JP2009524586A - Compositions and methods for skin treatment of pain - Google Patents

Abstract

The present invention is directed to a solidifying formulation for skin delivery of drugs for treating pain, such as musculoskeletal pain, inflammation, joint pain, or neuropathic pain. The formulation can include a drug selected from a specific drug class, 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, wherein at least some of the volatile solvents Evaporation converts the formulation on the skin into a solidified layer, and the non-volatile solvent system can facilitate local delivery of the drug over time at a therapeutically effective rate.

Description

(Field of Invention)
The present invention relates generally to formulations and methods for treating musculoskeletal or neuropathic pain. More particularly, the present invention relates to an adhesive formulation having a viscosity suitable for application to the skin surface and forming a transdermal drug-delivery solidified layer on the skin.

(Background of the Invention)
Pain can be caused by various sources. For example, neuropathic pain can be caused by diseases such as viral infections and diabetes. For example, postherpetic neuralgia is caused by a herpesvirus infection and typically causes moderate to severe pain in the infected skin area to the subject. Topical products such as creams or patches containing appropriate drugs can be used to control neuropathic pain; however, traditional semi-solid formulations such as patches and creams and ointments are both Has considerable drawbacks. Semi-solid formulations are usually volatile and thus contain a solvent such as water and ethanol that evaporates shortly after application. Such solvent evaporation can cause significant reduction or even cessation of dermal drug delivery, which is often undesirable. In addition, semi-solid formulations are often “rubbed into” the skin, which does not necessarily mean that the drug formulation has actually been delivered into the skin. Instead, this phrase often means that a very thin layer of drug formulation was applied to the surface of the skin. Such a thin layer of a traditional semi-solid formulation applied to the skin contains a sufficient amount of active drug to achieve sustained release over a long period of time that may be desirable in treating neuropathic pain Can not. In addition, traditional semi-solid formulations are often exposed to unintentional removal by contact with objects such as clothing, which can jeopardize sustained release and / or undesirably soil clothing. .

  The musculoskeletal system is also a common source of pain. However, for neuropathic pain, current topical dosage forms for these drugs are typically not appropriate for this application. For example, semi-solid NSAIDs and local anesthetic formulations such as creams and gels are usually volatile and thus contain solvents such as water and ethanol that evaporate shortly after application. Such solvent evaporation can cause a significant decrease or even cessation of local drug absorption.

  Patches containing appropriate drugs can be used to treat neuropathy or musculoskeletal pain. However, subjects often have to cut the patch to fit the shape and size of the skin area to be treated, which is inconvenient. Another disadvantage of the patch is that it is usually not fully extensible and flexible at each application location. If the patch is applied to skin areas that stretch significantly during body movements such as joints and muscles, separation between the patch and the skin may occur, thereby jeopardizing drug delivery. In addition, skin surface patches may prevent the skin from expanding during physical movement, causing discomfort and / or exacerbating pain. For these additional reasons, patches are not an ideal dosage form for skin areas that are subject to expansion and stretching during physical exercise.

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

  Another drawback of skin patches (including transdermal) is that it is usually not extensible 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 non-extensible materials. If the patch is applied to an area of skin that stretches significantly during body movements such as joints, separation between the patch and the skin may occur, thereby jeopardizing drug delivery. In addition, patches present on the skin surface can interfere with skin enlargement during body movements and can cause discomfort. For these additional reasons, patches are not an ideal dosage form for skin areas on muscles and joints that are subject to expansion and stretching during physical exercise.

  In light of the shortcomings of current delivery systems, i) can provide a more sustained delivery of pain relief medications such as NSAIDs, local anesthetics or certain steroids over time; ii) longer duration of application Not subject to much unintentional removal by contact with clothing, other objects, or humans; iii) Applying to areas of skin that are subject to stretch and enlargement without causing discomfort or poor skin contact It would be desirable to provide a system and / or method that can be conveniently removed after application and use.

(Summary)
In the form of an adhesive solidifying formulation that has a viscosity suitable for application to the skin surface as a layer and forms a drug-delivery adhesive solidified layer on the skin, such as NSAID, topical It has been recognized that it would be advantageous to treat neuropathy and / or musculoskeletal pain by providing local delivery of drugs from anesthetics or steroid formulations. In one embodiment, a formulation for treating musculoskeletal or neuropathic pain can include drugs, solvent excipients, and solidifying agents suitable for treating musculoskeletal or neuropathic pain. The solvent excipient may comprise 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 non-volatile solvent system is therapeutically effective Can facilitate transdermal delivery over a sustained period of time. The formulation can have a viscosity suitable for application to 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. The solidified layer can be formed after general evaporation. The drug can be continuously delivered at a therapeutically effective rate after the volatile solvent system has evaporated at least substantially to treat musculoskeletal pain or inflammation.

  In another embodiment, a method of dermal delivery of a drug for treating musculoskeletal or neuropathic pain can include applying the formulation to the skin surface. The formulation can be the formulation described in the previous embodiments. A further step solidifies the formulation by at least partial evaporation of the volatile solvent system to form a solidified layer on the skin surface; then a therapeutically effective rate for treating joint or muscle pain or inflammation Delivering the drug from the solidified layer to the skin surface for a duration of time.

  In another embodiment, a solidified layer for treating pain can include a drug effective to treat musculoskeletal or neuropathic pain, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system can include at least one non-volatile solvent, wherein the non-volatile solvent system can facilitate delivery of the drug over time at a therapeutically effective rate. In addition, the solidified layer is preferably extensible by 5% in at least one direction without cracking, breaking and / or separation from the skin surface to which it is applied.

  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 “musculoskeletal pain or inflammation” includes pain and / or inflammation of joints, tendons, ligaments, muscles, bones, synovial fluid and / or soft tissues that are part of the musculoskeletal system.

  The term “neuropathic pain” includes pain associated with the nervous system, including the brain, spinal cord, or peripheral nervous system. Neuropathic pain can be chronic or acute and can occur as a result of trauma, illness or other factors.

  The term “drug” refers to an active agent that can be used in the formulations of the present invention and is effective in treating either neuropathic or musculoskeletal pain. Examples of drugs that can be used to treat musculoskeletal pain include NSAIDs, local anesthetics, steroid drugs, and / or 5-HT2A receptor antagonists. An example of a 5-HT2A receptor antagonist includes, but is not limited to, ketanserin. Examples of NSAIDs include but are not limited to ketoprofen, piroxicam, diclofenac, indomethacin, and COX inhibitors. Examples of local anesthetics include, but are not limited to lidocaine, bupivacaine, ropivacaine, and tetracaine. Examples of steroid drugs used in the present invention include, but are not limited to, dexamethasone, hydrocortisone, prednisone, prednisolone, methylprednisolone, halobetasol propionate, betamethasone dipropionate, betamethasone, prodrugs thereof, or combinations thereof including. Examples of drugs suitable for treating neuropathic pain include, but are not limited to, local anesthetics including lidocaine, bupivacaine, ropivacaine, and tetracaine; steroids including dexamethasone; alpha including clonidine -2 antagonists; N-methyl-D-aspartate (NMDA) including amitriptyline, tricyclic antidepressants including anticonvulsants, dextromethorphan, memantine, amantadine, ketamine, methadone, dextropropoxyphene, and ketobemidone Antiviral drugs including acyclovir, pencyclovir, famciclovir, valacyclovir steroids; 5-HT2A receptor antagonists including ketanserin; or combinations thereof.

  In general, when referring to a “drug”, it is understood that there are various forms of a given drug, and that these various forms are expressly included. Accordingly, various drug forms include polymorphs, salts, hydrates, solvates, and co-crystals. For some drugs, one physical form of the drug can possess good physicochemical properties, making it more accessible to the skin, into or through the skin, A special form is defined as "a physical form favorable for skin delivery". For example, the steady state flux of diclofenac sodium from a flux-enabling non-volatile solvent is significantly higher than the steady-state flux of diclofenac acid from a non-fluxable non-volatile solvent. Accordingly, it is desirable to evaluate the physical form flux of the drug from the non-volatile solvent and select the desired physical form / non-volatile solvent combination.

  The term “NSAID” or “non-steroidal anti-inflammatory drug” refers to all non-steroidal anti-inflammatory agents, general COX inhibitors, COX-2 selective inhibitors, and COX-3 selective inhibitors. Including.

  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.

  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 “flux” values described herein can mean those 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”.

For lidocaine active agents, a non-volatile solvent system can be “fluxable” if it can produce a flux of at least about 20 mcg / cm ² / hour in the same or similar settings as described in Example 1. "Will. For tetracaine and ropivacaine active agents, the non-volatile solvent system is “flux” if it can produce a flux of at least about 5 mcg / cm ² / hour in the same or similar settings as described in Example 1. It will be possible. For ketoprofen and diclofenac, if it can produce a flux of at least about 5 mcg / cm ² / hour in the same or similar settings as described in Example 1, the non-volatile solvent system is “flux”. It's possible.

For example, the importance of selecting a suitable non-volatile solvent is shown in Table 1. The flux of ropivacaine (a local anesthetic effective in treating neuropathic pain) from saturated glycerol, isostearic acid (ISA) alone and ISA + trolamine, and ISA + trolamine peel is shown in Table 1. The flux value was generated in an in vitro experiment described later in Example 1. Estimated therapeutically beneficial ropivacaine flux is 5 to 10 mcg / cm ² / hour.

ＩＳＡ、およびＩＳＡ＋トロラミンからのロピバカインのイン・ビトロフラックス結果は適当な不揮発性溶媒の例であって、グリセロールは不適当な不揮発性溶媒の例である。ピール処方物に配合する場合、適当な不揮発性溶媒は処方物のフラックス−生成パワーを指令する。「選択された薬物に適した不揮発性溶媒系」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ことに注意すべきである。前記で分かるように、ＩＳＡ＋トロラミンの不揮発性溶媒系は純粋なＩＳＡの不揮発性溶媒系よりもフラックスを生じさせることができるが、恐らくは、共に特定の適用で適している。

The in vitro flux results for ropivacaine from ISA and ISA + trolamine are examples of suitable non-volatile solvents, and glycerol is an example of an inappropriate non-volatile solvent. When incorporated into a peel formulation, a suitable non-volatile solvent dictates the flux-generating power of the formulation. It should be noted that a “nonvolatile solvent system suitable for the selected drug” can be a single chemical or a mixture of two or more chemicals. As can be seen, the non-volatile solvent system of ISA + trolamine can produce a flux more than the non-volatile solvent system of pure ISA, but both are probably more suitable for certain applications.

  The phrases “effective amount”, “therapeutically effective amount”, “therapeutically effective rate” and the like are related to a drug, so that any recognizable level of therapeutic outcome in treating a disease to which the drug is delivered. 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. According to this definition, different drugs have different “therapeutically effective fluxes”. In addition, the therapeutically effective flux can differ at different times in different subjects, or even for the same subject. However, for each drug there is usually consensus among those skilled in the art about the dose or flux range that is sufficient for most subjects at most times.

The term “plastic” with respect to a non-volatile solvent (or non-volatile solvent system) and a solidifying agent is defined as a non-volatile solvent (or non-volatile solvent system) that acts as a plasticizer for the solidifying agent. A “plasticizer” is an agent that can provide the flexibility and / or elasticity of a solidified formulation layer 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 plasticizing non-volatile solvent for solidifying formulations containing ketoprofen as a drug and polyvinyl alcohol as a selected solidifying agent. However, propylene glycol in a solidified formulation of ketoprofen containing Gantrez S-97 or Avalure UR 405 as a solidifying agent does not provide the same plastic effect. The combination of propylene glycol and Gantrez S-97 or Avale UR 405 is less compatible and results in a less desirable formulation for topical application. Thus, whether a given non-volatile solvent is “plastic” or not depends on which solidifying agent is selected.
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.

  The term “adhesive” or “adhesive” as used herein refers to a solidified layer and skin such that the layer does not fall from the skin during its intended use in most controls. Say enough adhesion between. Thus, when used to describe a solidified layer, such as “adhesive”, the solidified layer adheres to the body surface to which the original formulation layer was originally applied (before evaporation of the volatile solvent). Means sex. In one embodiment, it does not mean that the solidified layer is adhesive on the opposite side. In addition, it should be noted that whether the solidified layer can adhere to the skin surface for the desired extended time depends in part on the condition of the body surface. For example, excessive sweating or oily skin, or oily material on the skin surface, makes the solidified layer less adherent to the skin. Thus, the adhesive solidified layer of the present invention maintains complete contact with the body surface and is unable to deliver the drug for each subject over a period of time under any body surface condition. The standard is that it maintains good contact with most of the body surface, for example 70% of the total area, over a specific time for most subjects under normal conditions of the body surface and experimental environment.

  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.

  An “adhesive solidified formulation” or “solidified formulation” has a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent and solidifies after evaporation of at least a portion of the volatile solvent. A composition that can be a layer. The solidified layer is very sustainable once formed. In one embodiment, the formulation can form a peel once solidified on the skin surface. The peel can be a soft cohesive solid that can be removed by peeling large pieces from the skin relative to the size of the applied formulation, and can often peel from the skin as a single piece. it can. The applied viscosity is typically more viscous than a water-like liquid, but less viscous than a soft solid. Examples of preferred viscosities include materials having a consistency similar to pastes, gels, ointments, etc., for example viscous liquids that flow but are not prone to spilling. Thus, when a composition has a “suitable” viscosity to the skin surface, this has a viscosity that is sufficiently high that the composition does not substantially drop off the skin after application to the skin. However, it also has a sufficiently low viscosity that it can be easily extended onto 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.

  With these definitions in mind, in one embodiment, a formulation for treating musculoskeletal pain or inflammation comprises a drug, solvent excipient and solidifying agent suitable for treating musculoskeletal pain or inflammation. be able to. 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, wherein the non-volatile solvent system is therapeutically effective Can facilitate transdermal delivery of a drug over a sustained period of time. The formulation can have a viscosity suitable for application and adhesion to the skin surface as a layer prior to evaporation of the volatile solvent system, and the formulation applied to the skin surface can be a volatile solvent. A solidified layer can be formed after at least partial evaporation of the system. The drug can be delivered continuously at a therapeutically effective rate to treat musculoskeletal pain or inflammation after the volatile solvent system has at least substantially evaporated.

  In another embodiment, a method for dermal delivery of a drug for treating joint or muscle pain or inflammation comprises applying an adhesive solidifying formulation to the skin surface adjacent to the pain or inflammation tissue (e.g., , The skin surface of the knee affected by arthritis, or the skin of the lower back affected by lower back pain). The adhesive solidified formulation can include drugs, solvent excipients, and solidifying agents suitable for treating musculoskeletal pain or inflammation. 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, wherein the non-volatile solvent system is therapeutically effective Can facilitate the dermal delivery of the drug over a sustained period of time. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. A further step is to solidify the formulation by at least partial evaporation of a volatile solvent system to form a solidified layer on the skin surface; then a therapeutically effective rate to treat joint or muscle pain or inflammation And dermal delivery of the drug from the solidified layer to the skin surface for a duration of time.

  In another embodiment, a solidified layer for treating musculoskeletal pain or inflammation can include a drug effective to treat musculoskeletal pain or inflammation, a non-volatile solvent system, and a solidifying agent. The non-volatile solvent system can include at least one non-volatile solvent, wherein the non-volatile solvent system can facilitate delivery of the drug over a period of time at a therapeutically effective rate. In addition, the solidified layer can be stretched 5% in at least one direction without cracking, breaking and / or separating from the skin surface to which it is applied.

In another embodiment, a formulation for treating musculoskeletal pain or inflammation can include ropivacaine, 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 solvent selected from the group consisting of triacetin, Span 20, isostearic acid, or combinations thereof. be able to. Ropivacaine can be in either base or salt form. The formulation has a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and is delivered to the skin surface and solidified after at least partial evaporation of the volatile solvent system Flexible, flexible and continuous layers can be formed. Further, ropivacaine can be delivered continuously with a transdermal flux of at least 5 mcg / cm ² / hour after at least substantially all of the volatile solvent system has evaporated. In another embodiment, the transdermal flux can be at least 10 mcg / cm ² / hour after the volatile solvent system has evaporated at least substantially all from the solidified layer.

In another embodiment, a formulation for treating musculoskeletal pain or inflammation can include lidocaine, a solvent excipient, and a solidifying agent. The solvent excipient may comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol and dipropylene glycol. Lidocaine can be in either base or salt form. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system, applied to the skin surface and solidified after at least partial evaporation of the volatile solvent system; A coherent, flexible and continuous layer can be formed. Lidocaine can be delivered continuously with a transdermal flux of at least 20 mcg / cm ² / hour after the volatile solvent system has evaporated at least substantially all from the solidified layer.

In another embodiment, a formulation for treating musculoskeletal pain or inflammation can include ketoprofen, a solvent excipient, and a solidifying agent. The solidifying agent can comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol and glycerol, isostearic acid, and triacetin. . Ketoprofen can be in either base or salt form. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and is applied to the skin surface to solidify after at least partial evaporation of the volatile solvent system. Thus, a coherent, flexible and continuous layer can be formed. Ketoprofen can be delivered continuously with a transdermal flux of at least 10 mcg / cm ² / hour after the volatile solvent system has evaporated at least substantially all from the solidified layer.

In yet another embodiment, a formulation for treating musculoskeletal pain or inflammation can include tetracaine, a solvent excipient, and a solidifying agent. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent system and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol and isostearic acid. Tetracaine can be in either base or salt form. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and applied to the skin surface to solidify after at least partial evaporation of the volatile solvent system. A coherent and flexible continuous layer can be formed. Tetracaine can be continuously delivered at a transdermal flux of at least 5 mcg / cm ² / hour after the volatile solvent system has evaporated at least substantially all from the solidified layer.

In yet another embodiment, a formulation for treating musculoskeletal pain or inflammation can include lidocaine and tetracaine, 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 solvent selected from the group consisting of propylene glycol and dipropylene glycol, and isostearic acid. Can do. Tetracaine and lidocaine can be in either base or salt form. The formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system and applied to the skin surface to solidify after at least partial evaporation of the volatile solvent system. Cohesive, flexible and continuous layers can be formed. Tetracaine and lidocaine can each be delivered continuously at a transdermal flux of at least 5 mcg / cm ² / hour, respectively, after the volatile solvent system has evaporated at least substantially all from the solidified layer.

  In another embodiment, the formulation for treating musculoskeletal pain or inflammation comprises a drug comprising at least one member selected from the group consisting of lidocaine, tetracaine, ropivacaine, ketoprofen, diclofenac, or combinations thereof; solvent An excipient; and a solidifying agent. The solvent excipient may comprise a volatile solvent system comprising a volatile solvent whose boiling point is less than 20 ° C. 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 prior to evaporation of the volatile solvent system and is applied to the skin surface to solidify after at least partial evaporation of the volatile solvent system. A coherent, flexible and continuous layer can be formed. The drug can be continuously delivered at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  In another embodiment, a formulation for treating neuropathic pain can include drugs, solvent excipients, and solidifying agents suitable for treating neuropathic pain. 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 non-volatile solvent system facilitates dermal delivery of the drug over a duration at a therapeutically effective rate. The formulation can have a viscosity suitable for application and adhesion to the skin surface as a layer prior to evaporation of the volatile solvent system. Formulations applied at the skin surface can form a solidified layer after at least partial evaporation of the volatile solvent system. Further, the drug can be continuously delivered at a therapeutically effective rate after the volatile solvent system is at least substantially evaporated.

  In another embodiment, a method of treating neuropathic pain can include applying a layer of adhesive formulation to a subject's skin surface. The formulation can include drugs suitable for treating neuropathic pain, solvent excipients, and solidifying agents. 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 non-volatile solvent system facilitates dermal delivery of the drug over a duration at a therapeutically effective rate. The formulation can have a viscosity suitable for application and adhesion to the skin surface prior to evaporation of the volatile solvent system. Further steps solidify the formulation by at least partial evaporation of the volatile solvent system to form a solidified layer on the skin surface; then target the drug from the solidified layer for a duration at a therapeutically effective rate. Dermal delivery to reduce neuropathic pain.

  In another embodiment, a solidified layer for treating neuropathic pain can include a drug suitable for neuropathic pain, a non-volatile solvent system suitable for the drug, and a solidifying agent. The solidified layer should have sufficient elasticity, flexibility, and adhesion to the skin so that it does not separate from the skin even when the skin surface is stretched or bent during the subject's normal daily activities Can do. For example, a solidified layer can be stretched 5% in one direction without cracking, breaking, and / or separating from the skin surface to which it is applied.

  In another embodiment, a formulation for treating neuropathic pain can include ropivacaine, a solvent excipient, and a solidifying agent. The solvent excipient can comprise a volatile solvent system comprising at least one volatile solvent, and the non-volatile solvent system is selected from the group consisting of an amine base, triacetin, Span 20, isostearic acid, or mixtures thereof. At least one solvent. The solidifying agent can include a copolymer of butyl methacrylate and methyl. The formulation can have a viscosity suitable for application to the skin surface as a layer prior to evaporation of the volatile solvent system. Further, the formulation layer applied to the skin surface can form a coherent, flexible and continuous layer that has solidified after at least partial evaporation of the volatile solvent system. Ropivacaine can be delivered continuously at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  In another embodiment, a formulation for treating neuropathic pain associated with a viral infection can comprise a drug, a solvent excipient, and a solidifying agent. The drug can comprise at least one member selected from the group consisting of acyclovir, rosecyclovir, and pencyclovir. 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 solvent selected from the group consisting of oleic acid, isostearic acid, and olive oil. . The solidifying agent can be selected from the group consisting of ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer, butyl methacrylate and methyl copolymer, and ethyl cellulose. The formulation can have a viscosity suitable for application to the skin surface as a layer prior to evaporation of the volatile solvent system. Furthermore, formulations applied to the skin surface can form a coherent, flexible and continuous layer that has solidified after at least partial evaporation of the volatile solvent system. The drug can also be delivered continuously at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  In another embodiment, a formulation for treating neuropathic pain can include a local anesthetic selected from the group consisting of lidocaine, tetracaine, and combinations thereof; a solvent excipient; and a solidifying agent. . The solvent excipient may comprise a volatile solvent system comprising at least one volatile solvent and a non-volatile solvent system comprising at least one solvent selected from the group consisting of propylene glycol and dipropylene glycol. The local anesthetic can be in either base or salt form and the formulation can have a viscosity suitable for application to the skin surface prior to evaporation of the volatile solvent system. The formulation applied to the skin surface can form a solidified, cohesive, flexible and continuous layer after at least partial evaporation of the volatile solvent system, the local anesthetic being After the volatile solvent system is at least substantially all evaporated, it can be delivered continuously at a therapeutically effective rate.

  In another embodiment, a formulation for treating neuropathic pain can comprise a drug selected from the group consisting of amitriptyline, ketamine, and combinations thereof; 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 to the skin surface prior to evaporation of the volatile solvent system. The formulation applied to the skin surface can form a solidified, cohesive, flexible and continuous layer after at least partial evaporation of the volatile solvent system. Further, the drug can be continuously delivered at a therapeutically effective rate after the volatile solvent system is at least substantially all evaporated.

  In another embodiment, the formulation for treating neuropathic pain is a drug selected from the group consisting of lidocaine, tetracaine, ropivacaine, amitriptyline, ketamine, and combinations thereof; solvent excipients; and solidifying agents Can be included. The solvent excipient may comprise a volatile solvent system comprising a volatile solvent whose boiling point is less than 20 ° C. 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 prior to evaporation of the volatile solvent system and, when applied to the skin surface, solidifies after at least partial evaporation of the volatile solvent system. A coherent, flexible continuous layer can be formed. The drug can be delivered continuously at a therapeutically effective rate after at least substantially all of the volatile solvent system has evaporated.

  Thus, the present invention relates to novel formulations, methods, and solidified layers that are typically semisolid initial forms (including creams, gels, pastes, ointments, and other viscous liquids). Can be easily applied to the skin as a layer, quickly (15 seconds to 4 minutes under standard skin and ambient conditions) to moderately fast (4 to 15 minutes under standard skin and ambient conditions) It can be transformed into a solidified layer for drug delivery to reduce musculoskeletal pain, for example a coherent and flexible solidified layer. The solidified layer thus formed allows the drug to be skinned for a sustained period of time, for example several hours to several tens of hours, so that most of the drug delivery occurs after the solidified layer is formed. It can be delivered into or across the skin. In addition, the solidified layer typically adheres to the skin, but is formed relatively shortly after application and moves substantially to clothing or other objects that the subject wears or can be inadvertently contacted with. It has a solidified, minimally adhesive outer surface that does not or otherwise does not soil it. The solidified layer is applied even if the skin stretches during physical movement, such as the knee, fingers, elbows, wrists, fingers, buttocks, neck, back, joints, or other areas where the skin typically stretches. It can also be formulated to be highly flexible and extensible and thus maintain good contact with the skin surface.

  Certain variables can be considered in selecting or formulating the various ingredients that can be used, for example, 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. In another embodiment of the invention, the volatile solvent system is iso-amyl acetate, denatured alcohol, methanol, propanol, isobutene, pentane, hexane, chlorobutanol, turpentine, cytopentasiloxane, cyclomethicone, methyl ethyl ketone, or the like. Combinations can be included. The volatile solvent system can comprise a mixture or combination of any of the volatile solvents described in the previous embodiments.

  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 on the skin. For most formulations, the volatile solvent weight percentage can be from about 10 wt% to about 85 wt%, more preferably from about 20 wt% to about 50 wt%.

  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. For example, the solidifying agent can be selected such that it is dispersible or soluble in the non-volatile solvent system. 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 in glycerol (non-volatile solvent) and water (volatile solvent) It 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 at the same time use PVA as a solidifying agent, a non-solvent system containing PEG 400 and glycerol (compatible with PVA) in an appropriate ratio can be formulated, Achieve a compromise of compatibility. 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 separates from the formulation and forms an oily layer on the surface of the solidified layer. Thus, the selection of a suitable solidifying agent / nonvolatile solvent is desirable to develop vigorous formulations and compatible combinations.

  The non-volatile solvents that can be used alone or in combination to form the non-volatile solvent system can be selected from a variety of pharmaceutically acceptable liquids. 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 monooleate, 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, grape seed oil fatty acids, 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, 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, diethyleneglycol Lumonoethyl 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, candelilla wax, carnau Wax, 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-diolate, PEG fatty acid diesters such as PEG-distearate, PEG-castor oil, glyceryl behenate, PEG glyceryl laurate, PEG glyceryl stearate, PEG glycerol such as PEG glyceryl oleate Fatty acid ester, hexylene glycerol, lanolin, lauric acid diethanolamide, lauryl lactate, lauryl sulfate, medronic acid, methacrylic acid, multisterol extract, myristic PEG-sorbitan such as alcohol, neutral oil, PEG-octylphenyl ether, PEG-cetyl ether, PEG-alkyl ether such as PEG-stearyl ether, PEG-sorbitan diisostearate, PEG-sorbitan monostearate Fatty acid esters, propylene glycol fatty acid esters such as propylene glycol stearate, propylene glycol, caprylate / caprate, sodium pyrrolidonecarboxylate, sorbitol, squalene, stear-o-wet, triglycerides, alkylaryl poly Ether alcohol, polyoxyethylene derivatives of sorbitan-ether, saturated polyglycolated C8-C10 glycerides, N-methylpyrrolidone, honey, poly Oxyethylated glycerides, dimethyl sulfoxide, azone and related compounds, dimethylformamide, N-methylformamide, fatty acid esters, fatty alcohol ethers, alkyl-amides (N, N-dimethylalkylamide), N-methylpyrrolidone related compounds, ethyl oleate Polyglycerolated 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, pyroglutamate sodium, avicinica 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, or combinations thereof. In still further embodiments, the non-volatile solvent system can comprise a combination or mixture of non-volatile solvents as described in any of the previously discussed embodiments.

  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. It can also act as a plasticizer in adhesive formulations. The plasticizer also has the ability to reduce the brittleness of the solidified formulation by making it more flexible and / or elastic. For example, polyethylene glycol is a plastic non-volatile solvent for a solidified layer comprising polyvinylalkylol as the selected solidifying agent and ketoprofen as the drug. However, propylene glycol in solidifying formulations containing Gantrez S-97 or Avalure UR 405 as a solidifying agent does not provide the same plastic effect. Therefore, whether a given non-volatile solvent is “plastic” or not depends on which solidifying agent is selected.

  Certain volatile and / or non-volatile solvents that are irritating to the skin may be desirable to use to achieve the desired solubility and / or permeability of the drug. It is also desirable to add compounds that can both interfere with 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 are not independently suitable non-volatile solvents for drugs, but may contain two or more non-volatile solvents that, when formulated together, become suitable non-volatile solvents. good. One possible reason for making these suitable non-volatile solvents when formulated together with these initially unsuitable non-volatile solvents is by optimizing the ionization state of the drug to a physical form with a higher flux Or the non-volatile solvent acts in some other synergistic manner. One further advantage of mixing the non-volatile solvent is that it can optimize the pH of the formulation, or skin tissue under the formulation layer, to minimize irritation. Examples of suitable combinations of non-volatile solvents that provide a suitable non-volatile solvent system include, but are not limited to, isostearic acid / trolamine, isostearic acid / diisopropylamine, oleic acid / trolamine, and propylene glycol / isostearic acid. Including.

  The selection of the solidifying agent can also be made taking into account other components present in the adhesive formulation. Suitable solidifying agents are those in which the formulation is in a liquid or semi-solid state (eg, cream, paste, gel, ointment) prior to evaporation of any volatile solvent and is soft after at least some evaporation of the volatile solvent. It is compatible with the formulation to be a coherent, adhesive solidified layer. The solidified layer is compatible with the drug and solvent excipients (including volatile and non-volatile solvent systems) and provides the desired physical properties for the solidified layer once it is formed. Can be selected or prescribed. Depending on the drug, solvent excipient, and / or other ingredients that may be present, the solidifying agent can be selected from a variety of agents. In one embodiment, 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, MW greater than 5,000, or Eudgr ag RLPO (Degussa) ethyl acrylate-methyl methacrylate-trimethylammonioethyl chloride copolymer with MW greater than 5,000 like zein with a MW of about 35,000 Zein (prolamin), pregelatinized starch with MW similar to Instant Pure-Cote B793, MW greater than 5,000, or Aqualon EC N7, N10, N14, N22, N50 or Ethylcellulose with MW similar to N100 (Hercules), Fish gelatin with MW 20,000 to 250,000 (Norland Products) ), Gelatin, other animal sources with MW greater than 5,000, MW greater than 5,000 or acrylate / octylacrylamide copolymers with MW similar to National Starch and Chemical Dermalyl 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 It can include pyrrolidone, polyisobutylene rubber, polyvinyl acetate, phthalate, or combinations thereof. In a further embodiment, the solidifying agent is ammonia methacrylate, carrageenan, aqueous cellulose acetate phthalate such as CAPNF from Eastman, carboxypolymethylene, cellulose acetate (microcrystalline), cellulose polymer, divinylbenzene styrene, ethylene vinyl acetate, Silicone, guar 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, trimethyl Siloxysilicate, maleic acid / anhydride copolymer, poracrine, poloxamer, polyethylene oxide, polygalactic acid / Li-lactic acid, turpentine resin, locust bean gum, acrylic copolymer, polyurethane dispersion, dextrin, polyvinyl alcohol-polyethylene glycol copolymer, methacrylic acid-ethyl acrylate copolymer such as BASF's Kollicoat polymer, methacrylic acid and It may include a methacrylate polymer such as poly (methacrylic acid), or a combination thereof. In another embodiment, the solidifying agent can comprise a combination of solidifying agents described in any of the previously discussed embodiments. Other polymers may still be suitable as solidifying agents depending on the components of the solvent excipient, the drug, and the specific functional requirements of a given formulation. Other polymers may still be suitable as solidifying agents, depending on the components of the solvent excipient, the drug, and the specific functional requirements of a given formulation.

  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 adhesion 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 copolymers of methyl vinyl ether and maleic anhydride (Gantrez polymer), copolymers of polyethylene glycol and polyvinyl pyrrolidone, gelatin, low molecular weight polyisobutylene rubber, acrylic sunalkyl / octyl Copolymers of acrylamide (Dermacryl 79), and various aliphatic and aromatic resins.

  The non-volatile solvent system and the solidifying agent are preferably compatible with each other. Compatibility is that i) the solidifying agent does not substantially negatively affect the function of the non-volatile solvent system; ii) the non-volatile solvent system does not allow the non-volatile solvent to escape the layer. Can be retained in the solidified layer, and iii) the solidified layer formed with the selected non-volatile solvent system and solidifying agent has acceptable flexibility, stiffness, tensile tension, elasticity, and adhesion; it can. The weight ratio of non-volatile solvent system to solidifying agent can be from about 0.1: 1 to about 10: 1, or from about 0.5: 1 to about 2: 1.

  The thickness of the formulation layer applied to the skin should still 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 long time desired. If the layer is too thick, it will take too long to form a non-messy outer surface of the solidified layer. If the drug is very good and the solidified layer has a very high tension, a layer as thin as 0.01 mm would be sufficient. If the drug has rather low capacity and the solidified layer has low tension, a layer as thick as 2-3 mm would be required. Thus, for most drugs and formulations, a suitable thickness may be from about 0.01 mm to about 3 mm, more typically from about 0.05 mm to about 1 mm.

  In some embodiments, the flexibility and extensibility of the solidified layer, or optionally solidified peelable layer, may be desirable. Skin areas on joints and certain muscle groups often stretch considerably during body movements. Such movement prevents the non-extensible patch from maintaining good skin contact. Lotions, ointments, creams, gels, pastes, etc. would also not be suitable for use for the above reasons. As such, in transdermal delivery of NSAIDs and other drugs for treating musculoskeletal pain in joints and / or muscles, the solidifying formulations of the present invention can provide unique advantages and benefits.

  A further feature of solid-forming formulations relates to the drying time. If the formulation dries too quickly, the user cannot have enough time to spread the formulation into a thin layer on the skin surface before the formulation solidifies, resulting in poor skin contact . If the formulation dries too slowly, the subject will need to wait a long time before resuming normal activities (eg, wearing) that can 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 4 minutes.

  Another feature of the formulations of the present invention is a drug for joint or muscle musculoskeletal pain or inflammation, a non-volatile solvent system comprising at least one non-volatile solvent, a solidifying agent, and a boiling point of less than 20 C. It relates to a solidifiable formulation comprising a volatile solvent system comprising a volatile solvent (such solvent is referred to as a gas volatile solvent). The formulation can be stored in a compressed container and sprayed onto the skin surface with the aid of gaseous volatile solvents. Hydrofluorocarbons as commonly used as gaseous volatile solvents in the pharmaceutical or cosmetic industry can work in this design, more specifically, gaseous volatile solvents include, but are not limited to, dimethyl ether, Butane, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,3,3,3 hexafluoropropane Or a mixture thereof. The formulation can be drained from the container and applied to the skin via a manual pump. Formulations containing gaseous volatile solvents are expected to “dry” fairly quickly. Spraying the formulation onto joint or muscle musculoskeletal pain or inflammation skin avoids skin contact with an applicator that can cause discomfort to sensitive skin and is inconvenient to reach with an applicator An easier means of application of the formulation to the body surface can be provided.

  The formulations of the present invention can further comprise a pH modifier to adjust the pH of the formulation to the point or range most suitable for drug delivery. This feature can be important for ionizable drugs.

  The adhesion to the skin and the elasticity of the material are such that the solidified layer cannot be easily separated from the skin. For example, in one embodiment, the solidified layer can extend in at least one direction up to about 5% or even 10% or more without cracking, breaking or separating from the skin surface to which the solidified layer has been applied.

  These and other advantages can be summarized by the following non-limiting application embodiments. The solidified formulation of the present invention can be prepared in an initial form that is easy to apply as a semi-solid dosage form. In addition, the dosage form can be applied to be relatively thick and can contain drugs that are significantly more active than typical layers such as traditional creams, gels, lotions, ointments, pastes, etc. Not exposed to unintentional removal. After evaporation of the volatile solvent and formation of the solidified layer, the drug in the solidified layer can be delivered at a desired delivery rate over a period of time. Furthermore, since the solidified layer remains adhesive and can be peeled off, easy removal of the solidified layer can usually occur without the aid of a solvent or surfactant. 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 fairly 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 without cracking, breaking and / or separation from the skin surface to which the solidified layer is applied. 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 ketoprofen, diclofenac, or another NSAID, or lidocaine, ropivacaine, or another local anesthetic is applied to joints such as ankles, knees, wrists, back, hips, and fingers. Can be prescribed to treat acute injuries. In another embodiment, treating a chronic disorder such as arthritis-induced pain (including osteoarthritis and rheumatoid arthritis) of the finger and / or toe joints using a solidified layer comprising the same active drug Can do.

  Yet another embodiment is selected from NSAID classes such as ketoprofen, piroxicam, diclofenac, and indomethacin applied topically to treat symptoms of back pain, muscle tension, or fascial pain or a combination thereof Including drug-containing formulations. NSAIDs are gradually released from the formulation to provide pain relief over 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 without leaving a formulation remaining on the skin surface.

  In another embodiment, solidifying formulations for the delivery of drugs that treat the causes or symptoms of joint and muscle related diseases can also benefit from the systems, formulations, and methods of the present invention. . Such diseases that can be applied include, but are not limited to, osteoarthritis (OA), rheumatoid arthritis (RA), various other causes of joint and skeletal pain, fascial pain, muscle pain, And including sports injuries. Drugs or drug classes that can be used for such applications include, but are not limited to, non-steroidal anti-inflammatory drugs (NSAIDs) such as ketoprofen, piroxicam, diclofenac, and indomethacin; COX inhibitors, COX-2 selective NSAIDs and agents, COX inhibitors such as COX-3 selective NSAIDs and agents; local anesthetics such as lidocaine, bupivacaine, ropivacaine, and tetracaine; 5HT such as ketanserin -2A receptor antagonists; steroids such as dexamethasone, hydrocortisone, prednisone, prednisolone, methylprednisolone, halobetasol propionate, betamethasone dipropionate, betamethasone, prodrugs thereof, or combinations thereof Including.

The solidifying formulations and methods of the present invention are useful for treating inflammation and / or pain of toes, wrists, ankles, elbows, and particularly small joints such as fingers, and chronic musculoskeletal pain not necessarily associated with inflammation. It is expected to be particularly useful. Since the path from the skin surface to the joint is shorter for smaller joints, it appears that a therapeutically effective amount of drug reaches the small joints before they are taken into the blood circulation. In addition, since fingers are often used, bent, and contact many objects during normal activities, it is difficult to keep conventional dosage forms or formulations such as patches or creams on the fingers. is there. In addition, some physical therapy devices such as the ThermoCare ^™ heating pad are too large for the finger joint. Thus, there are many unsatisfied demands for treating finger joint pain or inflammation. By applying the drug formulation to the skin present on the affected joint or muscle, the drug penetrates the skin and directly enters the target tissue (before being removed by blood circulation) and is associated with harmful side effects A therapeutic local tissue concentration can be achieved without causing a fairly high systemic drug concentration. Under such a scenario, the drug is delivered to the tissues of smaller joints, including the wrists, elbows, ankles, toes and especially the finger joints, because of the short pathway between the skin surface and the small joints, And will be easier than that of larger joints such as the buttocks. Thus, one method of the present invention uses solidifying formulations containing NSAIDs, local anesthetics and / or steroids to treat inflammation or pain in small joints, particularly finger joints. As stated above, treatment of larger joints or areas of the body, such as the back, neck, shoulders or buttocks, can also be performed and is still effective. Another embodiment includes a solidifying formulation containing a drug from the class of alpha-2 antagonists applied topically to treat neuropathic pain. The alpha-2 agonist is gradually released from the formulation to provide pain relief over time. The formulation can be a coherent, flexible solid and remains adhered to the body surface for the length of application. It is easily removed after drying without leaving any remaining formulation on the skin surface.

  Another embodiment includes a 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 be a coherent, soft solid and remains adhered to the body surface for the length of application. It is easily removed at any time after drying without leaving any remaining formulation on the skin surface.

  Further embodiments provide solidified formulations containing at least one alpha-2 agonist drug, at least one tricyclic antidepressant, and / or at least one local anesthetic applied topically to treat neuropathic pain. Including. The drug is gradually released from the formulation to provide pain relief over time. The formulation can be a coherent, soft solid and remains adhered to the body surface for the length of application. It is easily removed at any point after drying without leaving a residual formulation on the skin surface.

  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 are used to treat neuropathic pain, such as pain caused by postherpetic neuralgia. Due to the limitations of the patches discussed above, the solidified layer tailored according to the present invention offers several unique benefits, as well as providing a potentially inexpensive alternative to the use of such patches. Possible drugs delivered for such applications include, but are not limited to, local anesthetics such as lidocaine, prilocaine, tetracaine, bupivicaine, etidocaine; ketamine, amitriptyline, capsaicin, tricyclic antidepressants , Other drugs, including alpha-2 agonists such as clonidine, or combinations thereof.

In one embodiment, the drug can be an antiviral agent and the solidified layer can produce an antiviral flux of at least 2 mcg / cm ² / h. In another embodiment, the drug can be a local anesthetic and the solidified layer can produce a local anesthetic flux of at least 5 mcg / cm ² / h. In another embodiment, the drug can be an alpha-2 agonist and the solidified layer can produce a flux of alpha-2 agonist of at least 1 mcg / cm ² / h. In another embodiment, the drug can produce a capsaicin flux of at least 5 mcg / cm ² / h. In still further embodiments, the drug is ketamine and the solidified layer is capable of producing a ketamine flux of at least 1 mcg / cm ² / h.

  The solidifying formulation of the present invention comprising two or more active drugs can provide further advantages. For example, a formulation for treating neuropathic pain according to the present invention can include lidocaine and tetracaine. Lidocaine and tetracaine can be present in either salt or base form. Preferably, the non-volatile solvent system comprises at least one of propylene glycol and dipropylene glycol, and isostearic acid. Similar formulations can include other combinations of drugs such as amitriptyline and ketamine, amitriptyline and local anesthetics.

  As a further note, it is a unique feature of the solidified layer of the present invention that it can maintain on the body surface a substantial amount of a non-volatile solvent system optimized to deliver the drug. This feature can provide unique advantages over existing products. For example, in some semi-solid formulations, upon application to the skin surface, the volatile solvent evaporates quickly and the formulation layer solidifies into a hard lacquer layer. Drug molecules are anchored in the hard lacquer layer and are substantially unavailable for delivery to the skin surface. As a result, drug delivery is not believed to be sustained over time. In contrast to this type of formulation, the solidified layer formed using the formulation of the present invention keeps the drug molecules moving fairly in a non-volatile solvent system in contact with the skin surface, thus Ensures sustained delivery.

  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 is initiated by placing the test formulation on the keratinized layer (SC) of the skin sample. Franz cells are 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 cumulative amount of penetration-vs-time plot. It should be noted that human cadaver skin can be used as a model membrane for in vitro flux experiments as well. The placement of the skin and the sampling technique used is similar to that described above for the HSM experiment.

Example 2
Evaluate formulations of ropivacaine (the main drug) in various non-volatile solvent systems. Excess ropivacaine is present. The penetration of ropivacaine from the test formulation through HMS is shown in Table 2 below.

前記不揮発性溶媒からのロピバカイン主薬の定常状態フラックスは、２００ｍｃＬを、無毛マウス皮膚の角化層側（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に記載されているように行う。表２から、不揮発性溶媒グリセロール、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り、許容できるピール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のための良好な候補である。驚くべきことに、Ｓｐａｎ ２０はかなり高い定常状態フラックス値を有し、やはり、高フラックス化可能溶媒としての資格があろう。

The steady state flux of ropivacaine active agent from the non-volatile solvent is obtained by placing 200 mcL on the cornified layer side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 2, the non-volatile solvents glycerol and Tween 20 will have low steady state flux values and will 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 peel formulations. Surprisingly, Span 20 has a fairly high steady state flux value and will again qualify as a highly fluxable solvent.

Example 3
Evaluate formulations of diclofenac sodium 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 3 below.

前記不揮発性溶媒からのジクロフェナクナトリウムの定常状態フラックスは、無毛マウス皮膚の角化層側（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に記載したように行われる。表３より、不揮発性溶媒グリセロールは、１ｍｃｇ／ｃｍ^２／ｈの見積もられた治療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Ｓｐａｎ ２０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倍であって、フラックス化可能と考えられる。

The steady state flux of diclofenac sodium from the non-volatile solvent is obtained by placing 200 mcL on the cornified layer side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 3, the non-volatile solvent glycerol has a steady-state flux value comparable to the estimated therapeutic steady-state flux value of 1 mcg / cm ² / h and can be considered a fluxable solvent. However, the steady state flux values of isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are at least 10 times the flux values reported for glycerol and are considered feasible.

Example 4
Evaluate diclofenac acid formulations in various non-volatile solvent systems. Excess diclofenac acid is present. The penetration of diclofenac from the test formulation through the HMS is shown in Table 4 below.

前記不揮発性溶媒からのジクロフェナク酸の定常状態フラックスは、２００ｍｃＬを無毛マウス皮膚の角化層側（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４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、フラックス化可能な不揮発性溶媒の活力が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Ｓｐａｎ ２０の定常状態フラックス値は、現在利用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た。前記不揮発性溶媒の各々からのジクロフェナク酸についての定常状態フラックスは、ジクロフェナ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を増加させる必要があれば、フラックス化可能な不揮発性溶媒およびジクロフェナクの塩形態の利用は、ジクロフェナクの酸形態を用いるよりも高い定常状態フラックス値を生じるであろう。

A steady state flux of diclofenac acid from the non-volatile solvent is obtained by placing 200 mcL on the cornified layer side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 4, the non-volatile solvent glycerol does not have a reported steady state flux value and is not considered a non-volatile solvent candidate with the viability of a non-fluxable non-volatile solvent. However, the steady-state flux values of isopropyl myristate, ethyl oleate, propylene glycol, and Span 20 are less than 10 times the flux values reported for currently available commercial products and as such are fluxable solvents. I was able to think. It should be noted that the steady state flux for diclofenac acid from each of the non-volatile solvents is significantly lower than the steady state flux value obtained with diclofenac sodium. Thus, if it is necessary to increase the therapeutically effective flux value, use of a fluxable non-volatile solvent and the salt form of diclofenac will result in a higher steady state flux value than using the acid form of diclofenac. Let's go.

Examples 5 to 7
The prototype peel formulation is adjusted as follows. Some peel formulations are prepared according to embodiments of the present invention according to Table 5 as follows.

実施例５から７のピール処方物は以下の様式で調製する；
−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、Ｅｕｄｇｒａｇｉｔ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。
−得られた溶液を激しく十分に数分間混合する。
−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 peel formulations of Examples 5-7 are prepared in the following manner;
-The solidifying agent is dissolved in a volatile solvent (e.g. 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.
-Vigorously mix the resulting solution vigorously for several minutes.
-The drug is then added and the peel formulation is mixed again for a few minutes.

  In all of the above examples, the fluxable non-volatile / solidifying agent / volatile solvent combination provides a suitable single drying time and provides a homogeneous, single-piece with a stretchable peel and steady state flux for the drug. It is compatible as demonstrated by the phase system (see Example 8 below).

Example 8
Example formulations are tested in the hairless mouse skin (HMS) or human epidermis (HEM) in vitro model described in Example 1. Table 6 shows the data obtained using the experimental process described above.

表６中の全ての場合において、処方物におけるフラックス化可能な不揮発性溶媒の結果、実験した処方物の各々について治療上有効なフラックスが得られた。

In all cases in Table 6, the fluxable non-volatile solvent in the formulation resulted in a therapeutically effective flux for each of the formulations tested.

  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 were similar to those described in Examples 6 and 7. In these special embodiments, steady state delivery is shown over 28 hours and 30 hours, respectively.

Example 9
Placebo with the following composition: 10.4% polyvinyl alcohol, 10.4% polyethylene glycol 400, 10.4% polyvinylpyrrolidone K-90, 10.4% glycerol, 27.1% water, and 31.3% ethanol. The formulation was applied to the human skin surface at the elbow and finger joints, resulting in a thin, transparent, flexible and stretchable film. After several minutes of evaporation of volatile solvents (ethanol and water), a peelable solidified layer was formed. The stretchable peel had good adhesion to the skin and, when bent, did not separate from the skin on the joint and could be easily peeled off from the skin. The addition of active drug to this placebo formulation is not expected to significantly change the physical properties of the initial formulation or solidified layer. This is because the concentration of active drug as a percentage of the total weight of the formulation is typically small.

Examples 10 to 12
The three formulations are applied to the keratinized layer side of freshly separated hairless mouse skin. In vitro flux is determined for each formulation as outlined in Example 1. The composition of the formulation is shown in Table 7 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に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、実施例１０はフラックス化可能で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 non-fluxable fluxable solvent is used, and for ropivacaine HCl it is reasonable to conclude that Example 10 can be fluxed.

Examples 13 to 14
A peel-forming formulation for dermal delivery of ropivacaine is prepared, which includes a specific amount of ropivacaine in an excipient mixture to form an adhesive formulation according to embodiments of the present invention. The peel formulation contained the following composition;

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１３および１４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９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 in vitro flux experiments performed with the formulations in Examples 13 and 14 is listed in Table 9.

実施例１３および１４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１３および１４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 13 and 14, ethanol is used as the volatile solvent and ISA, glycerol, and PG mixture are 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 13 and 14 demonstrates the importance of the non-volatile solvent in commanding the flux-forming power of the entire formulation.

Example 15
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 16
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.

Example 17
The formulation prepared according to Example 16 was applied to HMS as described in Example 1 and ropivacaine flux was measured. A summary of the results is listed in Table 12 as follows.

実施例１６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で伸ばすことの容易性などを有し、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。固化層は２時間以内により容易に剥離可能となり、該ピールは、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無くして皮膚表面に付着したままである。意図した使用の最後に、ピールは１つの連続的破片で容易に除去される。

The ropivacaine peel formulation prepared according to Example 16 has acceptable application properties, such as ease of removal of peel from the sample tube, ease of stretching at the intended skin application site, and the like. A solidified film is formed 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 layer becomes more 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 with one continuous piece.

Example 18
A solidifying formulation is prepared for dermal delivery of lidocaine (the active ingredient), which includes a saturating amount of lidocaine in an excipient mixture to form an adhesive formulation in accordance with an embodiment of the present invention. Peel formulations are prepared from the ingredients shown in Table 13.

本実施例１８におけるリドカイン処方物の接着性処方物は、先に述べた実施例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でき、定常状態送達は８時間にわたって維持される。

The adhesive formulation of lidocaine formulation in this Example 18 has physical properties similar to the previously described examples. Transdermal flux across hairless mouse skin is acceptable and steady state delivery is maintained for 8 hours.

Examples 19 to 22
A solidifying formulation for dermal delivery of ropivacaine is prepared, which includes an excipient mixture to form an adhesive solidifying formulation according to embodiments of the present invention. Peel formulations are prepared from the ingredients shown in Table 15.

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 15 were applied to HMS according to Example 1 and ropivacaine flux was measured. The results are summarized in Table 16.

実施例１９から２２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２０から２２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 19 to 22 show the importance of the triacetin, isostearic acid, Span 20 combination in the formulation. In Examples 20 to 22, 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 23
The solidifiable formulation has the following ingredients in parts by weight:

この処方物においては、ポリビニルアルコール（ＡｍｒｅｓｃｏからのＵＳＰグレードＭＷ ３１，０００から５０，０００）が固化剤であり、エチルセルロースおよびＤｅｒｍａｃｒｙｌ ７９は補助的な固化剤である。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形成し、他方、エタノールおよび水は揮発性溶媒系を形成する。ロピバカインは薬物である。

In this formulation, polyvinyl alcohol (USP grade MW 31,000 to 50,000 from Amresco) is the solidifying agent, and ethylcellulose and Dermacryl 79 are auxiliary solidifying agents. Isostearic acid and glycerol form a non-volatile solvent system, while ethanol and water form a volatile solvent system. Lopivacaine is a drug.

Method to create a prescription:
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 the aforementioned mixtures together in one container, add glycerol and mix the entire 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-tacky surface is formed in less than 2 minutes.

Examples 24 to 27
An extensible adhesive formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin to treat joint and muscle inflammation or pain) is prepared, which is saturated in the excipient mixture Of ketoprofen (more ketoprofen than can be dissolved in the excipient mixture) to form an adhesive formulation, some of which is prepared according to embodiments of the present invention. An excipient mixture, a viscous and clear fluid, is prepared using the ingredients shown in Table 18.

実施例２４から２７の組成物の各々を、以下のように、表１９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 24 to 27 was examined for ketoprofen flux as shown in Table 19 as follows:

実施例２４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２４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、この実施形態において、グリセロールおよびＰＥＧ ４００は、揮発性溶媒の蒸発の後に形成された接着性処方物において可塑剤としても働く。グリセロールおよびＰＥＧ４００の存在なくして、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。

For the formulation described in Example 24, 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 24, PVA and PVP act as solidifying agents. Furthermore, in this embodiment, glycerol and PEG 400 also act as plasticizers in the adhesive formulation formed after evaporation of the volatile solvent. In the absence of glycerol and PEG 400, the film formed by PVA and PVP alone will be rigid and non-extensible.

  For the formulation of Example 25, the adhesive peelable formulation formed has the same physical properties as that of Example 24, but the transdermal flux across the hairless mouse skin is higher. This suggests that the solidifying agent, 1: 1 PVA: PVP-K-90 in Example 24 and pure PVA in Example 25 have an impact on penetration.

  The formulation in Example 26 delivers less ketoprofen than the formulation of Example 24 or 25. The formulation of Example 27 delivers significantly less ketoprofen than the formulations in Examples 24 and 25. 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 25, 26 and 27, respectively, relates to the non-volatile solvent system, more specifically the weight ratio of PEG 400: glycerol. These results reflect the impact of non-volatile solvent systems on skin flux.

Example 28
An extensible adhesive formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin to treat joint and muscle inflammation or pain) is prepared, which includes ketoprofen in an excipient mixture. Including to form an adhesive formulation, some of which are prepared according to embodiments of the present invention. Peel formulations are prepared from the ingredients shown in Table 20.

実施例２９から３１
（関節および筋肉上の皮膚を介する送達に適した）ケトプロフェンの経皮送達用の伸長可能な接着性処方物を調製し、これは賦形剤混合物中に飽和量のケトプロフェン（賦形剤混合物に溶解することができるよりも多くのケトプロフェン）を含んで、接着性処方物を形成し、そのいくつかは本発明の実施形態に従って調製される。粘性かつ透明な流体である賦形剤混合物は、表２２に示した成分を用いて調製される。

Examples 29 to 31
An extensible adhesive formulation for transdermal delivery of ketoprofen (suitable for delivery via the skin on joints and muscles) is prepared, which contains a saturating amount of ketoprofen in the excipient mixture (into the excipient mixture). More ketoprofen than can be dissolved) to form an adhesive formulation, some of which are prepared according to embodiments of the present invention. An excipient mixture, a viscous and clear fluid, is prepared using the ingredients shown in Table 22.

実施例２９から３１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 29 to 31 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 32
Formulations prepared according to Examples 29-31 are applied to HMS as described in Example 1 and ketoprofen flux is measured. A summary of the results is listed in Table 23 as follows.

実施例２９から３０に従って調製されたケトプロフェン接着性固化性処方物は許容される固化フイルム特性を有した（例えば、２から３分以内に固化層を形成）。実施例３１では、ケトプロフェン処方物は適用から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所望のフラックスおよび疲労特性を得るために、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を評価し、処方物を開発するにおいて考慮されることを示す。

The ketoprofen adhesive solidifying formulations prepared according to Examples 29 to 30 had acceptable solidified film properties (eg, forming a solidified layer within 2 to 3 minutes). In Example 31, the ketoprofen formulation does not form a solidified layer 30 minutes after application. This is to be considered in developing a formulation, evaluating the delicate balance between solidifying agents, non-volatile solvents, and volatile solvents in order to obtain the desired flux and fatigue properties in peel formulations. Show.

Example 33
Prepare an adhesive solidifying formulation for transdermal delivery of ketoprofen that can form an elastic solidified layer and is suitable for delivery through the skin on joints and muscles, which is saturated in the excipient mixture Of ketoprofen (more ketoprofen than can be dissolved in the excipient mixture) to form an adhesive formulation, some of which are prepared according to embodiments of the present invention. An excipient mixture, a viscous and clear fluid, is prepared using the ingredients shown in Table 24.

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 lack of cohesiveness of Formulation A is attributed to the lower molecular weight PVA sample (Celvol). Low molecular weight PVA does not possess the same cohesive strength as the higher molecular weight PVA material (Amresco) due to the reduced size of the polymer chains, the degree of crosslinking, and the physical interaction between the individual PVA polymer chains Cause a decline. The reduced PVA chain interaction leads to a weaker solidified layer that cannot withstand the mechanical forces to which it is applied upon removal.

Examples 34 to 35
Evaluable extensible adhesive formulations for transdermal delivery of ketoprofen (suitable for delivery via the skin on joints and muscles), which are adhesive properties prepared according to some embodiments of the present invention Contains a placebo excipient mixture that will form the formulation. An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 25.

実施例１および２におけるピール処方物は以下の様式で調製される：
−ＰＶＡ（固化剤）を水に溶解させる。
−フラックス適切不揮発性溶媒（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 Ｓ９７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。

The peel formulations in Examples 1 and 2 are prepared in the following manner:
-PVA (solidifying agent) is dissolved in water.
Mix the flux appropriate non-volatile solvent (glycerol, PG) with the solidifying agent / volatile solvent mixture.
-Then ethanol and Gantrez S97 are added to the mixture.
-Vigorously mix the resulting solution for several minutes.

  Drying time was assessed by applying the formulation to the forearm of an experimental volunteer, 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, and thereafter at 10 to 60 second intervals until the peel was lifted from the skin or removed without leaving the rest. The time for making this observation is defined as the drying time for the peel formulation. The results of the experiment are summarized in Table 26 below.

処方物中の水の量は、処方物が乾燥する時間に有意に影響しなかった。しかしながら、実験の間に、処方物は試料チューブから排出するのが困難だったと認められた。実施例１および２における処方物が作成されてからほぼ４週間後に、試料チューブを回収し、処方物を分注する容易性について評価した。処方物はチューブから排出するのが不可能であったと認められた。静電相互作用、疎水性相互作用、水素結合、またはファンデルワールス相互作用を通じてのＧａｎｔｒｅｚ Ｓ−９７およびＰＶＡの間のポリマー間複合体化が観察された増粘の理由であると仮定される。さらに、この相互作用の程度は、２つのポリマーの化学量論的比率に依存し得る。処方物の水含有量は許容される長期間物理的安定性を得るには余りにも低いが、より短い期間の粘度の処方物は許容されると考えられる。これは、いくつかの実施形態における、処方物中の十分な量の揮発性溶媒系を有する値を示す。

The amount of water in the formulation did not significantly affect the time that the formulation dried. However, during the experiment, it was found that the formulation was difficult to drain from the sample tube. Approximately four weeks after the formulations in Examples 1 and 2 were made, sample tubes were collected and evaluated for ease of dispensing the formulations. The formulation was found to be impossible to drain from the tube. It is hypothesized that interpolymer complexation between Gantrez S-97 and PVA through electrostatic interactions, hydrophobic interactions, hydrogen bonding, or van der Waals interactions is the reason for the observed thickening. Furthermore, the degree of this interaction can depend on the stoichiometric ratio of the two polymers. Although the water content of the formulation is too low to achieve acceptable long-term physical stability, it is believed that formulations with shorter durations are acceptable. This represents a value with a sufficient amount of volatile solvent system in the formulation in some embodiments.

Examples 36 to 39
Evaluate an extensible adhesive formulation for transdermal delivery of ketoprofen (suitable for delivery through the skin on joints and muscles), some of which are prepared according to embodiments of the present invention Contains an excipient mixture that will form an adhesive formulation. An excipient mixture that is a viscous and clear fluid is prepared using the ingredients shown in Table 27.

実施例１から４におけるピール処方物は以下の様式で調製される：
−ＰＶＡ（固化剤）を水に溶解させる。
−フラックス適切不揮発性溶媒（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、最終混合物を激しく再度数分間混合する。

The peel formulations in Examples 1 to 4 are prepared in the following manner:
-PVA (solidifying agent) is dissolved in water.
Mix the flux appropriate non-volatile solvent (glycerol, PG) with the solidifying agent / volatile solvent mixture.
-Then ethanol and Gantrez ES 425 are added to the mixture.
-Vigorously mix the resulting solution for several minutes.
-After mixing, ketoprofen is added and the final mixture is vigorously mixed again for several minutes.

  The formulation described above was placed in a laminate packaging tube and stored at 25 C / 60% RH and 40 C / 75% RH conditions until pulled for testing. Physical tests were performed for each formulation. Table 28 summarizes the data obtained for each formulation.

実施例３６および３７は４つの処方物の最低水含有量を有し、貯蔵の４週間内に、高い粘度値を達成した。実施例３６および３７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。エタノールレベルの低下は、ＰＶＡおよび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得ると仮定された。粘度のデータは、より高いエタノール処方物（実施例３６）がより低い初期粘度を有したが、４週間の貯蔵にわたって、実施例３６および３７双方の粘度は、活力のある処方物では余りにも高い粘度値に達した。処方物増粘についてのもう１つの仮説は、水に溶解させた場合に、ＰＶＡが高い濃度で適合しないことである。より高い水含有量を持つさらなる処方物を調製して、最適な水の量が処方物が経時的に増粘することを妨げ得るか判断した。１６週間後の実施例３８の粘度は、実施例３６および３７の初期粘度値の粘度値に到達しなかった。

Examples 36 and 37 had a minimum water content of 4 formulations and achieved high viscosity values within 4 weeks of storage. The only difference between Examples 36 and 37 is the amount of ethanol in the formulation. It was hypothesized that the reduction in ethanol levels could reduce the physical thickening of the formulation due to incompatibility between PVA and ethanol. Viscosity data showed that the higher ethanol formulation (Example 36) had a lower initial viscosity, but over 4 weeks of storage, the viscosity of both Examples 36 and 37 was too high for the vigorous formulation. The viscosity value has been reached. 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 amount of water could prevent the formulation from thickening over time. The viscosity of Example 38 after 16 weeks did not reach the initial viscosity value of Examples 36 and 37.

  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 was started approximately 3 to 4 minutes after application and thereafter at intervals of 10 to 60 seconds until the peel was lifted or the cotton was removed without leaving the rest. The results of the experiment are summarized in Table 29 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、固化層を形成すると仮定される。本実施例は、ある実施形態において、的確な混合物、および揮発性溶媒系における一定量の揮発性溶媒を用いる値を示す。

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 the water and as it evaporates from the skin, the water escapes with the ethanol, thereby forming a solidified layer. This example shows, in one embodiment, the value of using the correct mixture and a certain amount of volatile solvent in a volatile solvent system.

Examples 40 to 42
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 30.

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。次いで、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４１および４２）またはイソプロパノール（実施例４０）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ると、処方物を激しく２から３分間撹拌する。

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. Then, isostearic acid, triacetin, Span 20, and cetyl alcohol (Examples 41 and 42) or isopropanol (Example 40) 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 has cooled to room temperature, the formulation is vigorously stirred for 2 to 3 minutes.

  The formulations in Table 30 were applied to HMS according to Example 1 and the ropivacaine flux was measured. The results are summarized in Table 31.

実施例４３
種々の不揮発性溶媒系におけるケトプロフェンの溶媒処方物を評価する。過剰のケトプロフェンが存在する。ＨＭＳを通ってのテスト処方物からのケトプロフェンの浸透を以下の表３２に示す。

Example 43
Evaluate ketoprofen solvent formulations 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 32 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化層側（ドナー）へ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３２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。Ｓｐａｎ ２０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、ケトプロフェンについての１６ｍｃｇ／ｃｍ^２／ｈの見積もられた治療上有効なフラックスに基づく。治療上有効なフラックス未満の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 cornified layer side (donor) of hairless mouse skin. In vitro experiments are performed as described in Example 1. From Table 32, 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 an estimated therapeutically effective flux of 16 mcg / cm ² / h for ketoprofen. Steady state flux values of drugs from non-volatile solvents below therapeutically effective flux are not considered feasible, whereas steady state flux values of drugs from non-volatile solvents above therapeutically effective flux values are fluxes It is considered possible.

Examples 44 to 47
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 solidifying formulation according to embodiments of the present invention. The 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。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 11 were applied to HMS according to Example 1 and the flux of amitriptyline and / or ketamine was measured. The results are summarized in Table 34.

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処方物は、前記した実施例における処方物と同様な物理的特性を有する。

The adhesive formulations of amitriptyline and amitriptyline / ketamine formulations in this example have the same physical properties as the formulations in the previous examples.

Example 48
A formulation similar to that of the composition of Example 18 (without lidocaine) was applied to the human skin surface at the elbow and finger joints, resulting in a thin, transparent, flexible and stretchable film Get. After several minutes of evaporation of volatile solvents (ethanol and water), a solidified 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.

Example 49
A number of non-volatile solvents are tested for their fluxable ability for dermal delivery of tetracaine. Each of the solutions in the table below contains a saturating amount of tetracaine active. The transdermal flux of tetracaine produced by the saturated solution is measured with the same settings as in Example 1. The results are as follows:

治療上有効な皮膚薬物フラックスを達成するための不揮発性溶媒系を選択する重要性はここに明瞭に示される。

The importance of selecting a non-volatile solvent system to achieve a therapeutically effective skin drug flux is clearly demonstrated here.

  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 may 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 transdermally 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.

Claims (103)

A formulation for treating musculoskeletal or neuropathic pain,
a) a drug suitable for treating pain;
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;
Including
The formulation has a viscosity suitable for application and adhesion to the skin surface as a layer prior to evaporation of the volatile solvent system, the layer applied to the skin surface comprising at least the volatile solvent system After partial evaporation, a solidified layer is formed, and after the volatile solvent system has at least substantially evaporated, the drug is continuously administered at a therapeutically effective rate to treat musculoskeletal pain or inflammation. Delivered through the skin;
Formulation. The formulation of claim 1, wherein the non-volatile solvent system acts as a plasticizer for the solidifying agent. The formulation of Example 1, wherein the non-volatile solvent system facilitates transdermal delivery of the drug over a duration at a therapeutically effective rate. The formulation of claim 1, wherein the non-volatile solvent system is fluxable for the drug. The formulation of claim 1, further comprising a pH modifier. The formulation of claim 1, wherein the formulation further comprises an additional agent added to increase adhesion of the formulation when applied to the skin surface. The additional agent comprises 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 / octyl acrylamide, an aliphatic resin, an aromatic resin, and combinations thereof The formulation of claim 9, comprising at least one member selected from the group consisting of: The formulation of claim 1, wherein the volatile solvent system comprises water. The formulation of claim 1, wherein the volatile solvent system is substantially free of water. The formulation of claim 1, wherein the volatile solvent system comprises at least a member selected from the group consisting of ethanol, isopropyl alcohol, and combinations thereof. The formulation of claim 1, wherein the solidifying agent is present in the solidified layer at least 20% by weight after substantially all of the volatile solvent system has evaporated. The formulation of claim 1, wherein the non-volatile solvent system is present in the solidified layer at least 20% by weight after substantially all of the volatile solvent system has evaporated. The volatile solvent system includes 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 Selected from the group consisting of 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. 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, The formulation of claim 1, comprising at least one member selected from the group consisting of cyclomethicone, methyl ethyl ketone, and combinations thereof. The non-volatile solvent system comprises a plurality of non-volatile solvents mixed together, which together with other ingredients in the formulation solidify on the skin and maintain the drug at a therapeutically effective rate. The formulation of claim 1, forming a formulation for delivery over time. 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 at least one selected solvent. 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, The formulation of claim 1 comprising at least one solvent 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 monoethylate , 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, candelilla 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-octy Ruphenyl 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 poly Glycolated 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 formulation of claim 1 comprising at least one solvent selected from the group consisting of a combination thereof. The solidifying agent is polyvinyl alcohol, an ester of polyvinyl methyl ether / maleic anhydride copolymer, a neutral copolymer of butyl methacrylate and methyl methacrylate, a copolymer of dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate, ethyl acrylate- At least one member selected from the group consisting of methyl methacrylate-trimethylammonioethyl chloride copolymer, prolamin (zein), pregelatinized starch, ethylcellulose, 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 at least one member selected from the group consisting of poly vinyl 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. Acid calcium, 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, polygalactic acid / poly-1-lactic acid, turpen resin, locust bean Selected from the group consisting of acrylics, 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 formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation and is present in or around the knuckles. The formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation and is in or around the wrist, elbow, or knee. The formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation present on or around the back or neck. The pain is musculoskeletal pain or inflammation and the drug is a non-steroidal anti-inflammatory drug (NSAID), a COX inhibitor, a local anesthetic, a 5HT-2A receptor antagonist and a steroid, a prodrug thereof, and combinations thereof The formulation of claim 1 comprising at least one member from a class of drugs selected from the group consisting of: The formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation and the drug comprises at least one member selected from the group consisting of ketoprofen, diclofenac, ketanserin, and combinations thereof. The formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation and the drug comprises at least one member selected from the group consisting of lidocaine, ropivacaine, bupivacaine, tetracaine, and combinations thereof. The formulation of claim 1, wherein the pain is musculoskeletal pain or inflammation and the drug comprises a base form of a local anesthetic. The pain is musculoskeletal pain or inflammation, the drug comprises a non-steroidal anti-inflammatory drug, and the non-volatile solvent system has a flux for the non-steroidal anti-inflammatory drug of at least 1 μg / cm ² / hour. The formulation of claim 1 that can be produced. The pain is musculoskeletal pain or inflammation, the drug comprises a non-steroidal anti-inflammatory drug, and the solidified layer produces a flux for the non-steroidal anti-inflammatory drug of at least 1 μg / cm ² / hour Can be made. The formulation of claim 1. The pain is musculoskeletal pain or inflammation, the drug comprises a local anesthetic, and the non-volatile solvent system is capable of producing a flux for the local anesthetic of at least 5 μg / cm ² / hour. 1. The formulation according to 1. 2. The pain according to claim 1, wherein the pain is musculoskeletal pain or inflammation, the drug comprises a local anesthetic, and the solidified layer is capable of producing a flux for the local anesthetic of at least 5 μg / cm ² / hour. The described formulation. The pain is neuropathic pain and the drug is at least selected from the group consisting of local anesthetics, steroids, alpha-2 agonists, tricyclic antidepressants, antiviral drugs, 5-HT2A receptor antagonists, and combinations thereof The formulation of claim 1 comprising one member. The formulation of claim 1, wherein the pain is neuropathic pain and the drug comprises at least one local anesthetic selected from the group consisting of lidocaine, bupivacaine, ropivacaine, tetracaine, and combinations thereof. 36. The formulation of claim 35, wherein the at least one local anesthetic is in free base form. The formulation of claim 1, wherein the pain is neuropathic pain and the drug comprises dexamethasone. The formulation of claim 1, wherein the pain is neuropathic pain and the drug comprises clonidine. 2. The pain is neuropathic pain and the drug is a tricyclic antidepressant selected from the group consisting of amitriptyline, an anticonvulsant, N-methyl-D-aspartate antagonist, ketamine, and combinations thereof. The formulation described in 1. The pain is neuropathic pain, and the drug comprises an antiviral agent, and the antiviral agent is at least one selected from the group consisting of acyclovir, pencyclovir, famciclovir, and rosecyclovir The formulation of claim 1 comprising a member. The formulation of claim 1, wherein the pain is neuropathic pain and the drug comprises ketanserin. The pain is neuropathic pain, the drug comprises an alpha-2 agonist, and the non-volatile solvent system is capable of producing a flux for the alpha-2 agonist of at least 1 mcg / cm ² / h. 1. The formulation according to 1. The formulation of claim 1, wherein the pain is neuropathic pain, the drug comprises capsaicin, and the non-volatile solvent system is capable of producing a capsaicin flux of at least 5 mcg / cm ² / h. The formulation of claim 1, wherein the pain is neuropathic pain, the drug comprises amitriptyline, and the non-volatile solvent system is capable of producing a flux of the amitriptyline of at least 1 mcg / cm ² / h. The formulation of claim 1, wherein the pain is neuropathic pain, the drug comprises ketamine, and the non-volatile solvent system is capable of producing a flux of the ketamine of at least 1 mcg / cm ² / h. The solidified layer is sufficiently flexible and adheres to the skin so that when applied to the skin in a human joint, the solidified layer remains substantially intact on the skin upon bending of the joint. The formulation of claim 1 which is sex. The formulation of claim 1, wherein the volatile solvent system comprises a volatile solvent whose boiling point is less than 20 ° C. 48. The formulation of claim 47, wherein the volatile solvent having a boiling point less than 20 <0> C is completely dissolved in the formulation. 48. The formulation of claim 47, wherein the volatile solvent having a boiling point of less than 20C is included in the formulation as a propellant for pressurized spray-on applications. 48. The formulation of claim 47, wherein the volatile solvent having a boiling point less than 20 ° C is a hydrofluorocarbon. The at least one solvent having a boiling point of less than 20 ° C. is dimethyl ether, butane, 1,1 difluoroethane, 1,1,1,2 tetrafluoroethane, 1,1,1,2,3,3,3-hepta. 48. The formulation of claim 47, comprising at least one member selected from the group consisting of fluoropropane, 1,1,1,3,3,3 hexafluoropropane and combinations thereof. The formulation of claim 1, wherein the formulation is formulated 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 formulated to deliver the drug at a therapeutically effective rate for at least about 4 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 8 hours after formation of the solidified layer. The formulation of claim 1, wherein the formulation is formulated 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 solidifying agent is dispersed in the solvent excipient. The formulation of claim 1, wherein the solidifying agent is solvated in the solvent excipient. 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 the non-volatile solvent system can cause human skin irritation, and at least one non-volatile solvent of the non-volatile solvent system can reduce the skin irritation. 61. The formulation of claim 60, wherein the non-volatile solvent capable of reducing skin irritation comprises at least one member selected from the group consisting of glycerin, propylene glycol, honey, and combinations thereof. The formulation of claim 1, wherein the solidified layer is formed within about 15 minutes of application to the skin surface under standard skin and ambient conditions. The formulation of claim 1, wherein the solidified layer is formed within 4 minutes of application to the skin surface under standard skin 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 non-volatile solvent system comprises a plurality of non-volatile solvents, and at least one of the non-volatile solvents improves the compatibility of the non-volatile solvent system with the solidifying agent. The formulation of claim 1, wherein the non-volatile solvent comprises at least two non-volatile solvents, wherein one of the at least two non-volatile solvents is included to improve compatibility with the solidifying agent. . The formulation of claim 1, wherein the solidified layer is cohesive, flexible and continuous. 2. Formulation according to claim 1, wherein the solidified layer is a soft cohesive solid that can be peeled off the skin surface as it is formed, as a single piece for the application size, or as just a few large pieces. object. The formulation of claim 1, wherein the solidified layer is formulated to deliver the drug transdermally. A method for dermal delivery of a drug for treating musculoskeletal or neuropathic pain comprising:
a) applying the adhesive solidifying formulation of any one of claims 1 to 71 to the skin surface of a subject experiencing pain;
b) solidifying the formulation by at least partial evaporation of a volatile solvent system to form a solidified layer on the skin surface; and c) therapeutically effective to treat joint or muscle pain or inflammation. Delivering the drug from the solidified layer across the skin surface at a moderate rate over a period of time;
Including a method. 74. The method of claim 73, wherein the formulation is applied to a skin area on the wrist, ankle, elbow, or knee. 74. The method of claim 73, wherein the formulation is applied to a skin area on a finger or toe joint. 74. The method of claim 73, wherein the formulation is applied to a skin area on the back. 74. The method of claim 73, wherein the formulation is applied to a skin area on the neck. 74. The method of claim 73, wherein the applying step comprises applying the formulation at a thickness of about 0.01 mm to about 3 mm. 74. The method of claim 73, wherein the applying step comprises applying the formulation at a thickness of about 0.05 mm to about 1 mm. 74. The method of claim 73, wherein the formulation is sprayed on the skin. 74. The method of claim 73, wherein the formulation is applied to the skin using a manual pump. 74. The method of claim 73, wherein the pain is neuropathic pain and is associated with shingles or postherpetic neuralgia. 74. The method of claim 73, wherein the pain is neuropathic pain and is associated with post-surgical or post-traumatic pain. 74. The method of claim 73, wherein the pain is neuropathic pain and is associated with diabetes. 74. The method of claim 73, wherein the pain is musculoskeletal pain. A solidified layer for treating pain,
a) a drug for treating musculoskeletal or neuropathic pain,
b) a non-volatile solvent system comprising at least one non-volatile solvent; and c) a solidifying agent;
Including
The solidified layer adheres to the skin surface and can deliver the drug across the skin surface for a duration at a therapeutically effective rate;
Solidified layer. 90. The solidified layer of claim 86, wherein the solidified layer is formulated to be applied to a skin surface on a wrist, ankle, elbow, or knee. 90. The solidified layer of claim 86, wherein the solidified layer is formulated to be applied to the skin surface on a finger or toe joint. 90. The solidified layer of claim 86, wherein the solidified layer is formulated to be applied to the skin surface on the back, neck, shoulders or buttocks. The solidified layer of claim 86, wherein the solidified layer has a thickness of about 0.01 mm to about 3 mm. The pain is musculoskeletal pain, and the drug is a non-steroidal anti-inflammatory drug (NSAID), a COX inhibitor, a local anesthetic, a 5HT-2A receptor antagonist, and a steroid, a prodrug thereof, and a combination thereof 90. The solidified layer of claim 86, comprising at least one member from a class of drugs selected from the group consisting of: 87. The pain of claim 86, wherein the pain is musculoskeletal pain and the drug comprises at least one member selected from the group consisting of ketoprofen, diclofenac, lidocaine, ropivacaine, bupivacaine, tetracaine, ketanserin, and combinations thereof. Solidified layer. The pain is neuropathic pain and the drug is selected from the group consisting of a local anesthetic, a steroid, an alpha-2 agonist, a tricyclic antidepressant, an antiviral drug, a 5-HT2A receptor antagonist, and combinations thereof 90. The solidified layer of claim 86, comprising at least one member. When applied to the skin at a human joint, the solidified layer is sufficiently flexible with respect to the skin so that the solidified layer remains substantially intact on the skin when the joint is bent. The solidified layer according to claim 86, which is adhesive. 90. The solidified layer of claim 86, wherein the solidified layer is formulated to deliver the drug at a therapeutically effective rate for at least about 2 hours. 90. The solidified layer of claim 86, wherein the formulation is formulated to deliver the drug at a therapeutically effective rate for at least about 12 hours. 90. The solidified layer of claim 86, wherein the weight ratio of the non-volatile solvent system to the solidifying agent is from about 0.5: 1 to about 2: 1. 87. The solidified layer of claim 86, wherein the solidified layer is a soft cohesive solid layer that can be peeled from the skin surface as a single piece or just a few large pieces for the application size. 87. The solidified layer of claim 86, wherein the solidified layer is a soft cohesive solid layer that can be removed by washing. The solidified layer according to claim 86, 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 86, 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. 87. The solidified layer of claim 86, wherein the solidified layer is adhesive to the skin surface at one surface and non-adhesive at the opposite surface. 90. The solidified layer of claim 86, wherein the solidified layer is fluxable for the drug.

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