EP1968541A2 - Compositions et procedes d'administration dermique de medicaments - Google Patents

Compositions et procedes d'administration dermique de medicaments

Info

Publication number
EP1968541A2
EP1968541A2 EP06849969A EP06849969A EP1968541A2 EP 1968541 A2 EP1968541 A2 EP 1968541A2 EP 06849969 A EP06849969 A EP 06849969A EP 06849969 A EP06849969 A EP 06849969A EP 1968541 A2 EP1968541 A2 EP 1968541A2
Authority
EP
European Patent Office
Prior art keywords
formulation
volatile solvent
solidified layer
oil
skin
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Withdrawn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
EP06849969A
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 EP1968541A2 publication Critical patent/EP1968541A2/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Withdrawn legal-status Critical Current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
    • A61K9/0012—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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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

Definitions

  • the present invention relates generally to systems developed for dermal delivery of drugs. More particularly, the present invention relates to formulations including at least two non-volatile solvents, wherein the formulation as a whole has a viscosity suitable for application as a layer to a skin surface, and which forms a sustained drug-delivering adhesive solidified layer on the skin.
  • Semisolid formulations are available in a few different forms, including ointments, creams, foams, pastes, gels, or lotions and are applied topically to the skin.
  • transdermal patch dosage forms also are available in a few different forms, including matrix patch configurations and liquid reservoir patch configurations.
  • a 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.
  • a liquid reservoir patch 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.
  • most semisolid formulations usually contain solvent(s), such as water and ethanol, which are volatile and thus 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.
  • solvent(s) such as water and ethanol
  • 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 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 should have sufficient solubility in the adhesive, as primarily only dissolved drug contributes to the driving force required for skin permeation.
  • 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 patches including transdermal patches
  • 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. If the patch is applied to a skin area that is significantly stretched during body movements, such as a joint, separation between the patch and skin may occur thereby compromising the delivery of the drug.
  • a patch present on a skin surface may hinder the expansion of the skin during body movements and cause discomfort.
  • patches are not ideal dosage forms for skin areas subject to expansion, flexing and stretching during body movements.
  • an adhesive formulation for dermal delivery of a drug can comprise a drug, a solvent vehicle, and at least one solidifying agent.
  • the solvent vehicle can comprise a volatile solvent system including at least one volatile solvent and a non-volatile solvent system including at least one non-volatile solvents.
  • the at least two non-volatile solvents of the non-volatile solvent system can facilitate transdermal delivery of the drug at a therapeutically effective rate over a sustained period of time, even after the non-volatile solvent system is substantially evaporated from the solidified layer.
  • 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 formulated such that when applied to the skin surface, the formulation forms a solidified layer after at least a portion of the volatile solvent system is evaporated. Sustained drug delivery from the solidified layer can also occur.
  • the formulation is formulated such that it has at least two volatile solvents, at least two non-volatile solvents, at least two solidifying agents, or combinations thereof.
  • a method of dermally delivering a drug can comprise applying an adhesive formulation to a skin surface of a subject.
  • the formulation be any formulation as set forth above.
  • Other steps include solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system, and dermally delivering the drug from the solidified layer to the skin surface at therapeutically effective rates over a sustained period of time.
  • a solidified layer for delivering a drug can comprise a drug, a non-volatile solvent system including at least one nonvolatile solvents, wherein the non-volatile solvent system is capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time, and at least one solidifying agent.
  • the solidified layer can be stretchable by 5% in one direction without cracking, breaking, or separating from a skin surface to which the layer is applied.
  • the formulation is formulated such that it has at least two non-volatile solvents, at least two solidifying agents, or combinations thereof.
  • FIG. 1 is a graphical representation of cumulative amount of testosterone delivered across a biological membrane in vitro over time from a solidified adhesive formulation and a marketed product (AndroGel) in accordance with embodiments of the present invention.
  • FIG. 2 is a graphical representation of the cumulative amount of acyclovir delivered transdermal ⁇ over time from two separate formulations in accordance with embodiments of the present invention compared to the marketed product Zovirax cream.
  • a drug includes reference to one or more of such compositions.
  • 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.”
  • 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.
  • flux-enabling with respect to the non-volatile solvent system (or solidified layer including the same) refers to a non-volatile solvent system (including one or more non-volatile solvents) selected or formulated specifically to be able to provide therapeutically effective flux for a particular drug(s).
  • 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 effective 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 effective daily doses over 24 hours when the non-volatile 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 effective 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 effective drug flux, or whether it is flux-enabling.
  • the solidified layer can also be "flux enabling" for the drug while some of the nonvolatile solvents remain in the solidified layer, even after the volatile solvents (including water) have been substantially evaporated.
  • therapeutically effective rate(s), 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. However, for each drug, there is usually a consensus among those skilled in the art on the range of doses or fluxes that are sufficient in most subjects.
  • “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.
  • Therapeutically effective flux may also be different in different subjects and or at different times for even the same subject. However, for each drug, there is usually a consensus among the skilled in the art on the range of doses or fluxes that are sufficient in most subjects at most times.
  • the therapeutically effective flux values in Table 1 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, different individual subjects, etc. It should be noted that the flux listed may be more than therapeutically effective.
  • Table 2 illustrate screening of a nonvolatile solvent's flux enabling ability for some of the drugs specifically studied. Experiments were carried out as described in Example 1 below and the results are further discussed in the subsequent Examples 2-9.
  • 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 3 is a 9:1 for propylene glycol:isostearic acid mixture that generated much higher clobetasol flux than propylene glycol or ISA alone (see Table 2). 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 or "adhesive” 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.
  • adheresive or the like when used to describe the solidified layer means the solidified layer is adhesive to the skin 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.
  • whether a solidified layer can adhere to a skin surface for the desired extended period of time partially depends on the condition of the skin surface.
  • the adhesive solidified layer of the current invention may not be able to maintain perfect contact with the skin surface and deliver the drug over a sustained period of time for every subject under any conditions on the skin surface.
  • a standard is that it maintains good contact with most of the skin surface, e.g. 70% of the total area, over the specified period of time for most subjects under normal conditions of the skin surface and external environment.
  • the terms "flexible,” “elastic,” “elasticity,” or the like, as used herein refer to sufficient elasticity of the solidified layer so that it is not broken if it is stretched in at least one direction by up to about 5%,. and often to about 10% or even greater.
  • 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.
  • a flexible skin location e.g., elbow, finger, wrist, neck, lower back, lips, knee, etc.
  • 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.
  • 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.
  • 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.
  • Non-limiting examples of 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, and combinations thereof.
  • Non-volatile solvent system in this invention is defined as a mixture of at least two solvents that are each less volatile than water.
  • a non-volatile solvent is defined as a solvent that is less volatile than water.
  • the non-volatile solvent system can also contain substances that are solid or liquid at room temperatures, such as pH or ion-pairing agents. After evaporation of the volatile solvent system, most of the non-volatile solvent system should remain in the solidified layer for a period of time sufficient to adequately dermally deliver 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.
  • the non-volatile solvent system can also serve as a plasticizer of the solidified layer, so that the solidified layer is elastic and flexible.
  • the non-volatile solvent system provides better plasticizing effects for the solidifying agents than any single non-volatile solvent of the non-volatile solvent system alone.
  • Including multiple non-volatile solvents as part of the non-volatile solvent system can also provide various other benefits.
  • a single non-volatile solvent may not provide the formulation with adequate compatibility with other ingredients in the formulation, e.g. volatile solvent system or solidifying agent, and/or the ability to generate therapeutically effective flux of the drug.
  • the non-volatile solvent system provides better compatibility with the solidifying agent than any single non-volatile solvent of the non-volatile solvent system alone. In another aspect of the invention, the non-volatile solvent system provides higher flux than any single non-volatile solvent of the non-volatile solvent system alone.
  • the present invention allows for combinations of two or more non-volatile solvents which together are able to provide both therapeutically effective drug flux while maintaining formulation component compatibility.
  • 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 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.
  • “Adhesive solidifying formulation” or “solidifying formulation” 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. In one embodiment, once solidified on a skin surface, the formulation can form a peel.
  • the 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 when 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.
  • the additional adhesive 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 (Dermacryl 79), and/or various aliphatic resins and aromatic resins. .
  • washable 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.
  • the required force to remove the formulations by washing should not cause significant skin irritation or abrasion.
  • gentle washing force accompanied by the application of an appropriate washing solvent is sufficient to remove the adhesive formulations disclosed herein.
  • the 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.
  • washing solvents include but are not limited to water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, and combinations thereof.
  • the washing solvents can be selected from the group consisting of water, ethanol, isopropyl alcohol and combinations thereof.
  • Surfactants can also be used in some embodiments.
  • An acceptable length of time with respect 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°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.
  • 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. However, these lists should be construed as though each member of the list is individually identified as a separate and unique member. Thus, no individual member of such list should be construed as a de facto equivalent of any other member of the same list solely based on their presentation in a common group without indications to the contrary.
  • an adhesive 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 including at least one volatile solvent and a non-volatile solvent system including at least two non-volatile solvents.
  • the at least two non-volatile solvents of the non-volatile solvent system can facilitate transdermal delivery of the drug at a therapeutically effective rate over a sustained period of time, even after the non-volatile solvent system is substantially 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 formulated such that when applied to the skin surface, the formulation forms a solidified layer after at least a portion of the volatile solvent system is evaporated. Sustained drug delivery from the solidified layer can also occur.
  • a method of dermally delivering a drug can comprise applying an adhesive solidifying formulation to a skin surface of a subject.
  • the formulation can comprise a drug, solvent vehicle, and a solidifying agent.
  • the solvent vehicle can comprise a volatile solvent system including at least one volatile solvent, and a non-volatile solvent system including at least two non-volatile solvents, wherein the non-volatile solvent system facilitates dermal delivery of the drug at a therapeutically effective rate over a sustained period of time.
  • the formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system
  • Other steps include solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and dermally delivering the drug from the solidified layer to the skin surface at therapeutically effective rates over a sustained period of time.
  • a solidified layer for delivering a drug can comprise a drug, a non-volatile solvent system including at least two non-volatile solvents, wherein the non-volatile solvent system is capable of facilitating the delivery of the drug at therapeutically effective rates over a sustained period of time, and a solidifying agent.
  • the solidified layer can be stretchable by 5% in at least one direction without cracking, breaking, or separating from a skin surface to which the layer is applied.
  • an adhesive formulation for dermal delivery of a drug can comprise a drug, a solvent vehicle, and at least two solidifying agents.
  • 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 wherein the non-volatile solvent system can be flux-enabling for the drug such that the drug can be delivered in therapeutically effective amounts even after most of the volatile solvent(s) is(are) evaporated.
  • the formulation can have a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system, and can form a solidified layer after at least partial evaporation of the volatile solvent system after skin application.
  • a method of dermally delivering a drug can comprise applying an adhesive solidifying formulation to a skin surface of a subject.
  • the formulation can include a drug, a solvent vehicle, and at least two solidifying agents.
  • the solvent vehicle can comprise 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 suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system.
  • Other steps include solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and dermally delivering the drug from the solidified layer to the skin surface at therapeutically effective rates over a sustained period of time.
  • a solidified layer for delivering a drug can comprise a drug, a non-volatile solvent system comprising at least one nonvolatile solvent, and at least two polymeric solidifying agents.
  • 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 including at least two volatile solvents, and a non-volatile solvent system including at least one non-volatile solvent.
  • the formulation has a viscosity suitable for application and adhesion to a skin surface prior to evaporation of the volatile solvent system wherein the non-volatile solvent system can be flux-enabling for the drug such that the drug can be delivered at a therapeutically effective amount even after most of the volatile solvent(s) is(are) evaporated.
  • the formulation applied to the skin surface can form a solidified layer after at least partial evaporation of the volatile solvent system and can further be formulated such that when applied to the skin surface, the formulation forms a solidified layer after at least a portion of the volatile solvents is (are) evaporated, but yet continues to deliver drug after substantially solidifying. Additionally, the drug can continue to be delivered after the volatile solvent system is at least substantially evaporated.
  • a method of dermally delivering a drug can comprise applying an adhesive solidifying formulation to a skin surface of a subject.
  • the adhesive formulation can comprise a drug, a solvent vehicle, and a solidifying agent.
  • the solvent vehicle can comprise a volatile solvent system including at least two volatile solvent, and a non-volatile solvent system including at least one non-volatile solvent.
  • the formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system.
  • Other steps include solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and dermally delivering the drug from the solidified layer to the skin surface at therapeutically effective rates over a sustained period of time.
  • the formulations can also contain substances that are solid or liquid at room temperatures, such as pH or ion-pairing agents. After evaporation of the volatile solvent system, most of the non-volatile solvent system should remain in the solidified layer for a period of time sufficient to adequately dermally deliver 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.
  • the nonvolatile solvent system can also serve as a plasticizer of the solidified layer, so that the solidified layer is elastic and flexible.
  • these embodiments exemplify the present invention which is related to novel 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 which can be peelable, for drug delivery.
  • semi-solids including creams, gels, pastes, ointments, and other viscous liquids
  • a solidified layer thus formed is capable of delivering drug to the skin, into the skin, across the skin, etc., at substantially constant rates, over an sustained period of time, e.g., hours to tens of hours, so that most of the active drug is delivered after the solidified layer is formed.
  • a solid layer-forming formulation for dermal drug delivery can use a single solidifying agent
  • the use of two or more solidifying agents in the formulation herein can provide important advantages. This is because in addition to solidifying the formulations, the solidifying agent(s) in the formulation often impacts component compatibility as well as flexibility and skin adhesiveness of the solidified layer. Sometimes it takes two or more solidified agents to address all these needs.
  • the present invention is related to solidifying formulations that use two or more solidified agents to produce better formulation properties than any single solidifying agent alone within a given formulation could accomplish.
  • the solidified layer typically adheres to the skin, but has a solidified, minimally-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.
  • 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.
  • the volatile solvent system comprises at least one volatile solvent with a boiling point higher than 20 0 C (a liquid volatile solvent) and at least one volatile solvent with a boiling point lower than about 20 0 C (gaseous volatile solvents).
  • Boiling points refer to boiling points measured at normal atmospheric pressure.
  • Formulations of the present invention which have both liquid and gas volatile solvents can have significantly shorter drying times than those with only liquid volatile solvents.
  • concentration of the gas volatile solvent is below the formulations solubility. This allows the formulation to be stored in containers for conventional, un- pressurized semi-solid products. Alternatively, these solvents can be used as propellants for spray-on formulations.
  • gas volatile solvents which may be used in the present invention include but are not limited to ether, dimethyl ether, diethyl ether, propane, isobutene, diflouroethane, butane, 1,1 ,1 ,2 tetraflourethane, 1 ,1,1 ,2,3,3,3-heptaflouropropane, and 1,1,1,3,3,3, hexaflouropropane, and combinations thereof. 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. Too little of the volatile solvent system can make it difficult to spread the formulation on the skin.
  • the weight percentage of the volatile solvent(s) can be from about 10 wt% to about 85 wt%, and more preferably from about 20 wt% to about 50 wt%.
  • the volatile solvent system comprises at least 10 wt% of the formulation. In another embodiment, the volatile solvent system comprises at least about 20 wt% of the formulation.
  • the volatile solvent system can also be chosen to be compatible with the non-volatile solvent system, solidifying agent, drug, and any other excipients that may be present.
  • polyvinyl alcohol (PVA) is not soluble in ethanol. Therefore, a volatile solvent which will dissolve PVA needs to be formulated in the solidified layer. For instance, water will dissolve PVA and can be utilized as a volatile solvent in a formulation; however, the drying time in such a formulation 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 volatile solvent system can be chosen to reduce drying time for the formulation.
  • a second volatile solvent e.g., ethanol
  • the volatile solvent can be chosen to improve solubility of a particular drug form utilized in the formulation. For example, ropivacaine HCI is not soluble in non-volatile solvents isostearic acid, triacetin, and Span 20.
  • one of the volatile solvents of the volatile solvent system can be less volatile than the other.
  • the less volatile solvent can have better compatibility with the solidifying agent as compared to a more volatile solvent in the solvent system.
  • volatile solvent retaining substances can include water, hygroscopic substances, honey, glycerol, propylene glycol, and the like.
  • 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.
  • the solidifying agent can be chosen so that it is dispersible or soluble in the non-volatile solvent system. Most non-volatile solvent systems and solvent vehicles as a whole will be formulated appropriately after experimentation.
  • PEG 400 poly ethylene glycol
  • glycerol non-volatile solvent
  • water volatile solvent
  • PEG 400 cannot effectively dissolve poly vinyl alcohol (PVA), and thus, is not very compatible alone with PVA, a solidifying agent.
  • PVA poly vinyl alcohol
  • a non-solvent system including PEG 400 and glycerol (compatible with PVA) in an appropriate ratio can be formulated, achieving a compatibility compromise.
  • 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. Thus, appropriate solidifying agent/nonvolatile solvent selections are desirable in developing a viable formulation and compatible combinations. It is not necessary that both the non-volatile solvents of the non-volatile solvent system be compatible with the solidifying agent. In some embodiments one of the non-volatile solvents of the non-volatile solvent system can be present to provide compatibility with the solidifying agent while a second non-volatile solvent can act as the flux enabling non-volatile solvent.
  • the at least two non-volatile solvents that can be used to form non-volatile solvent systems can be selected from a variety of pharmaceutically acceptable liquids.
  • the non-volatile solvent system can include glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, 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, diethanolami ⁇ e, dietthylene glycol monoethyl ether, diglycer
  • non-volatile solvent system can include a combination or mixture of non-volatile solvents set forth in any of the above discussed embodiments.
  • the non-volatile solvent system or at least one of the non-volatile solvents in the non-volatile solvent system can also serve as plasticizer in the adhesive formulation 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) that are irritating to the skin may be 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. Examples of solvents that are known to be capable of preventing or reducing skin irritation include, but are not limited to, glycerin, honey, and propylene glycol.
  • non-volatile solvents can provide advantageous benefits such as acting as a plasticizer, improve adhesion, reducing skin irritation, inhibiting phase separation, and the like.
  • at least on of the at least two non-volatile solvents present in the non-volatile solvent system can act to promote the flux of one of the drugs while the other non-volatile solvent promotes the flux of the other drug.
  • the two or more non-volatile solvents of the non-volatile solvent system of the present invention may be such that the non-volatile solvents used independently are not flux-enabling non-volatile solvents for a drug but when formulated together become a flux-enabling non-volatile solvent.
  • One possible reason for these initially non enabling non-volatile solvents to become enabling non-volatile solvents 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.
  • non-volatile solvents may optimize the pH of the formulation or the skin tissues under the formulation layer to minimize irritation.
  • suitable combinations of non-volatile solvents that result in an adequate non-volatile solvent system 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 polymethylene, 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 casei ⁇ ate, 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
  • 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.
  • 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 ratio between the non-volatile solvent system and the solidifying agent can be from about 0.5:1 to about 2:1.
  • the use of at least two solidifying agents can provide superior peel characteristics. Desirable characteristics can include enhanced elasticity, enhanced skin adhesion, enhanced tensile strength, and the like.
  • the combination of the at least two solidifying agents can provide a more homogenous formulation with minimal if any phase separation.
  • polyvinyl alcohol (PVA) can be used as one of the solidifying agents in combination with Gantrez. In that combination, the PVA functions to provide enhanced elasticity while the Gantrez provides enhanced skin adhesion.
  • a formulation can be made which utilizes Eudgragit E-100 in combination with PVA as the solidifying agent. The formulation has quicker solidifying characteristics and results in a solidified layer with enhanced tensile strength.
  • 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. If the drug is very potent and the solidified layer has very high tensile strength, a layer as thin as 0.01 mm may be sufficient. If the drug has rather low potency and the solidified layer has low tensile strength, a layer as thick as 2-3 mm may be desirable. Thus, for most drugs and formulations, 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.
  • the flexibility and stretchability of a solidified layer can be desirable in some applications.
  • the solidified layer is coherent, flexible, and continuous.
  • Such flexible and coherent nature can greatly enhance the ease of use of the formulation.
  • certain nonsteroidal anti-inflammatory agents NSAIDs
  • NSAIDs nonsteroidal anti-inflammatory agents
  • skin areas over joints and certain muscle groups are often significantly stretched during body movements. Such movement prevents non-stretchable patches from maintaining good skin contact.
  • Lotions, ointments, creams, gels, foams, pastes, or the like also may not be suitable for use for the reasons cited above.
  • the solidifying formulations of the present invention can offer unique advantages and benefits. It should be pointed out that although good stretchability can be desirable in some applications.
  • 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 un-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.
  • Other benefits of the solidified layers of the present invention include the presence of a physical barrier that can be formed by the material itself.
  • 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 resulting solidified layer 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 not as subject to unintentional removal. Further, as the solidified layer remains adhesive and optionally peelable, easy removal of the solidified layer can occur, usually 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 solidified layer is applied.
  • the solidified layer can be formulated to advantageously deliver drug and protect sensitive skin areas without cracking or breaking.
  • the solidified layers made using the formulations of the present invention can be soft and coherent solids that are peelable from a skin surface as a single piece or as only a few large pieces relative to the application size.
  • the solidified layer can be removable by use of a solvent, such as water, alcohol, surfactant, or mixture thereof.
  • 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 skin surface.
  • This feature can provide unique advantages over existing products. For example, in some semi-solid formulations, upon application to a skin surface the volatile solvents quickly evaporate and the formulation layer solidifies into a hard lacquer-like layer. The drug molecules are immobilized in the hard lacquer layer and are substantially unavailable for delivery into the skin surface. As a result, it is believed that the delivery of the drug is not sustained over a long period of time. In contrast to this type of formulation, the solidified layers formed using the formulations of the present invention keep the drug molecules quite mobile in the non-volatile solvent system which is in contact with the skin 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 clonidine can be formulated in a solidified layer 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 solidified layer 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, or an antihistamine solidified layer can be prepared for treating allergic rashes such as poison ivy.
  • Additional applications include delivering drugs for treating certain skin conditions, e.g., dermatitis, psoriasis, eczema, skin cancer, 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
  • viral infections such as cold sore, genital herpes, shingles, etc.
  • solidifying formulations containing imiquimod can be formulated for treating skin cancer, common and genital warts, and actinic keratosis.
  • Solidifying formulations containing antiviral drugs such as acyclovir, penciclovir, famciclovir, vaiacyclovir, 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.
  • solidified adhesive formulations of the present invention address the shortcomings of both of these types of delivery systems.
  • a further embodiment involves a 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 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 2-5 minutes and remains adhered to the skin 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 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 2-5 minutes and remains adhered to the skin 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 containing tazorac for treating stretch marks, wrinkles, sebaceous hyperplasia, seborrheic keratosis.
  • solidifying formulations containing glycerol can be made so as to provide a protective barrier for fissuring on finger tips.
  • Still another embodiment can include a 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 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 2-5 minutes and remains adhered to the skin 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 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 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 2-4 minutes and remains adhered to the skin 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 diclofanec, 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
  • COX-2 selective NSAIDs and agents COX-3 selective NSAIDs and agents, local anesthetics such as
  • 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 and diabetes induced neuropathic pain. 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, posaco ⁇ azole, ravuconazole, vori
  • 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, nevirapine, 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 alcohol
  • 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, mupiroci ⁇ , polymyxin B, quinolones such as ciproflaxin, or combinations thereof.
  • an antibacterial drug such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupiroci ⁇ , 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 alpha-2 agonists such as clonidine.
  • a local anesthetic such as lidocaine, bupivacaine, ropivacaine, and tetracaine
  • an alpha-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, or combinations thereof.
  • 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, or combinations thereof.
  • the delivery of medication for treating warts and other skin conditions would also benefit from long periods of sustained drug delivery.
  • 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, chlormadinone acetate, megestrol, promegestone, norethisterone, lynestrenol, gestodene, tibolene, androgens consisting of testosterone, methyl testosterone, oxandrolone, androstenedione, dihydrotestosterone.
  • estrogens consisting of estradiol, ethniyl estradiol, estiol, estrone, conjug
  • 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, desox ⁇ methasone, 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
  • 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.
  • Other drugs that can be delivered using the formulations and methods of the current invention include humectants, emollients, and other skin care compounds.
  • HMS Hairless mouse skin
  • HEM human epidermal membrane
  • SC stratum corneum
  • 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.
  • 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.
  • 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 5.
  • compositions shown above are studied for flux of clobetasol propionate as shown in Table 6 as follows:
  • 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 3 As seen from Table 6 formulation described in Example 3 that contains polyvinyl alcohol as solidifying agent has high flux of clobetasol propionate.
  • Polyvinyl alcohol is known to form stretchable films and it is likely that this formulation will have acceptable wear properties.
  • the toughness of the resulting film can be modified by adding appropriate plasticizers if needed. Tackiness can also be modified by adding appropriate amounts of tackifier or by adding appropriate amounts of another solidifying agent such as Dermacryl 79.
  • a higher percentage of ethanol is needed to dissolve the polymer.
  • the solidifying agent used in Example 8 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.
  • Formulations of acyclovir in various non-volatile solvent systems are evaluated. Excess acyclovir is present. The permeation of acyclovir from the test formulations through HMS is presented in Table 7 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 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 2, where the flux was about 3mcg/cm 2 /h).
  • Prototype solidifying 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 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 peel formulations are prepared as follows. Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 9, as follows:
  • compositions of Examples 14 and 15 as shown in Table 8 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 solidifying formulations are prepared as follows. Several acyclovir solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 10, as follows:
  • compositions in Table 10 are prepared as follows. Ethyl cellulose ECN7 or ethyl cellulose ECN 100 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 10-17 The formulations of Examples 10-17 are tested in a hairless mouse skin (HMS) in vitro model described in Example 1.
  • Table 11 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 10-12 and 17 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 10, 11 , and Zovirax Cream are shown in FIG. 2. Each value shown indicates the mean ⁇ SD of at least three experiments.
  • Examples 10-13 show the impact of the trolamine to isostearic acid (ISA) ratio on acyclovir flux enhancement.
  • the optimal ISA:trolamine ratio is 1 :1 to 2:1 and ratio greater than 4:1 show a significant decrease in the acyclovir skin flux.
  • Example 16 Additions of diisopropanol amine and Neutrol in place of trolamine (Examples 14 and 15 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 16 and 17 utilize a different solidifying agent to evaluate the impact of the solidifying agent on acyclovir flux. Surprisingly, Example 16 shows a significant decrease in acyclovir skin flux, but Example 17, which differed from Example 16 only by the molecular weight of the solidifying agent, shows no impact on acyclovir skin flux compared to a similar ISA:trolamine ratio in Example 10.
  • Examples 10 and 11 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 solidifying formulation affixed to the skin.
  • Solidifying formulations are prepared as follows. Several solidifying formulations are prepared in accordance with embodiments of the present invention in accordance with Table 12, as follows:
  • Solidifying formulations of Examples 19-21 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 22 below).
  • HMS hairless mouse skin
  • HEM HEM in vitro model described in Example 1.
  • Table 13 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 formulation. 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 solidifying 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 formulation. 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 solidifying formulation) resulting in lower flux values. The steady state flux value for imiquimod is unchanged when comparing the solidifying formulation with the flux-enabling non-volatile solvent flux values.
  • a 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 non-volatile solvent system of polyethylene glycol and glycerol acts a plasticizer in the formulation.
  • 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 27 Three formulations similar to the formulation in Example 27 (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 14 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 4-9 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.
  • formulation Examples 27 and 28 demonstrate the importance of the amount of non-volatile solvent in added to the formulation in dictating the flux-generating power of the entire formulation.
  • Formulation Examples 29-31 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/troIamine/triacetin combination showed no change in the in vitro flux.
  • the increase 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 solidifying formulation.
  • Example 29 demonstrated comparable imiquimod flux to the other formulation Examples, but the importance of the non-volatile solvent system and solidifying agent compatibility necessitated the removal of trolamine because this non-volatile solvent negatively influenced the function of the Plastoid B polymer.
  • 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: Table 17 - Imi uimod formulation ingredients
  • In vitro flux of Examples 32-35 is substantially increased compared to the Aldara control.
  • the reason for the improved in vitro flux values is attributed to the addition of salicylic acid.
  • Improved in vitro flux of imiquimod in Examples 32-35 is thought to be due to an ion pair interaction between imiquimod and salicylic acid.
  • the ion pair mechanism is thought that the lipophilicity of the counter ion (salicylic acid) improves the flux of imiquimod across the stratum corneum because it makes imiquimod less 'comfortable' in the formulation.
  • Comparison of the flux of Examples 32-34 show that the selection of the polymer and/or volatile solvents will impact the flux of imiquimod.
  • Example 32 contains PVA and water, one or both of these elements may contribute to an unfavorable medium in which the ion pair can form resulting in a negligible increase in imiquimod flux versus the Aldara control.
  • TEWL transepidermal water loss
  • Placebo Plastoid B formulation similar to the formulation described in Example 5 was applied to the top of the hand and the TEWL was measured on a side immediately adjacent to the solidified layer and on top of the solidified layer.
  • the TEWL measurement on the site covered by the solidified layer was 30% lower than the untreated skin site.
  • 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 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
  • ethanol is used as the volatile solvent
  • ISA, glycerol, trolamine, and PG mixture is used as the non-volatile solvent system.
  • ISA and propylene glycol used together to provide the appropriate solubility for the drug, while being compatible with the Eudragit RL-100 solidifying agent.
  • 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 37 and 38 demonstrate the importance of the non-volatile solvent in dictating the flux- generating power of the entire formulation.
  • a formulation for dermal delivery of lidocaine is prepared which includes a saturated amount of lidocaine in an excipient mixture to form an adhesive formulation in accordance with embodiments of the present invention.
  • the solidifying formulation is prepared from the ingredients as shown in Table 26. Table 21 - Lidocaine formulation com onents
  • 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.
  • a formulation for dermal delivery of amitriptyline and a combination of amitripyline and ketamine is prepared which includes an excipient mixture to form an adhesive formulation in accordance with embodiments of the present invention.
  • the solidifying formulation is prepared from the ingredients as shown in Table 23.
  • the ingredients listed above are combined according to the following procedure.
  • the drug(s), 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.
  • a formulation for dermal delivery of ropivacaine is prepared which includes an excipient mixture to form an adhesive formulation in accordance with embodiments of the present invention.
  • the solidifying formulation is prepared from the ingredients as shown in Table 25.
  • the ropivacaine HCI, 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 26 Steady-state flux of Ropivacaine HCI through hairless mouse skin from various adhesive formulations at 35 0 C
  • Example 44-47 shows the importance of the triacetin, isostearic acid, Span 20 combination in the formulation.
  • formulations were made without Span 20, triacetin, and isostearic acid respectively.
  • the in vitro flux of ropivacaine was impacted.
  • the synergistic combination of the flux-enabling non volatile solvent system is important in obtaining the maximum in vitro flux of ropivacaine.
  • This 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.
  • Ropvicaine is mixed with ISA.
  • Ethyl cellulose and Dermacryl 79 are dissolved in ethanol.
  • 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. Examples 49-50
  • Anti-fungal solidifying formulations are prepared and a qualitative assessment of the solidified layer's flexibility and viscosity are evaluated.
  • the formulation components are presented in Table 28 below.
  • the solidifying formulation in Example 49 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 layer with this formulation is longer than the desired drying time.
  • the formulation in Example 50 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 50 has a viscosity suitable for application and an improved drying time.
  • a solidifying formulation was prepared in accordance with Table 29, 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.
  • Example 51 The formulation prepared in Example 51 was tested for Skin Flux, as set forth in Table 30 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 1. It should be noted, the steady- state flux value reported in Table 3 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 formulation in Example 51 will deliver a steady-state amount of testosterone for at least g hours.
  • Example 53 A stretchable adhesive formulation for transdermal delivery of ketoprofen
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 31.
  • Example 53 The compositions of Example 53 were studied for flux of ketoprofen, as shown in Table 32, as follows:
  • Skin flux measurement represents 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.
  • Example 53 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 formulation formed after the evaporation of the volatile solvents. Without the presence of glycerol and PEG 400, a solidified layer formed by PVA and PVP alone would be rigid and non- stretchable.
  • Example 53 composition A formulation similar to the formulation of Example 53 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 solidified layer. After a few minutes of evaporation of the volatile solvents (ethanol and water), a solidified layer is formed.
  • the stretchable solidified layer 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 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 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 33. Table 33
  • Formulations A and B are prepared in the following manner:
  • PVA solidifying agent
  • the flux adequate non-volatile solvent glycerol, PG
  • the flux adequate non-volatile solvent is mixed together with the solidifying agent/volatile solvent mixture.
  • 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 solidified layers 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 solidified layer that is unable to withstand the mechanical forces the solidified layer is subjected to upon removal.
  • the excipient mixture which is a viscous and transparent fluid, is prepared using the ingredients as shown in Table 34.
  • Solidifying formulations in Examples 56 and 57 are prepared in the following manner:
  • PVA solidifying agent
  • the amount of water in the formulation did not significantly influence the time for the formulation to dry. However, it was noted during the study that the formulation was difficult to expel from the sample tube. After approximately 4 weeks after the formulation in Examples 56 and 57 were made the sample tubes were retrieved and were evaluated for ease of dispensing the formulation. It was noted that the formulation was impossible to expel from the tube. lnterpolymer complexation between Gantrez S-97 and PVA through electrostatic interactions, hydrophobic interactions, hydrogen bonding, or Van derWaals interactions is hypothesized to be the reason(s) for the observed thickening. Moreover, the extent of this interaction may be dependent on the stoichiometric ratio of the two polymers.
  • excipient mixture which will form an adhesive 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 36. Table 36
  • Solidifying formulations in Examples 58-61 are prepared in the following manner: • PVA (solidifying agent) is dissolved in water.
  • 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. Examples 57-59 have been studied the longest and the resulting viscosity increase necessitated the desire to study the viscosity of Example 60. Table 37 summarizes the data generated on each formulation.
  • Examples 58 and 59 had the lowest water content of the four formulations and within 4 weeks of storage attained high viscosity values.
  • the only difference between Examples 58 and 59 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 (Example 58) had lower initial viscosity, but over the 4 weeks storage the viscosity of both Examples 58 and 59 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.
  • Example 60 viscosity after 16 weeks has not reached the viscosity values of the initial viscosity values of Examples 58 and 59.
  • 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 solidified layer or leaving residue behind.
  • Table 38 The results of the study are summarized in Table 38 below.
  • a stretchable adhesive 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 ketoprofen in an exctpient mixture to form an adhesive formulation, some of which is prepared in accordance with embodiments of the present invention.
  • the solidifying formulation is prepared from 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.
  • Placebo formulations containing Gantrez ES 425 as an adhesive polymer were prepared for wear studies by volunteers.
  • the formulations are shown as examples in Table 41. All the formulations have polyvinyl alcohol as a solidifying agent to provide tensile strength to the solidifying formulation.
  • the amount of propylene glycol in the formulations was decreased from 19.6% (w/w) to 8.7% (w/w), and the amount of glycerol was increased by the same amount to keep the total non-volatile ratio constant. Keeping the non-volatile ratio constant is important as it determines the drying time and the duration of delivery.
  • the placebo formulations are worn on the palms of hand and percentage adherence of the solidified layer formed after evaporation of volatile solvents was observed after 5-6 hours.
  • clobetasol propionate 0.15% (w/w) clobetasol propionate with polyvinyl alcohol as solidifying polymer are prepared for in-vitro flux evaluation.
  • Propylene glycol and oleic acid are the non volatile solvents selected for facilitation of clobetasol propionate delivery.
  • glycerol is added as the non volatile solvent for its plasticizing properties. Ratios of ingredients used in the two formulations are shown in Table 42.
  • Skin flux measurements represent the mean and standard deviation of three determinations. Flux measurements reported are determined from the linear region of the cumulative amount versus time plots. The linear region are observed to be between 6-28 hours. If the experiment is continued, it is anticipated the steady state would continue.
  • Example 43 As seen from Table 43 formulation described in Example 67 that contained polyvinyl alcohol as a solidifying agent and 0.05% clobetasol propionate had 46% flux of clobetasol propionate when compared to the control formulation. Increasing the clobetasol propionate concentration drug concentration to 0.15% (w/w) increased the steady state flux and the flux values were 94% of the control formulation. It is expected that longer duration of application with the solidifying formulation would increase cumulative delivery in-vivo resulting in effective treatment of dermatitis.
  • Adhesive formulations containing 0.05% (w/w) clobetasol propionate with gelatin as solidifying agent are prepared for in-vitro flux evaluation.
  • Propylene glycol, isostearic acid, and oleic acid are used as non-volatile solvents to facilitate delivery of clobetasol.
  • Talc is added as a filler to reduce the drying time the formulation. Ratio of ingredients used in the formulation is shown in Table 44.
  • Table 44 Clobetasol Propionate formulations*
  • the fish gelatin based formulation shown in Example 44 is a water washable formulation and can be easily removed by subjects suffering from hand dermatitis. Steady state flux across human cadaver skin from 3 donors with formulation as described in Example 69 is compared to the commercial clobetasol ointment. The permeation results are shown in Table 45.
  • Skin flux measurements represent e mean and standard deviation of three determinations. Flux measurements reported are determined from the linear region of the cumulative amount versus time plots. The linear region are observed to be between 6-28 hours. If the experiment is continued, it is anticipated the steady state would continue.
  • Example 69 As seen from Table 45, formulation described in Example 69 has 62% higher steady state flux when compared to the commercial ointment. Higher steady state flux would result is expected to reduce inflammation in difficult to treat dermatitis and psoriasis cases.
  • Adhesive formulations containing 0.05% (w/w) clobetasol propionate with gelatin as solidifying polymer are prepared for in-vitro flux evaluation.
  • Propylene glycol, and isostearic acid are used as non-volatile solvents to facilitate delivery of clobetasol.
  • Fumed silica is added as a filler to reduce the drying time the formulation. Ratio of ingredients used in the formulation is shown in Table 46.
  • the fish gelatin based formulation shown in Example 70 is a water washable formulation and can be easily removed by subjects suffering from hand dermatitis. Steady state flux across human cadaver skin from 4 donors with formulation as described in Example 70 is compared to the commercial clobetasol ointment. The permeation results are shown in Table 47. Table 47 - Steady state flux of clobetasol propionate through human cadaver skin at 35 0 C
  • Example 70 has at-least similar or better steady state flux when to compared to the steady state flux with the commercial ointment.
  • fumed silica had a low density and is expected to have a less potential to separate from the formulation.
  • 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 48.
  • ingredients are noted as weight percent. ** from Degussa.
  • a prototype peel is prepared in accordance with Table 50 as follows:
  • Example 74 illustrates the necessity of an appropriate selection of a nonvolatile solvent and a solidifying agent. After mixing the formulation of Example 74 together, the formulation turned from a flowable solution into two distinct layers: a soft solid and a liquid layer. The formulation in this state is not spreadable on the skin surface. An incompatibility between trolamine and the Plastoid B polymer is suggested because of the hydrophilic nature of the trolamine and the hydrophobic nature of the polymer resulted in the trolamine being squeezed out of the formulation.
  • Prototype peel formulations are prepared as follows. Several peel formulations are prepared in accordance with embodiments of the present invention in accordance with Table 51 , as follows:
  • the solidifying agents are dissolved in the volatile solvent (e.g., dissolve polyvinyl alcohol in water, Eudragit polymers in ethanol),
  • 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 peel and steady state flux for the drug (see Example 78 below).
  • Example 78 The formulations of the Examples are tested in a hairless mouse skin
  • HMS human epidermal membrane
  • HEM human epidermal membrane
  • Prototype peels are prepared as follows. Several acyclovir peel formulations are prepared in accordance with embodiments of the present invention in accordance with Table 53 as follows:
  • the formulation was prepared by mixing Plastoid B in isopropyl alcohol until the polymer dissolved, then the remaining components were added and the mixture vigorously stirred until a uniform mixture was obtained.
  • Examples 80 and 81 show the importance of an additional polymer to solve the trolamine/polymer incompatibility.
  • Addition of ethylcellulose (N7 and N100) to the formulation reduced the amount of Plastoid B polymer to a level that is compatible with trolamine.
  • the resulting formulation produced a thickened, easily spreadable formulation.
  • the formulation in Example 82 exhibited precipitation, but the thickening due to addition of the N100 ethylcellulose will prevent the settling of the precipitation.
  • Example 80-72 The formulations of Examples 80-72 are tested in a hairless mouse skin (HMS) in vitro model described in Example 1.
  • Table 54 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.
  • Examples 71-82 show similar in vitro flux increase (based on ratio to control) over the Zovirax control. Addition of ethylcellulose to the formulations in Examples 81-83 may increase the occlusion due to the addition of the hydrophobic polymers.
  • Prototype peel formulations are prepared as follows. Several peel formulations are prepared in accordance with embodiments of the present invention in accordance with Table 55, as follows:
  • Example 84 The peel formulation of Example 84 is 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 agents/volatile solvent mixture.
  • the flux-enabling non-volatile solvent/solidifying agents/volatile solvent combination is compatible as evidenced by a homogeneous, single phase system that exhibited appropriate drying time, and provided a stretchable peel and steady state flux for the drug (see Example 85 below).
  • Diclofenac have lower steady state flux values when the enabling non-volatile solvent is incorporated into the peel formulation. This could be the result of the volatile solvent system or the solidifying agents having the opposite impact on the chemical environment (e.g., decreasing solubility, physical interactions between drug and peel formulation) resulting in lower flux values.
  • the steady state flux value for imiquimod is unchanged when comparing the peel formulation with the flux-enabling non-volatile solvent flux values.

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Abstract

La présente invention concerne des formulations adhésives, des procédés d'administration de médicament, et des couches solidifiées pour administration dermique d'un médicament. La formulation peut comprendre un médicament, un véhicule solvant, et au moins un agent solidifiant. Le véhicule solvant peut présenter un système de solvants volatil comprenant au moins un solvant volatil, et un système de solvants non volatil comprenant au moins un solvant non volatil. La formulation peut être formulée pour contenir au moins deux solvants volatils, au moins deux solvants non volatils, ou au moins deux agents solidifiants. La formulation peut présenter une viscosité convenant à une application sur la surface de la peau avant évaporation du système de solvants volatil. Une fois appliquée à la peau, la formulation peut constituer une couche solidifiée après évaporation d'au moins une partie du système de solvants volatil.
EP06849969A 2005-12-14 2006-12-14 Compositions et procedes d'administration dermique de medicaments Withdrawn EP1968541A2 (fr)

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CA2738831C (fr) * 2008-10-08 2016-05-24 Takata Seiyaku Co., Ltd. Preparation de tacrolimus pour applications externes
US11957753B2 (en) 2010-11-22 2024-04-16 Bausch Health Ireland Limited Pharmaceutical formulations containing corticosteroids for topical administration
US8809307B2 (en) 2010-11-22 2014-08-19 Dow Pharmaceutical Sciences, Inc. Pharmaceutical formulations containing corticosteroids for topical administration
DE102011085509A1 (de) * 2011-10-31 2013-05-02 Beiersdorf Ag Fixierung von Parfum auf nasser Haut
GB2496656B (en) * 2011-11-18 2015-12-09 Lrc Products Film-Forming Formulation
ES2745093T5 (es) * 2013-11-14 2022-11-10 Lipidor Ab Portador tópico pulverizable y composición que comprende fosfatidilcolina
BR112017016010B1 (pt) * 2015-01-30 2023-02-14 Medrx Co., Ltd Preparação aquosa para uso externo.
DK3310389T3 (da) 2015-06-18 2020-08-10 Bausch Health Ireland Ltd Topiske sammensætninger omfattende et kortikosteroid og et retinoid til behandling af psoriasis
EP4285931A1 (fr) 2021-01-29 2023-12-06 Kao Corporation Composition pour application externe

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US6653346B1 (en) * 2002-02-07 2003-11-25 Galileo Pharmaceuticals, Inc. Cytoprotective benzofuran derivatives

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CA2633464A1 (fr) 2007-09-07

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