile strength so that it can be peeled off the skin at the end of the application in one piece or several large pieces (as opposed to a layer with weak tensile strength that breaks into many small pieces or crumbles when removed from the skin).
  • a plurality of drugs, compounds, and/or solvents may be presented in a common list for convenience.
  • a formulation for dermal delivery of a drug can comprise a drug, a solvent vehicle, and a solidifying agent.
  • the solvent vehicle can comprise a volatile solvent system having one or more volatile solvent(s) and a non-volatile solvent system having one or more non-volatile solvent(s), wherein the non-volatile solvent system is flux-enabling for the drug such that the drug can be delivered in therapeutically effective amounts over a period of time, even after most of the volatile solvent(s) is (are) evaporated.
  • the formulation can have viscosity suitable for application to the skin surface prior to evaporation of at least one volatile solvent, and can further be configured such that when applied to the skin surface, the formulation forms a solidified layer after at least a portion of the volatile solvent(s) is (are) evaporated, but yet continues to deliver drug after substantially solidifying.
  • the solidified layer can be coherent so that it can be peeled from the skin in one piece or several large pieces, or is washable from the skin using a solvent.
  • the drug can be a sex hormone, and in another particular embodiment, the drug can be an anti-wart drug, though many other drug types can be used, as described herein.
  • a method of dermally delivering a drug to, into, or through the skin can comprise applying a formulation to a skin surface of a subject, where the formulation comprises a drug; a solvent vehicle, and a solidifying agent.
  • the solvent vehicle comprises a volatile solvent system including one or more volatile solvent, and a non-volatile solvent system that is flux-enabling for the drug.
  • the formulation can have a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and the formulation can be applied such that the skin surface forms a solidified layer adhered to the skin after at least partial evaporation of the volatile solvent system.
  • An additional step includes dermally delivering the drug from the solidified layer to the subject at therapeutically effective rates over a sustained period of time, wherein the drug continues to be delivered after the volatile solvent system is substantially evaporated.
  • the solidified layer can be a soft or flexible, coherent, continuous solid, and can be removed by peeling.
  • the thickness of the formulation layer applied on the skin should also be appropriate for a given formulation and desired drug delivery considerations. If the layer is too thin, the amount of the drug may not be sufficient to support sustained delivery over the desired length of time. If the layer is too thick, it may take too long to form a non-messy outer surface of the solidified layer.
  • the appropriate thickness can be from about 0.01 mm to about 3 mm, but more typically, from about 0.05 mm to about 1 mm.
  • a method of preparing a formulation for dermal drug delivery can comprise steps of selecting a drug suitable for dermal delivery; selecting or formulating a non-volatile solvent or a mixture of nonvolatile solvents that is flux-enabling for the selected drug, selecting a solidifying agent that is compatible with the drug and the non-volatile solvent, selecting or formulating a volatile solvent system that is compatible with the drug, the nonvolatile solvent and the solidifying agent; and formulating all above ingredients into a formulation.
  • the formulation can have a viscosity suitable for application to a skin surface prior to evaporation of the volatile solvent system, and can be applied to the skin surface where it forms a solidified layer after at least a portion of the volatile solvent system is evaporated.
  • the drug continues to be delivered at a therapeutically effective rate after the volatile solvent system is substantially evaporated.
  • a solidified layer for delivering a drug can comprise a drug, a non-volatile solvent system, and a solidifying agent.
  • the non-volatile solvent system is flux-enabling for the drug.
  • the solidified layer can be a soft, coherent solid that is adhered to a body surface, and while dermally delivering at least a portion of the drug therefrom, the solidified layer is at least substantially devoid of water and solvents more volatile than water, e.g., the solidified layer can be considered substantially devoid of water and solvents more volatile than water when the solidified layer contains no more than 10 wt% or even 5 wt% of water and solvents more volatile than water. Additionally, the solidified layer is also flux-enabling for the drug.
  • the solidified layer can be so coherent and elastic that it can be stretched in at least one direction by 5%, or even 10% without breaking, cracking, or separation from a skin surface to which the solidified layer is applied, and/or can be peelable from the skin.
  • reducing the moisture vapor loss from the skin surface can be desirable, and a solidified layer with a selected or formulated non-volatile solvent system that is hydrophobic can help achieve this goal. Therefore, another embodiment of the current invention is related to a solidifying formulation whose solidified layer is capable of providing significant occlusion effect (defined as decreasing the moisture vapor loss from body surfaces by at least about 20%, preferably at least about 40%).
  • inventions exemplify the present invention which is related to formulations, methods, and solidified layers that are typically in the initial form of semi-solids (including creams, gels, pastes, ointments, and other viscous liquids), which can be easily applied onto the skin as a layer, and can quickly (from 15 seconds to about 4 minutes under standard skin and ambient conditions) to moderately quickly (from about 4 to about 15 minutes under standard skin and ambient conditions) change into a solidified layer, e.g., a coherent and soft solid layer, for drug delivery.
  • the solidified layer is optionally peelable.
  • a solidified layer thus formed is capable of delivering drug to the skin, into the skin, across the skin, etc., over an sustained period of time, e.g., hours to tens of hours, so that most of the drug delivery occurs after the solidified layer is formed.
  • the solidified layer typically adheres to the skin, but has a solidified, minimally or non-adhering, outer surface which is formed relatively soon after application and which does not substantially transfer to or otherwise soil clothing or other objects that a subject is wearing or that the solidified layer may inadvertently contact.
  • the solidified layer can also be formulated such that it is highly flexible and stretchable, and thus capable of maintaining good contact with a skin surface, even if the skin is stretched during body movement, such as at a knee, finger, elbow, or other joints.
  • various components that can be used e.g., drug, solvent vehicle of volatile solvent system and non-volatile solvent system, solidifying agent(s), etc., various considerations can occur.
  • the volatile solvent system can be selected from pharmaceutically or cosmetically acceptable solvents known in the art.
  • the volatile solvent system can include ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1 ,1 , difluoroethane, 1,1 ,1 ,2 tetrafluorethane, 1 ,1 ,1 ,2,3,3,3-heptafluoropropane, 1,1 ,1 ,3,3,3 hexafluoropropane, ethyl acetate, acetone or combinations thereof.
  • the volatile solvent system can include iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, or combinations thereof.
  • the volatile solvent system can include a mixture or combination of any of the volatile solvents set forth in the embodiments above. Additionally, these volatile solvents should be chosen to be compatible with the rest of the formulation. It is desirable to use an appropriate weight percentage of the volatile solvent(s) in the formulation. Too much of the volatile solvent system prolongs the drying time.
  • the weight percentage of the volatile solvent(s) can be from about 10 wt% to about 85 wt%, from about 20 wt% to about 50 wt%, and in a preferred embodiment, at least 20 wt%.
  • the volatile solvent system can also be chosen to be compatible with the non-volatile solvent, solidifying agent, drug, and any other excipients that may be present.
  • PVA polyvinyl alcohol
  • a volatile solvent which can dissolve PVA needs to be formulated in the solidified layer.
  • water can dissolve PVA and can be utilized as a volatile solvent in a solidifying formulation; however the drying time in a formulation in which water is the only volatile solvent may be too long to certain applications. Therefore, a second volatile solvent (e.g., ethanol) can be formulated into the formulation to reduce the water content but maintain a sufficient amount of water to keep PVA in solution and thereby reduce the drying time for the formulation.
  • a second volatile solvent e.g., ethanol
  • the non-volatile solvent system can also be chosen or formulated to be compatible with the solidifying agent, the drug, the volatile solvent, and any other ingredients that may be present.
  • Most non-volatile solvent systems and solvent vehicles as a whole will be formulated appropriately after experimentation.
  • certain drugs have good solubility in poly ethylene glycol (PEG) having a molecular weight of 400 (PEG 400, non-volatile solvent) but poor solubility in glycerol (non-volatile solvent) and water (volatile solvent).
  • PEG 400 cannot effectively dissolve poly vinyl alcohol (PVA), and thus, is not very compatible alone with PVA, a solidifying agent.
  • a non-solvent system including PEG 400 and glycerol (compatible with PVA) in an appropriate ratio can be formulated, achieving a compatibility compromise.
  • compatibility non-volatile solvent/solidifying agent incompatibility is observed when Span 20 is formulated into a formulation containing PVA. With this combination, Span 20 can separate out of the formulation and form an oily layer on the surface of the solidified layer after the evaporation of the volatile solvent.
  • appropriate solidifying agent/non-volatile solvent selections are desirable in developing a viable formulation.
  • non-volatile solvent(s) that can be used alone or in combination to form non-volatile solvent systems can be selected from a variety of pharmaceutically acceptable liquids, including but not limited to
  • the non-volatile solvent system can include glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan mo ⁇ olaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, or combinations thereof.
  • the non-volatile solvent system can include benzoic acid, butyl alcohol, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol, fatty acids such as coconut oil, fish oil, palm oil, grape seed oil, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, or combinations thereof.
  • benzoic acid butyl alcohol, dibutyl sebecate, diglycerides, dipropylene glycol, eugenol, fatty acids such as coconut oil, fish oil, palm oil, grape seed oil, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, or combinations thereof.
  • the non-volatile solvent system can include 1 ,2,6-hexanetriol, alkyltriols, alkyldiols, acetyl monoglycerides, tocopherol, alkyl dioxolanes, p-propenylanisole, anise oil, apricot oil, dimethyl isosorbide, alkyl glucoside, benzyl alcohol, bees wax, benzyl benzoate, butylene glycol, caprylic/capric triglyceride, caramel, cassia oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglycerides, coriander oil, corn oil, coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglycerides, diethanolamine, dietthylene glycol monoethyl ether, diglycerides,
  • the non-volatile solvent system can, and preferably should, also serve as plasticizer in the formulations of the current invention so that when the solidified layer is formed, the layer is flexible, stretchable, and/or otherwise "skin friendly."
  • Certain volatile and/or nonvolatile solvent(s) are irritating to the skin but are desirable to use to achieve the desired solubility and/or permeability of the drug. It is also desirable to add compounds that are both capable of preventing or reducing skin irritation and are compatible with the formulation. For example, in a formulation where the volatile solvent is capable of irritating the skin, it would be helpful to use a non-volatile solvent that is capable of reducing skin irritation.
  • solvents that are known to be capable of preventing or reducing skin irritation include, but are not limited to, glycerin, honey, and propylene glycol.
  • the formulations of the current invention may also contain two or more non-volatile solvents that independently cannot generate as high flux for a drug as when formulated together according to a certain and often experimentally determined ratio.
  • One possible reason for these initially non or less flux-enabling non-volatile solvents to become more flux-enabling when formulated together may be due to the optimization of the ionization state of the drug to a physical form which has higher flux or the non-volatile solvents act in some other synergistic manner.
  • One further benefit of the mixing of the non-volatile solvents is that it may optimize the pH of the formulation or the skin tissues under the formulation layer to minimize irritation.
  • non-volatile solvents examples include but are not limited to isostearic acid /trolamine, isostearic acid /diisopropyl amine, oleic acid/trolamine, and propylene glycol /isostearic acid.
  • the selection of the solidifying agent can also be carried out in consideration of the other components present in the adhesive formulation.
  • the solidifying agent can be selected or formulated to be compatible to the drug and the solvent vehicle (including the volatile solvent(s) and the non-volatile solvent system), as well as to provide desired physical properties to the solidified layer once it is formed.
  • the solidifying agent can be selected from a variety of agents.
  • the solidifying agent can include polyvinyl alcohol with a MW range of 20,000-70,000 (Amresco), esters of polyvinylmethylether/maleic anhydride copolymer (ISP Gantrez ES-425 and Gantrez ES-225) with a MW range of 80,000-160,000, neutral copolymer of butyl methacrylate and methyl methacrylate (Degussa Plastoid B) with a MW range of 120,000-180,000, dimethylaminoethyl methacrylate-butyl methacrylate- methyl methacrylate copolymer (Degussa Eudragit E100) with a MW range of 100,000-200,000, ethyl acrylate-methyl methacrylate-trimethylammonioethyl methacrylate chloride copolymer with a MW greater than 5,000 or similar MW to Eudragit RLPO (Degussa), Zein (prolamine) with a MW greater than
  • the solidifying agent can include ethyl cellulose, hydroxy ethyl cellulose, hydroxy methyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amides, corn starch, pregelatinized corn starch, polyether amides, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate or combinations thereof.
  • the solidifying agent can include ammonia methacrylate, carrageenan, cellulose acetate phthalate aqueous such as CAPNF from Eastman, carboxy poly methylene, cellulose acetate (microcrystalline), cellulose polymers, divinyl benzene styrene, ethylene vinyl acetate, silicone, guar gum, guar rosin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG/PVP, xantham gum, trimethyl siloxysilicate, maleic acid/anhydride colymers, polacrilin, poloxamer, polyethylene oxide, poly glactic acid/poly-l-lactic acid, turpene resin, locust bean gum, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-
  • the solidifying agent can include a combination of solidifying agents set forth in the any of the above discussed embodiments.
  • Other polymers may also be suitable as the solidifying agent, depending on the solvent vehicle components, the drug, and the specific functional requirements of the given formulation.
  • Other polymers may also be suitable as the solidifying agent, depending on the solvent vehicle components, the drug, and the specific functional requirements of the given formulation.
  • the non-volatile solvent system and the solidifying agent(s) should be compatible with each other.
  • Compatibility can be defined as i) the solidifying agent does not substantially negatively influence the function of the non-volatile solvent system, except for some reduction of flux; ii) the solidifying agent can hold the non-volatile solvent system in the solidified layer so that substantially no non-volatile solvent oozes out of the layer, and/or iii) the solidified layer formed with the selected non-volatile solvent system and the solidifying agent has acceptable flexibility, rigidity, tensile strength, elasticity, and adhesiveness to skin.
  • the weight ratio of the non-volatile solvent system to the solidifying agent(s) can be from about 0.1 :1 to about 10:1. In another aspect, the weight ratio of the non-volatile solvent system to the solidifying agent can be from about 0.2:1 to about 4:1, and more preferably from about 0.5:1 to about 2:1.
  • a solidified layer which is optionally also a peel
  • NSAIDs nonsteroidal anti-inflammatory agents
  • the solidifying formulations of the present invention can offer unique advantages and benefits.
  • the solidifying formulations of the present invention do not always need to be stretchable, as certain applications of the present invention do not necessarily benefit from this property. For instance, if the formulation is applied on a small facial area overnight for treating acne, a subject would experience minimal discomfort and formulation-skin separation even if the solidified layer is not stretchable, as facial skin usually is not stretched very much during a sleep cycle.
  • a further feature of a formulation prepared in accordance with embodiments of the present invention is related to drying time. If a formulation dries too quickly, the user may not have sufficient time to spread the formulation into a thin layer on the skin surface before the formulation is solidified, leading to poor skin contact. If the formulation dries too slowly, the subject may have to wait a long time before resuming normal activities (e.g. putting clothing on) that may remove u ⁇ -solidified formulation. Thus, it is desirable for the drying time to be longer than about 15 seconds but shorter than about 15 minutes, and preferably from about 0.5 minutes to about 5 minutes.
  • the solidified layers of the present invention include the presence of a physical barrier that can be formed by the material itself.
  • the skin surface is sensitive to the touch of foreign objects or vulnerable to infection if contact by foreign objects.
  • the solidified layer can provides physical protection to the skin surface.
  • local anesthetic agents and other agents such as clonidine may be delivered topically for treating pain related to neuropathy, such as diabetic neuropathic pain. Since many of such subjects feel tremendous pain, even when their skin area is only gently touched, the physical barrier of the solidified layer can prevent or minimize pain caused by accidental contact with objects or others.
  • the solidified layers of the present invention can be prepared in an initial form that is easy to apply as a semisolid dosage form. Additionally, upon volatile solvent system evaporation, the formulation layer applied to the skin is relatively thick and can contain much more active drug than a typical layer of traditional cream, gel, lotion, ointment, paste, etc., and further, is resistant to unintentional removal.
  • the solidified layer comprises a non-volatile solvent system that is flux-enabling for the drug so that the drug can be delivered over sustained period of time at therapeutically effective rates. Further, as the solidified layer remains adhesive to skin and is preferably peelable, easy removal of the solidified layer can occur, may be without the aid of a solvent or surfactant.
  • the adhesion to skin and elasticity of the material is such that the solidified layer will not separate from the skin upon skin stretching at highly stretchable skin areas, such as over joints and muscles.
  • the solidified layer can be stretched by 5%, or even 10% or greater, in at least one direction without cracking, breaking, and/or separating form a skin surface to which the layer is applied.
  • the solidified layer can be configured to advantageously deliver drug and protect sensitive skin areas without cracking or breaking.
  • the solidified layer may be washed off with a solvent, such as water or ethanol, at the end of the desired drug delivery.
  • a solvent such as water or ethanol
  • Other solvents which could also be used to wash off the solidified formulation include but are not limited to the volatile solvents listed herein.
  • the ability to be removed by washing is particularly advantageous for certain applications. For example, if the solidifying formulation is applied to a body area with a lot of hair (e.g. an anti genital herpes solidifying formulation applied on genital skin area with pubic hair), removal by peeling might cause discomfort and therefore be undesirable, and hence washing can be a preferred form of removal in this type of application.
  • the ability for removal by peeling may be secondary consideration to a formulation that will adhere to the skin surface.
  • a solidified layer configured to be easily washed off by water or ethanol may be more desirable.
  • the solvent used to wash off the solidified layer may dissolve the layer or make it less adhesive to the skin so that it can be easily removed from the skin.
  • the solidified layers of the present invention can keep a substantial amount of the non-volatile solvent system, which is optimized for delivering the drug, on the body surface. This feature can provide unique advantages over existing products.
  • Penlac is a product widely used for treating nail fungal infections. It contains the drug ciclopirox, volatile solvents (ethyl acetate and isopropyl), and a polymeric substance. After being applied on the nail surface, the volatile solvents quickly evaporate and the formulation layer solidifies into a hard lacquer. The drug molecules are immobilized in the hard lacquer layer and are substantially unavailable for delivery into the nail. As a result, it is believed that the delivery of the drug is not sustained over a long period of time. As a result, without being bound by any particular theory, it is believed that this is at least one of the reasons why Penlac, while widely used, has an efficacy rate of only about 10%.
  • the drug molecules are quite mobile in the non-volatile solvent system which is in contact with the skin surface, e.g., skin, nail, mucosal, etc., surface, thus ensuring sustained delivery.
  • a solidified layer including bupivacaine, lidocaine, or ropivacaine can be formulated for treating diabetic and post herpetic neuralgia.
  • dibucanine and an alpha-2 agonist such as clo ⁇ idi ⁇ e can be formulated in a solidifying formulation for treating the same disease.
  • retinoic acid and benzoyl peroxide can be combined in a solidified layer for treating acne, or alternatively, 1 wt% clindamycin and 5 wt% benzoyl peroxide can be combined in a solidifying formulation for treating acne.
  • a retinol solidifying formulation can be prepared for treating wrinkles, or a lidocaine solidifying formulation can be prepared for treating back pain.
  • a zinc oxide solidifying formulation (OTC) can be prepared for treating diaper rash (the physical barrier provided by the solidified layer against irritating urine and feces is believed to be beneficial), or an antihistamine solidified layer can be prepared for treating allergic rashes such as that caused by poison ivy.
  • Additional applications include delivering drugs for treating certain skin conditions, e.g., dermatitis, psoriasis, eczema, skin cancer, alopecia, wrinkles, viral infections such as cold sore, genital herpes, shingles, etc., particularly those that occur over joints or muscles where a transdermal patch may not be practical.
  • drugs for treating certain skin conditions e.g., dermatitis, psoriasis, eczema
  • skin cancer e.g., dermatitis, psoriasis, eczema
  • wrinkles e.g., wrinkles, viral infections such as cold sore, genital herpes, shingles, etc.
  • viral infections such as cold sore, genital herpes, shingles, etc.
  • solidifying formulations containing imiquimod can be formulated for treating skin cancer, prematurely aged skin, photo-damaged skin, common and genital warts, and actinic kera
  • Solidifying formulations containing antiviral drugs such as acyclovir, penciclovir, famciclovir, valacyclovir, steroids, behenyl alcohol can be formulated for treating herpes viral infections such as cold sores on the face and genital areas.
  • Solidifying formulations containing non-steroidal anti-inflammatory drugs (NSAIDs), capsaicin, alpha-2 agonists, and/or nerve growth factors can be formulated for treating soft tissue injury and muscle-skeletal pains such as joint and back pain of various causes. As discussed above, patches over these skin areas typically do not have good contact over sustained period of time, especially for a physically active subject, and may cause discomfort.
  • solidifying formulations of the present invention address the shortcomings of both of these types of delivery systems.
  • One embodiment can entail a solidified layer containing a drug from the class of alpha-2 antagonists which is applied topically to treat neuropathic pain.
  • the alpha-2 agonist is gradually released from the formulation to provide pain relief over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 5 minutes and remains adhered to the body surface for the length of its application, typically hours to tens of hours.
  • the solidified layer is easily removed after the intended application without leaving residual formulation on the skin surface.
  • Another embodiment involves a solidifying formulation containing capsaicin which is applied topically to treat neuropathic pain.
  • the capsaicin is gradually released from the formulation for treating this pain over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 5 minutes and remains adhered to the body surface for the length of its application. It is easily removed any time after drying without leaving residual formulation on the skin surface.
  • Another embodiment involves a solidifying formulation containing clobetasol propionate which is applied topically to treat hand dermatitis.
  • the clobetasol propionate is gradually released from the formulation for treating dermatitis over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 7 minutes and remains adhered to the body surface for the length of its application.
  • the physical barrier also protects the compromised skin from potentially harmful substances. It is easily removed any time after drying without leaving residual formulation on the skin surface.
  • Another embodiment involves a solidifying formulation containing clobetasol propionate which is applied topically to treat alopecia.
  • the clobetasol propionate is gradually released from the formulation for promoting hair growth over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 5 minutes and remains adhered to the body surface for the length of its application. It is easily removed any time after drying by peeling to showering.
  • Another embodiment involves solidifying formulations containing tazorac for treating stretch marks, wrinkles, sebaceous hyperplasia, or seborrheic keratosis.
  • solidifying formulations containing glycerol can be made so as to provide a protective barrier for fissu ring on fingertips.
  • Still another embodiment can include a solidifying formulation containing a drug selected from the local anesthetic class such lidocaine and ropivacaine or the like, or NSAID class, such as ketoprofen, piroxicam, diclofenac, indomethacin, or the like, which is applied topically to treat symptoms of back pain, muscle tension, or myofascial pain or a combination thereof.
  • the local anesthetic and/or NSAID is/are gradually released from the formulation to provide pain relief over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 5-10 minutes and remains adhered to the body surface for the length of its application. It is easily removed any time after drying without leaving residual formulation on the skin surface.
  • a further embodiment involves a solidifying formulation containing at least one alpha-2 agonist drug, at least one tricyclic antidepressant agent, and/or at least one local anesthetic drug which is applied topically to treat neuropathic pain.
  • the drug(s) are gradually released from the formulation to provide pain relief over a sustained period of time.
  • the formulation can become a coherent, soft solid after 2-10 minutes and remains adhered to the body surface for the length of its application. It is easily removed any time after drying without leaving residual formulation on the skin surface.
  • a similar embodiment can include a solidifying formulation containing drugs capsaicin and a local anesthetic drug which is applied topically to the skin to provide pain relief.
  • Another embodiment can include a solidifying formulation containing the combination of a local anesthetic and a NSAID.
  • the drugs are gradually released from the formulation to provide pain relief over a sustained period of time.
  • the formulation can become a coherent, soft solid after about 2-10 minutes and remains adhered to the body surface for the length of its application. It is easily removed any time after drying without leaving residual formulation on the skin surface.
  • solidifying formulations for the delivery of drugs that treat the causes or symptoms of diseases involving joints and muscles can also benefit from the systems, formulations, and methods of the present invention.
  • diseases that may be applicable include, but not limited to, osteoarthritis (OA), rheumatoid arthritis (RA), joint and skeletal pain of various other causes, myofascial pain, muscular pain, and sports injuries.
  • Drugs or drug classes that can be used for such applications include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and diclofanac, COX-2 selective NSAIDs and agents, COX-3 selective NSAIDs and agents, local anesthetics such as lidocaine, bupivacaine, ropivacaine, and tetracaine, steroids such as dexamethasone.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • ketoprofen and diclofanac COX-2 selective NSAIDs and agents
  • COX-3 selective NSAIDs and agents COX-3 selective NSAIDs and agents
  • local anesthetics such as lidocaine, bupivacaine, ropivacaine, and tetracaine
  • steroids such as dexamethasone.
  • Delivering drugs for the treatment of acne and other skin conditions can also benefit from principles of the present invention, especially when delivering drugs having low skin permeability.
  • topical retinoids, peroxides, and antibiotics for treating acne are mostly applied as traditional semisolid gels or creams.
  • sustained delivery over many hours is unlikely.
  • clindamycin, benzoyl peroxide, and erythromycin may be efficacious only if sufficient quantities are delivered into hair follicles.
  • a traditional semisolid formulation such as the popular acne medicine benzaclin gel, typically loses most of its solvent (water in the case of benzaclin) within a few minutes after the application.
  • the formulations of the present invention typically do not have this limitation.
  • the delivery of drugs for treating neuropathic pain can also benefit from the methods, systems, and formulations of the present invention.
  • a patch containing a local anesthetic agent, such as LidodermTM is widely used for treating neuropathic pain, such as pain caused by post-herpetic neuralgia. Due to the limitations of the patch as discussed above, the solidified layers prepared in accordance with the present invention provide some unique benefits, as well as provide a potentially less expensive alternative to the use of a patch.
  • Possible drugs delivered for such applications include, but are not limited to, local anesthetics such as lidocaine, prilocaine, tetracaine, bupivicaine, etidocaine; and other drugs including capsaicin and alpha-2 agonists such as clonidine, dissociative anesthetics such as ketamine, tricyclic antidepressants such as amitriptyline.
  • local anesthetics such as lidocaine, prilocaine, tetracaine, bupivicaine, etidocaine
  • other drugs including capsaicin and alpha-2 agonists such as clonidine, dissociative anesthetics such as ketamine, tricyclic antidepressants such as amitriptyline.
  • the solidifying formulations of the present invention can be formulated to treat a variety of conditions and disease such as musculoskeletal pain, neuropathic pain, alopecia, skin disease including dermatitis and psoriasis as well as skin restoration (cosmetic skin treatment), and infections including viral, bacterial, and fungal infection.
  • the formulations can deliver a wide ranging number and types of drugs and active agents.
  • the solidifying formulation can be formulated to include acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, tretinoin, isotretinoin, clobetasol propionate, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, or combinations thereof
  • the formulation can include an antifungal drug such as amorolfine, butenafine, naftifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, ravuconazole, voriconazole
  • the formulation can include an antifungal drug such as acyclovir, penciclovir, famciclovir, valacyclovir, behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclovir, podofilox, podophyllotoxin, ribavirin, abacavir, delavirdine, didanosine, efavirenz, lamivudine, rievirapine, stavudine, zalcitabine, zidovudine, amprenavir, indinavir, nelfinavir, ritonavir, saquinavir, amantadine, interferon, oseltamivir, ribavirin, rimantadine, zanamivir, or combinations thereof.
  • an antifungal drug such as acyclovir, penciclovir, famciclovir, valacyclovir, behenyl
  • the formulation When the formulation is intended to provide antibacterial treatment it can be formulated to include an antibacterial drug such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciproflaxin, or combinations thereof.
  • an antibacterial drug such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciproflaxin, or combinations thereof.
  • the formulation when the formulation is intended to relieve pain, particularly neuropathic pain, can include a local anesthetic such as lidocaine, bupivacaine, ropivacaine, and tetracaine; an aipha-2 agonists such as clonidine.
  • a local anesthetic such as lidocaine, bupivacaine, ropivacaine, and tetracaine
  • an aipha-2 agonists such as clonidine.
  • the formulation when the formulation is intended to treat pain associated with inflammation it can be formulated to include an non-steroidal anti-inflammatory drug such as ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitors general COX inhibitors, COX-2 selective inhibitors, COX-3 selective inhibitors, or combinations thereof.
  • the formulation can be formulated to treat skin disorders or blemishes by including active agents such as anti-acne drugs such as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as tazarotene and isotretinoin, cyclosporin, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, etc.
  • active agents such as anti-acne drugs such as clindamycin and benzoyl peroxide, retinol, vitamin A derivatives such as tazarotene and isotretinoin, cyclosporin, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipotriol, tacalcitol, calcipotriene, etc.
  • active agents such as anti-acne drugs such as clindamycin and benzoyl peroxid
  • anti-wart compounds include but are not limited to:imiquimod, rosiquimod, keratolytic agents: salicylic acid, alpha hydroxy acids, sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, benzoic acid, or combinations thereof.
  • a further embodiment involves the use of the solidifying formulations for the delivery of sex steroids including but not limited to progestagens consisting of progesterone, norethindrone, norethindroneacetate, desogestrel, drospirenone, ethynodiol diacetate, norelgestromin, norgestimate, levonorgestrel, dl-norgestrel, cyproterone acetate, dydrogesterone, medroxyprogesterone acetate, chlormadi ⁇ one acetate, megestrol, promegestone, norethisterone, lynestrenol, gestodene, tibolene, androgens consisting of testosterone, methyl testosterone, oxandrolone, androstenedione, dihydrotestosterone, estrogens consisting of estradiol, ethniyl estradiol, estiol, estrone, conjugated
  • Non-sex steroids can also be delivered using the formulations of the present invention.
  • examples of such steroids include but are not limited to betamethasone dipropionate, halobetasol propionate, diflorasone diacetate, triamcinolone acetonide, desoximethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, flurandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alclometasone dipropionate, flumethasone pivolate, hydrocortisone, hydrocortisone acetate, or combinations thereof.
  • a further embodiment involves controlled delivery of nicotine for treating nicotine dependence among smokers and persons addicted to nicotine.
  • Formulations of the present invention would be a cost effective way of delivering therapeutic amounts of nicotine transdermally.
  • Another embodiment involves using the formulation to deliver antihistamine agents such as diphenhydramine and tripelennamine. These agents would reduce itching by blocking the histamine that causes the itch and also provide relief by providing topical analgesia.
  • antihistamine agents such as diphenhydramine and tripelennamine.
  • drugs which can be delivered using the solidifying formulations of the present invention include but are not limited to tricyclic anti-depressants such as amitriptyline; anticonvulsants such as carbamazepine and alprazolam; N-methyl-D-aspartate (NMDA) antagonists such as ketamine; 5-HT2A receptor antagonists such as ketanserin; and immune modulators such as tacrolimus and picrolimus.
  • tricyclic anti-depressants such as amitriptyline
  • anticonvulsants such as carbamazepine and alprazolam
  • N-methyl-D-aspartate (NMDA) antagonists such as ketamine
  • 5-HT2A receptor antagonists such as ketanserin
  • immune modulators such as tacrolimus and picrolimus.
  • a further embodiment involves the following steps: selecting a drug for dermal delivery, selecting or formulating a flux-enabling or high flux-enabling non-volatile solvent system for the selected drug, selecting a solidifying agent that is compatible with the non-volatile solvent system and volatile solvent system, selecting a volatile solvent system that meets a preferred drying time frame and is compatible with the above ingredients, and formulating above ingredients into a solidifying formulation that optionally further includes other ingredients such as viscosity modifying agent(s), pH modifying agent(s), and emollients.
  • Another embodiment involves a method of maintaining a liquid flux- enabling or high liquid flux-enabling non-volatile solvent on human skin (including mucosa or nail surfaces) for delivery of a drug into tissues under the surfaces, comprising selecting a drug for dermal delivery, selecting or formulating a flux-enabling or high flux-enabling non-volatile solvent system for the selected drug, selecting a solidifying agent that is compatible with the flux- enabling or high flux-enabling non-volatile solvent system and volatile solvent system, and formulating above ingredients into a solidifying formulation.
  • Another embodiment involves a method for keeping a liquid flux- enabling non-volatile solvent system on human skin for delivery of a drug into the human skin or tissues under the human skin.
  • the method includes applying to a human skin a layer a formulation comprising a drug, a flux enabling nonvolatile solvent system, a solidifying agent capable of gelling the liquid flux- enabling non-volatile solvent system into a soft solid, and a volatile solvent system that is compatible with the rest of components of the formulation.
  • the formulation layer is such that the evaporation of at least some of the volatile solvent system transforms the formulation from an initial less than solid state into a soft-coherent solid layer.
  • the drug in the soft-coherent solid layer is delivered at therapeutically effective rates for a sustained period of time.
  • a formulation for dermal delivery of a sex hormone can include a sex hormone, a solvent vehicle, and a solidifying agent that contributes to solidification of the formulation applied as a layer on a skin surface upon at least partial evaporation of the volatile solvent system.
  • the solvent vehicle can include a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one nonvolatile solvent.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • An antiwart formulation can include an anti- wart drug, a solvent vehicle, and a solidifying agent.
  • the solvent vehicle can include a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • the antiwart hormone continues to be delivered therapeutically sufficient rates even after the volatile solvent system is at least substantially evaporated.
  • a formulation for delivering clobetasol propionate can include clobetasol propionate, a solvent vehicle, and a solidifying agent.
  • the solvent vehicle includes a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system.
  • the non-volatile solvent system can include propylene glycol and/or a fatty acid.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • the clobetasol propionate continues to be delivered therapeutically sufficient rates even after the volatile solvent system is at least substantially evaporated.
  • the solidifying agent can be a protein based solidifying agent.
  • a solidifying formulation for delivering ropivacaine can include ropivacaine, a solvent vehicle, and a solidifying agent.
  • the volatile solvent system including at least one volatile solvent and the nonvolatile solvent system which can comprise solvents such as isostearic acid span 20, and triacetin.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • a solidifying formulation for delivering imiquimod can include imiquimod, a solvent vehicle, and a solidifying agent.
  • the volatile solvent system including at least one volatile solvent, and the non-volatile solvent system can comprise solvents such as isostearic acid span 20, and triacetin.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system. When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system.
  • a solidifying formulation for delivering imiquimod can include imiquimod, a solvent vehicle, and a solidifying agent.
  • the volatile solvent system including at least one volatile solvent and the non-volatile solvent system can comprise solvents such as isostearic acid span 20, and triacetin.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system.
  • a solidifying formulation for delivering ketoprofen can include ketoprofen, a solvent vehicle, and a solidifying agent.
  • the volatile solvent system includes a volatile solvent system including at least one volatile solvent and a non-volatile solvent system comprising glycerol and propylene glycol.
  • the formulation can have a viscosity which is suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system.
  • the formulation When applied to a skin surface the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Even after the at least a portion of the partial evaporation of the volatile the ketoprofen continues to be delivered across the skin at a rate of no less than 10 mcg/hr/cm 2 for at least 6 hours after the volatile solvent system has at least substantially evaporated.
  • Hairless mouse skin (HMS) or human epidermal membrane (HEM) is used as the model membranes as noted for the in vitro flux studies described in herein.
  • Hairless mouse skin (HMS) is used as the model membrane for the in vitro flux studies described in herein.
  • Freshly separated epidermis removed from the abdomen of a hairless mouse is mounted carefully between the donor and receiver chambers of a Franz diffusion cell.
  • the receiver chamber is filled with pH 7.4 phosphate buffered saline (PBS).
  • PBS pH 7.4 phosphate buffered saline
  • the experiment is initiated by placing test formulations (of Examples 2-5) on the stratum corneum (SC) of the skin sample.
  • Franz cells are placed in a heating block maintained at 37 0 C and the HMS temperature is maintained at 35 0 C.
  • Skin flux ( ⁇ g/cm 2 /h) is determined from the steady-state slope of a plot of the cumulative amount of permeation versus time. It is to be noted that human cadaver skin can be used as the model membrane for the in vitro flux studies as well. The mounting of the skin and the sampling techniques used as the same as described above for the HMS studies.
  • Example 2 Human cadaver skin is used as membrane to select "flux-enabling" non-volatile solvent for betamethasone dipropionate. About 200 mcL of saturated solutions of BDP in various solvents are added to the donor compartment of the Franz cells. In vitro analysis as described in Example 1 is used to determine the steady state flux of BDP. In vitro methodology used is described in Example 1. Active enzymes in the skin convert betamethasone dipropionate to betamethasone. The steady state flux values reported in Table 1 are quantified using external betamethasone standards and are reported as amount of betamethasone permeating per unit area and time. Table 1 - Non-volatile solvents for betamethasone di ro ionate
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the experiment was continued it is anticipated the steady state would continue.
  • triacetin, labrasol, oleic acid, and light mineral oil have flux values close to the estimated therapeutically effective flux of 10 ng/cm 2 /hr.
  • Addition of solidifying agents and other components could possible decrease the flux and hence the above mentioned non-volatile solvents may not be an ideal choice as "flux-enabling" solvents.
  • sorbitan monolaurate has 3 times higher flux than one possible therapeutic level and hence has better chances to be a "flux-enabling" solvent. Its compatibility with various solidifying agents would determine the appropriate levels at which it can be used.
  • propylene glycol has 19 times higher flux than therapeutic level needed, and hence provides significantly higher flux than other non-volatile solvent systems tested.
  • Formulations of clobetasol propionate in various non-volatile solvent systems are evaluated. All solvents have 0.1% (w/w) clobetasol propionate.
  • the permeation of clobetasol from the test formulations through HEM is presented in Table 2 below.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the experiment was continued it is anticipated the steady state would continue.
  • betamethasone dipropionate which is similar in structure to clobetasol propionate has good flux with propylene glycol.
  • the solvent system which is a mixture of propylene glycol and isostearic acid at a weight ratio of 9:1 has significantly higher flux than either of the solvents alone or the other solvents tested.
  • the average flux is 20 times higher than light mineral oil which appears to be the best non-mixed solvent.
  • the propylene glycol/isostearic acid provided the highest flux for a non-volatile solvent system.
  • the nonvolatile solvents listed in Table 2 only 9:1 propylene glycol: ISA is considered to be flux enabling.
  • flux enabling non-volatile solvent system is not a pure, single substance, but rather a mixture of two or more substances at a flux-enabling ratio. This being stated, other ratios or substance combinations may be used to generate a flux-enabling non-volatile solvent system.
  • Adhesive formulations containing 0.05% (w/w) clobetasol propionate with propylene glycol and isostearic acid as non volatile solutions and various solidifying agents are prepared.
  • the formulations are prepared from the ingredients as shown in Table 3.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-28 hours. If the experiment was continued it is anticipated the steady state would continue.
  • Example 4 As seen from Table 4 formulation described in Example 4 that contains polyvinyl alcohol as a solidifying agent has high flux of clobetasol propionate.
  • Polyvinyl alcohol is known to form stretchable solidified layers and it is likely that this formulation will have acceptable wear properties.
  • the toughness of the resulting solidified layer can be modified by adding appropriate plasticizers if needed (the non-volatile solvent system itself can serve as a plasticizer).
  • Tackiness can also be modified by adding appropriate amounts of tackifier or by adding appropriate amounts of another solidifying agent such as dermacryl 79.
  • Example 9 a higher percentage of ethanol is needed to dissolve the polymer.
  • the solidifying agent used in Example 9 provides the highest flux of clobetasol propionate among the solidifying agents studied.
  • the wear properties of this formulation can be modified by adding appropriate levels of other ingredients including but not limited to plasticizers, tackifiers, non-volatile solvents and or solidifying agents.
  • Example 10 Formulations of acyclovir in various non-volatile solvent systems are evaluated. Excess acyclovir is present.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours.
  • Steady state flux of acyclovir from the above non-volatile solvents are obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin.
  • the in vitro studies are carried out as described in Example 1.
  • the surprising result showed the polyethylene glycol 400, span 80, ethyl oleate, or ethyl oleate plus trolamine are not flux-enabling solvents for acyclovir (e.g., steady state flux values significantly less than the steady state flux of acyclovir in the marketed product noted in Table 1, where the flux was about 3mcg/cm 2 /h).
  • Prototype formulations are prepared as follows. Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 6, as follows:
  • compositions in Table 6 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. The isostearic acid and trolamine is added to the RL-PO/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously mixed.
  • Prototype formulations are prepared as follows. Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 7, as follows:
  • compositions of Examples 15 and 16 as shown in Table 3 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. The isostearic acid and diisopropanol amine or Neutrol TE Polyol (BASF) is added to the RL-PO/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously mixed.
  • Prototype peel formulations are prepared as follows. Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 8, as follows:
  • compositions in Table 8 are prepared as follows. Ethyl cellulose (EC)N7 or EC N 100 from Aqualon and ethanol are combined in a glass jar and heated with stirring until the solid cellulose is dissolved. The isostearic acid and trolamine is added to the cellulose/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously mixed.
  • Ethyl cellulose (EC)N7 or EC N 100 from Aqualon and ethanol are combined in a glass jar and heated with stirring until the solid cellulose is dissolved.
  • the isostearic acid and trolamine is added to the cellulose/ethanol mixture and the mixture is vigorously stirred. Once a uniform mixture is obtained, acyclovir is added to the mixture and the formulation is vigorously mixed.
  • Example 11-18 The formulations of Examples 11-18 are tested in a hairless mouse skin (HMS) in vitro model described in Example 1.
  • Table 9 shows data obtained using the experimental process outlined above.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed the steady state flux would extend beyond the 8 hours measured.
  • the formulations of the invention shown above generally provide for significant penetration of the active ingredient, and further, the formulations of Examples 11-13 and 18 are found to be much greater in permeability than the marketed product Zovirax Cream.
  • the quantity of acyclovir that permeated across the HMS stratum corneum over time for Examples 11 , 12, and Zovirax Cream are shown in FIG. 4. Each value shown indicates the mean ⁇ SD of at least three experiments.
  • Examples 11-14 show the impact of the trolamine to isostearic acid (ISA) ratio on acyclovir flux enhancement.
  • the optimal ISAitrolamine ratio is 1:1 to 2:1 and ratio greater than 4:1 show a significant decrease in the acyclovir skin flux.
  • Additions of diisopropanol amine and Neutrol in place of trolamine (Examples 15 and 16) in the formulation show a significant decrease in acyclovir flux values. This may be due to a specific chemical interaction between trolamine and ISA creating an environment within the formulation which facilitates higher skin flux.
  • Examples 17 and 18 utilize a different solidifying agent to evaluate the impact of the solidifying agent on acyclovir flux.
  • Example 17 shows a significant decrease in acyclovir skin flux
  • Examples 11 and 12 show sustained delivery of acyclovir up to 8 hours, it is reasonable to assume based on the drug load and the continued presence of the non volatile solvent that the delivery of acyclovir would continue at the reported flux values for as long as the subject desires to leave the solidified formulation affixed to the skin.
  • Example 21 A solidifying formulation similar to Example 12 (with no acyclovir) is applied onto a human skin surface, resulting in a thin, transparent, flexible, and stretchable solidified layer. After a few minutes of evaporation of the volatile solvent (ethanol), a solidified adhesive layer that is peelable is formed. The stretchable solidified layer has good adhesion to the skin and did not separate from the skin, and could easily be peeled away from the skin. The absence of acyclovir has minimal to impact on the physical and wear properties of the formulation and soft, coherent solid because it is present at such low concentration, when present.
  • Example 21 A solidifying formulation similar to Example 12 (with no acyclovir) is applied onto a human skin surface, resulting in a thin, transparent, flexible, and stretchable solidified layer. After a few minutes of evaporation of the volatile solvent (ethanol), a solidified adhesive layer that is peelable is formed. The stretchable solidified layer has good adhesion to the skin and did not separate from the skin, and could easily be peele
  • ketoprofen Solidifying formulations of ketoprofen in various non-volatile solvent systems are evaluated. Excess ketoprofen is present. The permeation of ketoprofen from the test formulations through HMS is presented in Table 10 below.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between
  • Steady state flux values of a drug from the non-volatile solvent that are below the therapeutically effective flux are not considered flux-enabling while steady state flux values of a drug from a non-volatile solvent above the therapeutically effective flux value is considered flux-enabling.
  • Solidifying formulations of ropivacaine in various non-volatile solvent systems are evaluated. Excess ropivacaine is present. The permeation of ropivacaine from the test formulations through HMS is presented in Table 11 below.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours.
  • Steady state flux values of a drug from the non-volatile solvent that are below the therapeutically effective flux are not considered flux-enabling while steady state flux values of a drug from a non-volatile solvent above the therapeutically effective flux value is considered flux-enabling.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours.
  • Steady state flux of diclofenac sodium from the above non-volatile solvents are obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin.
  • the in vitro studies are carried out as described in Example 1.
  • the non-volatile solvent glycerol has a steady state flux value comparable to the estimated therapeutic steady state flux value and maybe considered a flux-enabling solvent.
  • the steady state flux values of isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are at least 10 times the flux value reported for glycerol. These non-volatile solvents are considered flux-enabling solvents.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state, delivery would likely continue well beyond 8 hours. Steady state flux of diclofenac acid from the above non-volatile solvents are obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. The in vitro studies are carried out as described in Example 1. From Table 13, the non-volatile solvent glycerol has no reported steady state flux value and is not considered a viable non-volatile solvent candidate.
  • the steady state flux values of isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are no more than 10 times the flux value reported for currently available marketed products, and as such, could be considered flux-enabling solvents. It should be noted that the steady state flux values for diclofenac acid from each of the above non-volatile solvents are much lower than the steady state flux values obtained with diclofenac sodium.
  • Solidifying formulations of testosterone in various non-volatile solvent systems are evaluated. Excess testosterone is present.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours. Steady state flux of testosterone from the above non-volatile solvents are obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. The in vitro studies are carried out as described in Example 1. From Table 14, the non-volatile solvent Tween 60 (Polyoxyethylene sorbitan mono-stearate) have no reported steady state flux value and is not considered a viable non-volatile solvent candidate.
  • Tween 60 Polyoxyethylene sorbitan mono-stearate
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours.
  • Steady state flux of hydromorphone from the above non-volatile solvents are obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin.
  • the in vitro studies are carried out as described in Example 1.
  • the non-volatile solvents propylene glycol and isostearic acid may qualify as flux-enabling solvents (based on an estimated therapeutically effective flux for hydromorphone is 2 mcg/cm 2 /h).
  • the steady state flux value of hydromorphone from ethyl oleate is much higher and would qualify as a high flux-enabling solvent.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed, the steady-state delivery would likely continue well beyond 8 hours.
  • Steady state flux of hydromorphone from the above non-volatile solvents are obtained by placing 200 ⁇ l_ on the stratum corneum side (donor) of hairless mouse skin.
  • the in vitro studies are carried out as described in Example 1.
  • the non-volatile solvent propylene glycol may qualify as flux- enabling solvents (based on an estimated therapeutically effective flux for hydromorphone is 2 ⁇ g/cm 2 /h).
  • the steady state flux value of hydromorphone from isostearic acid and ethyl oleate would also qualify as flux-enabling solvents.
  • Prototype solidifying formulations are prepared as follows. Several formulations are prepared in accordance with embodiments of the present invention in accordance with Table 17, as follows: Table 17
  • Solidifying formulations of Examples 28-32 are prepared in the following manner:
  • the solidifying agents are dissolved in the volatile solvent (e.g., dissolve polyvinyl alcohol in water, Eudragit polymers in ethanol),
  • the non-volatile solvent is mixed with the solidifying agent/volatile solvent mixture.
  • the flux-enabling non-volatile solvent/solidifying agent/volatile solvent combination is compatible as evidenced by a homogeneous, single phase system that exhibited appropriate drying time, and provided a stretchable solidified layer and steady state flux for the drug (see Example 33 below).
  • HMS hairless mouse skin
  • HEM HEM in vitro model described in Example 1.
  • Table 18 shows data obtained using the experimental process outlined above.
  • Acyclovir, ropivacaine, and testosterone have surprisingly higher steady state flux values when the flux-enabling non-volatile solvent is incorporated into the solidifying formulations. It is speculated that the higher flux values may be the result of contributions of the volatile solvent or the solidifying agent impacting the chemical environment (e.g., increasing solubility) of the drug in the solidified formulation resulting in higher flux values. Conversely, ketoprofen and diclofenac have lower steady state flux values when the enabling non-volatile solvent is incorporated into the solidifying formulations. This could be the result of the volatile solvent system or solidifying agent having the opposite impact on the chemical environment (e.g., decreasing solubility, physical interactions between drug and formulation) resulting in lower flux values.
  • 1 and 2 provide a graphical representation of the cumulative amount of diclofenac and ropivacaine, respectively, delivered transdermally across human cadaver skin.
  • the formulations tested were similar to those described in Examples 30 and 31. In these particularly embodiments, steady- state delivery is shown over 28 hours, and over 30 hours, repsectively.
  • a solidifying formulation with the following composition: 10.4% polyvinyl alcohol, 10.4% polyethylene glycol 400, 10.4% polyvinyl pyrrolidone K-90, 10.4% glycerol, 27.1 % water, and 31.3% ethanol was applied onto a human skin surface at an elbow joint and a finger joint, resulting in a thin, transparent, flexible, and stretchable solidified layer. After a few minutes of evaporation of the volatile solvents (ethanol and water), a solidified layer that was peelable was formed. The stretchable solidified layer had good adhesion to the skin and did not separate from the skin on joints when bent, and could easily be peeled away from the skin.
  • Example 36 Three formulations similar to the formulation in Example 36 (replacing ropivacaine base with ropivacaine HCI) are applied on the stratum corneum side of freshly separated hairless mouse skin. The in vitro flux is determined for each formulation as outlined in Example 1. The formulation compositions are noted in Table 19 below.
  • Flux values represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 6-31 hours. If the experiment was continued it is anticipated the steady state would continue.
  • a solidifying formulation for dermal delivery of imiquimod is prepared which includes a specified amount of imiquimod in an excipient mixture to form an adhesive formulation in accordance with embodiments of the present invention.
  • the solidifying formulations contained the following components:
  • the flux values represent the mean and SD of three determinations ** Ratio to control calculated by dividing the flux value for each example by the flux value for Aldara control flux.
  • the steady state flux of formulation Examples 38 and 39 demonstrate the value of the amount of nonvolatile solvent in added to the formulation in dictating the flux-generating power of the entire formulation.
  • Formulation Examples 41 and 42 utilize a different solidifying agent which is compatible in a non-aqueous volatile solvent system (isopropanol).
  • the selection of non-volatile solvent system ISA/triacetin or ISA/Span 20/trolamine/triacetin combination showed no change in the in vitro flux.
  • the increase in in vitro flux is shown to be influenced by an increase in the amount of imiquimod present in the formulation. At imiquimod levels above 4% the drug is saturated in the peel formulation.
  • the increase in in vitro flux as a function of increased drug addition (Examples 41 and 42) may be due to the increased solubility of drug in the solidified peel formulation once the volatile solvent is evaporated off.
  • Example 38 demonstrates comparable imiquimod flux to the other formulation examples, and the value of the non-volatile solvent system and solidifying agent compatibility caused by the removal of trolamine because this non-volatile solvent negatively influenced the function of the Plastoid B polymer.
  • Example 43-46
  • a solidifying formulation for dermal delivery of imiquimod is prepared which includes a specified amount of imiquimod in an excipient mixture to form an adhesive formulation in accordance with embodiments of the present invention.
  • the peel formulations contained the following components:
  • a solidifying formulation for dermal delivery of ropivacaine is prepared which includes a specified amount of ropivacaine in an excipient mixture to form an adhesive solidifying formulation in accordance with embodiments of the present invention.
  • the peel formulations contain the following components:
  • ethanol is used as the volatile solvent
  • ISA, glycerol, and PG mixture is used as the nonvolatile solvent system.
  • ISA, PG and glycerol serve as a plasticizer in the peelable formulation after the ethanol (volatile solvent) has evaporated.
  • the steady state flux of ropivacaine from formulation Examples 47 and 48 demonstrate the importance of the non-volatile solvent in dictating the flux-generating power of the entire formulation.
  • Ropivacaine base solubility in isostearic acid is experimentally determined to be slightly above 1 :4, meaning 1 gram ropivacaine base can completely dissolve in 4 gram isostearic acid.
  • Solution A includes 1 part ropivacaine base and 4 parts isostearic acid.
  • Solution B includes 1 part ropivacaine base, 4 parts isostearic acid, and 1 part trolamine. (all parts are in weight). All ropivacaine in Solution A is dissolved, but only a portion of ropivacaine in solution B is dissolved.
  • the transdermal flux across hairless mouse skin generated by the solutions is measured by a typical Franz Cell system, with the following results:
  • Solution B 43.2 35.0 50.0 42.7 As can be seen, the flux generated by Solution B is about 4 times that of
  • Example 50 A solidifying formulation for dermal delivery of ropivacaine is prepared from the following ingredients: Table 27 - Ro ivacaine solidif in formulation components
  • the ingredients listed above are combined according to the following procedure.
  • the Eudragit RL-100 and ethanol are combined in a glass jar and heated to about 60 0 C until the Eudragit RL-100 is completely dissolved.
  • the appropriate amount of ropivacaine HCI is added and mixed thoroughly for 1 minute.
  • isostearic acid (ISA) is added and the mixture is stirred vigorously for 2-3 minutes.
  • the solution is vigorously mixed again for 2-3 minutes.
  • glycerol, propylene glycol, and trolamine are added in sequential order. After addition of each ingredient the solution is stirred for 1 minute.
  • the flux values represent the mean and SD of three determinations
  • the ropivacaine peel formulations prepared in accordance with Example 6 possessed acceptable application properties, e.g., ease of removal of peel from the sample tube, ease of spreading on intended skin application site, etc., and forms a solidified film in 2-3 minutes after being applied to normal human skin surface as a thin layer with a thickness of about 0.1 mm.
  • the solidified peelable layer becomes more easily peelable In 2 hours, and the peel remains affixed to the skin surface without any unintended removal of the peel for at least 12 hours. At the end of intended use, the peel is easily removed in one continuous piece.
  • a solidifying formulation for dermal delivery of lidocaine is prepared which includes a saturated amount of lidocaine in an excipient mixture to form an adhesive peelable formulation in accordance with embodiments of the present invention.
  • the peel formulation is prepared from the ingredients as shown in Table 29.
  • the adhesive peelable formulation of lidocaine formulation in the present example has similar physical properties to the formulations in examples noted above.
  • the transdermal flux across hairless mouse skin is acceptable and steady-state delivery is maintained over 8 hours. Examples 52-55
  • a solidifying formulation for dermal delivery of amitriptyline and a combination of amitripyline and ketamine is prepared which includes an excipient mixture to form an adhesive peelable formulation in accordance with embodiments of the present invention.
  • the peel formulation is prepared from the ingredients as shown in Table 31.
  • the drug(s), water, and triisopropanolamine are combined in a glass jar and mixed until the drug is dissolved. Then the isostearic acid, triacetin, Span 20, and isopropanol are added to the formulation and mixed well.
  • the polymer Plastoid B is added last and heated to about 60 0 C until the Plastoid B is completely dissolved. Once the polymer solution cooled to room temperature, the formulation is stirred vigorously for 2-3 minutes.
  • Table 32 Steady-state flux of amitriptyline and amitriptyline/ketamine through hairless mouse skin from various adhesive solidif in formulations at 35 0 C
  • the adhesive peelable formulation of amitriptyline and amitriptyline/ketamine formulations in the present examples have similar physical properties to the formulations in examples noted above.
  • the transdermal flux is proportional to the amount of drug added into the formulation.
  • a solidifying formulation for dermal delivery of ropivacaine is prepared which includes an excipient mixture to form an adhesive peelable formulation in accordance with embodiments of the present invention.
  • the peel formulation is prepared from the ingredients as shown in Table 33.
  • ingredients are noted as parts by weight. ** from Degussa.
  • the ingredients listed above are combined according to the following procedure.
  • the ropivacaine HCI, water, and triisopropanolamine are combined in a glass jar and mixed until the drug is dissolved.
  • the isostearic acid, triacetin, Span 20, and isopropanol are added to the formulation and mixed well.
  • the polymer Plastoid B is added last and heated to about 60 0 C until the Plastoid B is completely dissolved. Once the polymer solution cooled to room temperature, the formulation is stirred vigorously for 2-3 minutes.
  • Examples 56-59 show the importance of the triacetin, isostearic acid, Span 20 combination in the formulation. In Examples 56-59 formulations were made without Span 20, triacetin, and isostearic acid respectively.
  • the in vitro flux of ropivacaine was impacted.
  • the synergistic combination of the non volatile solvents is an important in obtaining the maximum in vitro flux of ropivacaine.
  • This solidifying formulation has the following ingredients in the indicated weight parts:
  • polyvinyl alcohol (USP grade, from Amresco) is a solidifying agent
  • ethyl cellulose and Dermacryl 79 are auxiliary solidifying agents.
  • Isostearic acid and glycerol form the non-volatile solvent system while ethanol and water form the volatile solvent system.
  • Ropivacaine is the drug.
  • Ropivacaine is mixed with ISA.
  • PVA is dissolved in water at temperature of about 60-70 C.
  • the resulting formulation is a viscous fluid.
  • a layer of about 0.1 mm thick is applied on skin, a non-tacky surface is formed in less than 2 minutes.
  • Anti-fungal solidifying formulations are prepared and a qualitative assessment of peel flexibility and viscosity are evaluated.
  • the formulation components are presented in Table 36 below.
  • the peel formulation in Example 61 has a low viscosity that was lower than may be desirable for application on a nail or skin surface.
  • the time to form a solidified peel with this formulation is longer than the desired drying time.
  • the formulation in Example 62 had an increase in the amount of solidifying agent (Eudgragit RL-PO) and decrease in amount of ethanol, which improves the viscosity and drying time.
  • Example 62 has a viscosity suitable for application and an improved drying time.
  • Example 63
  • a solidifying formulation was prepared in accordance with Table 37, as follows:
  • the solidifying agent is dissolved in the volatile solvent (i.e. dissolve polyvinyl alcohol in water).
  • the flux enabling non-volatile solvent is mixed with the solidifying agent/volatile solvent mixture.
  • the resulting solution is vigorously mixed well for several minutes.
  • Example 63 The formulation prepared in Example 63 was tested for skin flux, as set forth in Table 38 below.
  • AndroGel currently marked product, is applied directly on the hairless mouse skin and the flux determinations are made as outlined in Example 1.
  • the steady state flux data is shown in FIG 3. It should be noted, the steady- state flux value reported in Table 38 is determined using the linear region between 2-6 hours.
  • the in vitro flux of testosterone from AndroGel substantially decreases beyond 6 hours. This may be due in part to the evaporation of the volatile solvent which may act as the main vehicle for delivery.
  • the solidifying formulation in Example 63 will deliver a steady-state amount of testosterone for at least 9 hours.
  • a stretchable adhesive solidifying formulation for transdermal delivery of ketoprofen (which is suitable for delivery via skin for treating inflammation or pain of joints and muscles) is prepared which includes saturated amount of ketoprofen in an excipient mixture (more ketoprofen than that can be dissolved in the excipient mixture) to form an adhesive peelable formulation, some of which is prepared in accordance with embodiments of the present invention.
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 39.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed the steady state flux would extend beyond the 8 hours measured.
  • ethanol and water formed the volatile solvent system, while a 1:1 mixture of glycerol and PEG 400 formed the non-volatile solvent system.
  • PEG 400 is a slightly better solvent than glycerol for ketoprofen, while glycerol is much more compatible with PVA than PEG 400.
  • the non-volatile solvent system of glycerol and PEG 400 are used together to provide a non-volatile solvent system for the drug, while being reasonably compatible with PVA.
  • PVA and PVP act as the solidifying agents.
  • glycerol and PEG 400 also serve as plasticizers in the adhesive peelable formulation formed after the evaporation of the volatile solvents. Without the presence of glycerol and PEG 400, a film formed by PVA and PVP alone would be rigid and non- stretchable.
  • Example 66 the adhesive peelable formation formed has similar physical properties as that of Example 65, though the transdermal flux across hairless mouse skin is higher. This suggests that the solidifying agent, 1:1 PVA:PVP-K-90 in Example 65 and pure PVA in Example 66, have an impact on permeation.
  • Example 67 delivers less ketoprofen than the formulations of Examples 65 or 66.
  • the formulation of Example 68 delivers much less ketoprofen than the formulations in Examples 65 and 66.
  • One possible reason for the reduced flux is believed to be the reduced permeation driving force caused by the high concentration of PEG 400 in the non-volatile solvent system, which resulted in too high of solubility for ketoprofen.
  • a stretchable adhesive solidifying formulation for transdermal delivery of lidocaine is prepared which includes saturated amount of lidocaine in an excipient mixture to form an adhesive solidifying formulation in accordance with embodiments of the present invention.
  • the formulation is prepared from the ingredients as shown in Table 41.
  • ingredients are noted as parts by weight. ** from Rohm & Haas.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed the steady state flux would extend beyond the 8 hours measured.
  • the adhesive solidifying formulation of lidocaine in the present example has similar physical properties to the formulations in Examples 65-68. The transdermal flux across hairless mouse skin is acceptable and steady-state delivery is maintained over 8 hours.
  • Example 65 composition A formulation similar to the formulation of Example 65 composition (with no ketoprofen) is applied onto a human skin surface at an elbow joint and a finger joint, resulting in a thin, transparent, flexible, and stretchable film. After a few minutes of evaporation of the volatile solvents (ethanol and water), a solidified peelable layer is formed.
  • the stretchable film has good adhesion to the skin and does not separate from the skin on joints when bent, and can easily be peeled away from the skin.
  • a stretchable adhesive solidifying formulation for transdermal delivery of ketoprofen (which is suitable for delivery via skin on joints and muscles) is prepared which includes saturated amount of ketoprofen in an excipient mixture (more ketoprofen than that can be dissolved in the excipient mixture) to form an adhesive peelable formulation, some of which are prepared in accordance with embodiments of the present invention.
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 43.
  • Peel formulations of Examples 71-73 are prepared in the following manner: The solidifying agents are dissolved in the volatile solvent (i.e., dissolve Eudragit polymers in ethanol).
  • the flux adequate non-volatile solvent (glycerol, PEG) is mixed together with the solidifying agent/volatile solvent mixture.
  • the resulting solution is vigorously mixed for several minutes. Drug is then added and the formulation is mixed again for several minutes.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported were determined from the linear region of the cumulative amount versus time plots. The linear region was observed to be between 4-8 hours. If experimental conditions allowed the steady state flux would extend beyond the 8 hours measured.
  • ketoprofen formulations prepared in accordance with Examples 71-72 possessed acceptable solidified layer properties (e.g., formed a solidified layer in 2-3 minutes). With Example 73, the ketoprofen peel does not form a solidified layer 30 minutes after application. This demonstrates that order to obtain desired flux and wear properties in a peel formulation, a delicate balance between solidifying agents, non-volatile solvents, and volatile solvents is evaluated and considered in developing a formulation.
  • a stretchable adhesive solidifying formulation for transdermal delivery of ketoprofen (which is suitable for delivery via skin on joints and muscles) is prepared which includes saturated amount of ketoprofen in an excipient mixture (more ketoprofen than that can be dissolved in the excipient mixture) to form an adhesive peelable formulation, some of which are prepared in accordance with embodiments of the present invention.
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 45.
  • Formulations A and B are prepared in the following manner:
  • PVA solidifying agent
  • Formulation C demonstrates that the correct polymer molecular weight for PVA is important to obtain the desired formulation properties.
  • Formulations A and B are placed on the skin of human volunteers. After a period of several hours, long enough for the volatile solvent to evaporate, the peels were removed by the volunteers and the peelability properties were evaluated. In all instances the volunteers reported that formulation example A could not be removed in one or two pieces, but was removed in numerous small pieces. Formulation example B removed in one or two pieces. The brittle nature of formulation A is attributed to the lower molecular weight PVA sample (Celvol).
  • Low molecular weight PVA does not possess the same cohesive strength as higher molecular weight PVA material (Amresco) due to the reduced size of the polymer chain leading to a reduction in the degree of cross linking and physical interactions between individual PVA polymer chains.
  • the reduced PVA chain interactions lead to a weakened peel that is unable to withstand the mechanical forces the peel is subjected to upon removal.
  • a stretchable adhesive solidifying formulation for transdermal delivery of ketoprofen (which is suitable for delivery via skin on joints and muscles) was evaluated which includes an excipient mixture which will form an adhesive peelable formulation, some of which are prepared in accordance with embodiments of the present invention.
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 46.
  • Peel formulations in formulations D-G are prepared in the following manner:
  • PVA solidifying agent
  • Formulations noted above were placed in laminate packaging tubes and stored at 25 C/60% RH and 40 C/ 75% RH conditions until pulled for testing. Physical testing was performed on each formulation. Formulations D-F have been studied the longest and the resulting viscosity increase necessitated the desire to study the viscosity of formulation G. Table 47 summarizes the data generated on each formulation.
  • Formulations D and E of this example had the lowest water content of the four formulations and within 4 weeks of storage attained high viscosity values.
  • the only difference between formulations 1 and 2 is the amount of ethanol in the formulations. It was hypothesized that reducing the level of ethanol may reduce the physical thickening of the formulation due to an incompatibility between the PVA and ethanol.
  • the viscosity data show that the higher ethanol formulation (formulation D) had lower initial viscosity, but over the 4 weeks storage the viscosity of both formulation D and E attained viscosity values that were too high for a viable formulation.
  • Another hypothesis for the formulation thickening is that PVA is not compatible in high concentrations when dissolved in water. Additional formulations with higher water content were prepared to determine if an optimal water amount would keep the formulation from thickening up over time.
  • Formulation F viscosity after 16 weeks has not reached the viscosity values of the initial viscosity values of formulations 1 and 2.
  • Placebo versions of the formulations above were applied on study volunteers and the drying time was assessed by placing a piece of cotton to the application site and then applying a 5 gram weight on the cotton. The cotton and weight was removed after 5 seconds. This procedure was started approximately 3 — 4 minutes after application and at 10 to 60 second intervals thereafter until the cotton was removed without lifting the peel or leaving residue behind.
  • Table 48 The results of the study are summarized in Table 48 below.
  • Solidifying formulations for dermal delivery of ropivacaine HCI are prepared which include excipient mixtures in accordance with embodiments of the present invention.
  • the formulations are prepared from the ingredients as shown in Table 49.
  • Table 50 Steady-state flux of ropivacaine HCI through hairless mouse skin from various adhesive solidifying formulations at 35 0 C

Abstract

L'invention concerne des formulations adhésives pouvant se solidifier, des procédés pour administrer des médicaments, et des couches solidifiées destinées à être administrer par voie cutanée. La formulation peut comprendre un médicament, un excipient de solvants, et un agent de solidification. L'excipient de solvants peut comprendre un système de solvants volatiles comprenant au moins un solvant volatile, et un système de solvants non volatiles comportant au moins un solvant non volatile, ce dernier étant un solvant non volatile, fluidifiant, facilitant l'administration de médicaments dans des quantités thérapeutiquement efficaces sur une période soutenue. La formulation peut présenter une viscosité permettant son application à la surface de la peau, avant l'évaporation du système de solvants. Lorsqu'elle est appliquée sur la peau, la formulation peut former une couche solidifiée après l'évaporation d'au moins une partie du système de solvants volatiles.
EP06847684A 2005-12-14 2006-12-14 Compositions de fluidification et procede pour administrer par voie cutanee des medicaments Withdrawn EP1959930A2 (fr)

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