JP2009519958A - Fluxable compositions and methods for skin delivery of drugs - Google Patents

Abstract

The present invention is directed to adhesive solidified formulations, methods of drug delivery, and solidified layers for skin delivery of drugs. The formulation can include a drug, a solvent excipient, and a solidifying agent. The solvent excipient comprises a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent, wherein the at least one non-volatile solvent is A fluxable non-volatile solvent that can facilitate drug delivery at a therapeutically effective rate. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin, the formulation can form a solidified layer after evaporating at least a portion of the volatile solvent system.

Description

(Field of Invention)
The present invention relates generally to systems developed for skin delivery of drugs. More particularly, the present invention relates to an adhesive solidification formulation having a viscosity suitable for application to the skin surface and forming a sustained drug-delivery adhesive solidification layer.

(Background of the Invention)
Traditional dermal drug delivery systems can generally be divided into two forms: semisolid formulations and dermal patch dosage forms. Semi-solid formulations are available in a few different forms, including ointments, creams, foams, pastes, gels, or lotions, and are applied topically to the skin. Skin patch dosage forms (including transdermal patches) are also available in a number of different forms, including matrix patch arrangements and liquid reservoir patch arrangements. In the matrix patch, the active drug is mixed into the adhesive coated on the backing film. The drug-lace adhesive layer is typically applied directly to the skin, both as a means for attaching the patch to the skin and as a reservoir or excipient to facilitate drug delivery. Work in Conversely, in a liquid reservoir patch, the drug is typically entrapped in a solvent system 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 to adhere 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) to control the transport of the drug from within the thin bag to the required delivery skin. it can.

  Patches and semi-solid formulations are widely used to deliver drugs to and through the skin, both of which have considerable limitations. For example, many semi-solid formulations typically contain only water and volatile solvents such as ethanol that evaporate shortly after application. Such solvent evaporation can often cause a significant reduction or even termination of skin drug delivery, which may be undesirable. Some traditional semi-solid formulations have been selected or formulated to spread the formulation or to improve the aesthetics of the formulation rather than delivering the drug with sufficient flux It can also contain some non-volatile liquid material. Drug delivery from these formulations may not be sufficient or sustained. In addition, semi-solid formulations are often “stolen” by the skin, which does not necessarily mean that the drug formulation is actually delivered to the skin. Instead, this phrase often means that a very thin layer of drug formulation is applied to the surface of the skin but still outside the skin. Such thin layers of traditional semi-solid formulations applied to the skin cannot contain sufficient amounts of active drug to achieve sustained delivery over an extended period of time. In addition, traditional semi-solid formulations are often subjected to unintentional removal due to sustained delivery and / or contact with objects such as clothing that can endanger undesirably soiled clothing. Drugs present in a semi-solid formulation may also be unintentionally delivered to an individual who comes into contact with a subject undergoing treatment with a topical semi-solid formulation.

  For matrix patches, in order to be properly delivered, the drug should have sufficient solubility in the adhesive, since only the dissolved drug contributes mainly to the driving force required for skin penetration. Unfortunately, too low adhesive solubility does not produce adequate skin penetration driving force over a period of time. In addition, many components, such as liquid solvents and penetration enhancers that can be used to help dissolve the drug or increase skin penetration, are effective in sufficient adhesion in sufficient amounts. It may not be incorporated into the agent matrix system. For example, at a functional level, most of these materials can adversely modify the wear characteristics of the adhesive. As such, the choice in adhesive-based matrix patches, and acceptable amounts of adhesives, accelerators, excipients, etc. can be limited. To illustrate, many drugs can achieve optimal transdermal flux when the drug is dissolved in a liquid solvent system, but a thin layer of adhesive in a typical matrix patch is often therapeutically Insufficient adequate drug and / or adhesive to be effective. In addition, adhesive properties such as cohesion and tackiness can also be significantly altered by the presence of liquid solvents or accelerators.

  For liquid reservoir patches, even if the drug is compatible with a particular liquid or semi-solid solvent system carried by the patch's thin bag, the solvent system is still adhesive coated on a permeable or semi-permeable membrane. Must be compatible with the adhesive layer; otherwise, the drug may be adversely affected by the adhesive layer, or the drug / solvent system may reduce the tackiness of the adhesive layer. In addition to these dosage form considerations, reservoir patches are more bulky and are usually more expensive to manufacture than matrix patches.

  Another disadvantage of skin patches (including transdermal) is that they are usually not stretchable or flexible. This is because the backing film (in the matrix patch) and the thin fluid bag (in the reservoir patch) are typically made from polyethylene or polyester, both of which are relatively inextensible materials. If the patch is applied to a skin area that stretches significantly during body movements, such as joints, separation between the patch and the skin occurs, thereby jeopardizing drug delivery. In addition, patches present on the skin surface can interfere with skin stretch during body movements and can cause discomfort. For these additional reasons, patches are not an ideal dosage form for skin areas that are affected by stretching, bending and stretching during body movements.

  In view of the many shortcomings of current dermal drug delivery systems, i) can provide sustained drug delivery for extended periods of time; ii) by contact with clothing, other objects, or people during application time Not susceptible to unintended removal; iii) can be applied to areas of skin affected by stretching and stretching without causing discomfort or poor skin contact; and / or iv) easily removed after application and use It would be desirable to provide systems, formulations and / or methods that can be used.

(Summary of the Invention)
Although film-forming techniques have been used in cosmetic and pharmaceutical formulations, typically the solvents used in such systems do not last very long on the skin surface, and thus are not optimal for sustained-release applications. Absent. Accordingly, the inventors of the present invention have recognized that the use of both volatile solvents as well as fluxable non-volatile solvents in the formulation can improve or even optimize sustained drug delivery. Thus, an adhesive solidifying composition that has a viscosity suitable for application to the skin surface and forms a drug-delivery solidified layer on the skin that can be easily removed, such as by peeling or washing with a solvent. It would be advantageous to provide a skin delivery formulation system and / or method in the form of a formulation. In one embodiment, the adhesive solidifying composition or formulation can be cohesive once solidified.

  According to this, a solidified formulation for skin delivery of a drug can include a drug, a solvent excipient, and a solidifying agent. Solvent excipients can include a volatile solvent system having one or more volatile solvents and a non-volatile solvent system having one or more non-volatile solvents, wherein the non-volatile solvent system is a volatile solvent system. It contains at least one fluxable non-volatile solvent for the drug so that the drug can be delivered in a therapeutically effective amount over a period of time, even after most has evaporated. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the at least one volatile solvent, and when applied to the skin surface, the formulation is at least one of the volatile solvents. The solidified layer is formed after the part has evaporated, but can be configured to continue to deliver the drug after it has substantially solidified. In certain embodiments, the solidified layer can be coherent so that it can be peeled off the skin or washed out of the skin using a solvent. In one particular embodiment, the drug can be a sex hormone, and in another particular embodiment, the drug can be an anti-warm drug, although many other drugs as described herein. Type can be used. The solidifying agent is typically a polymer that forms a rigid solid without a plasticizer (plasticizer). Thus, the non-volatile solvent system must be a plasticizer for the solidifying agent.

  In another embodiment, a method for dermal delivery of a drug to or through the skin can include applying the formulation to the skin surface of a subject, wherein the formulation is a drug; solvent shaping Agent and solidifying agent. The solvent excipient includes a volatile solvent system including one or more volatile solvents, and a non-volatile solvent system including one or more non-volatile solvents, wherein the non-volatile solvent system is fluxable for the drug is there. In this embodiment, the formulation can have a viscosity suitable for application and adhesion to the skin prior to evaporation of the volatile solvent system, and the formulation has a skin surface at least partially of the volatile solvent system. And can be applied to form a solidified layer after evaporation. Further steps include dermal delivery of the drug from the solidified layer over a sustained time at a therapeutically effective rate, wherein the drug is continuously delivered after substantially evaporating the volatile solvent system. The In some embodiments, the solidified layer can be a soft or flexible, coherent continuous solid that can be removed by peeling.

  In another embodiment, a method of preparing a formulation for dermal drug delivery selects a drug suitable for dermal delivery; a non-volatile solvent or mixture of non-volatile solvents that is fluxable for the selected drug Select a solidifying agent compatible with the drug and non-volatile solvent, select or prescribe a volatile solvent system compatible with the drug, non-volatile solvent and solidifying agent; then formulate all the above ingredients A step of prescribing. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and can be applied to the skin surface, where it evaporates at least a portion of the volatile solvent system. Then, a solidified layer is formed. In this embodiment, the drug is continuously delivered in a therapeutically effective amount after the volatile solvent system is substantially evaporated.

  In yet another embodiment, a solidified layer for delivering a drug can include a drug, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system can include at least one fluxable non-volatile solvent or a mixture of non-volatile solvents that are fluxable for the drug. The solidified layer is a soft and cohesive solid that adheres to the body surface and then delivers at least a portion of the drug to the skin, while the solidified layer is at least substantially devoid of water and a volatile solvent than water, Here, the solidified layer can also be fluxed for the drug.

  Further features and advantages of the present invention will become apparent from the following detailed description and drawings which illustrate, by way of example, features of the invention.

Detailed Description of Preferred Embodiments
Before disclosing and describing specific embodiments of the present invention, it should be understood that the present invention is not limited to the specific processes and materials disclosed herein, and may itself vary to some extent. . It should also be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting, as the scope of the present invention This is because it is defined only by the appended claims and their equivalents.

  In describing and claiming the present invention, the following terminology will be used.

  The singular forms “a” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a drug” includes reference to one or more such compositions.

  “Skin” is usually at least in the air, such as human skin (intact, diseased, ulcerative, destroyed), finger and toe nail surfaces, and lips, genital and anal mucosa, and nasal and oral mucosa. Includes partially exposed mucosal surfaces.

  The term “drug” refers to a bioactive agent that is applied to, into, or through the skin that is applied to achieve a therapeutic effect. This is for compositions that are traditionally identified as drugs, as well as for certain diseases, such as peroxides, humectants, emollients, etc., which are not always considered “drugs” in the classical sense. Includes other bioactive agents that can provide a therapeutic effect. In general, when referring to “drug”, it is understood that there are various forms of a given drug, and that various forms are expressly included. According to this, the various drug forms include polymorphs, salts, hydrates, solvates and co-crystals. For some drugs, one physical form of the drug can retain good physico-chemical properties that allow it to pass into, into, or through the skin. Is defined as a physical form favorable for dermal delivery. For example, the steady state flux of diclofenac sodium from fluxable non-volatile solvents is significantly higher than the steady state flux of diclofenac acid from non-fluxable non-volatile solvents. Therefore, it is desirable to estimate the physical form flux of the drug from the non-volatile solvent and select the desired physical form / non-volatile solvent combination.

  The phrase “skin drug delivery” or “skin delivery of drug” includes both transdermal and topical drug delivery and includes delivery of the drug to, through, or into the skin. “Transdermal delivery” of a drug can be targeted to the skin tissue directly under the skin, the regional tissue or organ under the skin, the systemic circulation, and / or the central nervous system. “Local delivery” includes delivery of the drug to the skin tissue and subsequent absorption into the deeper possible tissue.

  The term “flux”, such as the relationship of “skin flux” or “transdermal flux”, respectively, refers to the amount of drug that permeates the skin per unit area per unit time or across the skin. A typical unit of flux is micrograms per square centimeter per hour. One way to measure flux is to place the formulation on the known skin area of a human volunteer and measure how much drug can penetrate into or across the skin within a certain time constraint It is. Various methods (in vivo methods) could be used in the measurement as well. The flux can also be measured using the method described in Example 1 or other similar methods (in vitro methods). The in vitro method uses human skin obtained from cadaver or freshly isolated skin tissue from hairless mice rather than measuring drug flux across the skin using human volunteers. It will generally be appreciated by those skilled in the art that the results from in vitro tests designed and executed can be used to estimate or predict in vivo test results with reasonable reliability. Thus, the value of “flux” referred to in this patent application can mean that measured by either in vivo or in vitro methods.

The term “fluxable” in the context of a non-volatile solvent system (or a solidified layer containing it) is selected or specially selected to be able to provide a therapeutically effective flux for a particular drug. A prescribed non-volatile solvent system (including one or more non-volatile solvents). For drugs that are delivered locally or locally, a fluxable non-volatile solvent system alone, when the non-volatile solvent system is saturated with the drug, without the aid of any other component, It is defined as a non-volatile solvent system capable of delivering a therapeutically sufficient level of drug across, onto or into the subject's skin. For systemically targeted drugs, a fluxable non-volatile solvent system is one where the non-volatile solvent system is saturated with the drug and it is in full contact with the subject's skin with a contact area of 500 cm ² or less. , A non-volatile solvent system that can provide a therapeutically effective daily dose over 24 hours. Preferably, the contact area for the non-volatile solvent system is 100 cm ² or less. A test using the state of the drug in a saturated solvent can be used to measure the maximum flux-producing capacity of the non-volatile solvent system. In order to measure flux, the drug solvent mixture needs to be kept on the skin for a clinically sufficient amount of time. In reality, it may be difficult to maintain a liquid solvent on the skin of a human volunteer for a long time. Thus, an alternative method for determining whether a solvent system is “fluxable” is to use in vitro across hairless mouse skin or human cadaver skin using the apparatus and method described in Example 1. It is to measure drug penetration. This method, and similar methods, are commonly used by those skilled in the art to estimate the permeability and usability of a formulation. Alternatively, whether a non-volatile solvent system can be fluxed can be tested on the skin of a living human subject with a means to maintain the non-volatile solvent system with a saturated drug on the skin. Yes, such means would not be realistic for the product. For example, a non-volatile solvent system with saturated drug can be immersed in an absorbent fabric material, which is then applied onto the skin and covered with a protective film. Such a system is not practical as a pharmaceutical product, but it tests whether a non-volatile solvent system has the inherent ability to provide sufficient drug flux or whether it can be fluxed. Suitable for

  Also, once the formulation has formed a solidified layer, even after the volatile solvent (including water) has substantially evaporated, some of the non-volatile solvent remains in the solidified layer while the solidified layer is a drug. May be “fluxable”.

  The phrases “effective amount”, “therapeutically effective amount”, “therapeutically effective rate” and the like refer to any recognizable level of therapeutic outcome in treating a disease to which the drug is delivered, as it relates to the drug. Refers to a sufficient amount or rate of delivery of a drug to achieve It is understood that a “recognizable level of treatment outcome” may or may not meet the efficiency standards of any government authority for authorizing product commercialization. Various biological factors can affect a substance's ability to perform its intended work. Thus, an “effective amount”, “therapeutically effective amount”, or “therapeutically effective rate” may in some cases depend to some extent on such biological factors. However, for each drug, there is usually consensus among those skilled in the art for a sufficient dose or flux range in most subjects. Furthermore, the achievement of a therapeutic effect can be measured by a physician or other qualified medical personnel using estimates known in the art, although individual variations and responses to treatment are subjective It is recognized that this can be a judgment. Determination of a therapeutically effective amount or delivery rate is within the ordinary skill in the medicinal chemistry and medical fields.

“Therapeutically effective flux” refers to a sufficient amount of drug to or through the skin that is clinically beneficial in that some of the patient population can benefit from the drug flux. It is defined as the osmotic flux of the selected drug to be delivered. Most patient populations can benefit to some extent, or the benefits do not necessarily mean that they are fairly sufficient to be considered “effective” by the relevant government authorities or medical professionals. More specifically, at least in part, target the skin (such as joints, certain muscles, or tissues / organs within 5 cm of the skin surface), or regional tissues or organs close to the skin surface. As used herein, “therapeutically effective flux” refers to a drug flux that can deliver a sufficient amount of drug to a target tissue within a clinically reasonable amount of time. For drugs that target the systemic circulation, “therapeutically effective flux” means that a sufficient amount of the selected drug is delivered through a clinically reasonable skin contact area and is clinically reasonable. A drug flux that can produce a clinically beneficial plasma or blood drug concentration within a short period of time. The clinically reasonable skin contact area is defined as the size of the skin application area that most subjects will tolerate. Typically, a skin contact area of 400 cm ² or less is considered reasonable. Therefore, in order to deliver to systemic circulation through the skin contact area of 400 cm ² of the drug 4000Mcg for 10 hours, the flux should be at least 4000mcg / 400cm ^2/10 hours, which is 1 mcg / ^cm 2 / equal to hr. By this definition, different drugs have different “therapeutically effective fluxes” and may differ at different times, even for different subjects, or even for the same subject. However, for each drug, there is usually something in common among those skilled in the art regarding the dose or flux range that is sufficient for most subjects at many times.

  Below is an estimate of the flux for several drugs that are therapeutically effective or well over.

（ロピバカインを例外として）表Ａ中の治療上有効量のフラックス値は、実施例１に記載されたイン・ビトロ系における無毛マウスまたはヒト表皮膜を通じての市販製品の定常状態フラックス値を表す。これらの値は、見積もりであり、処方物の開発および最適化のための比較の基礎を提供することのみを意図する。選択された薬物についての治療上有効なフラックスは、異なる病気が、異なる段階の病気、および異なる個々の対象について治療されるのが非常に困難であり得る。リストしたフラックスは治療的に有効なものを超え得ることに注意すべきである。

The therapeutically effective amount of flux value in Table A (with the exception of ropivacaine) represents the steady state flux value of the commercial product through the hairless mouse or human epidermis in the in vitro system described in Example 1. These values are estimates and are intended only to provide a basis for comparison for formulation development and optimization. The therapeutically effective flux for a selected drug can be very difficult for different illnesses to be treated for different stages of illness and different individual subjects. It should be noted that the listed flux can exceed that which is therapeutically effective.

  The following example, listed in Table B, shows a screen for fluxable ability of non-volatile solvents for some of the specifically tested drugs. The experiment was performed as described in Example 1 below, and the results are further discussed in subsequent Examples 2-9.

不揮発性溶媒からの表Ｂ中のイン・ビトロ定常状態フラックス値は、驚くべきフラックス化可能および非フラックス化可能溶媒を示す。この情報を用いて、処方物開発を導くことができる。

The in vitro steady state flux values in Table B from non-volatile solvents indicate surprising fluxable and non-fluxable solvents. This information can be used to guide formulation development.

  The term “plasticizing” in the context of a fluxable non-volatile solvent is defined as a fluxable non-volatile solvent that acts as a plasticizer for the solidifying agent. A “plasticizer” is an agent that can increase the percentage elongation of a formulation after the volatile solvent system has at least substantially evaporated. The plasticizer also has the ability to reduce the brittleness of the solidified formulation by making it more flexible and / or elastic. For example, propylene glycol is a “fluxable plasticizing non-volatile solvent” for the drug ketoprofen with polyvinyl alcohol as the chosen solidifying agent. However, propylene glycol in a formulation of ketoprofen with Gantrez S-97 or Avalure UR405 as a solidifying agent does not provide the same plasticizing effect. The combination of propylene glycol and Gantrez S-97 or Avale UR405 is less compatible and results in a less desirable formulation for topical application. Thus, whether a given non-volatile solvent is “plasticizing” or not depends on which solidifying agent is selected.

  Different drugs often have different matching fluxable non-volatile solvents that provide particularly good results. Such examples are found in Table C. The experiment was performed as described in Example 1 below and the results are further discussed in subsequent Examples 2 through 9.

「フラックス化可能な不揮発性溶媒」、「フラックス化可能可塑化不揮発性溶媒」または「高フラックス化可能な不揮発性溶媒」は、単一の化学物質、または２以上の化学物質の混合物であり得る。例えば、表Ｃ中のクロベタゾールプロピオネートについての定常状態フラックス値は、プロピレングリコールまたはＩＳＡ単独よりもかなり高いクロベタゾールフラックスを生じたプロピレングリコール：イソステアリン酸混合物について９：１である（表Ｂ参照）。従って、９：１プロピレングリコール：イソステアリン酸混合物は「高フラックス化可能な不揮発性溶媒」であるが、プロピレングリコールまたはイソステアリン酸単独はそうではない。

A “fluxable non-volatile solvent”, “fluxable plasticizing non-volatile solvent” or “high-fluxable non-volatile solvent” can be a single chemical or a mixture of two or more chemicals. . For example, the steady state flux value for clobetasol propionate in Table C is 9: 1 for the propylene glycol: isostearic acid mixture that produced a much higher clobetasol flux than propylene glycol or ISA alone (see Table B). Thus, the 9: 1 propylene glycol: isostearic acid mixture is a “non-volatile solvent capable of high flux”, but propylene glycol or isostearic acid alone is not.

  When referring to a solidified layer, the term “adhesion” as used herein is sufficient to ensure that the layer does not fall from the skin during intended use in most subjects. Refers to adhesion.

  “Adhesive”, when used to describe a solidified layer, adheres to the body surface to which the solidified layer was originally applied (before evaporation of the volatile solvent). It means that. In one embodiment, it does not mean that the solidified layer is adhesive to the opposite side. In addition, it should be noted that whether the solidified layer can adhere to the human body surface for a desired extended time depends in part on the condition of the body surface. For example, excessive sweating or greasy skin, or oily material on the skin surface may make the solidified layer less adhesive to the skin. Thus, the adhesive solidified layer of the present invention will maintain complete contact with the body surface and will not be able to deliver the drug over time for each subject under any condition on the body surface. The standard is that it maintains good contact with most of the body surface, for example 70% of the total area, over a certain period of time for most subjects under normal conditions and in the external environment. is there.

  The terms “flexible”, “elastic”, “elastic” and the like, as used herein, are in at least one direction with a solidified layer up to about 5%, often up to about 10%, or more. When it is stretched, it means sufficient elasticity of the solidified layer so that it does not break. For example, a solidified layer that exhibits acceptable elasticity and adhesion to the skin should adhere to human skin on flexible skin locations such as elbows, fingers, wrists, neck, lower back, lips, knees, etc. And will remain substantially intact on the skin as the skin stretches. It should be noted that the solidified layer of the present invention need not necessarily have any elasticity in some embodiments.

  The term “peelable” when used to describe a solidified layer means that the solidified layer can be lifted from the skin surface into one large piece or several large pieces, as opposed to many small pieces or pieces. .

  The term “sustained” refers to a therapeutically effective rate of dermal drug delivery for a continuous time of at least 30 minutes, and in some embodiments, at least about 2 hours, 4 hours, 8 hours, 12 hours. , About 24 hours or more.

  The use of the term “substantially” when referring to evaporation of a volatile solvent means that most of the volatile solvent contained in the original formulation has evaporated. Similarly, if the solidified layer is “substantially lacking” volatile solvents including water, the solidified layer as a whole has less than 10 wt%, preferably less than 5 wt% volatile solvent in the solidified layer.

  A “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 isoamyl acetate, denatured alcohol, methanol, ethanol, isopropyl alcohol, water, propanol, C4-C6 hydrocarbons, butane, isobutene, pentane, hexane, acetone, chloro Butanol, ethyl acetate, fluro-chloro-hydrocarbon, turpentine, methyl ethyl ketone, methyl ether, hydrofluorocarbon, ethyl ether, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3- Includes heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, or combinations thereof.

  A “non-volatile solvent system” can be a single solvent or a mixture of such solvents that is less volatile than water. It can also include substances that are solid or liquid at room temperature, such as pH or ion-pairing agents. After evaporation of the volatile solvent system, most of the non-volatile solvent systems provide skin delivery to, into, or through the subject's skin with sufficient flux over a period of time for a given drug. Should be present in the solidified layer for a sufficient amount of time to go and provide a therapeutic effect. In some embodiments, a mixture of two or more non-volatile solvents is used to obtain the desired permeability to the active drug and / or compatibility with the solidifying agent, or other ingredients of the formulation, A non-volatile solvent system can be formed. In one embodiment, the combination of two or more non-volatile solvents to form a solvent system individually provides a higher transdermal flux for the drug than the flux provided for the drug by each of the non-volatile solvents. To do. The non-volatile solvent system can also act as a plasticizer for the solidified layer so that the solidified layer is elastic and flexible.

  The term “solvent excipient” describes a composition comprising both volatile and non-volatile solvent systems. The volatile solvent system is selected to rapidly evaporate from the adhesive peelable formulation to form a solidified layer, and the non-volatile solvent system is volatile solvent system to provide continued delivery of the drug. Is formulated or selected to remain substantially as part of the solidified layer after evaporation of. Typically, the drug as a whole can be partially or completely dissolved in the solvent excipient or formulation. Similarly, the drug may be partially or completely soluble in the non-volatile solvent system once the volatile solvent system has evaporated. Formulations in which the drug is only partially dissolved in the non-volatile solvent system after evaporation of the volatile solvent system has the ability to maintain sustained maintenance duration longer. This is because undissolved drug can be dissolved in the non-volatile solvent system because the dissolved drug is depleted from the solidified layer during drug delivery.

  In the context of a solidified layer, the term “adhesive” means that it is adhesive to the skin to which the original formulation has been applied and is not necessarily and preferably adhesive on the other side to other objects. Means not.

  An “adhesive solidified formulation”, “solidified formulation” or “formulation”, in certain embodiments, has a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent, and A composition that can become a solidified layer after evaporation of at least a portion of the volatile solvent. The solidified layer, once formed, can be very persistent. In one embodiment, the formulation can form a peel once solidified on the skin surface. Such peels can be soft cohesive solids that can be removed by peeling large pieces from the skin against the size of the applied formulation, and often peel off from the skin as a single piece be able to. The applied viscosity is typically more viscous than an aqueous liquid, but less viscous than a soft solid. Examples of preferred viscosities include materials having a consistency similar to pastes, gels, ointments and the like, for example viscous fluids that flow but do not spill. Thus, if a composition has a “suitable” viscosity to the skin surface, it has a viscosity that is sufficiently high that it does not substantially fall off the skin after the composition is applied to the skin, It means having a sufficiently low viscosity so that it can spread well into the skin. A viscosity range that satisfies this definition may be from about 100 cP to about 3,000,000 cP (centipoise), more preferably from about 1,000 cP to about 1,000,000 cP.

  In some embodiments of the present invention, it may be desirable to add additional agents or substances to the formulation to provide enhanced or increased adhesive characteristics. The additional adhesive or substance can be an additional non-volatile solvent or an additional solidifying agent. Non-limiting examples of materials that can be used as additional adhesion enhancers include methyl vinyl ether and maleic anhydride (Gantrez polymer), copolymers of polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, acrylic sunalkyl / octylacrylamide (Dermacryl 79), and copolymers of various aliphatic resins and aromatic resins.

  The terms “washable”, “washing” or “removed from washing”, as used in connection with the adhesive formulation of the present invention, refer to the application of a washing solvent using a normal or moderate amount of washing power. Refers to the ability of the adhesive formulation to be removed. The necessary force to remove the formulation by washing should not cause significant skin irritation or wear. In general, the mild detergency associated with the application of a suitable cleaning solvent is sufficient to remove the adhesive formulations disclosed herein. Although many solvents can be used to remove the formulations of the present invention by washing, they are preferably selected from the commonly recognized solvents including the volatile solvents listed herein. Preferred solvents do not significantly irritate human skin and are generally available to the average subject. Examples of cleaning solvents include, but are not limited to, water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, or combinations thereof. In an embodiment of the invention, the cleaning solvent is selected from the group consisting of water, ethanol, isopropyl alcohol, or combinations thereof. Surfactants can also be used in some embodiments.

  The length of time allowed is that if it relates to “drying time”, the formulation will have a solidified surface that is not soiled after application to the skin under standard skin and ambient conditions and in standard test procedures. The time required to form. The term “drying time” does not mean the time required for complete evaporation of the volatile solvent in this application. Instead, it refers to the time required to form a solidified surface that is not dirty as described above.

  “Standard skin” is defined as healthy human skin dried at a surface temperature between about 30 ° C. and about 36 ° C. Standard ambient conditions are defined by a temperature range of 20 ° C. to 25 ° C. and a relative humidity range of 20% to 80%. The term “standard skin” by no means limits the types of skin or skin conditions in 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 uninjured (standard skin), diseased skin, or damaged skin. Although skin diseases having different characteristics can be treated using the formulations of the present invention, the term “standard skin” is only used as a standard for testing the compositions of the various embodiments of the present invention. It is done. In reality, formulations that perform well on standard skin (eg, solidify and provide a therapeutically effective flux) can also perform well on diseased or damaged skin.

“Standard Test Procedure” or “Standard Test Conditions” are as follows: For standard skin at standard ambient conditions, apply approximately 0.1 mm layer of adhesive solidification formulation and measure dry time . The drying time is a surface that is not soiled so that the formulation does not lose mass by adhesion to a piece of 100% cotton cloth that has been pressed to the surface of the formulation for 5 seconds at a pressure between about 5 and about 10 g / cm ^2. Is defined as the time required for the formulation to form.

  “Solidified layer” describes a solidified or dried layer of an adhesive solidified formulation after at least a portion of the volatile solvent system has been 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 is preferably the skin at the end of application to one piece or several large pieces (as opposed to a layer with weak tension that is broken into many small pieces or pieces when removed from the skin) Exhibit sufficient tension so that it can be peeled off.

  As used herein, multiple drugs, compounds, and / or solvents can be listed on a common list for convenience. However, these lists should be construed as if each member of the list is individually identified as a separate and unique member. Thus, an individual member of such a list, unless indicated to the contrary, is interpreted as a virtual equivalent of any other member of the same list based solely on its display in the normal group. Should be.

  Concentrations, amounts, and numerous other data can be expressed or shown herein in a range format. Such range formats are used for convenience and brevity only, and thus each numeric value and sub-range is explicitly cited as well as a number of values explicitly cited as range limitations. As such, it should be understood to include all individual numerical values or sub-ranges within that range. By way of illustration, the numerical range of “about 0.01 to 2.0 mm” not only includes explicitly cited values from about 0.01 mm to about 2.0 mm, but also individual values within the indicated range. And sub-ranges. Thus, this numerical range includes the indicated values such as 0.5, 0.7, and 1.5, and from 0.5 to 1.7, 0.7 to 1.5, and 1.0. Sub-ranges such as 1.5 are included. This same principle applies to ranges that quote only one numerical range. Moreover, such an interpretation should apply regardless of the breadth of the range or the characteristics described.

  In keeping with these definitions and in accordance with this, formulations for dermal delivery of drugs can include drugs, solvent excipients, and solidifying agents. Solvent excipients can include a volatile solvent system having one or more volatile solvents, and a non-volatile solvent system having one or more non-volatile solvents, where the drug evaporates most of the volatile solvents. Even after, the non-volatile solvent system can be fluxed for the drug so that it can be delivered in a therapeutically effective amount over a period of time. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the at least one volatile solvent, and further, when applied to the skin surface, at least a portion of the volatile solvent is evaporated. The formulation then forms a solidified layer, but can be configured to continue to deliver the drug after substantial solidification. In certain embodiments, the solidified layer can be cohesive so that the solidified layer can be peeled from the skin into one piece or several large pieces, or washed out from the skin using a solvent. In one particular embodiment, the drug can be a sex hormone and in another particular embodiment, the drug can be an anti-warm drug, although many other drug types are described herein. Can be used.

  In other embodiments, a method of dermal delivery of a drug to, into or through the skin can include applying the formulation to the subject as well as to the skin surface, wherein the formulation is a drug. A solvent excipient, and a solidifying agent. Solvent excipients include volatile solvent systems that include one or more volatile solvents and non-volatile solvent systems that can be fluxed for drugs. In this embodiment, the formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and after at least partial evaporation of the volatile solvent system, the skin The formulation can be applied such that the surface forms a solidified layer that adheres to the skin. Further steps include dermal delivery of the drug from the solidified layer to the subject at a therapeutically effective rate for a sustained period, wherein the drug is continuously delivered after the volatile solvent system has substantially evaporated. Is done. In some embodiments, the solidified layer can be a soft or flexible, coherent continuous solid that can be removed by peeling. The thickness of the formulation layer applied to the skin should also be appropriate for a given formulation and desired drug delivery considerations. If the layer is too thin, the amount of drug will not be sufficient to support sustained delivery over the desired length of time. If the layer is too thick, it will take too long to form another clean surface of the solidified layer. If the drug is very good and the solidified layer has a very high tension, a thin layer such as 0.01 mm will suffice. If the drug has rather low capacity and the solidified layer has low tension, a layer of 2 to 3 mm thickness would be desirable. Thus, for most drugs and formulations, a suitable thickness can be from about 0.01 mm to about 3 mm, but more typically can be from about 0.05 mm to about 1 mm.

  In another embodiment, a method of adjusting a formulation for dermal drug delivery selects a drug suitable for dermal delivery; a non-volatile solvent or a mixture of non-volatile solvents that is fluxable for the selected drug Selecting or formulating a solidifying agent compatible with the drug and non-volatile solvent, selecting or prescribing a volatile solvent compatible with the drug, non-volatile solvent and solidifying agent; A prescribing step can be included. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system, and can be applied to the skin surface, where at least a portion of the volatile solvent system is A solidified layer is formed after evaporation. In this embodiment, the drug is continuously delivered at a therapeutically effective rate after the volatile solvent system has substantially evaporated.

  In yet another embodiment, a solidified layer for delivering a drug can include a drug, a non-volatile solvent system, and a solidifying agent. Nonvolatile solvent systems can be fluxed for drugs. The solidified layer can be a soft cohesive solid adhered to the body surface, and when delivering at least a portion of the drug therefrom, the solidified layer substantially lacks water and a volatile solvent than water, e.g. If the solidified layer contains more than 10 wt%, or even 5 wt% water, and a solvent more volatile than water, the solidified layer should be considered substantially devoid of water and volatile solvent than water Can do. In addition, the solidified layer can also be fluxed for the drug. In one embodiment, the solidified layer is agglomerated and so cohesive that the solidified layer can extend at least 5%, or even 10% in at least one direction without breaking, cracking or separating from the skin surface to which the solidified layer has been applied. It can be elastic and / or can peel from the skin.

  In some applications, it may be desirable to reduce water vapor loss from the skin surface, and a solidified layer comprising a selected or formulated non-volatile solvent system that is hydrophobic will help achieve this goal. Can do. Thus, another embodiment of the present invention is that the solidified layer provides a significant closure effect (defined as a reduction in water vapor from the body surface at least about 20%, preferably at least about 40%). It relates to a solidified formulation.

  These embodiments exemplify the present invention, which can be easily applied to the skin as a layer for drug delivery and quickly (15 seconds under standard skin and ambient conditions). To about 4 minutes) to moderately fast (about 4 to about 15 minutes under standard skin and ambient conditions), typically to a solidified layer, eg, a coherent and soft solidified layer, Relates to formulations, methods and solidified layers that are semi-solid initial forms (including creams, gels, pastes, ointments, and other viscous liquids). The solidified layer can be peeled off if desired. The solidified layer so formed will allow the drug to last for a period of time, for example several hours to several tens of hours, across the skin, across the skin, so that most of the drug delivery occurs after the solidified layer is formed. Can be delivered over time.

  In addition, the solidified layer is typically adhered to the skin, but is formed relatively soon after application and to a dirty garment or other object that the subject wears or can be inadvertently contacted with the solidified layer. It has a solidified, minimal or non-adhesive outer surface that does not move substantially. The solidified layer is highly flexible and stretchable, so that if the skin is stretched during physical movement, such as in a knee, finger, elbow or other joint, it is in contact with the skin surface. It can also be formulated so that good contact can be maintained.

  Various considerations can occur in selecting the various ingredients that can be used, such as drugs, volatile and non-volatile solvent-based solvent excipients, solidifying agents, and the like. For example, the volatile solvent system can be selected from pharmaceutically or cosmetically acceptable solvents known in the art. In one embodiment of the invention, the volatile solvent system is ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1, 1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone or combinations thereof may be included. In another embodiment of the invention, the volatile solvent system is iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cyclopentasiloxane, cyclomethicone, methyl ethyl ketone, or combinations thereof Can be included. The volatile solvent system can comprise a mixture of volatile solvents as described in the previous embodiments, or any combination.

  In addition, these volatile solvents should be selected to be compatible with the rest of the formulation. It is desirable to use an appropriate weight percentage of volatile solvent in the formulation. Too many volatile solvent systems extend the drying time. Too few volatile solvent systems can make it difficult to spread the formulation to the skin. For most formulations, the volatile solvent weight percentage can be from about 10 wt% to about 85 wt%, from about 20 wt% to about 50 wt%, and in a preferred embodiment is at least 20 wt%.

  Volatile solvent systems can also be selected to be compatible with non-volatile solvents, solidifying agents, drugs, and other excipients that may be present. For example, polyvinyl alcohol (PVA) does not dissolve in ethanol, so a volatile solvent that can dissolve PVA needs to be formulated in the solidified layer. For example, water can dissolve PVA and can be utilized as a volatile solvent in solidified formulations; however, drying time in formulations where water is the only volatile solvent is too much for certain applications. It will be long. Therefore, a second volatile solvent (eg, ethanol) is formulated into the formulation to reduce the water content, but maintain a sufficient amount of water to keep the PVA in solution, thereby The drying time can be reduced.

  The non-volatile solvent system can also be selected or formulated to be compatible with the solidifying agent, drug, volatile solvent, and any other ingredients that may be present. Most non-volatile solvent systems and solvent excipients as a whole will be properly formulated after the experiment. For example, certain drugs have good solubility in polyethylene glycol (PEG) having a molecular weight of 400 (PEG 400, non-volatile solvent), but glycerol (non-volatile solvent) and water (volatile solvent) Has poor solubility. However, PEG 400 cannot effectively dissolve polyvinyl alcohol (PVA) and thus is not very compatible alone with the solidifying agent PVA. In order to dissolve a sufficient amount of active drug and use PVA as a solidifying agent at the same time, a non-solvent system containing PEG 400 and glycerol (compatible with PVA) in an appropriate ratio can be formulated. Achieving a sexual compromise. As a further example of compatibility, non-volatile solvent / solidifying agent incompatibility is observed when Span 20 is formulated into a formulation containing PVA. In this combination, Span 20 can separate from the formulation and form an oily layer on the surface of the solidified layer after evaporation of the volatile solvent. Thus, proper solidifying / nonvolatile solvent selection is desirable in developing vigorous formulations.

  More particularly, the non-volatile solvents that can be used alone or in combination to form the non-volatile solvent system include, but are not limited to, a variety of pharmaceutically acceptable liquids. it can. In one embodiment of the invention, the non-volatile solvent system is glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monoorlate, sorbitan monopalmitate, butanol , Or a combination thereof. In another embodiment, the non-volatile solvent system is benzoic acid, butyl alcohol, dibutyl sebacate, diglyceride, dipropylene glycol, eugenol, coconut oil, fish oil, coconut oil, fatty acids such as grape seed oil, isopropyl myristate, Mineral oil, oleyl alcohol, vitamin E, triglycerides, sorbitan fatty acid surfactants, triethyl citrate, or combinations thereof can be included. In a further embodiment, the non-volatile solvent system is 1,2,6-hexanetriol, alkyltriol, alkyldiol, acetyl monoglyceride, tocopherol, alkyldioxolane, p-propenylanisole, anise oil, apricot oil, dimethylisosorbide, alkyl glucoside , Benzyl alcohol, beeswax, benzyl benzoate, butylene glycol, capryl / capric acid triglyceride, caramel, cinnamon oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglyceride, coriander oil, corn oil , Coriander oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride, diethanolamine, diethyleneglycol Monoethyl ether, diglyceride, ethylene glycol, eucalyptus oil, fat, fatty alcohol, flavoring, liquid sugar ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, milk , Monoacetin, monoglyceride, nutmeg oil, octyldodecanol, olive alcohol, orange oil, coconut oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, Plant shortening, vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, candela wax, carnauba , Ceteareth-20, cetyl alcohol, polyglyceryl, dipolyhydroxystearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG-stearate, PEG-oleate, PEG- PEG-fatty acid esters such as laurate, PEG dioleate, PEG-fatty acid diesters such as PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glyceryl laurate, PEG glyceryl stearate, PEG such as PEG glyceryl oleate Glycerol fatty acid ester, hexylene glycerol, lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl PEG-sorbitan fatty acids such as alcohol, neutral oil, PEG-octylphenyl ether, PEG-cetyl ether, PEG-alkyl ethers such as PEG-stearyl ether, PEG-sorbitan diisostearate, PEG-sorbitan monostearate Esters, propylene glycol fatty acid esters such as propylene glycol stearate, propylene glycol, caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stea-o-wet, triglyceride, alkylaryl polyether alcohol, sorbitan-ether poly Oxyethylene derivatives, saturated polyglycolated C8-C10 glycerides, N-methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl Sulfoxide, azone and related compounds, dimethylformamide, N-methylformamide, fatty acid ester, fatty alcohol ether, alkyl-amide (N, N-dimethylalkylamide), N-methylpyrrolidone related compounds, ethyl oleate, polyglycerin Fatty acid, glycerol monooleate, glyceryl monomyristate, glycerol ester of fatty acid, silk amino acid, PPG-3 benzyl ether myristate, Di-PPG2 milles 10-adipate, honey quat, sodium pyroglutamate, abyssinica oil, Dimethicone, macadamia nut oil, Limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, fe Niltrimethicone, hydrolyzed wheat protein or combinations thereof can be included. In still further embodiments, the non-volatile solvent system can include a combination or mixture of non-volatile solvents as described in any of the embodiments discussed above.

  In addition to these and other considerations, the non-volatile solvent system is such that when a solidified layer is formed, the layer is flexible, stretchable, and / or otherwise “skin-friendly”. As such, it can also act as a plasticizer in the formulations of the present invention, and should preferably do so.

  Certain volatile and / or non-volatile solvents are irritating to the skin but are desirably used to achieve the desired solubility and / or permeability of the drug. It is also desirable to add compounds that can both prevent or reduce skin irritation and are compatible with the formulation. For example, in formulations where volatile solvents can irritate the skin, it may be helpful to use non-volatile solvents that can reduce skin irritation. Examples of solvents known to be able to prevent or reduce skin irritation include, but are not limited to, glycerin, honey, and propylene glycol.

  The formulations of the present invention contain two or more non-volatile solvents that cannot independently produce high flux per drug when formulated together according to certain, often experimentally determined ratios. You may contain. One possible reason for these initially non- or low fluxable non-volatile solvents being more fluxable when formulated together is the ionization state of the drug into a physical form with higher flux Non-volatile solvent behavior in some other synergistic manner. One further advantage of mixing non-volatile solvents is that it can optimize the pH of the formulation or the skin tissue under the formulation to minimize irritation. Examples of suitable combinations of non-volatile solvents that result in non-volatile solvent systems that would be more fluxable include, but are not limited to, isostearic acid / trolamine, isostearic acid / diisopropylamine, oleic acid / trolamine, and propylene Contains glycol / isostearic acid.

  The selection of the solidifying agent can also be made taking into account other components present in the adhesive formulation. The solidifying agent is compatible with the drug and solvent excipient (including volatile and non-volatile solvent systems) and is selected to provide the desired physical properties to the solidified layer once it is formed Or can be prescribed. Depending on the drug, solvent excipient, and / or other ingredients that can be present, the solidifying agent can be selected from a variety of agents. In one example, the solidifying agent is polyvinyl alcohol (Amresco) having a MW range of 20,000 to 70,000, an ester of a polyvinyl methyl ether / maleic anhydride copolymer having a MW range of 80,000 to 160,000 ( ISP Gantrez ES-425 and Gantrez ES-225), neutral copolymer of butyl methacrylate and methyl methacrylate (Degussa Plastoid B) with a MW range of 120,000 to 180,000, MW of 100,000 to 200,000 Dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer (Degussa Eudragit E100) with a range, more than 5,000 MW, or Eudragit R Zein (Prolamin) with MW over 5,000, such as ethyl acrylate-methyl methacrylate-trimethylaminoethyl chloride copolymer with MW similar to LPO (Degussa), Zein with MW of about 35,000 (Freeman industries), pregelatinized starch with a MW similar to Instant Pure-Cote B793 (Grain Processing Corporation), greater than 5,000, or similar to Aqualon EC N7, N10, N14, N22, N50 or N100 (Hercules) Ethyl cellulose with a good MW, fish gelatin with a MW 20,000 to 250,000 (Norland Products), gelatin, over 5,000 Other animal sources with that MW, can include acrylates / octylacrylamide copolymer with a MW similar than 5,000 or National Starch and Chemical Dermacryl 79,.

  In another embodiment, the solidifying agent is ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amide, corn starch, pregelatinized corn starch, polyether amide, shellac, polyvinyl Pyrrolidone, polyisobutylene rubber, polyvinyl acetate phthalate, or combinations thereof can be included. In a further embodiment, the solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate such as CAPNF from Eastnan, carboxypolymethylene, cellulose acetate (microcrystal), cellulose polymer, divinylbenzene styrene, ethylene vinyl acetate, silicone, Guam gum, guarodin, gluten, casein, calcium caseinate, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethyl cellulose, acrylate, PEG / PVP, xanthan gum, trimethylsiloxysilicate , Maleic acid / anhydride copolymer, polacrilin, poloxamer, polyethylene oxide, glass Methacrylic acid-ethyl acrylate such as lactic acid / poly-L-lactic acid, turpentine resin, locust bean gum, acrylic copolymer, polyurethane dispersion, dextrin, polyvinyl alcohol-polyethylene glycol copolymer, BASF's Kollicoat polymer Copolymers, methacrylate polymers such as methacrylic acid, and poly (methacrylic acid), or combinations thereof can be included. In another embodiment, the solidifying agent can comprise a combination of solidifying agents described in any of the embodiments discussed above. Depending on the solvent excipient component, the drug, and the specific functional requirements of a given formulation, other polymers may also be suitable as solidifying agents. Depending on the solvent excipient component, the drug, and the specific functional requirements of a given formulation, other polymers may also be suitable as solidifying agents.

  In one embodiment, the non-volatile solvent system and the solidifying agent should be compatible with each other. Compatibility is that i) the solidifying agent does not substantially negatively affect the function of the non-volatile solvent system, except for some reduction in flux; ii) the solidifying agent is substantially non-volatile solvent. The solidifying agent can retain the non-volatile solvent system in the solidifying layer and / or iii) the solidifying layer formed with the selected non-volatile solvent system and solidifying agent is acceptable to the skin It can be defined as having flexibility, stiffness, tension, elasticity, and adhesion. The ratio of non-volatile solvent to solidifying agent can be from about 0.1: 1 to about 10: 1. In another embodiment, the weight ratio of the non-volatile solvent system to the solidifying agent can be from 0.2: 1 to about 4: 1, more preferably from about 0.5: 1 to about 2: 1.

  The flexibility and extensibility of the solidified layer, which is also optionally peeled, may be desirable in some applications. For example, certain non-steroidal anti-inflammatory agents (NSAIDs) can be applied directly to joints and muscles for transdermal delivery to the joints and muscles. However, skin areas on joints and certain muscle groups are often significantly elongated during body movements. Such movement prevents the non-extensible patch from maintaining good skin contact. Lotions, ointments, creams, gels, foams, pastes, etc. would also not be suitable for use for the above reasons. As such, in transdermal delivery of NSAIDs to joints and / or muscles, the solidified formulations of the present invention can provide unique advantages and benefits. Although good extensibility is desirable in some applications, it is pointed out that certain applications of the present invention do not necessarily benefit from this property, so that the solidified formulations of the present invention need not necessarily be extensible. Should be. For example, if the formulation is applied to a small facial area overnight to treat acne, the subject will experience minimal discomfort and formulation-skin separation, for example, even if the solidified layer is not extensible Will. This is because facial skin is usually not very stretched during the sleep cycle.

  A further feature of formulations prepared according to embodiments of the present invention relates to drying time. If the formulation is dried too quickly, the user may not have enough time to spread the formulation into a thin layer on the skin surface before the formulation solidifies, which can lead to poor skin contact . If the formulation dries too slowly, the subject must wait a long time before recovering normal activity (eg wearing clothes) that would remove the unsolidified formulation. Thus, it is desirable that the drying time be longer than about 15 seconds but shorter than about 15 minutes, preferably from about 0.5 minutes to about 5 minutes.

  Other advantages of the solidified layer of the present invention include the presence of a physical barrier that can be formed by the material itself. In some illnesses or injuries, the skin surface is sensitive to contact with foreign objects, and if in contact with foreign objects, infection is possible. In those situations, the solidified layer can provide physical protection to the skin surface. For example, local anesthetics and other agents such as clonidine can be delivered locally to treat pain associated with neurological disorders such as diabetic neuropathic pain. Many such subjects feel a great deal of pain even when their skin area is only mildly touched, so the physical barrier of the solidified layer prevents the pain caused by accidental contact with the object or others. Or can be minimized.

  These and other advantages can be summarized in the following non-limiting list of advantages, as follows: The solidified layer of the present invention can be prepared in an initial form that is easy to adapt as a semi-solid dosage form. In addition, upon volatile solvent-based evaporation, the formulation layer applied to the skin is relatively thick and contains significantly more active drugs than typical layers such as traditional creams, gels, lotions, ointments, pastes, etc. Furthermore, it is resistant to unintentional removal. The solidified layer includes a non-volatile solvent that is fluxable for the drug so that the drug can be delivered over a sustained period at a therapeutically effective rate. Furthermore, since the solidified layer remains adhered to the skin and is preferably peelable, easy removal of the solidified layer is possible and no solvent or surfactant assistance will be required. In some embodiments, the adhesion to the skin, and the elasticity of the material, is such that the solidified layer does not separate from the skin upon skin stretching in highly stretchable skin areas such as on joints and muscles. For example, in one embodiment, the solidified layer can stretch 5%, or even 10% or more in one direction without cracking, breaking, and / or separating from the skin to which the layer is applied. Still further, the solidified layer can be configured to advantageously deliver the drug and protect sensitive skin areas without cracking or breaking.

  In one embodiment of the invention, the solidified layer may be washed away with a solvent such as water or ethanol at the end of the desired drug delivery. Other solvents that can also be used to wash the solidified formulation include, but are not limited to, the solvents listed herein. The ability to be removed by washing is particularly advantageous in certain applications. For example, if a solidifying formulation is applied to a body region with a large number of hair (eg, an anti-herpes solidifying formulation applied to a genital skin region with pubic hair), removal by peeling causes discomfort. Therefore, undesired and thus cleaning may be the preferred form of removal in this type of application. In another example, if the solidifying formulation is applied to the surface of a limb, such as the palm or sole, the ability to be removed by peeling is a secondary to the formulation that will adhere to the skin surface. Will be considered. In these cases, a solidified layer configured to be easily washed away by washing or ethanol would be more desirable. In cleaning embodiments, the solvent used to wash the solidified layer can dissolve the layer or make it less adhesive to the skin so that it can be easily removed from the skin.

  As a further note, it is a unique feature that the solidified layer of the present invention is capable of maintaining a substantial amount of non-volatile solvent system that is optimized to deliver the drug to the body surface. This feature can provide unique advantages over existing products. For example, Penlac is a widely used product for treating nail fungal infections. It contains the drug ciclopirox, volatile solvents (ethyl acetate and isopropyl) and polymeric materials. After being applied to the nail surface, the volatile solvent evaporates quickly and the formulation layer solidifies into a hard lacquer. The drug molecules solidify into a hard lacquer layer and are virtually unavailable for delivery to the nail. As a result, drug delivery is not believed to be sustained over time. As a result, while not intending to be bound by any particular theory, this is believed to be at least one of the reasons why the widely used Penlac has an effectiveness rate of only about 10%. Conversely, in the solidified layer of the present invention, drug molecules can move significantly in non-volatile solvents that are in contact with the surface of the skin, such as skin, nails, mucous membranes, and thus maintain sustained delivery. Make sure.

  Specific examples of applications that can benefit from the systems, formulations and methods of the present invention are as follows. In one embodiment, a solidified layer comprising bupivacaine, lidocaine, or ropivacaine can be formulated to treat diabetes and postherpetic neuralgia. Alternatively, dibucanin and alpha-2 agonists such as clonidine can be formulated into solidifying formulations to treat the same disease. In another embodiment, retinoic acid and benzoyl peroxide can be combined in a solidified layer to treat acne, or alternatively 1 wt% clindamycin and 5 wt% benzoyl peroxide are used to treat acne. Can be combined in a solidifying formulation. In another embodiment, a retinol solidifying formulation (OTC) can be prepared to treat epilepsy, or a lidocaine solidifying formulation can be prepared to treat back pain. In another embodiment, a zinc oxide solidifying formulation (OTC) can be prepared to treat diaper rash (a physical barrier provided by a solidified layer against irritating urine and stool is beneficial. An antihistaminic layer can be prepared to treat allergic rashes such as those caused by poison ivy.

  Further applications include certain skin diseases such as dermatitis, psoriasis, eczema, skin cancer, alopecia, epilepsy, herpes simplex, herpes simplex, herpes zoster, etc., especially transdermal patches are not practical Delivery of drugs to treat what happens on joints or muscles. For example, solidifying formulations containing imiquimod can be formulated to treat skin cancer, premature age skin, photodamaged skin, vulgaris and genital warts, and actinic keratosis. Solidifying formulations containing antiviral drugs such as acyclovir, penicivir, famciclovir, valacyclovir, steroids, behenyl alcohol treat herpes virus infections such as herpes simplex in the face and genital area Can be prescribed. Solidifying formulations containing non-steroidal anti-inflammatory drugs (NSAIDs), capsaicin, alpha-2 agonists, and / or nerve growth factors can cause soft tissue injuries and muscles such as joint and back pain of various causes -It can be prescribed to treat skeletal pain. As discussed above, patches on these skin areas typically do not have good contact for a long time, especially in physically active subjects, and can cause discomfort. Similarly, traditional semi-solid formulations such as creams, lotions, ointments and the like may stop drug delivery before the goal is achieved due to solvent evaporation and / or unintentional removal of the formulation. The solidifiable formulation of the present invention addresses both drawbacks of these types of delivery systems.

  One embodiment can include a solidified layer containing a drug from the class of alpha-2 antagonists administered topically to treat neuropathic pain. The alpha-2 agonist is gradually released from the formulation to provide pain relief over the duration. The formulation can become a coherent soft tissue after about 5 minutes and remains adhered to the surface of the body for the length of its application, typically several hours to tens of hours . The solidified layer is easily removed after the intended application without leaving a residual formulation on the skin surface.

  Another embodiment includes a solidified formulation containing capsaicin applied topically to treat neuropathic pain. Capsaicin is gradually released from the formulation to treat this pain over a period of time. The formulation can become a coherent soft solid after about 5 minutes and remains adhered to the body surface for the length of its application. It is easily removed at any time after drying without leaving a formulation remaining on the skin surface.

  Another embodiment includes a solidifying formulation containing clobetasol propionate topically applied to treat hand dermatitis. Clobetasol propyronate is gradually released from the formulation to treat dermatitis over a maintenance time. The formulation can become a coherent soft tissue after about 7 minutes and remains adhered to the body surface for the length of its application. A physical barrier also protects the compromised skin from potentially harmful substances. It is easily removed at any time after drying without leaving a residual formulation on the skin surface.

  Another embodiment contains a solidifying formulation containing clobetasol propionate topically applied to treat alopecia. Clobetasol propionate is gradually released from the formulation to promote hair growth over a period of time. The formulation can become a coherent soft solid after about 5 minutes and remains adhered to the body surface for the length of its application. It is easily removed at any point after drying by peeling to showering.

  Another embodiment includes a solidifying formulation containing tazolac to treat pregnancy lines, epilepsy, adiposity hyperplasia, or seborrheic keratosis.

  In another embodiment, a solidifiable formulation containing glycerol can be provided to provide a protective barrier for cracking at the fingertips.

  Yet another embodiment can include solidifying formulations containing drugs selected from local anesthetic classes such as lidocaine and ropivacaine, NSAID classes such as ketoprofen, piroxicam, diclofenac, indomethacin, and the like. This is applied topically to treat symptoms of back pain, muscle tension, or fascial pain or a combination thereof. Local anesthetics and / or NSAIDs are gradually released from the formulation to provide pain relief for the duration. The formulation can become a coherent soft tissue after about 5 to 10 minutes and remains adhered to the body surface for the length of its application, which leaves a residual formulation on the skin surface And easily removed at any time after drying.

  A further embodiment is a solid formulation comprising at least one alpha-2 agonist drug, at least one tricyclic antidepressant, and / or at least one local anesthetic drug administered locally to treat neuropathic pain including. The drug is gradually released from the formulation to provide pain relief over time. The formulation can become a coherent soft solid after 2 to 10 minutes and remains adhered to the body surface for the length of its application. It is easily removed at any time after drying without leaving a residual formulation on the skin surface.

  Similar embodiments can include a solidifying formulation containing the drug capsaicin and a local anesthetic drug, which is applied topically to the skin to provide pain relief. Another embodiment can include a solidifiable formulation containing a combination of a local anesthetic and an NSAID. In both of the embodiments, the drug is gradually released from the formulation to provide pain relief over time. The formulation can become a coherent soft solid after about 2 to 10 minutes and remains adhered to the body surface for the length of its application. It is easily removed at any time after drying without leaving a residual formulation on the skin surface.

  In another embodiment, solidifying formulations for the delivery of drugs that treat the cause or symptoms of joint and muscle related diseases may also benefit from the systems, formulations, and methods of the present invention. it can. Such diseases that may be applicable include, but are not limited to, osteoarthritis (OA), rheumatoid arthritis (RA), various other causes of joint and skeletal pain, fascial pain, muscle Including pain and sports injuries. The drugs or drug classes that can be used in such applications are not limited, but include non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen and diclofenac, COX-2 selective NSAIDs and agents, COX- Includes 3-selective NSAIDs and agents, local anesthetics such as lidocaine, bupivacaine, ropivacaine and tetracaine, and steroids such as dexamethasone.

  Delivery of drugs for the treatment of acne and other skin diseases can also benefit from the principles of the present invention, particularly when delivering drugs with low skin permeability. Currently, topical retinoids, peroxides, and antioxidants for treating acne are best applied as traditional semi-solid gels or creams. However, due to the above-mentioned drawbacks, it seems that sustained delivery over many hours is not possible. For example, clindamycin, benzoyl peroxide, and erythromycin will only be effective if sufficient amounts are delivered to the hair follicle. However, traditional semi-solid formulations such as popular acne medical benzacrine gels typically lose most of their solvent (water in the case of benzacrine) within minutes after application. This short time of a few minutes seems to jeopardize the sustained delivery of the drug. The formulations of the present invention typically do not have this limitation.

In another embodiment, delivery of drugs to treat neuropathic pain can also benefit from the methods, systems, and formulations of the present invention. Patches containing local anesthetics such as Lidoderm ^™ are widely used to treat neuropathic pain, such as pain caused by postherpetic neuralgia. Due to the patch limitations discussed above, solidified layers prepared in accordance with the present invention offer some unique benefits, as well as a potentially inexpensive alternative to the use of patches. Possible drugs delivered for such applications include, but are not limited to, local anesthetics such as lidocaine, perilocaine, tetracaine, bupivacaine, etidocaine; and alpha-, such as capsaicin, and clonidine. 2- Other drugs including agonists, dissociative anesthetics such as ketamine, and tricyclic antidepressants such as amitriptyline.

  The solidifying formulations of the present invention included musculoskeletal pain, neuropathic pain, alopecia, skin diseases including dermatitis and psoriasis, and skin recovery (cosmetic skin treatment), and viral, bacterial and fungal infections It can be prescribed to treat various diseases and conditions such as infections. As such, the formulation can deliver a wide range of numbers and types of drugs and active agents. In one embodiment, the solidifying formulation is acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl It can be formulated to include peroxide, tretinoin, isotretinoin, clobetasol propionate, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, or combinations thereof.

  In one embodiment, the formulation is amorolfine, butenafine, naphthifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, rubconazole, voriconazole, clotrimazole, butocnazole, econazole, miconazole, oxyconazole, sulconazole, terconazole, Antifungal drugs such as caspofungin, micafungin, anidollaphingin, amphotericin B, AmB, nystatin, pimaricin, griseofulvin, cyclopirox olamine, haloprozin, tolnaftate, and undecylate, or combinations thereof can be included.

  In another embodiment, the formulation is acyclobeer, pencyclobeer, famcyclobeer, valacyclobeer, behenyl alcohol, trifluridine, idoxuridine, cidofovir, gancyclobeer, podophyllox, podophyllotoxin, ribavirin , Abaca beer, doravirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amphena beer, indina beer, nelfina beer, ritona beer, sakina beer, amantadine, interferon, oseltami beer, ribavirin, rimantadin, nabir Antifungal drugs such as combinations can be included.

  Where the formulation is intended to provide antibacterial treatment, it may be an antibacterial such as erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, kilolons such as ciproflavin, or combinations thereof. It can be formulated to contain a drug.

  Where the formulation is intended to reduce pain, particularly neuropathic pain, the formulation includes a local anesthetic such as lidocaine, bupivacaine, ropivacaine, and tetracaine; an alpha-2 agonist such as clonidine Can do. If the formulation is intended to treat inflammation-related pain, it may be ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitors, general COX inhibitors, COX-2 selective inhibitors, COX-3 It can be formulated to include non-steroidal anti-inflammatory drugs such as selective inhibitors or combinations thereof.

  In another embodiment, the formulation comprises an anti-acne drug such as clindamycin and benzoyl peroxide, a vitamin A derivative such as retinol, tazarotene and isotretinoin, cyclosporine, anthracin, vitamin D3, cholecalci By including active agents such as ferrol, calcitriol, calcipotriol, tacalcitol, calcipotriene and the like, it can be formulated to treat skin disorders or wounds.

  In yet another embodiment, delivery of a medicament for treating warts and other skin disorders will also benefit from prolonged sustained drug delivery. Examples of anti-ivo compounds include, but are not limited to: imiquimod, resiquimod, keratin solubilizers: salicylic acid, alpha hydroxy acid, sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, Contains benzoic acid, or a combination thereof.

  Further embodiments include, but are not limited to, progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethinodiol diacetate, norergestromine, norgestimate, levonorgestrel, dl-norgestrel, cyproterone acetate, didrogesterone, Medroxyprogesterone acetate, Chlormadinone acetate, Megestrol, Promegestone, Norethisterone, Limestenol, Guestden, Progestagen composed of tivolene, Testosterone, Methyltestosterone, Oxandrolone, Androstenedione, Androgen composed of dihydrotestosterone, Estradiol, Ethinyl Estradiol, esthiol, estrone, conjugated follicular hormone, esterified ester Torogen, including the use of solidifying formulation for delivery of sex steroids, including from consisting estrogen or a combination thereof, estropipate.

  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, diflorazone diacetate, triamcinolone acetonide, dezoxymethazone, fluocinonide, harsinonide, mometasone furoate, betamethasone valerate. , Fluocinonide, fluticasone propionate, triamcinolone acetonide, fluocinolone acetonide, furandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alcromethasone dipropionate, flumethasone pivalate, hydrocortisone acetic acid or combinations thereof including.

  Further embodiments include the controlled delivery of nicotine to treat nicotine addiction in smokers and nicotine addicted individuals. The formulations of the present invention would be a cost-effective way to deliver a therapeutic amount of nicotine transdermally.

  Another embodiment involves using the formulation to deliver anti-histamine agents such as diphenhydramine and tripelamine. These agents will reduce itching by blocking histamine that causes itching and will provide relief by providing topical analgesics.

  Other drugs that can be delivered using the solidifying formulation of the present invention include, but are not limited to, tricyclic antidepressants such as amitriptyline; anticonvulsants such as carbamazepine and alprazolam; N-methyl-D-aspartate (NMDA) antagonists; 5-HT2A receptor antagonists such as ketanserin; immunomodulators such as tacrolimus and picrolimus.

  Further embodiments include the following steps: selecting a drug for skin delivery, selecting or formulating a fluxable or highly fluxable non-volatile solvent system for the selected drug, the non-volatile solvent system and Select a solidifying agent that is compatible with the volatile solvent system, select a volatile solvent system that meets the preferred drying time frame and is compatible with the components, and then optionally mixes the components with a viscosity modifier, pH Formulating a solidifying formulation comprising a modifier and other ingredients such as emollients.

  Another embodiment selects a drug for skin delivery, selects or formulates a fluxable or high fluxable non-volatile solvent system for the selected drug, the fluxable or high flux A non-volatile solvent system and a solidifying agent compatible with the volatile solvent and then formulating said ingredients into a solidifying formulation (for mucosal delivery) Or a non-volatile solvent capable of being liquid fluxable or highly liquid fluxable on human skin (including nail surfaces).

  Another embodiment includes a method of maintaining a liquid fluxable non-volatile solvent system on human skin or for delivering a drug to human skin or tissue under human skin. The method is compatible with human skin, drug, fluxable non-volatile solvent system, solidifying agent capable of gelling liquid flux-able non-volatile solvent system into soft solids, and the rest of the ingredients of the formulation Adapting a formulation comprising a volatile solvent system. The formulation layer is such that at least some evaporation of the volatile solvent converts the formulation from an initial lower than solid state to a soft-cohesive solid layer. The drug in the soft-cohesive solid layer is delivered at a therapeutically effective rate for a sustained period.

  One use of the present invention may be for delivering sex hormones. In one embodiment, a formulation for skin delivery of a sex hormone is used to solidify the formulation that is applied as a layer to the skin surface upon at least partial evaporation of the sex hormone, solvent excipient, and volatile solvent system. A contributing solidifying agent can be included. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one non-volatile solvent. The formulation can have a viscosity suitable for application to the skin surface and adhesion prior to evaporation of the volatile solvent system. When applied to the skin surface, a solidified layer is formed after at least partial evaporation of the volatile solvent system. Sex hormones are continuously delivered at a therapeutically effective rate, even after the volatile solvent system has at least substantially evaporated.

  The formulations of the present invention can be used in the treatment and elimination of warts. The anti-wart formulation can include an anti-wart drug, a solvent excipient, and a solidifying agent. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising 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. When applied to the skin surface, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. The anti-ivory hormone is continuously delivered at a therapeutically effective rate even after the volatile solvent system has at least substantially evaporated.

  In a further embodiment, a formulation for delivering clobetasol propionate can include clobetasol propionate, a solvent excipient, and a solidifying agent. The solvent excipient includes a volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system. The non-volatile solvent system can include propylene glycol and / or a fatty acid. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin surface, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Clobetasol propionate is continuously delivered at a therapeutically effective rate even after the volatile solvent system has at least substantially evaporated. The solidifying agent can be a protein-based solidifying agent.

In another embodiment, a solidifying formulation for delivering ropivacaine can include ropivacaine, a solvent excipient, and a solidifying agent. A volatile solvent system comprising at least one volatile solvent, and a non-volatile solvent system that can comprise solvents such as isostearic acid, Span20, and triacetin. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin surface, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Even after partial evaporation of at least a portion of the volatiles, ropivacaine is applied to the skin at a rate of 5 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent system has at least substantially evaporated. Are continuously delivered across.

In another embodiment, a solidifying formulation for delivering imiquimod can comprise imiquimod, a solvent excipient, and a solidifying agent. Volatile solvent systems including at least one volatile solvent, and non-volatile solvent systems can include isostearic acid and solvents such as Span 20 and triacetin. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin surface, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Even after partial evaporation of at least a portion of the volatile, ropivacaine is applied to the skin at a rate of at least 5 mcg / hr / cm ^{2 for} at least 6 hours after the volatile solvent system is at least substantially evaporated. Or delivered continuously across the skin.

In another embodiment, a solidifying formulation for delivering imiquimod can comprise imiquimod, a solvent excipient, and a solidifying agent. Volatile solvent systems that include at least one volatile solvent, and non-volatile solvent systems can include solvents such as isostearic acid, Span 20, and triacetin. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin surface, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Even after partial evaporation of at least a portion of the volatiles, imiquimod is applied to the skin at a rate of 0.8 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent system has evaporated at least substantially. Or delivered continuously across the skin.

In another embodiment, a solidifying formulation for delivering ketoprofen can include ketoprofen, a solvent excipient, and a solidifying agent. Volatile solvent systems include volatile solvent systems comprising at least one volatile solvent and non-volatile solvent systems comprising glycerol and propylene glycol. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. When applied to the skin, the formulation forms a solidified layer after at least partial evaporation of the volatile solvent system. Even after partial evaporation of at least a portion of the volatile, ketoprofen continues across the skin at a rate of 10 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent, at least substantially evaporated. Delivered.

  Other drugs that can be delivered using the formulations and methods of the present invention include humectants, emollients, and other skin care compounds.

(Example)
The following examples illustrate the best-known embodiments of the present invention. However, it is to be understood that the following are only examples of the application of the principles of the present invention or are illustrative thereof. Numerous modifications and alternative compositions, methods and systems can be devised by those skilled in the art without departing from the spirit and scope of the invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the invention has been described using specifics, the following examples provide further details relating to what is currently considered the most realistic and preferred embodiment of the invention.

Example 1
Hairless mouse skin (HMS) or human epithelium (HEM) is used as the model membrane noted for the in vitro flux experiments described herein. Hairless mouse skin (HMS) is used as a model membrane for the in vitro flux experiments described herein. A freshly isolated epidermis removed from the abdomen of hairless mice is carefully placed between the donor and receiver chambers of the Franz diffusion cell. The receiver chamber is filled with pH 7.4 phosphate buffered saline (PBS). The experiment begins by placing the test formulation (of Examples 2-5) on the stratum corneum (SC) of the skin sample. The Franz cell is placed in a heating block maintained at 37 ° C and the HMS temperature is maintained at 35 ° C. At predetermined time intervals, discard 800 μL aliquots and replace with fresh PBS solution. Skin flux (μg / cm ² / h) is determined from the steady state slope of the plot of cumulative amount of penetration-vs-time. It should be noted that human cadaver skin can be used as a model membrane for in vitro flux experiments as well. The skin placement and sampling technique was the same as described above for the HMS experiment.

Example 2
Human cadaver skin is used as a membrane to select “fluxable” non-volatile solvents for betamethasone dipropionate. Approximately 200 mcL of a saturated solution of BDP in various solvents is added to the donor compartment of the Franz cell. The in vitro analysis described in Example 1 is used to determine the steady state flux of BDP. The in vitro method used is described in Example 1. An active enzyme in the skin converts betamethasone dipropionate to betamethasone. The steady state flux values reported in Table 1 are quantified using an external betamethasone standard and reported as the amount of betamethasone permeation per unit area and time.

結果からわかるように、トリアセチン、ラブラゾール、オレイン酸および軽質鉱油は、１０ ｎｇ／ｃｍ^２／ｈｒの見積もられた治療上有効なフラックスに近いフラックス値を有する。固化剤および他の成分の添加は、恐らくは、フラックスを減少させ、よって、前記した不揮発性溶媒は「フラックス化可能」溶媒として理想的な選択ではないであろう。しかしながら、ソルビタンモノラウレートは、１つの可能な治療レベルよりも３倍高いフラックスを有し、よって、「フラックス化可能」溶媒である良好な機会を有する。種々の固化剤とのその適合性は、それを用いることができる適切なレベルを決定するであろう。加えて、プロピレングリコールは必要な治療レベルよりも１９倍高いフラックスを有し、よって、テストした他の不揮発性溶媒系よりも有意に高いフラックスを提供する。丁度辛うじて「可能化」よりも高いフラックスを生じる不揮発性溶媒の能力は有利であり得る。というのは、処方物への他の必要なまたは望まれる成分の配合はフラックスを減少させる傾向があり、それは、処方物において比較的低い薬物濃度にて望まれる治療効果を達成することができ、これは、処方物を安価かつより安全とする傾向があるからである。

As can be seen from the results, triacetin, labrazole, oleic acid and light mineral oil have flux values close to the estimated therapeutically effective flux of 10 ng / cm ² / hr. The addition of solidifying agents and other components probably reduces the flux, so the non-volatile solvents described above may not be an ideal choice as a “fluxable” solvent. However, sorbitan monolaurate has a flux that is three times higher than one possible therapeutic level and thus has a good opportunity to be a “fluxable” solvent. Its compatibility with various solidifying agents will determine the appropriate level at which it can be used. In addition, propylene glycol has a 19 times higher flux than the required therapeutic level, thus providing a significantly higher flux than other non-volatile solvent systems tested. The ability of non-volatile solvents to produce a flux that is just barely higher than “enable” may be advantageous. This is because the incorporation of other necessary or desired ingredients in the formulation tends to reduce the flux, which can achieve the desired therapeutic effect at relatively low drug concentrations in the formulation, This is because the formulation tends to be cheaper and safer.

Example 3
Evaluate formulations of clobetasol propionate in various non-volatile solvent systems. All solvents have 0.1% (w / w) clobetasol propionate. The penetration of clobetasol from the test formulation through HEM is listed in Table 2 below.

ヒト死体皮膚を、クロベタゾールプロピオネート用の「フラックス化可能」溶媒を選択するための膜として用いる。イン・ビトロ方法を実施例１に記載する。種種の不揮発性溶媒中の約２００ ｍｃｌのクロベタゾールの０．１％（ｗ／ｗ）溶液を、Ｆｒａｎｚセルのドナー区画に加える。ＬＣ分析後に得られる結果を表２に示す。全ての正味の本明細書中で実験された不揮発性溶液は３０時間にわたって５０ ｎｇ／ｃｍ^２／ｈｒ以上の平均フラックスを有する。プロピレングリコールおよびグリセロールは、クロベタゾールプロピオネートについての最低浸透を有する。結果は、構造がクロベタゾールプロピオネートに似たベタメタゾンジプロピオネートがプロピレングリコールにて良好なフラックスを有するという驚くべき考慮である。プロピレングリコールおよびイソステアリン酸の９：１の重量比率の混合物である溶媒系は、溶媒単独、またはテストした他の溶媒のいずれかよりも有意に高いフラックスを有する。平均フラックスは、最良の非−混合溶媒であると見える軽質鉱油よりも２０倍高い。よって、クロベタゾールプロピオネートでは、プロピレングリコール／イソステアリン酸は、不揮発性溶媒系について最高のフラックスを供した。表２にリストした不揮発性溶媒の中では、９：１プロピレングリコール：ＩＳＡのみがフラックス化可能であると考えられる。この例において、フラックス化可能な不揮発性溶媒系は純粋な単一の物質ではなく、むしろフラックス化可能比率の２つ以上の物質の混合物である。他の比率または物質の組合せを用いて、フラックス化可能な不揮発性溶媒系を生じさせることができる。

Human cadaver skin is used as a membrane to select a “fluxable” solvent for clobetasol propionate. The in vitro method is described in Example 1. A 0.1% (w / w) solution of about 200 mcl clobetasol in various non-volatile solvents is added to the donor compartment of the Franz cell. The results obtained after LC analysis are shown in Table 2. All net non-volatile solutions tested herein have an average flux over 50 ng / cm ² / hr over 30 hours. Propylene glycol and glycerol have the lowest penetration for clobetasol propionate. The result is a surprising consideration that betamethasone dipropionate, similar in structure to clobetasol propionate, has a good flux with propylene glycol. A solvent system that is a 9: 1 weight ratio mixture of propylene glycol and isostearic acid has a significantly higher flux than either the solvent alone or the other solvents tested. The average flux is 20 times higher than the light mineral oil that appears to be the best non-mixed solvent. Thus, for clobetasol propionate, propylene glycol / isostearic acid provided the highest flux for the non-volatile solvent system. Of the non-volatile solvents listed in Table 2, only 9: 1 propylene glycol: ISA is considered to be fluxable. In this example, the fluxable non-volatile solvent system is not a pure single substance, but rather a mixture of two or more substances in a fluxable ratio. Other ratios or combinations of materials can be used to produce a fluxable non-volatile solvent system.

Examples 4 to 9
An adhesive formulation containing 0.05% (w / w) clobetasol propionate is prepared with a non-volatile solvent and propylene glycol and isostearic acid as various solidifying agents. The formulation is prepared from the ingredients shown in 3.

先に示した組成物の各々を、以下のように、表４に示したようにクロベタゾールプロピオネートのフラックスについて実験する。

Each of the previously shown compositions is tested for clobetasol propionate flux as shown in Table 4 as follows.

表４からわかるように、固化剤としてポリビニルアルコールを含有する実施例４に記載された処方物は、クロベタゾールプロピオネートの高いフラックスを有する。ポリビニルアルコールは伸長可能な固化層を形成することが知られており、この処方物は許容される疲労特性を有するようである。得られた固化層の靭性は、必要であれば、適当な可塑剤を加えることによって修飾することができる（不揮発性溶媒系それ自体は可塑剤として働くことができる）。粘着性もまた、適当な量の粘着剤を加えることによって、あるいは適当な量のＤｅｒｍａｃｒｙｌ ７９のようなもう１つの固化剤を加えることによって修飾することもできる。

As can be seen from Table 4, the formulation described in Example 4 containing polyvinyl alcohol as a solidifying agent has a high flux of clobetasol propionate. Polyvinyl alcohol is known to form an extensible solidified layer and this formulation appears to have acceptable fatigue properties. The toughness of the resulting solidified layer can be modified, if necessary, by adding a suitable plasticizer (the non-volatile solvent system itself can act as a plasticizer). Tackiness can also be modified by adding an appropriate amount of an adhesive, or by adding an appropriate amount of another solidifying agent such as Dermacryl 79.

  For the formulation described in Example 9, a higher percentage of ethanol is required to dissolve the polymer. However, the solidifying agent used in Example 9 provides the highest flux of clobetasol propionate among the experimental solidifying agents. The fatigue properties of this formulation can be modified by adding other components including appropriate levels of, but not limited to, plasticizers, adhesives, non-volatile solvents and solidifying agents.

Example 10
Acyclovir formulations in various non-volatile solvent systems are evaluated. Excess acyclobeer is present.

  The penetration of acyclovir from the test formulation through the HMS is shown in Table 5 below.

前記不揮発性溶媒からのアシクロビールの定常状態フラックスは、無毛マウスの皮膚の角質層側（ドナー）上に２００ｍｃＬを置くことによって得られる。イン・ビトロ実験は実施例１に記載したように行う。驚くべき結果は、ポリエチレングリコール４００、Ｓｐａｎ８０、オレイン酸エチル、またはオレイン酸エチル＋トロラミンが、アシクロビールについてフラックス化可能溶媒ではないことを示した（例えば、定常状態フラックス値は、表１に示した市販の製品におけるアシクロビールの定常状態フラックスよりも有意に低く、ここに、フラックスは約３ｍｃｇ／ｃｍ^２／ｈであった）。しかしながら、イソステアリン酸およびトロラミンまたはオレイン酸および増大させる量のトロラミンの組合せは、アシクロビールについてフラックス化可能溶媒である。分かるように、最高フラックスは、不揮発性溶媒系としてオレイン酸を含む３０％トロラミンを用いて達成された。

A steady state flux of acyclovir from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. Surprising results indicated that polyethylene glycol 400, Span 80, ethyl oleate, or ethyl oleate + trolamine is not a fluxable solvent for acyclovir (eg, steady state flux values are shown in Table 1). Significantly lower than the steady-state flux of acyclobeer in other commercial products, where the flux was about 3 mcg / cm ² / h). However, the combination of isostearic acid and trolamine or oleic acid and increasing amounts of trolamine is a fluxable solvent for acyclovir. As can be seen, the highest flux was achieved using 30% trolamine with oleic acid as the non-volatile solvent system.

Examples 11 to 14
Prototype formulations are prepared as follows. Several acyclovir solidifying formulations are prepared according to embodiments of the present invention according to Table 6 as follows.

実施例１１から１４において、表６中の組成物を以下のように調製する。Ｅｕｄｒａｇｉｔ ＲＬ−ＰＯおよびエタノールをガラスジャー中で合わせ、ＲＬ−ＰＯが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびトロラミンをＲＬ−ＰＯ／エタノール混合物に加え、混合物を激しく撹拌する。一旦均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

In Examples 11 to 14, the 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. Isostearic acid and trolamine are added to the RL-PO / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Examples 15 to 16
Prototype formulations are prepared as follows. Several acyclovir solidifying formulations are prepared according to embodiments of the present invention according to Table 7 as follows.

表３に示された実施例１５および１６の組成物は以下の通りに調製する。Ｅｕｄｒａｇｉｔ ＲＬ−ＰＯおよびエタノールをガラスジャー中で合わせ、ＲＬ−ＰＯが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびジイソプロパノールアミンまたはＮｅｕｔｒｏｌ ＴＥ Ｐｏｌｙｏｌ（ＢＡＳＦ）をＲＬ−ＰＯ／エタノール混合物に加え、混合物を激しく撹拌する。一旦均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

The compositions of Examples 15 and 16 shown in Table 3 are prepared as follows. Eudragit RL-PO and ethanol are combined in a glass jar and heated with stirring until the RL-PO is dissolved. Isostearic acid and diisopropanolamine or Neuteol TE Polyol (BASF) are added to the RL-PO / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Examples 17 to 18
A prototype peel formulation is prepared as follows. Several acyclovir solidifying formulations are prepared according to embodiments of the present invention according to Table 8 as follows.

実施例１７から１８において、表８中の組成物を以下のように調製する。Ａｑｕａｌｏｎからのエチルセルロース（ＥＣ）Ｎ７またはＥＣ Ｎ１００およびエタノールをガラスジャー中で合わせ、固体セルロースが溶解するまで撹拌しつつ加熱する。イソステアリン酸およびトロラミンをセルロース／エタノール混合物に加え、混合物を激しく撹拌する。一旦、均一な混合物が得られれば、アシクロビールを混合物に加え、処方物を激しく混合する。

In Examples 17 to 18, the compositions in Table 8 are prepared as follows. Ethyl cellulose (EC) N7 or EC N100 from Aqualon and ethanol are combined in a glass jar and heated with stirring until the solid cellulose is dissolved. Isostearic acid and trolamine are added to the cellulose / ethanol mixture and the mixture is stirred vigorously. Once a uniform mixture is obtained, acyclobeer is added to the mixture and the formulation is mixed vigorously.

Example 19
The formulations of Examples 11-18 are tested in the hairless mouse skin (HMS) in vitro model described in Example 1. Table 9 shows the data obtained using the experimental process outlined above.

前記で示した本発明の処方物は、一般には、有効成分の有意な浸透を供し、さらに、実施例１１から１３および１８の処方物は、市販の製品Ｚｏｖｉｒａｘ Ｃｒｅａｍよりも浸透性がかなり大きいことが判明する。実施例１１、１２についての経時的なＨＭＳ角質層を通って浸透するアシクロビール、およびＺｏｖｉｒａｘ Ｃｒｅａｍの量を図４に示す。示された各値は、少なくとも３つの実験の平均±ＳＤを示す。

The formulations of the present invention shown above generally provide significant penetration of the active ingredient, and further, the formulations of Examples 11 to 13 and 18 are significantly more permeable than the commercial product Zovirax Cream. Becomes clear. The amount of acyclovir and Zovirax Cream that permeate through the HMS stratum corneum over time for Examples 11 and 12 is shown in FIG. Each value shown represents the mean ± SD of at least 3 experiments.

  Examples 11-14 show the impact of the ratio of trolamine to isostearic acid (ISA) on acyclovir flux enhancement. The optimal ISA: trolamine ratio is from 1: 1 to 2: 1, and ratios greater than 4: 1 indicate a significant reduction in acyclovir skin flux. Addition of diisopropanolamine and Neutrol instead of trolamine in the formulation (Examples 15 and 16) shows a significant decrease in acyclovir flux values. This may be due to a specific chemical interaction between trolamine and ISA that creates an environment within the formulation that promotes higher skin flux. Examples 17 and 18 utilize different solidifying agents to estimate the impact of the solidifying agent on acyclovir flux. Surprisingly, Example 17 shows a significant reduction in acyclovir skin flux, but Example 18, which differs from Example 17 by the molecular weight of the solidifying agent, compares to a similar ISA: trolamine ratio in Example 11. No impact on acyclovir skin flux.

  As can be seen from FIG. 4, Examples 11 and 12 showed sustained delivery of acyclovir up to 8 hours, and delivery of acyclovir was reported as long as the subject wanted to remove the solidified formulation attached to the skin. It would be reasonable to estimate what will continue at the flux value based on the drug load and the continued presence of the non-volatile solvent.

Example 20
A solidified formulation similar to Example 12 (without acyclovir) is applied to the human skin surface, resulting in a thin, transparent, flexible, stretchable solidified layer. A few minutes after evaporation of the volatile solvent (ethanol), a peelable solidified adhesive layer is formed. The stretchable solidified layer had good adhesion to the skin, did not separate from the skin, and could be easily peeled off from the skin. The absence of acyclovir has a minimal impact on the formulation and the physical and fatigue properties of soft cohesive solids. Because it is present at such a low concentration, if present.

Example 21
Evaluate solidified formulations of ketoprofen in various non-volatile solvent systems. Excess ketoprofen is present. The penetration of ketoprofen from the test formulation through the HMS is shown in Table 10 below.

前記不揮発性溶媒からのケトプロフェンの定常状態フラックスは、２００ｍｃＬを、無毛マウス皮膚の角質層側（ドナー）上に置くことによって得られる。イン・ビトロ実験は実施例１に記載したように行う。表１０から、不揮発性溶媒のグリセロールおよびポリエチレングリコール４００は低い定常状態フラックス値を有し、「フラックス化可能」と考えられないであろう。Ｓｐａｎ２０はフラックス化可能と考えることができ、プロピレングリコールまたはオレイン酸は最高のフラックスを提供し、フラックス化可能な不揮発性溶媒系と考えられる。フラックス化可能溶媒の評価は、ケトプロフェンの見積もられた治療上有効なフラックスに基づく（表Ａ中の１６ｍｃｇ／ｃｍ^２／ｈ）。治療上有効なフラックス未満である不揮発性溶媒からの薬物の定常状態フラックス値（表Ａ）はフラックス化可能と考えられず、他方、治療上有効なフラックス値を超える不揮発性溶媒からの薬物の定常状態フラックス値はフラックス化可能と考えられる。

A steady state flux of ketoprofen from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 10, the non-volatile solvents glycerol and polyethylene glycol 400 would have low steady state flux values and would not be considered “fluxable”. Span 20 can be considered fluxable, and propylene glycol or oleic acid provides the best flux and is considered a fluxable non-volatile solvent system. The assessment of fluxable solvents is based on the estimated therapeutically effective flux of ketoprofen (16 mcg / cm ² / h in Table A). Steady state flux values of drugs from non-volatile solvents that are less than the therapeutically effective flux (Table A) are not considered fluxable, while steady state drugs from non-volatile solvents that exceed the therapeutically effective flux values. It is considered that the state flux value can be converted into flux.

Example 22
Evaluate solidifying formulations of ropivacaine in various non-volatile solvent systems. Excess ropivacaine is present. The penetration of ropivacaine from the test formulation through HMS is shown in Table 11 below.

前記不揮発性溶媒からのロピバカイン塩基の定常状態フラックスは、無毛マウス皮膚の角質層側（ドナー）に２００ｍｃＬを置くことによって得られる。イン・ビトロ実験は実施例１に記載されたように行う。表１１から、不揮発性溶媒のグリセロール、およびＴｗｅｅｎ ２０は低い定常状態フラックス値を有し、「フラックス化可能」とは考えられないであろう。しかしながら、鉱油およびイソステアリン酸はフラックス化可能溶媒であって、許容される固化処方物を設計するための固化剤および揮発性溶媒での評価について良好な候補である。驚くべきことに、Ｓｐａｎ２０はより高い定常状態フラックス値を有し、高度にフラックス化可能溶媒としての資格があろう。治療上有効なフラックス未満である不揮発性溶媒からの薬物の定常状態フラックス値（表Ａ）はフラックス化可能と考えられる、他方、治療上有効なフラックス値を超える不揮発性溶媒からの薬物の定常状態フラックス値はフラックス化可能と考えられる。

The steady state flux of ropivacaine base from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 11, the non-volatile solvents glycerol and Tween 20 have low steady state flux values and would not be considered “fluxable”. However, mineral oil and isostearic acid are fluxable solvents and are good candidates for evaluation with solidifying agents and volatile solvents to design acceptable solidified formulations. Surprisingly, Span 20 has a higher steady state flux value and would qualify as a highly fluxable solvent. Steady state flux values of drugs from non-volatile solvents that are less than the therapeutically effective flux (Table A) are considered feasible, whereas steady states of drugs from non-volatile solvents that exceed the therapeutically effective flux values The flux value can be considered as flux.

Example 23
Evaluate solidifying formulations of diclofenac sodium (obtained from spectra) in various non-volatile solvent systems. Excess diclofenac sodium is present. The penetration of diclofenac sodium from the test formulation through the HMS is shown in Table 12 below.

前記不揮発性溶媒からのジクロフェナックナトリウムの定常状態フラックスは、２００ｍｃＬを無毛マウスの皮膚の角質層側（ドナー）に置くことによって得られる。イン・ビトロ実験は実施例１に記載したように行われる。表１２から、不揮発性溶媒グリセロールは、見積もられた治療的定常状態フラックス値と匹敵する定常状態フラックス値を有し、フラックス化可能溶媒と考えることができる。しかしながら、ミリスチン酸イソプロピル、オレイン酸エチル、プロピレングリコール、およびＳｐａｎ２０の定常状態フラックス値は、グリセロールについて報告されたフラックス値の少なくとも１０倍である。これらの不揮発性溶媒はフラックス化可能溶媒と考えられる。

A steady state flux of diclofenac sodium from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 12, the non-volatile solvent glycerol has a steady state flux value comparable to the estimated therapeutic steady state flux value and can be considered a fluxable solvent. However, the steady state flux values for isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are at least 10 times that reported for glycerol. These non-volatile solvents are considered as fluxable solvents.

Example 24
Evaluate solidifying formulations of diclofenac acid in various solvent systems. Excess diclofenac acid is present. The penetration of diclofenac from the test formulation through HMS is shown in Table 13 below.

前記不揮発性溶媒からのジクロフェナック酸の定常状態フラックスは、２００ｍｃＬを無毛マウス皮膚の角質層側（ドナー）に置くことによって得られる。イン・ビトロ実験は実施例１に記載したように行う。表１３から、不揮発性溶媒グリセロールは報告された定常状態フラックス値を有さず、活力のある不揮発性溶媒候補と考えられない。しかしながら、ミリスチン酸イソプロピル、オレイン酸エチル、プロピレングリコール、およびＳｐａｎ２０の定常状態フラックス値は、現在入手可能な市販の製品について報告されたフラックス値の１０倍以下であり、それ自体、フラックス化可能溶媒と考えることができよう。前記不揮発性溶媒の各々からのジクロフェナック酸についての定常状態フラックス値は、ジクロフェナックナトリウムで得られた定常状態フラックス値よりもかなり低いことに注意すべきである。従って、もし治療上有効なフラックス値が増加される必要があれば、フラックス化可能な不揮発性溶媒、およびジクロフェナックのナトリウム形態の利用は、ジクロフェナックの酸形態を用いるよりもより高い定常状態フラックス値を生じるようであろう。

A steady state flux of diclofenac acid from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 13, the non-volatile solvent glycerol does not have a reported steady state flux value and is not considered a viable non-volatile solvent candidate. However, the steady state flux values of isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are no more than 10 times the flux values reported for currently available commercial products, and as such, with fluxable solvents I can think about it. It should be noted that the steady state flux values for diclofenac acid from each of the non-volatile solvents are significantly lower than the steady state flux values obtained with diclofenac sodium. Thus, if a therapeutically effective flux value needs to be increased, the use of a fluxable non-volatile solvent and the sodium form of diclofenac will result in higher steady state flux values than using the acid form of diclofenac. It will happen.

Example 25
Evaluate solidifying formulations of testosterone in various non-volatile solvent systems. Excess testosterone is present. The penetration of testosterone from the test formulation through the HMS is shown in Table 14 below.

前記不揮発性溶媒からのテストステロンの定常状態フラックスは、２００ｍｃＬを無毛マウスの皮膚の角質層側（ドナー）に置くことによって得られる。イン・ビトロ実験は、実施例１に記載したように行われる。表１４から、不揮発性溶媒Ｔｗｅｅｎ ６０（ポリオキシエチレンソルビタンモノステアレート）は報告された定常状態フラックス値を有さず、活力のある不揮発性溶媒候補と考えられない。しかしながら、Ｓｐａｎ ２０、ポリエチレングリコール４００、イソステアリン酸、およびプロピレングリコールの定常状態フラックス値は、現在入手可能な市販の製品に匹敵する定常状態フラックス値を有し（表Ａ）、かくして、フラックス化可能溶媒と考えることができよう。しかしながら、Ｔｗｅｅｎ ６０以外の全ての不揮発性溶媒はフラックス化可能であるが、プロピレングリコールは現実的な処方物について良好であり得る。なぜならば、それによって生じた高いフラックスは、同一量の薬物をより小さな皮膚接触面積にて送達できることを意味するからである。

A steady state flux of testosterone from the non-volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of the hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 14, the non-volatile solvent Tween 60 (polyoxyethylene sorbitan monostearate) does not have the reported steady state flux value and is not considered a viable non-volatile solvent candidate. However, the steady state flux values of Span 20, polyethylene glycol 400, isostearic acid, and propylene glycol have steady state flux values that are comparable to currently available commercial products (Table A), thus, fluxable solvents. Can be considered. However, all non-volatile solvents other than Tween 60 can be fluxed, but propylene glycol can be good for practical formulations. This is because the resulting high flux means that the same amount of drug can be delivered with a smaller skin contact area.

Example 26
Evaluate solidifying formulations of hydromorphone HCI in various non-volatile solvent systems. There is an excess of hydromorphone HCI. The penetration of hydromorphone HCl from the test formulation through HMS is shown in Table 15 below.

前記揮発性溶媒からのヒドロモルフォンの定常状態フラックスは、２００ｍｃＬを無毛マウスの皮膚の角質層側（ドナー）に置くことによって得られる。イン・ビトロ実験は、実施例１に記載したように行う。表１５から、不揮発性溶媒のプロピレングリコールおよびイソステアリン酸は、（見積もられたヒドロモルフォンについての治療上有効なフラックスが２ ｍｃｇ／ｃｍ^２／ｈであることに基づいて）フラックス化可能溶媒としての資格があり得る。明らかに、オレイン酸エチルからのヒドロモルフォンの定常状態フラックス値はかなり高く、高フラックス化可能溶媒としての資格があろう。

A steady state flux of hydromorphone from the volatile solvent is obtained by placing 200 mcL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 15, the non-volatile solvents propylene glycol and isostearic acid (based on the estimated therapeutically effective flux for hydromorphone of 2 mcg / cm ² / h) as fluxable solvents. Can be qualified. Clearly, the hydromorphone's steady state flux value from ethyl oleate is quite high and would qualify as a highly fluxable solvent.

Example 27
Evaluate solidifying formulations of hydromorphone in various non-volatile solvent systems. There is an excess of hydromorphone. The penetration of hydromorphone from the test formulation through HMS is shown in Table 16 below.

前記不揮発性溶媒からのヒドロモルフォンの定常状態フラックスは、２００μＬを無毛マウスの皮膚の角質層側（ドナー）に置くことによって得られる。イン・ビトロ実験は実施例１に記載したように行われる。表１６から、不揮発性溶媒プロピレングリコールは、（ヒドロモルフォンについての見積もられた治療上有効なフラックスが２ μｇ／ｃｍ^２／ｈであることに基づき）フラックス化可能溶媒としての資格があり得る。イソステアリン酸およびオレイン酸エチルからのヒドロモルフォンの定常状態フラックス値もまた、フラックス化可能溶媒としての資格があろう。

A steady state flux of hydromorphone from the non-volatile solvent is obtained by placing 200 μL on the stratum corneum side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 16, the non-volatile solvent propylene glycol may qualify as a fluxable solvent (based on the estimated therapeutically effective flux for hydromorphone of 2 μg / cm ² / h). The steady state flux values of hydromorphone from isostearic acid and ethyl oleate may also qualify as fluxable solvents.

Examples 28 to 32
A prototype solidifying formulation is prepared as follows. Some formulations are prepared according to embodiments of the present invention according to Table 17 as follows.

実施例２８から３２の固化性処方物は以下のようにして調製される：
−固化剤を揮発性溶媒に溶解させる（例えば、ポリビニルアルコールを水に溶解させＥｕｄｒａｇｉｔポリマーをエタノールに溶解させる）。
−不揮発性溶媒を固化剤／揮発性溶媒混合物と混合する。
−得られた溶液を数分間激しく十分に混合する。
−次いで、薬物を加え、処方物を再度数分間混合する。

The solidifiable formulations of Examples 28-32 are prepared as follows:
-The solidifying agent is dissolved in a volatile solvent (for example, polyvinyl alcohol is dissolved in water and Eudragit polymer is dissolved in ethanol).
Mix the non-volatile solvent with the solidifying agent / volatile solvent mixture.
Mix the resulting solution vigorously well for several minutes.
-The drug is then added and the formulation is mixed again for a few minutes.

  In all the above examples, the fluxable non-volatile solvent / solidifying agent / volatile solvent combination is compatible as demonstrated by a homogeneous single phase system that exhibits a suitable drying time and elongation. A steady state flux for the possible solidified layer and drug was provided (see Example 33 below).

Example 33
The example formulations were tested on the hairless mouse skin (HMS) or HEM in vitro model described in Example 1. Table 18 shows the data obtained using the experimental process outlined above.

アシクロビール、ロピバカイン、およびテストステロンは、フラックス化可能な不揮発性溶媒を固化性処方物に配合した場合、驚くべきことにより高い定常状態フラックス値を有する。より高いフラックス値は、より高い値をもたらす固化処方物中の薬物の化学的環境（例えば、増大する溶解性）にインパクトを与える揮発性溶媒または固化剤の寄与の結果であろうと推定される。逆に、ケトプロフェンおよびジクロフェナックは、可能化不揮発性溶媒を固化性処方物に配合した場合、より低い定常状態フラックス値を有する。これは、より低いフラックス値をもたらす化学的環境（例えば、減少する溶解性、薬物および処方物の間の物理的相互作用）に対して反対のインパクトを有する揮発性溶媒系または固化剤の結果であり得る。

Acyclovir, ropivacaine, and testosterone have surprisingly higher steady state flux values when fluxable non-volatile solvents are incorporated into the solidifiable formulation. It is estimated that higher flux values may be the result of contributions of volatile solvents or solidifying agents that impact the chemical environment (eg, increased solubility) of the drug in the solidified formulation resulting in higher values. Conversely, ketoprofen and diclofenac have lower steady state flux values when enabling non-volatile solvents are incorporated into the solidifiable formulation. This is the result of volatile solvent systems or solidifying agents that have an opposite impact on the chemical environment (eg, reduced solubility, physical interaction between drug and formulation) resulting in lower flux values. possible.

  1 and 2 provide a graphical representation of the cumulative amount of diclofenac and ropivacaine, respectively, delivered transdermally across human cadaver skin. The tested formulations are similar to those described in Examples 30 and 31. In these particular embodiments, steady state delivery is indicated over 28 hours and 30 hours, respectively.

Example 34
The following composition: solidified with 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. The sex formulation was applied to the human skin surface at the elbow and finger joints, resulting in a thin, transparent, flexible and extensible solidified layer. A few minutes after evaporation of the volatile solvents (etaone and water), a peelable solidified layer was formed. The stretchable solidified layer had good adhesion to the skin and, when bent, did not separate from the skin on the joint and could be easily peeled from the skin.

Examples 35 to 37
Three formulations similar to those in Example 36 (replacing ropivacaine base with ropivacaine HCl) are applied to the stratum corneum side of freshly separated hairless mouse skin. In vitro flux is determined for each formulation as outlined in Example 1. The formulation composition is shown in Table 19 below.

全ての３つの処方物は固化剤、揮発性溶媒、およびフラックス化可能な不揮発性溶媒の正確な同一の組成を有する。唯一の差は、いずれのフラックス化可能な不揮発性溶媒を用いるかであり、ロピバカインＨＣｌについては、Ｓｐａｎ ２０、ポリエチレングリコール４００、およびＴｗｅｅｎ ４０はフラックス化可能な不揮発性溶媒としての資格があると結論するのが合理的である。

All three formulations have the exact same composition of solidifying agent, volatile solvent, and fluxable non-volatile solvent. The only difference is which fluxable non-volatile solvent is used, and for ropivacaine HCl, it is concluded that Span 20, Polyethylene Glycol 400, and Tween 40 are eligible as fluxable non-volatile solvents. It is reasonable to do.

Examples 38 to 42
A solidified formulation for imiquimod skin delivery is prepared, which includes a specific amount of imiquimod in an excipient mixture to form an adhesive formulation according to an embodiment of the present invention. The solidifying formulation contained the following ingredients:

これらの処方物は実施例１に記載したようにＨＭＳ皮膚に適用し、イミキモドフラックスを測定する。実施例３８から４２における処方物で行ったイン・ビトロフラックス実験からの結果のまとめを表２１にリストする。

These formulations are applied to HMS skin as described in Example 1 to measure imiquimod flux. A summary of the results from the in vitro flux experiments performed with the formulations in Examples 38-42 is listed in Table 21.

実施例３８および３９に記載された処方物に関しては、水を揮発性溶媒として用い、ＩＳＡ、トロラミン混合物を不揮発性溶媒系として用いる。実験を通じて、ＩＳＡおよびＳｐａｎ ２０は薬物に対する適当な溶解性を提供するが、しかしながら、これらの不揮発性溶媒は疎水性であって、固化剤ＰＶＡを溶解させるのに用いられる揮発性溶媒系と適合しない。乳化剤Ｐｅｍｕｌｅｎ ＴＲ−２を用いて、不揮発性溶媒を水相に乳化した。さらに、この実施形態において、ＩＳＡおよびトロラミンは、水（揮発性溶媒）が蒸発した後に、剥離性処方物において可塑剤として作用する。実施例３８および３９の処方物の定常状態フラックスは、全処方物のフラックス−生成パワーを指令するにおける処方物に加えて一定量の不揮発性溶媒の値を示す。さらに、実施例４１および４２は、非水性揮発性溶媒系（イソプロパノール）に適合する異なる固化剤を利用する。不揮発性溶媒系ＩＳＡ／トリアセチンまたはＩＳＡ／Ｓｐａｎ ２０／トロラミン／トリアセチン組合せの選択は、イン・ビトロフラックスの変化を示さなかった。イン・ビトロフラックスの増加は、処方物に存在するイミキモドの量の増加によって影響されることが示される。４％を超えるイミキモドレベルにおいて、薬物はピール処方物において飽和している。増大した薬物添加の関数としてのイン・ビトロフラックスの増加（実施例４１および４２）は、一旦揮発性溶媒が蒸発すれば、固化したピール処方物中の薬物の増大した溶解性によるものであろう。

For the formulations described in Examples 38 and 39, water is used as the volatile solvent and the ISA, trolamine mixture is used as the non-volatile solvent system. Through experimentation, ISA and Span 20 provide adequate solubility for drugs, however, these non-volatile solvents are hydrophobic and are not compatible with the volatile solvent system used to dissolve the solidifying agent PVA. . The non-volatile solvent was emulsified in the aqueous phase using the emulsifier Pemulen TR-2. Furthermore, in this embodiment, ISA and trolamine act as plasticizers in the peelable formulation after the water (volatile solvent) has evaporated. The steady state flux of the formulations of Examples 38 and 39 shows a certain amount of non-volatile solvent value in addition to the formulation in commanding the flux-generating power of the entire formulation. In addition, Examples 41 and 42 utilize different solidifying agents that are compatible with non-aqueous volatile solvent systems (isopropanol). Selection of the non-volatile solvent system ISA / triacetin or ISA / Span 20 / trolamine / triacetin combination showed no change in vitro flux. It is shown that the increase in in vitro flux is affected by an increase in the amount of imiquimod present in the formulation. At imiquimod levels above 4%, the drug is saturated in the peel formulation. The increase in vitro flux as a function of increased drug addition (Examples 41 and 42) may be due to the increased solubility of the drug in the solidified peel formulation once the volatile solvent has evaporated. .

  Example 38 shows comparable imiquimod flux to other formulation examples, and non-volatile solvent system values, and solidifying agent compatibility caused by removal of trolamine. This is because this non-volatile solvent negatively affected the function of the Plastoid B polymer.

Examples 43 to 46
A solidifying formulation for dermal delivery of imiquimod is prepared, which includes a specific amount of imiquimod in an excipient mixture to form an adhesive formulation according to embodiments of the present invention. The peel formulation contained the following ingredients:

これらの処方物は実施例１に記載したようにＨＭＳ皮膚に適用し、イミキモドフラックスを測定する。実施例４３から４６における処方物で行ったイン・ビトロフラックス実験からの結果のまとめを表２３にリストする。

These formulations are applied to HMS skin as described in Example 1 to measure imiquimod flux. A summary of the results from the in vitro flux experiments performed with the formulations in Examples 43 to 46 are listed in Table 23.

実施例４３から４６のイン・ビトロフラックスは、Ａｌｄａｒａ対照と比較して有意に増加した。改良されたイン・ビトロフラックスの値についての理由は、サリチル酸の負荷に帰属するであろう。実施例４３から４６におけるイミキモドの改良されたイン・ビトロフラックスは、イミキモドおよびサリチル酸の間のイオン対相互作用によるものと考えられる。イオン対メカニズムが考えられ、そこでは、対イオン（サリチル酸）の親油性が角質層を横切るイミキモドのフラックスを改良する。なぜならば、それはイミキモド処方物においてあまり「心地よい」ものではなくするからである。サリチル酸による改良されたフラックスについてのもう１つの理由は、それが浸透促進剤として作用することにある。実施例４３から４５のフラックスの比較は、ポリマーおよび／または揮発性溶媒の選択がイミキモドのフラックスにインパクトを与えるであろうことを示す。

The in vitro flux of Examples 43 to 46 was significantly increased compared to the Aldara control. The reason for the improved in vitro flux value will be attributed to the salicylic acid loading. The improved in vitro flux of imiquimod in Examples 43 to 46 is believed to be due to ion-pair interactions between imiquimod and salicylic acid. An ion pairing mechanism is conceivable, where the lipophilicity of the counterion (salicylic acid) improves the imiquimod flux across the stratum corneum. This is because it makes it less “comfortable” in an imiquimod formulation. Another reason for the improved flux with salicylic acid is that it acts as a penetration enhancer. A comparison of the fluxes of Examples 43 to 45 shows that the choice of polymer and / or volatile solvent will impact imiquimod flux.

Examples 47-48
A solidifying formulation for dermal delivery of ropivacaine is prepared, which includes a specific amount of ropivacaine in an excipient mixture to form an adhesive solidifying formulation according to an embodiment of the present invention. The peel formulation contains the following ingredients:

これらの処方物は実施例１に記載したようにＨＭＳ皮膚に適用され、ロピバカインフラックスを測定する。実施例４７および４８における処方物で行ったイン・ビトロフラックス実験からの結果のまとめを表２５にリストする。

These formulations are applied to HMS skin as described in Example 1 to measure ropivacaine flux. A summary of the results from the in vitro flux experiments performed with the formulations in Examples 47 and 48 are listed in Table 25.

実施例４７および４８に記載された処方物に関し、エタノールを揮発性溶媒として用い、ＩＳＡ、グリセロール、およびＰＧ混合物を不揮発性溶媒系として用いる。実験を通じて、一緒に用いられるＩＳＡおよびプロピレングリコールは、Ｅｕｄｒａｇｉｔ ＲＬ−１００固化剤と適合しつつ、薬物に対する適当な溶解性を提供すると決定される。さらに、この実施形態において、ＩＳＡ、ＰＧおよびグリセロールは、エタノール（揮発性溶媒）が蒸発した後に、剥離性処方物において可塑剤として働く。処方物実施例４７および４８からのロピバカインの定常状態フラックスは、全処方物のフラックス−生成パワーを指令するにおける不揮発性溶媒の重要性を示す。

For the formulations described in Examples 47 and 48, ethanol is used as the volatile solvent and an ISA, glycerol, and PG mixture is used as the non-volatile solvent system. Throughout the experiment, the ISA and propylene glycol used together are determined to be compatible with Eudragit RL-100 solidifying agent while providing adequate solubility for the drug. Furthermore, in this embodiment, ISA, PG and glycerol act as plasticizers in the peelable formulation after the ethanol (volatile solvent) has evaporated. The steady state flux of ropivacaine from Formulation Examples 47 and 48 demonstrates the importance of the non-volatile solvent in directing the flux-generation power of the entire formulation.

Example 49
The effect of solubility on compatibility between osmotic, non-volatile solvent systems and solidifying agents is shown in this example. The solubility of ropivacaine base in isostearic acid (ISA) was experimentally determined to be slightly above 1: 4, which means that 1 gram of ropivacaine base can be completely dissolved in 4 grams of isostearic acid. In one experiment, two solutions are made: Solution A contains 1 part ropivacaine base and 4 parts isostearic acid. Solution B contains 1 part ropivacaine base, 4 parts isostearic acid, and 1 part trolamine. (All parts are expressed by weight). All ropivacaine in solution A is dissolved, but only a portion of ropivacaine in solution B is dissolved. The transdermal flux across the hairless mouse skin produced by the solution is measured by a typical Franz cell system with the following results:

分かるように、溶液Ｂによって生じたフラックスは溶液Ａのそれの約４倍である。これらの結果は、イオン対合剤トロラミンの添加が経皮フラックスを有意に増大させることを示す。しかしながら、このシステムをポリビニルアルコール（ＰＶＡ）系ピール処方物へ取り入れる試みは失敗した。なぜならば、該処方物におけるＰＶＡは、トロラミンの効果を阻害した強いｐＨ緩衝液として作用したからである。より多くのトロラミンの添加は、ＰＶＡのｐＨ緩衝能力を増大させる試みにおいて、ＰＶＡの所望の固化特性の喪失を引き起こした（言い換えると、ＩＳＡおよびあまりにも多くのトロラミンを含有する不揮発性溶媒系はＰＶＡと適合しない）。ＰＶＡをもう１つの固化剤、Ｅｕｄｒａｇｉｔ ＲＬ−１００（Ｒｏｈｍ＆Ｈａａｓ）によって置き換えると、トロラミンの効果は阻害されず、３０μｇ／ｈｒ／ｃｍ^２程度のフラックスを生じさせることができる処方物が得られた。トロラミン、ＩＳＡ、およびＥｕｄｒａｇｉｔ ＲＬ １００の添加の副産物は、３つの成分のイオン性相互作用から沈殿が形成されたことである。後者の例はフラックスおよび疲労特性の点で、良好な処方物を生じたが、沈殿は、依然として、改良の必要性を示す。不揮発性溶媒および固化剤の間のイオン性相互作用を排除する努力において、トロラミン、ＩＳＡ混合物をイソプロパノール中のＰｌａｓｔｏｉｄ Ｂポリマーに加えた。しかしながら、この場合には、トロラミンはＰｌａｓｔｏｉｄ Ｂポリマーと適合しないことが判明し、該塩基はトリイソプロパノールアミンに変化した。この組合せは、Ｅｕｄｒａｇｉｔ ＲＬ １００ポリマーを用い、３０μｇ／ｈｒ／ｃｍ^２程度のフラックス値を生じさせることができる透明な処方物を生じさせた場合に形成された沈殿を排除した。これは、不揮発性溶媒系および固化剤の間の適合性の重要性を示す。

As can be seen, the flux produced by solution B is about four times that of solution A. These results indicate that the addition of the ion pairing agent trolamine significantly increases the transdermal flux. However, attempts to incorporate this system into polyvinyl alcohol (PVA) peel formulations have failed. This is because the PVA in the formulation acted as a strong pH buffer that inhibited the effect of trolamine. The addition of more trolamine caused a loss of the desired solidification properties of PVA in an attempt to increase the pH buffering capacity of PVA (in other words, non-volatile solvent systems containing ISA and too much trolamine are PVA Does not fit). Replacing PVA with another solidifying agent, Eudragit RL-100 (Rohm & Haas) resulted in a formulation that did not inhibit the effect of trolamine and could produce a flux on the order of 30 μg / hr / cm ² . A byproduct of the addition of trolamine, ISA, and Eudragit RL 100 is that a precipitate formed from the ionic interaction of the three components. The latter example yielded a good formulation in terms of flux and fatigue properties, but precipitation still indicates a need for improvement. In an effort to eliminate ionic interactions between the non-volatile solvent and the solidifying agent, the trolamine, ISA mixture was added to the Plastoid B polymer in isopropanol. However, in this case, trolamine was found to be incompatible with Plastoid B polymer and the base was changed to triisopropanolamine. This combination eliminated the precipitate formed when Eudragit RL 100 polymer was used to produce a clear formulation capable of producing flux values on the order of 30 μg / hr / cm ² . This indicates the importance of compatibility between the non-volatile solvent system and the solidifying agent.

Example 50
A solidifying formulation for dermal delivery of ropivacaine is prepared from the following ingredients:

前記リストの成分を以下の手法に従って合わせる。Ｅｕｄｒａｇｉｔ ＲＬ−１００およびエタノールをガラスジャー中で合わせ、Ｅｕｄｒａｇｉｔ ＲＬ−１００が完全に溶解するまで約６０℃まで加熱する。一旦、Ｅｕｄｒａｇｉｔ溶液が室温まで冷却されると、適当な量のロピバカインＨＣｌを加え、徹底的に１分間混合する。この溶液に、イソステアリン酸（ＩＳＡ）を加え、混合物を激しく２から３分間撹拌する。１時間後に、溶液を再度激しく２から３分間混合する。この溶液に、グリセロール、プロピレングリコール、およびトロラミンを順次の順番で加える。各成分の添加の後に、溶液を１分間撹拌する。

The components of the list are combined according to the following procedure. Eudragit RL-100 and ethanol are combined in a glass jar and heated to about 60 ° C. until Eudragit RL-100 is completely dissolved. Once the Eudragit solution is cooled to room temperature, an appropriate amount of ropivacaine HCl is added and mixed thoroughly for 1 minute. To this solution is isostearic acid (ISA) and the mixture is stirred vigorously for 2 to 3 minutes. After 1 hour, the solution is again vigorously mixed for 2-3 minutes. To this solution, glycerol, propylene glycol, and trolamine are added in sequential order. The solution is stirred for 1 minute after the addition of each component.

  In addition, the formulation prepared according to this example was added to HMS as described in Example 1 and ropivacaine flux was measured. A summary of the results is listed in Table 28 as follows.

実施例６に従って調製されたロピバカインピール処方物は許容される適用特性、例えば、試料チューブからのピールの除去の容易性、意図した皮膚適用部位への展延の容易性等を保有し、約０．１ｍｍの厚みを持つ薄い層として正常なヒト皮膚表面に適用された後に２から３分以内に固化フイルムを形成する。固化した剥離可能層は２時間以内に容易に剥離可能となり、ピールは、少なくとも１２時間の間、ピールのいずれの意図しない除去もなくして皮膚表面に付着されたままである。意図した使用の最後に、ピールは１つの連続破片に容易に除去される。

The ropivacaine peel formulation prepared according to Example 6 possesses acceptable application characteristics such as ease of removal of peel from the sample tube, ease of spreading to the intended skin application site, etc. Form a solidified film within 2 to 3 minutes after being applied to normal human skin surface as a thin layer with a thickness of 1 mm. The solidified peelable layer becomes easily peelable within 2 hours, and the peel remains attached to the skin surface for at least 12 hours without any unintentional removal of the peel. At the end of the intended use, the peel is easily removed in one continuous piece.

Example 51
A solidifying formulation for skin delivery of lidocaine is prepared, which includes a saturating amount of lidocaine in an excipient mixture to form an adhesive peelable formulation according to embodiments of the present invention. Peel formulations are prepared from the ingredients shown in Table 29.

本実施例におけるリドカイン処方物の接着性剥離可能処方物は、前記実施例における処方物と同様な物理的特性を有する。無毛マウス皮膚を横切っての経皮フラックスは許容され、定常状態送達は８時間にわたって維持される。

The adhesive peelable formulation of the lidocaine formulation in this example has the same physical properties as the formulation in the previous example. Transdermal flux across hairless mouse skin is tolerated and steady state delivery is maintained for 8 hours.

Examples 52-55
A solidifying formulation for dermal delivery of amitriptyline and a combination of amitriptyline and ketamine is prepared, which includes an excipient mixture to form an adhesive peelable formulation according to embodiments of the present invention. Peel formulations are prepared from the ingredients shown in Table 31.

前記リストの成分を、以下の手法に従って合わせる。薬物、水、およびトリイソプロパノールアミンをガラスジャー中で合わせ、薬物が溶解するまで混合する。次いで、イソステアリン酸、トリアセチン、Ｓｐａｎ ２０、およびイソプロパノールを処方物に加え、よく混合する。ポリマーＰｌａｓｔｏｉｄ Ｂを最後に加え、Ｐｌａｓｔｏｉｄ Ｂが完全に溶解するまで約６０℃まで加熱する。一旦、ポリマー溶液を室温まで冷却すれば、処方物を２から３分間激しく撹拌する。

The components of the list are combined according to the following procedure. Drug, water, and triisopropanolamine are combined in a glass jar and mixed until the drug is dissolved. Then, isostearic acid, triacetin, Span 20, and isopropanol are added to the formulation and mixed well. Polymer Plastoid B is added last and heated to about 60 ° C. until Plastoid B is completely dissolved. Once the polymer solution is cooled to room temperature, the formulation is stirred vigorously for 2 to 3 minutes.

  The formulations in Table 31 were applied to HMS according to Example 1 and the flux of amitriptyline and / or ketamine was measured. The results are summarized in Table 32.

本実施例におけるアミトリプチリンおよびアミトリプチリン／ケタミン処方物の接着性剥離可能処方物は、前記実施例における処方物と同様な物理的特性を有する。経皮フラックスは処方物に加えた薬物の量に比例する。

The adhesive peelable formulations of amitriptyline and amitriptyline / ketamine formulations in this example have the same physical properties as the formulations in the previous examples. Transdermal flux is proportional to the amount of drug added to the formulation.

Examples 56 to 59
A solidifying formulation for dermal delivery of ropivacaine is prepared, which includes an excipient mixture to form an adhesive peelable formulation according to embodiments of the present invention. The peel formulation is prepared from the ingredients shown in Table 33.

前記リストの成分を、以下の手法に従って合わせる。ロピバカインＨＣｌ、水、およびトリイソプロパノールアミンをガラスジャー中で合わせ、薬物が溶解するまで混合する。次いで、イソステアリン酸、トリアセチン、Ｓｐａｎ ２０、およびイソプロパノールを処方物に加え、よく混合する。ポリマーＰｌａｓｔｏｉｄ Ｂを最後に加え、Ｐｌａｓｔｏｉｄ Ｂが完全に溶解するまで約６０℃まで加熱する。一旦、ポリマー溶液を室温まで冷却すれば、処方物を２から３分間激しく撹拌する。

The components of the list are combined according to the following procedure. Combine ropivacaine HCl, water, and triisopropanolamine in a glass jar and mix until the drug is dissolved. Then, isostearic acid, triacetin, Span 20, and isopropanol are added to the formulation and mixed well. Polymer Plastoid B is added last and heated to about 60 ° C. until Plastoid B is completely dissolved. Once the polymer solution is cooled to room temperature, the formulation is stirred vigorously for 2 to 3 minutes.

  The formulations in Table 33 were applied to HMS according to Example 1 and ropivacaine flux was measured. The results are summarized in Table 34.

実施例５６から５９のフラックスは、処方物中のトリアセチン、イソステアリン酸、Ｓｐａｎ ２０組合せの重要性を示す。実施例５６から５９において、処方物は、各々、Ｓｐａｎ ２０、トリアセチン、およびイソステアリン酸なくして作成した。ロピバカインのイン・ビトロフラックスにインパクトを与えた。不揮発性溶媒の相乗的組合せは、ロピバカインの最大イン・ビトロフラックスを得るのに重要である。

The fluxes of Examples 56-59 show the importance of the triacetin, isostearic acid, Span 20 combination in the formulation. In Examples 56-59, formulations were made without Span 20, triacetin, and isostearic acid, respectively. It had an impact on ropivacaine in vitro flux. A synergistic combination of non-volatile solvents is important to obtain the maximum in vitro flux of ropivacaine.

Example 60
The solidifiable formulation has the following ingredients in parts by weight:

本処方物においては、ポリビニルアルコール（ＡｍｒｅｓｃｏからのＵＳＰグレード）は固化剤であり、エチルセルロースおよびＤｅｒｍａｃｒｙｌ ７９は補助的固化剤である。イソステアリン酸およびグリセロールは不揮発性溶媒系を組成し、他方、エタノールおよび水は揮発性溶媒系を組成する。ロピバカインは薬物である。
処方物を製造する手法：
１．ロピバカインをＩＳＡと混合する。
２．エチルセルロースおよびＤｅｒｍａｃｒｙｌ ７９をエタノールに溶解させる。
３．ＰＶＡを約６０から７０Ｃの温度の水に溶解させる。
４．前記混合物の全てを１つの容器中で一緒に合わせ、グリセロールを加え、全混合物をよく混合する。

In this formulation, polyvinyl alcohol (USP grade from Amresco) is a solidifying agent, and ethylcellulose and Dermacryl 79 are auxiliary solidifying agents. Isostearic acid and glycerol constitute a non-volatile solvent system, while ethanol and water constitute a volatile solvent system. Lopivacaine is a drug.
Techniques for manufacturing formulations:
1. Mix ropivacaine with ISA.
2. Ethylcellulose and Dermacry 79 are dissolved in ethanol.
3. PVA is dissolved in water at a temperature of about 60-70C.
4). Combine all of the mixtures together in one container, add glycerol and mix the whole mixture well.

  The resulting formulation is a viscous fluid. When a layer of about 0.1 mm thickness is applied to the skin, a non-stick surface is formed within 2 minutes.

Examples 61 to 62
An anti-fungal solidification formulation is prepared and a quantitative assessment of peel flexibility and viscosity is estimated. The ingredients of the formulation are shown in Table 36 below.

実施例６１のピール処方物は、爪または皮膚表面への適用で望ましいであろうよりも低い粘度を有する。この処方物で固化ピールを形成するための時間は望まれる乾燥時間よりも長い。実施例６２における処方物は、固化剤（Ｅｕｄｒａｇｉｔ ＲＬ−ＰＯ）の量の増加、およびエタノールの量の減少を有し、これは、粘度および乾燥時間を改良する。実施例６２は、適用に適した粘度および改良された乾燥時間を有する。

The peel formulation of Example 61 has a lower viscosity than would be desirable for nail or skin surface applications. The time to form a solidified peel with this formulation is longer than the desired drying time. The formulation in Example 62 has an increase in the amount of solidifying agent (Eudragit RL-PO) and a decrease in the amount of ethanol, which improves viscosity and drying time. Example 62 has a viscosity suitable for application and an improved drying time.

Example 63
Solidifying formulations were prepared according to Table 37 as follows.

表３７の成分を以下のように合わせた：
−固化剤を揮発性溶媒に溶解させる（すなわち、ポリビニルアルコールを水に溶解させる）。
−フラックス化可能な不揮発性溶媒を固化剤／揮発性溶媒混合物と混合する。
−得られた溶液を数分間激しくよく混合する。
−次いで、薬物を加え、ピール処方物を再度数分間混合する。

The ingredients in Table 37 were combined as follows:
-The solidifying agent is dissolved in a volatile solvent (ie polyvinyl alcohol is dissolved in water).
Mix the fluxable non-volatile solvent with the solidifying agent / volatile solvent mixture.
Mix the resulting solution vigorously well for several minutes.
-The drug is then added and the peel formulation is mixed again for a few minutes.

Example 64
The formulation prepared in Example 63 was tested for skin flux as described in Table 38 below.

現在市販されている製品であるＡｎｄｒｏＧｅｌを無毛マウス皮膚に直接適用し、フラックス決定は実施例１に概説したように作成する。定常状態フラックスデータは図３に示す。表３８に報告する定常状態フラックス値は２から６時間の間の直線領域を用いて決定する。図３から分かるように、ＡｎｄｒｏＧｅｌからのテストステロンのイン・ビトロフラックスは６時間を超えて実質的に減少する。これは、部分的には、送達用の主要賦形剤として作用し得る揮発性溶媒の蒸発によるものであろう。実施例６３における固化性処方物は、少なくとも９時間の間、定常状態量のテストステロンを送達するであろう。

The currently marketed product, AndroGel, is applied directly to hairless mouse skin and the flux determination is made as outlined in Example 1. Steady state flux data is shown in FIG. The steady state flux values reported in Table 38 are determined using a linear region between 2 and 6 hours. As can be seen from FIG. 3, the in vitro flux of testosterone from AndroGel is substantially reduced over 6 hours. This may be due in part to the evaporation of volatile solvents that can act as the primary excipient for delivery. The solidifying formulation in Example 63 will deliver a steady state amount of testosterone for at least 9 hours.

Examples 65 to 68
An extensible adhesive solidifying formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin to treat joint and muscle inflammation or pain) is prepared, which is incorporated into an excipient mixture A saturated amount of ketoprofen (more ketoprofen that can be dissolved in the excipient mixture) is formed to form an adhesive release formulation, some of which are prepared according to embodiments of the present invention . An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 39.

実施例６５から６８の組成物の各々を、以下のように、表４０に示したように、ケトプロフェンのフラックスについて調べた：

Each of the compositions of Examples 65-68 was examined for ketoprofen flux as shown in Table 40 as follows:

実施例６５に記載された処方物に関しては、エタノールおよび水は揮発性溶媒系を組成し、他方、グリセロールおよびＰＥＧ ４００の１：１混合物は不揮発性溶媒系を組成した。実験を通じて、ＰＥＧ ４００はケトプロフェンについてグリセロールよりもわずかに良好な溶媒であり、他方、グリセロールはＰＥＧ ４００よりもＰＶＡに対してより適合していると決定される。かくして、グリセロールおよびＰＥＧ ４００の不揮発性溶媒系を一緒に用いて、ＰＶＡと合理的に適合しつつ、薬物に対する不揮発性溶媒系を提供する。実施例６５での処方物に関する更なる詳細において、ＰＶＡおよびＰＶＰは固化剤として作用する。さらに、この実験においては、グリセロールおよびＰＥＧ ４００もまた、揮発性溶媒の蒸発の後に形成された接着性剥離可能処方物において可塑剤として働く。グリセロールおよびＰＥＧ ４００の存在がなければ、ＰＶＡおよびＰＶＰ単独によって形成されたフイルムは剛性かつ非―伸長性であろう
実施例６６の処方物に関しては、形成された接着性剥離可能処方物は実施例６５のそれと同量な物理的特性を有するが、無毛マウス皮膚を横切っての経皮フラックスはより高い。これは、固化剤、実施例６５における１：１ ＰＶＡ：ＰＶＰ−Ｋ−９０および実施例６８における純粋なＰＶＡが浸透に対してインパクトを有することを示唆する。

For the formulation described in Example 65, ethanol and water constituted a volatile solvent system, while a 1: 1 mixture of glycerol and PEG 400 constituted a non-volatile solvent system. Through experimentation, PEG 400 is determined to be a slightly better solvent than glycerol for ketoprofen, while glycerol is more compatible with PVA than PEG 400. Thus, the non-volatile solvent system of glycerol and PEG 400 is used together to provide a non-volatile solvent system for the drug while being reasonably compatible with PVA. In further details regarding the formulation in Example 65, PVA and PVP act as solidifying agents. Furthermore, in this experiment, glycerol and PEG 400 also act as plasticizers in the adhesive peelable formulation formed after evaporation of the volatile solvent. In the absence of glycerol and PEG 400, the film formed by PVA and PVP alone would be rigid and non-extensible. For the formulation of Example 66, the adhesive peelable formulation formed was It has the same physical properties as that of 65, but the transdermal flux across hairless mouse skin is higher. This suggests that the solidifying agent, 1: 1 PVA: PVP-K-90 in Example 65 and pure PVA in Example 68 have an impact on penetration.

  The formulation in Example 67 delivers less ketoprofen than the formulation of Example 65 or 66. The formulation of Example 68 delivers significantly less ketoprofen than the formulations in Examples 65 and 66. One possible reason for the reduced flux is believed to be the reduced osmotic driving force caused by PEG 400 in a non-volatile solvent system that results in too high solubility for ketoprofen.

  The only difference between the formulations in Examples 66, 67 and 68, respectively, relates to the non-volatile solvent system, more specifically the PEG 400: glycerol weight ratio. These results reflect the impact of non-volatile solvent systems on skin flux.

Example 69
An extensible adhesive solidifying formulation for transdermal delivery of lidocaine is prepared, which includes a saturating amount of lidocaine in an excipient mixture to produce an adhesive solidifying formulation according to an embodiment of the invention. Form. The formulation is prepared from the ingredients shown in Table 41.

本実施例におけるリドカインの接着性固化性処方物は、実施例６５から６８における処方物に対して同様な物理的特性を有する。無毛マウス皮膚を通っての経皮フラックスは許容でき、定常状態送達は８時間にわたって維持される。

The lidocaine adhesive solidifying formulation in this example has similar physical properties to the formulations in Examples 65-68. Transdermal flux through hairless mouse skin is acceptable and steady state delivery is maintained for 8 hours.

Example 70
A formulation similar to that of Example 65 (without ketoprofen) was applied to the human skin surface at the elbow and finger joints, resulting in a thin, transparent, and flexible stretchable film. It was. After several minutes of evaporation of volatile solvents (ethanol and water), a solidified peelable layer is formed. The stretchable film has good adhesion to the skin, and when bent, does not separate from the skin on the joint and can be easily peeled off from the skin.

Examples 71-73
A stretchable adhesive solidifying formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin on joints and muscles) was prepared, which contained a saturating amount of ketoprofen (shaped) in the excipient mixture. More ketoprofen that can be dissolved in the agent mixture) to form an adhesive peelable formulation, some of which are prepared according to embodiments of the present invention. An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 43.

実施例７１から７３のピール処方物は以下のように調製される：
―固化剤を揮発性溶媒に溶解させる（すなわち、Ｅｕｄｒａｇｉｔポリマーをエタノールに溶解させる）。
―フラックスに適切な不揮発性溶媒（グリセロール、ＰＥＧ）を固化剤／揮発性溶媒の混合物と一緒に混合する。
―得られた溶液を激しく数分間混合する。
―ついで、薬物を加え、処方物を再度数分間混合する。

The peel formulations of Examples 71 to 73 are prepared as follows:
-The solidifying agent is dissolved in a volatile solvent (ie the Eudragit polymer is dissolved in ethanol).
Mix the non-volatile solvent appropriate for the flux (glycerol, PEG) with the solidifying agent / volatile solvent mixture.
-Mix the resulting solution vigorously for several minutes.
-Then add the drug and mix the formulation again for a few minutes.

Example 74
Formulations prepared according to Examples 71-73 are applied to HMS as described in Example 1 and ketoprofen flux is measured. A summary of the results is listed in Table 44 as follows.

実施例７１から７２に従って調製されたケトプロフェン処方物は、許容される固化した層の特性を保有した（例えば、２から３分以内に固化した層を形成した）。実施例７３に関しては、ケトプロフェンピールは適用から３０分後に固化層を形成しない。これは、ピール処方物において望まれるフラックスおよび疲労特性を得るためには、処方物を開発するにおいて、固化剤、不揮発性溶媒、および揮発性溶媒の間のデリケートなバランスが見積もられ、考慮されることを示す。

Ketoprofen formulations prepared according to Examples 71 to 72 retained acceptable solidified layer properties (eg, formed solidified layers within 2 to 3 minutes). For Example 73, the ketoprofen peel does not form a solidified layer 30 minutes after application. This is because a delicate balance between solidifying agent, non-volatile solvent, and volatile solvent is estimated and considered in developing the formulation in order to obtain the desired flux and fatigue properties in peel formulations. Indicates that

Example 75
An extensible adhesive solidifying formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin on joints and muscles) was prepared, which contained a saturating amount of ketoprofen (shaped) in an excipient mixture. More ketoprofen that can be dissolved in the agent mixture) to form an adhesive peelable formulation, some of which are prepared according to embodiments of the present invention. An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 45.

処方物ＡおよびＢは以下のような方法で調製される：
―ＰＶＡ（固化剤）を水に溶解させる。
―フラックスに適切な不揮発性溶媒（グリセロール、ＰＧ）を固化剤／揮発性溶媒の混合物と一緒に混合する。
―次いで、エタノール、およびＧａｎｔｒｅｚ ＥＳ ４２５を混合物に加える。
―得られた溶液を激しく数分間混合する。

Formulations A and B are prepared in the following manner:
-Dissolve PVA (solidifying agent) in water.
Mix the non-volatile solvent appropriate for the flux (glycerol, PG) with the solidifying agent / volatile solvent mixture.
-Then ethanol and Gantrez ES 425 are added to the mixture.
-Mix the resulting solution vigorously for several minutes.

  Preparation of PVA in aqueous solution in formulation C was not possible with this molecular weight of PVA in the indicated percentage. Formulation C shows that the correct polymer molecular weight for PVA is important to obtain the desired formulation properties.

  Formulations A and B are placed on the skin of human volunteers. After a few hours long enough for the volatile solvent to evaporate, the volunteers removed the peel and evaluated the peel properties. In all cases, volunteers reported that formulation example A could not be removed with 1 or 2 debris, but was removed with a large number of small debris. Formulation Example B was removed with 1 or 2 debris. The brittle nature of Formulation A is attributed to lower molecular weight PVA samples (Celvol). Low molecular weight PVA does not possess the same cohesive strength as the higher molecular weight PVA material (Amresco) due to the reduced size of the polymer chains, and the degree of cross-linking between the individual PVA polymer chains and the physical interaction This leads to a decrease in action. The reduced PVA chain interaction leads to a weakened peel, which cannot withstand the mechanical forces that are peeled off upon removal.

Example 76
Evaluating an extensible adhesive solidifying formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin on joints and muscles), which is an excipient that forms an adhesive peelable formulation Including mixtures, some of which are prepared according to embodiments of the present invention. An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 46.

処方物ＤからＧにおけるピール処方物は以下の方法で調製される：
―ＰＶＡ固化剤を水に溶解させる。
―フラックスに適切な不揮発性溶媒（グリセロール、ＰＧ）を固化剤／揮発性溶媒混合物と一緒に混合する。
―次いで、エタノールおよびＧａｎｔｒｅｚ ＥＳ ４２５を混合物に加える。
―得られた溶液を激しく数分間混合する。
―混合の後、ケトプロフェンを加え、最終混合物を再度激しく数分間混合する。

The peel formulations in formulations D to G are prepared in the following manner:
-Dissolve the PVA solidifying agent in water.
Mix the non-volatile solvent appropriate for the flux (glycerol, PG) with the solidifying agent / volatile solvent mixture.
-Then ethanol and Gantrez ES 425 are added to the mixture.
-Mix the resulting solution vigorously for several minutes.
-After mixing, ketoprofen is added and the final mixture is vigorously mixed again for several minutes.

  The above formulation was placed in a laminate packaging tube and stored at 25 C / 60% RH and 40 C / 75% RH conditions until pulled for testing. A physical test was performed on each formulation. Formulations D through F were examined the longest and the resulting increase in viscosity required the desire to examine the fuel in Formulation G. Table 47 summarizes the data obtained for each formulation.

この例の処方物ＤおよびＥは４つの処方物の最低の水含有量を有し、４週間の貯蔵内に、高い粘度の値を達成した。処方物１および２の間の唯一の差は、処方物におけるエタノールの量である。エタノールのレベルの低下は、ＰＶＡとエタノールの間の不適合性のため処方物の物理的増粘を低下させるであろうと仮定された。粘度のデータは、より高いエタノール処方物（処方物Ｄ）がより低い初期粘度を有するが、４週間の貯蔵に渡って、処方物ＤおよびＥ双方の粘度は、活力のある処方物にとって余りにも高い粘度値を達成したことを示す。処方物増粘についてのもう一つの仮説は、水に溶解した場合の、ＰＶＡは高濃度において適合しないことである。より高い水含有量を持つ更なる処方物を調製して、最適な水含有量が処方物が経時的に増粘することを維持するかを決定した。処方物Ｆの粘度は、１６週間の後に、処方物１および２の初期粘度値の粘度値に到達しなかった。

Formulations D and E in this example had the lowest water content of the four formulations and achieved high viscosity values within 4 weeks of storage. The only difference between formulations 1 and 2 is the amount of ethanol in the formulation. It was hypothesized that a decrease in the level of ethanol would reduce the physical thickening of the formulation due to incompatibility between PVA and ethanol. Viscosity data show that higher ethanol formulations (Formula D) have lower initial viscosities, but over 4 weeks of storage, the viscosities of both Formulas D and E are too high for vigorous formulations. Indicates that a high viscosity value has been achieved. Another hypothesis for formulation thickening is that PVA does not fit at high concentrations when dissolved in water. Additional formulations with higher water content were prepared to determine if the optimal water content kept the formulation thickening over time. The viscosity of Formulation F did not reach the initial viscosity value of Formulations 1 and 2 after 16 weeks.

  The placebo version of the formulation described above was applied to experimental volunteers, the dry time was assessed by placing a piece of cotton at the application site and then applying a 5 gram weight to the cotton. Cotton and weight were removed after 5 seconds. This procedure started approximately 3 to 4 minutes after application, after which it was started at 10-60 second intervals until the cotton was removed without lifting the peel or leaving any residue. The results of the experiment are summarized in Table 48 below.

第二の揮発性溶媒としてのエタノールの存在は、乾燥するための該時間を有意に低下させるようである。示さないデータにおいて、揮発性溶媒として水のみを含有し、ＰＶＡに対する水の比率が２：１である局所麻酔剤処方物は＞１５分の乾燥時間を有する。水を含有する処方物における更なる揮発性溶媒の比率および存在の最適化は、乾燥時間を有意に低下させる。更なる揮発性溶媒、この場合、エタノールは水と水素結合し、皮膚から蒸発する際に、水はエタノールと共に逃げ、それにより、固化ピールを形成すると仮定される。

The presence of ethanol as the second volatile solvent appears to significantly reduce the time to dry. In the data not shown, local anesthetic formulations containing only water as the volatile solvent and a 2: 1 ratio of water to PVA have a dry time of> 15 minutes. Optimization of the proportion and presence of additional volatile solvents in water-containing formulations significantly reduces the drying time. It is hypothesized that the further volatile solvent, in this case ethanol, hydrogen bonds with water and when it evaporates from the skin, the water escapes with the ethanol, thereby forming a solidified peel.

Examples 77 to 79
A solidifying formulation for dermal delivery of ropivacaine HCl is prepared, which includes an excipient mixture according to embodiments of the present invention. The formulation is prepared from the ingredients shown in Table 49.

前記リストの成分を以下の手法に従って合わせる。ロピバカインＨＣｌ、水、およびアミン塩基（トリエチルアミンまたはジイソプロパノールアミン）をガラスジャー中で合わせ、薬物が溶解するまで混合する。ついで、イソステアリン酸、トリアセチン、Ｓｐａｎ ２０およびセチルアルコール（実施例７８および７９）またはイソプロパノール（実施例７７）を処方物に加え、よく混合する。ポリマーＰｌａｓｔｏｉｄ Ｂを最後に加え、Ｐｌａｓｔｏｉｄ Ｂが完全に溶解するまで約６０℃まで加熱する。一旦、ポリマー溶液が室温まで冷却されれば、処方物を激しく２から３分撹拌する。

The components of the list are combined according to the following procedure. Combine ropivacaine HCl, water, and amine base (triethylamine or diisopropanolamine) in a glass jar and mix until the drug is dissolved. The isostearic acid, triacetin, Span 20, and cetyl alcohol (Examples 78 and 79) or isopropanol (Example 77) are then added to the formulation and mixed well. Polymer Plastoid B is added last and heated to about 60 ° C. until Plastoid B is completely dissolved. Once the polymer solution is cooled to room temperature, the formulation is vigorously stirred for 2 to 3 minutes.

  The formulation in Table 49 is applied to HMS according to Example 1 and the ropivacaine flux is measured. The results are summarized in Table 50:

本発明をある好ましい実施形態を参照して記載してきたが、当業者であれば、本発明の精神を逸脱することなく種々の改良、変形、省略、および置換をなすことができるのを認識するであろう。従って、本発明は特許請求の範囲のみによって限定されることを意図する。

Although the present invention has been described with reference to certain preferred embodiments, those skilled in the art will recognize that various modifications, changes, omissions, and substitutions can be made without departing from the spirit of the invention. Will. Accordingly, it is intended that the invention be limited only by the claims.

FIG. 1 is a graphical representation of the cumulative amount of diclofenac delivered percutaneously across human cadaver skin over time from a formulation according to an embodiment of the invention where steady state delivery is shown over 28 hours. FIG. 2 shows the cumulative amount of ropivacaine delivered transdermally across human cadaver skin over time from a formulation with a similar composition according to an embodiment of the invention where steady state delivery is shown over 30 hours. It is a graph display. FIG. 3 is a graph of the cumulative amount of testosterone delivered across a biological membrane over time from a solid adhesive formulation according to an embodiment of the present invention compared to a commercial product (AndroGel). It is a display. FIG. 4 is a graphical representation of the cumulative amount of acyclovir delivered transdermally over time from two separate formulations according to embodiments of the present invention compared to the commercial product Zovirax cream.

Claims (107)

a) Drug:
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system that is fluxable for the drug;
And c) a solidifying agent that contributes to the solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
A formulation for dermal delivery of a drug comprising
Wherein the formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface comprises the volatile solvent A formulation that forms an adhesive solidified layer after at least partial evaporation of the system, and wherein the drug is delivered continuously after the volatile solvent system is at least substantially evaporated. The formulation of claim 1, wherein the non-volatile solvent system is a plasticizer for the solidifying agent. The non-volatile solvent system comprises at least two non-volatile solvents, and the non-volatile solvent system can individually produce a higher skin flux for the drug than each of the non-volatile solvents. The formulation described in 1. The formulation of claim 1, wherein the formulation further comprises a further agent that is included to increase adhesion of the formulation when applied to the skin surface. The further agent is a copolymer of methyl vinyl ether and maleic anhydride, a copolymer of polyethylene glycol and polyvinyl pyrrolidone, gelatin, a low molecular weight polyisobutylene rubber, a copolymer of acrylic sun alkyl and octyl acrylamide, and an aliphatic resin, an aromatic resin, and The formulation of claim 4, comprising at least one member selected from the group consisting of the combination. The formulation of claim 1, wherein the volatile solvent system comprises water. The formulation of claim 1, wherein the formulation is substantially free of water. The volatile solvent system comprises at least one solvent that is more volatile than water, and ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1 difluoroethane, 1,1,1 , 2 tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, and combinations thereof The formulation of claim 1, comprising at least one member selected from. The volatile solvent system comprises at least one solvent that is more volatile than water and is iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone 2. The formulation of claim 1, comprising at least one member selected from the group consisting of, methyl ethyl ketone, and combinations thereof. The formulation of claim 1, wherein the volatile solvent system comprises at least one member selected from the group consisting of ethanol, iso-propyl alcohol, and combinations thereof. At least twice the flux for the drug when the drug is present in the non-volatile solvent system alone than the fluxable non-volatile solvent system is required to achieve a therapeutically effective flux. The formulation of claim 1, which provides The non-volatile solvent system is selected from the group consisting of glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, and combinations thereof The formulation of claim 1, comprising one or more selected solvents. The non-volatile solvent system is benzoic acid, butyl alcohol, dibutyl sebacate, diglyceride, dipropylene glycol, eugenol, fatty acid, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglyceride, sorbitan fatty acid surfactant, triethyl citrate, 2. The formulation of claim 1, comprising one or more solvents selected from the group consisting of and combinations thereof. The non-volatile solvent system is 1,2,6-hexanetriol, alkyltriol, alkyldiol, acetyl monoglyceride, tocopherol, alkyldioxolane, p-propenylanisole, anise oil, apricot oil, dimethylisosorbide, alkylglucoside, benzyl alcohol , Beeswax, benzyl benzoate, butylene glycol, caprylic / capric triglyceride, caramel, cinnamon oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglyceride, coriander oil, corn oil, coriander Oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride, diethanolamine, diethylene glycol monoethyl ether , Diglyceride, ethylene glycol, eucalyptus oil, fat, fatty alcohol, flavoring, liquid sugar, ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, milk, monoacetin , Monoglyceride, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, plant shortening , Vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, canderia wax, carnauba wax, setea -20, cetyl alcohol, polyglyceryl, dipolyhydroxystearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG-fatty acid ester, PEG-stearate, PEG-oleate , PEG-laurate, PEG-fatty acid diester, PEG-diolate, PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid ester, PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene glycerol Lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-o Cutyl phenyl ether, PEG-alkyl ether, PEG-cetyl ether, PEG-stearyl ether, PEG-sorbitan fatty acid ester, PEG-sorbitan diisostearate, PEG-sorbitan monostearate, propylene glycol fatty acid ester, propylene glycol stearate, Propylene glycol, caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stear-o-wet, triglyceride, alkylaryl polyether alcohol, sorbitan-ether polyoxyethylene derivative, saturated polyglycol C8-C10 glycerides, N-methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azo And related compounds, dimethylformamide, N-methylformamide, fatty acid ester, fatty alcohol ether, alkyl-amide (N, N-dimethylalkylamide), N-methylpyrrolidone-related compound, ethyl oleate, polyglycerinated fatty acid, glycerol mono Oleate, glyceryl monomyristate, glycerol ester of fatty acid, silk amino acid, PPG-3 benzyl ether myristate, Di-PPG2 milles 10-adipate, honey quat, sodium pyroglutamate, abyssinica oil, dimethicone, macadamia nut oil Limnanthes alba seed oil, cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, E cycloalkenyl trimethicone, hydrolyzed wheat protein and formulations according to claim 1 comprising one or more solvents selected from the group consisting of a combination thereof. The solidifying agent is polyvinyl alcohol, an ester of polyvinyl methyl ether / maleic anhydride copolymer, neutral copolymer of butyl methacrylate and methyl methacrylate, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, ethyl acrylate-methacrylic acid. At least one member selected from the group consisting of methyl acid-trimethylammonioethyl chloride copolymer, prolamin (Zein), pregelatinized starch, ethyl cellulose, fish gelatin, gelatin, acrylate / octylacrylamide copolymer, and combinations thereof The formulation of claim 1 comprising. The solidifying agent is ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amide, corn starch, pregelatinized corn starch, polyether amide, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, The formulation of claim 1, comprising a member selected from the group consisting of polyvinyl acetate phthalate and combinations thereof. The solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate, carboxypolymethylene, cellulose acetate (microcrystalline), cellulose polymer, divinylbenzenestyrene, ethylene vinyl acetate, silicone, guar gum, guarodin, gluten, casein, casein. Calcium oxide, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethylcellulose, acrylate, PEG / PVP, xanthan gum, trimethylsiloxysilicate, maleic acid / anhydride copolymer, polacrilin , Poloxamer, polyethylene oxide, polygalactic acid / poly-1-lactic acid, turpen resin, locust Selected from the group consisting of Ningham, acrylic copolymers, polyurethane dispersions, dextrin, polyvinyl alcohol-polyethylene glycol copolymers, methacrylic acid-ethyl acrylate copolymers, methacrylic acid, and methacrylate polymers such as poly (methacrylic acid), and combinations thereof The formulation of claim 1, comprising at least one member. The formulation of claim 1, wherein the drug comprises a plurality of pharmaceutically active agents. The drug is acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, tretinoin, isotretinoin, clobetasol pro The formulation of claim 1 comprising at least one member selected from the group consisting of pionate, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, and combinations thereof. The drug is amorolfine, butenafine, naphthifine, terbinafine, fluconazole, itraconazole, ketoconazole, posaconazole, rubconazole, voriconazole, clotrimazole, butconazole, econazole, miconazole, oxyconazole, sulconazole, terconazole, thioconazole, thioconazole Gin, amphotericin B, AmB, nystatin, pimalysin, griseofulvin, cyclopirox olamine, haloprozine, tolnaftate, undecylenate, acyclobeer, pencyclobeer, famcyclobeer, valacyclobeer, behenyl alcohol, trifluridine, idoxuridine , Sidfo Beer, Gancyclo Beer, Pod Phillock , Podophyllotoxin, ribavirin, abaca beer, delavirdine, didanosine, efavirenz, lamivudine, nevirapine, stavudine, zalcitabine, zidovudine, amprenabine, indina beer, nelfina beer, ritona beer, saquina beer, amantadine, interferon, oseltami beer Ribavirin, rimantadine, zanamibe, erythromycin, clindamycin, tetracycline, bacitracin, neomycin, mupirocin, polymyxin B, quinolones such as ciprofluxin, lidocaine, bupivacaine, ropivacaine, tetracaine, alpha-2 agonist clonidine, tricyclic antidepressant Agent, carbamazepine, alprazolam, N-methyl-D-aspartate (NMDA) antagonist, 5-HT2 Receptor antagonist, betamethasone dipropionate, halobetasol propionate, diflorazone diacetate, triamcinolone acetonide, desoxymethasone, fluocinonide, halcinonide, mometasone furoate, betamethasone valerate, fluocinonide, fluticasone propionate , Triamcinolone acetonide, fluocinolone acetonide, flulandrenolide, desonide, hydrocortisone butyrate, hydrocortisone valerate, alcromethasone dipropionate, flumethasone pivalate, hydrocortisone, hydrocortisone acetic acid, tacrolimus, picrolimus, tazarotene, Isotretinoin, cyclosporine, anthralin, vitamin D3, cholecalciferol, calcitriol, calcipo Triol, tacalcitol, calcipotriene, ketoprofen, piroxicam, diclofenac, indomethacin, COX inhibitor, general COX inhibitor, COX-2 selective inhibitor, and COX-3 selective inhibitor, imiquimod, rosikimod, salicylic acid, Alpha hydroxy acid, sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, benzoic acid, progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethinodiol diacetate, norergestromine, norgestimate, Levonorgestrel, dl-Norgestrel, Cyproterone acetate, Didrogesterone, Medoxyprogesterone acetate, Chlormadinone acetate, Megest Androgen, estradiol, ethinylestradiol, esthiol, estrone, conjugation consisting of quinol, promegestone, norethisterone, linenesterenol, guestden, tivolene, tibolene, testosterone, methyltestosterone, oxandrolone, androstenedione, dihydrotestosterone 2. The formulation of claim 1, comprising at least one member selected from the group consisting of follicular hormone, esterified estrogens, estropipetes, anti-acne drugs and combinations thereof. When applied to the skin in a human joint, the solidified layer is sufficiently flexible against the skin so that the solidified layer remains substantially intact on the skin upon bending of the joint for at least 2 hours. The formulation of claim 1 which is flexible and adhesive. When applied to a bent body surface or a weight bearing surface on the body, the solidified layer remains substantially intact on the skin upon bending or stretching of the bent body surface or weight bearing surface. The formulation of claim 1, wherein the solidified layer is sufficiently flexible and adhesive to the skin. The formulation of claim 1, wherein the formulation is configured to deliver the drug at a therapeutically effective rate for at least about 2 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is configured to deliver the drug at a therapeutically effective rate for between 2 and 12 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is configured to deliver the drug at a therapeutically effective rate for at least about 12 hours after formation of the solidified layer. The formulation of claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.1: 1 to about 10: 1. The formulation of claim 1, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. The formulation of claim 1, wherein at least one non-volatile solvent of the non-volatile solvent system can reduce skin irritation. 30. The formulation of claim 28, wherein the non-volatile solvent capable of reducing skin irritation is selected from the group consisting of glycerin, propylene glycol, and honey. The formulation of claim 1, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin conditions and ambient conditions. The formulation of claim 1, wherein the solidified layer is formed within about 5 minutes of application to the skin surface under standard skin conditions and ambient conditions. The formulation of claim 1, wherein the formulation has an initial viscosity prior to dermal application of about 100 cP to about 3,000,000 cP. 2. The formulation of claim 1, wherein the formulation has an initial viscosity prior to dermal application of about 1,000 cP to about 1,000,000 cP. The formulation of claim 1, wherein the weight percentage of the volatile solvent system is from about 10 wt% to about 85 wt%. The formulation of claim 1, wherein the weight percentage of the volatile solvent system is from about 20 wt% to about 50 wt%. The formulation of claim 1, wherein the weight percentage of the volatile solvent system in the formulation is at least about 20%. The formulation of claim 1, wherein the non-volatile solvent system comprises a plurality of non-volatile solvents, and at least one of the non-volatile solvents can improve the compatibility of the non-volatile solvent system with the solidifying agent. . The formulation of claim 1, wherein the solidified layer is cohesive and can be peeled from the skin. The formulation of claim 1, wherein the solidified layer is cohesive, flexible and continuous. The formulation according to claim 1, wherein the solidified layer is a soft, cohesive solid that, upon formation, can be peeled from the skin surface as a single piece, or just a few large pieces, for the application size. The formulation of claim 1, wherein the solidified layer can be removed by washing. 42. The formulation of claim 41, wherein the washing comprises the use of a solvent selected from the group consisting of water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, and combinations thereof. 42. The formulation of claim 41, wherein the washing comprises the use of a non-volatile solvent. 42. The formulation of claim 41, wherein the washing comprises the use of water, ethanol, isopropanol, or a combination thereof. The formulation of claim 1, wherein the solidified layer delivers the drug transdermally. A method of dermally delivering a drug comprising:
a) applying the formulation of any one of claims 1 to 45 as a layer to the skin surface of a subject;
b) solidifying the formulation to form a solidified layer on the skin surface by at least partial evaporation of the volatile solvent system; and c) the solidified layer at a therapeutically effective rate over time. Transdermally delivering the drug from to the skin surface:
Including a method. 47. The method of claim 46, wherein the applying step comprises applying the formulation at a thickness of about 0.01 mm to about 3 mm. 47. The method of claim 46, wherein the applying step comprises applying the formulation at a thickness of about 0.05 mm to about 1 mm. When the skin surface is in contact with an exogenous object, the skin surface is susceptible to or may be infected by the exogenous object, and the solidified layer provides physical protection to the skin surface 47. The method of claim 46. 47. The method of claim 46, wherein the solidified layer remains on the skin surface for at least 2 hours. 47. The method of claim 46, wherein the solidified layer remains on the skin for at least 6 hours. 47. The method of claim 46, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions. 47. The method of claim 46, further comprising the step of peeling the solidified layer from the skin with a single piece or only a few large pieces for the size of the application. 49. The method of claim 46, further comprising removing the solidified layer by washing after the drug is delivered and removed. 55. The method of claim 54, wherein the washing comprises the use of a solvent selected from the group consisting of water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol and combinations thereof. 55. The method of claim 54, wherein the washing includes the use of a non-volatile solvent. 55. The method of claim 54, wherein the washing comprises the use of water, ethanol, isopropanol, or a combination thereof. A method for preparing a formulation for dermal drug delivery comprising:
a) selecting a drug suitable for dermal delivery;
b) selecting or formulating a non-volatile solvent system that is fluxable for the drug;
c) selecting or formulating a solidifying agent compatible with the fluxable non-volatile solvent;
d) selecting or formulating a volatile solvent system comprising the fluxable non-volatile solvent and at least one volatile solvent compatible with the solidifying agent; and e) the drug, the non-volatile solvent system, Formulating the solidifying agent, the volatile solvent system, and any other ingredients into a formulation having a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system;
The formulation applied to the skin surface as a layer forms a solidified layer after at least a portion of the volatile solvent system evaporates, and the drug is at least substantially evaporated after the volatile solvent system evaporates. A method of continuous delivery at a therapeutically effective rate. 59. The method of claim 58, wherein the volatile solvent system comprises water. The volatile solvent system is ethanol, isopropyl alcohol, water, dimethyl ether, diethyl ether, butane, propane, isobutene, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3, 59. The method of claim 58, comprising at least one member selected from the group consisting of 3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane, ethyl acetate, acetone, and combinations thereof. Method. The volatile solvent system is at least one selected from the group consisting of iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, and combinations thereof. 59. The method of claim 58, comprising one member. The non-volatile solvent system is selected from the group consisting of glycerol, propylene glycol, isostearic acid, oleic acid, propylene glycol, trolamine, tromethamine, triacetin, sorbitan monolaurate, sorbitan monooleate, sorbitan monopalmitate, butanol, and combinations thereof 59. The method of claim 58, comprising at least one member selected. The non-volatile solvent system is benzoic acid, butyl alcohol, dibutyl sebacate, diglyceride, dipropylene glycol, eugenol, fatty acid, isopropyl myristate, mineral oil, oleyl alcohol, vitamin E, triglyceride, sorbitan fatty acid surfactant, triethyl citrate, 59. The method of claim 58, comprising one or more members selected from the group consisting of and combinations thereof. The non-volatile solvent system is 1,2,6-hexanetriol, alkyltriol, alkyldiol, acetyl monoglyceride, tocopherol, alkyldioxolane, p-propenylanisole, anise oil, apricot oil, dimethylisosorbide, alkylglucoside, benzyl alcohol , Beeswax, benzyl benzoate, butylene glycol, caprylic / capric triglyceride, caramel, cinnamon oil, castor oil, cinnamaldehyde, cinnamon oil, clove oil, coconut oil, cocoa butter, cocoglyceride, coriander oil, corn oil, coriander Oil, corn syrup, cottonseed oil, cresol, cyclomethicone, diacetin, diacetylated monoglyceride, diethanolamine, diethylene glycol monoethyl ether , Diglyceride, ethylene glycol, eucalyptus oil, fat, fatty alcohol, flavoring, liquid sugar, ginger extract, glycerin, high fructose corn syrup, hydrogenated castor oil, IP palmitate, lemon oil, lime oil, limonene, milk, monoacetin , Monoglyceride, nutmeg oil, octyldodecanol, olive alcohol, orange oil, palm oil, peanut oil, PEG vegetable oil, peppermint oil, petrolatum, phenol, pine needle oil, polypropylene glycol, sesame oil, spearmint oil, soybean oil, vegetable oil, plant shortening , Vinyl acetate, wax, 2- (2- (octadecyloxy) ethoxy) ethanol, benzyl benzoate, butylated hydroxyanisole, canderia wax, carnauba wax, setea -20, cetyl alcohol, polyglyceryl, dipolyhydroxystearate, PEG-7 hydrogenated castor oil, diethyl phthalate, diethyl sebacate, dimethicone, dimethyl phthalate, PEG-fatty acid ester, PEG-stearate, PEG-oleate , PEG-laurate, PEG-fatty acid diester, PEG-diolate, PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glycerol fatty acid ester, PEG glyceryl laurate, PEG glyceryl stearate, PEG glyceryl oleate, hexylene glycerol Lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristyl alcohol, neutral oil, PEG-o Cutyl phenyl ether, PEG-alkyl ether, PEG-cetyl ether, PEG-stearyl ether, PEG-sorbitan fatty acid ester, PEG-sorbitan diisostearate, PEG-sorbitan monostearate, propylene glycol fatty acid ester, propylene glycol stearate, Propylene glycol, caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stea-o-wet, triglyceride, alkylaryl polyether alcohol, polyoxyethylene derivative of sorbitan-ether, saturated polyglycolated C8-C10 glyceride, N -Methylpyrrolidone, honey, polyoxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethyl Formamide, N-methylformamide, fatty acid ester, fatty alcohol ether, alkyl-amide (N, N-dimethylalkylamide), N-methylpyrrolidone related compound, ethyl oleate, polyglycerinated fatty acid, glycerol monooleate, glyceryl mono Myristate, glycerol ester of fatty acid, silk amino acid, PPG-3 benzyl ether myristate, Di-PPG2 milles 10-adipate, honey quat, sodium pyroglutamate, abyssinica oil, dimethicone, macadamia nut oil, limnanthes alba seed oil , Cetearyl alcohol, PEG-50 shea butter, shea butter, aloe vera juice, phenyl trimethicone, hydrolyzed wheat protein and combinations thereof 59. The method of claim 58, comprising one or more members selected from the group consisting of a combination. The solidifying agent is polyvinyl alcohol, an ester of polyvinyl methyl ether / maleic anhydride copolymer, neutral copolymer of butyl methacrylate and methyl methacrylate, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, ethyl acrylate-methacrylic acid. At least one member selected from the group consisting of methyl acid-trimethylammonioethyl chloride copolymer, prolamin (Zein), pregelatinized starch, ethyl cellulose, fish gelatin, gelatin, acrylate / octylacrylamide copolymer, and combinations thereof 59. The method of claim 58, comprising. The solidifying agent is ethyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, polyether amide, corn starch, pregelatinized corn starch, polyether amide, shellac, polyvinyl pyrrolidone, polyisobutylene rubber, 59. The method of claim 58, comprising a member selected from the group consisting of polyvinyl acetate phthalate and combinations thereof. The solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate, carboxypolymethylene, cellulose acetate (microcrystalline), cellulose polymer, divinylbenzenestyrene, ethylene vinyl acetate, silicone, guar gum, guarodin, gluten, casein, casein. Calcium oxide, ammonium caseinate, sodium caseinate, potassium caseinate, methyl acrylate, microcrystalline wax, polyvinyl acetate, PVP ethylcellulose, acrylate, PEG / PVP, xanthan gum, trimethylsiloxysilicate, maleic acid / anhydride copolymer, polacrilin , Poloxamer, polyethylene oxide, polygalactic acid / poly-1-lactic acid, turpentine resin, locust bean gum, acrylic At least selected from the group consisting of copolymers, polyurethane dispersions, dextrins, polyvinyl alcohol-polyethylene glycol copolymers, methacrylic acid-ethyl acrylate copolymers, methacrylate polymers such as methacrylic acid, and poly (methacrylic acid), and combinations thereof 59. The method of claim 58, comprising one member. The drug is acyclovir, econazole, miconazole, terbinafine, lidocaine, bupivacaine, ropivacaine, and tetracaine, amitriptyline, ketanserin, betamethasone dipropionate, triamcinolone acetonide, clindamycin, benzoyl peroxide, tretinoin, isotretinoin, clobetasol pro 59. The method of claim 58, comprising at least one member selected from the group consisting of pionate, halobetasol propionate, ketoprofen, piroxicam, diclofenac, indomethacin, imiquimod, salicylic acid, benzoic acid, and combinations thereof. 59. The method of claim 58, wherein the formulation is configured to deliver the drug at a therapeutically effective rate for at least about 2 hours after formation of the solidified layer. 59. The method of claim 58, wherein the solidifying agent is dispersed or solvated in a solvent excipient. 59. The method of claim 58, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. 59. The method of claim 58, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions. 59. The method of claim 58, wherein the formulation has an initial viscosity prior to dermal application of about 100 cP to about 3,000,000 cP. 59. The method of claim 58, wherein the weight percentage of the volatile solvent system is from about 10 wt% to about 85 wt%. 59. The method of claim 58, wherein the non-volatile solvent system comprises a plurality of non-volatile solvents, and at least one of the non-volatile solvents can improve the compatibility of the non-volatile solvent system with the solidifying agent. . 59. The method of claim 58, wherein the non-volatile solvent system comprises a non-volatile solvent that is a plasticizer for the solidifying agent. 59. The method of claim 58, wherein the non-volatile solvent system comprises a non-volatile solvent that can reduce water vapor loss from the skin surface. 59. The method of claim 58, wherein the non-volatile solvent system comprises a non-volatile solvent that can enhance adhesion to the skin. 59. The method of claim 58, wherein the fluxable non-volatile solvent maintains delivery of the drug to human skin or tissue. A solidified layer for skin delivery of a drug,
a) drugs;
b) a non-volatile solvent system that is fluxable for the drug; and c) a solidifying agent;
Including
The solidified layer is a soft cohesive solid that adheres to the body surface, and the solidified layer is at least substantially devoid of water and a solvent more volatile than water while the solidified layer is then capable of skin delivery. A solidified layer that is formulated to deliver most of the drug and that the solidified layer is also fluxable for the drug. 81. The solidified layer of claim 80, wherein the solidified layer can extend in at least one direction by 5% without separation from the skin surface. The solidified layer of claim 80, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent. 81. The solidified layer of claim 80, wherein the solidified layer is sufficiently adhesive and flexible to remain substantially intact on the skin surface adjacent to a joint or muscle group where regular skin stretch occurs. . 81. The solidified layer of claim 80, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. 81. The solidified layer of claim 80, wherein the solidified layer can be washed with water, an alcohol solvent, or a combination thereof. The solidified layer of claim 80, wherein the solidified layer can be removed by washing. 81. The solidified layer of claim 80, wherein the washing comprises the use of a solvent selected from the group consisting of water, ethanol, methanol, isopropyl alcohol, acetone, ethyl acetate, propanol, and combinations thereof. 81. The solidified layer of claim 80, wherein the cleaning includes the use of a non-volatile solvent. 81. The solidified layer of claim 80, wherein the washing comprises the use of water, ethanol, isopropanol, or combinations thereof. 81. The solidified layer according to claim 80, wherein the solidified layer is a peel and can be removed from the skin surface by peeling as a single piece for application size or as only a few large pieces. The solidified layer according to claim 80, wherein when the solidified layer contains 10 wt% or less of water and a solvent more volatile than water, the solidified layer substantially lacks water and a volatile solvent than water. . The solidified layer according to claim 80, wherein when the solidified layer contains 5 wt% or less of water and a solvent more volatile than water, the solidified layer substantially lacks water and a volatile solvent than water. . A formulation for skin delivery of sex hormones,
a) sex hormones;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising at least one non-volatile solvent;
C) a solidifying agent that contributes to the solidification of the formulation applied as a layer to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface is at least a portion of the volatile solvent system. A formulation that forms a solidified layer after spontaneous evaporation and wherein the sex hormone is continuously delivered at a therapeutically sufficient rate after the volatile solvent system is at least substantially evaporated. 94. The formulation of claim 93, wherein the sex hormone comprises at least one member selected from the group of androgens consisting of testosterone, methyltestosterone, oxandrolone, androstenedione, dihydrotestosterone, and combinations thereof. 94. The formulation of claim 93, wherein the sex hormone comprises at least one member selected from the group of estrogens consisting of estradiol, ethinyl estradiol, esthiol, estrone, conjugated follicular hormone, esterified estrogens, estropipate and combinations thereof. The sex hormone is progesterone, norethindrone, norethindrone acetate, desogestrel, drospirenone, ethinodiol diacetate, norergestromine, norgestimate, levonorgestrel, dl-norgestrel, cyproterone acetate, didrogesterone, medroxyprogesterone acetate, chlormadinone acetate 94. The formulation of claim 93, comprising at least one member selected from the group of progestagens consisting of, megestrol, promegestone, norethisterone, linenesterenol, guestden, tivolene, and combinations thereof. 94. The formulation of claim 93, wherein the formulation comprises a combination of at least two steroid hormones selected from the group of progestagens, estrogens, and androgens. A formulation for dermal delivery of an anti-warm drug, comprising:
a) anti-wart drugs;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising at least one non-volatile solvent;
A solvent excipient comprising: c) a solidifying agent that contributes to solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
Wherein the formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and wherein the formulation applied to the skin surface is A formulation wherein an adhesive solidified layer is formed after at least partial evaporation of the soluble solvent system, wherein the drug is continuously delivered after the volatile solvent system is at least substantially evaporated. 99. The formulation of claim 98, wherein the solidified layer is formulated to provide substantial occlusion to the skin and warts under the solidified layer. 99. The formulation of claim 98, wherein the anti-warm drug comprises a plurality of anti-warm agents. A group wherein the drug comprises imiquimod, a keratolytic agent comprising salicylic acid, alpha hydroxy acid, sulfur, rescorcinol, urea, benzoyl peroxide, allantoin, tretinoin, trichloroacetic acid, lactic acid, antiviral agent, and combinations thereof 99. The formulation of claim 98, comprising at least one member selected from. a) Clobetasol propionate;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising propylene glycol and a fatty acid;
And c) a solidifying agent that contributes to solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface is at least partly of the volatile solvent system. A solidifying formulation of clobetasol propionate characterized in that it forms an adhesive solidified layer after complete evaporation and the drug is delivered continuously after the volatile solvent system is at least substantially evaporated. 103. The formulation of claim 102, wherein the solidifying agent is a protein based solidifying agent. 105. The formulation of claim 102, wherein the non-volatile solvent system comprises propylene glycol, isostearic acid, oleic acid, or a combination thereof. a) ropivacaine;
b)
i) a volatile solvent system comprising at least one volatile solvent, and ii) a non-volatile solvent system comprising a solvent selected from the group consisting of isostearic acid, Span 20, and triacetin;
A solvent excipient comprising: c) a solidifying agent that contributes to solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface is at least a portion of the volatile solvent system. An adhesive solidified layer is formed after chemical evaporation, and the ropivacaine is applied to the skin at a rate of 5 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent system has at least substantially evaporated; or A solidifying formulation of ropivacaine, characterized in that it is continuously delivered through the skin. a) imiquimod;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising a solvent selected from isostearic acid, Span 20, and triacetin;
C) a solidifying agent that contributes to the solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface is at least partially of the volatile solvent system. An adhesive solidified layer is formed after complete evaporation, wherein imiquimod is applied to the skin at a rate of 0.8 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent system is at least substantially evaporated. A solidifying formulation of imiquimod, characterized in that it is delivered continuously to or across the skin. a) ketoprofen;
b)
i) a volatile solvent system comprising at least one volatile solvent; and ii) a non-volatile solvent system comprising glycerol, propylene glycol;
A solvent excipient comprising: c) a solidifying agent that contributes to solidification of the layer of the formulation applied to the skin surface upon at least partial evaporation of the volatile solvent system;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface is at least partially of the volatile solvent system. An adhesive solidified layer is formed after complete evaporation, and the ketoprofen continues across the skin at a rate of 10 mcg / hr / cm ² or more for at least 6 hours after the volatile solvent system has at least substantially evaporated. Solidified formulation of ketoprofen, characterized in that it is delivered in a functional manner.

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