Priority of application date of U.S. provisional patent application serial No. 61/467,337 filed 2011 3/24/c. § 119 (e); the disclosure of this application is incorporated herein by reference.
Detailed Description
Transdermal compositions are provided. The transdermal composition structure comprises: an active agent layer and a conversion layer, wherein the conversion layer comprises a weak base and optionally a carboxylated component. Methods of using the transdermal compositions and kits containing the transdermal compositions are also provided.
Before the present invention is described in greater detail, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
When referring to a range of values, it is understood that every intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. When the specified range includes one or both of the upper limit and the lower limit, the invention also includes ranges excluding either or both of the included upper limit and the included lower limit.
Certain ranges of values are referred to herein by the term "about". The term "about" as used herein provides literal support for the exact numerical value following it, as well as numerical values that are close or approximate to the numerical value following the term. In determining whether a value is near or approximate to the specifically mentioned value, an unrecited value that is near or approximate may be a value that, in the context of its occurrence, provides a value that is substantially equal to the explicitly mentioned value.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Representative exemplary methods and materials are now described, although methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and were set forth in its entirety herein to disclose and describe the methods and/or materials in connection with which the publications were cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Moreover, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
It should be noted that, as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It should also be noted that the drafting of the claims may exclude any optional elements. As such, this description is intended to serve as a basis for the use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or the use of a "negative" limitation.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has individual components and features which may be readily separated from or combined with the features of any of the other various embodiments without departing from the scope and spirit of the present invention. Any described methods may be performed in the order of events recited or in any other order that is logically possible.
In further describing various embodiments of the present invention, the structure of the transdermal composition is first described in more detail, followed by a detailed description of embodiments utilizing the transdermal delivery system and a review of kits that include the transdermal delivery system.
Transdermal composition
In summary, transdermal compositions are provided herein. The transdermal composition of the present invention is a formulation configured to transdermally deliver an active agent to a subject when topically applied to a skin surface of the subject. The compositions of the present invention comprise two or more layers, wherein the two or more layers comprise at least one active agent layer and a conversion layer, wherein the two or more layers are configured to provide multi-day delivery of a therapeutically effective amount of an active agent to a subject when the composition is topically applied to the subject.
By multi-day delivery is meant that the layer is formulated to provide a therapeutically effective amount of the active agent to the subject over a period of 1 day or more, such as 2 days or more, for example 3 days or more, such as 5 days or more, including 7 days or more, such as 10 days or more, when the composition is applied to the skin site of the subject. By therapeutically effective amount is meant that the composition provides a systemic amount of the active agent with the desired therapeutic activity when the composition is applied to the skin site of the subject within the intended application time (e.g., within 7 days of application). In some embodiments, the composition provides a target dose of active agent delivery (i.e., 0.5 mg/day or greater) over a period of one week (i.e., 7 days or 168 hours), including 1.0 mg/day or greater over a period of one week, such as 10 mg/day or greater over a period of one week.
Transdermal compositions according to certain embodiments of the present invention exhibit a substantially constant flux of an active agent (e.g., propynylaminoindan) over an extended period of time. By substantially constant flux is meant that any amount of change in flux over an extended period of time is 100% change in flux or less, such as 80% change in flux or less, and includes 50% change in flux or less, such as 40% change in flux or less, 30% change in flux or less, such as 25% change in flux or less, such as 20% change in flux or less, including 15% change in flux or less, such as 10% change in flux or less. This with substantially constant flux observedThe extended time period can be different, and in some examples is 24 hours or more, such as 48 hours or more, including 72 hours or more, such as 96 hours or more. Although the actual flux may vary, in some cases (e.g., as determined using the skin permeation test described in the experimental section below), the composition provides a skin permeation rate of 0.5 μ g/cm2Hour or more, e.g. 1. mu.g/cm2Hour or more, including 10. mu.g/cm2Hour or more. In some examples, the formulations of the present invention exhibit substantially reduced burst delivery of the agent upon application of the formulation to the skin, e.g., as compared to a control formulation in which the pressure sensitive adhesive (e.g., the control pressure sensitive adhesive employed in the experimental section below) does not include a carboxylated functional group. A substantial reduction in burst delivery means a reduction of more than 10%, such as more than 20%, e.g. more than 25%, more than 33%, more than 40%, more than 50%, including more than 66%, more than 75%, including more than 90%. In some examples, the formulation is configured to provide substantially zero-order delivery of the active agent.
The size (i.e., area) of the transdermal compositions can vary. In certain embodiments, the size of the composition is selected based on the desired transdermal flux rate (flux rate) of the active agent and the targeted dose. For example, if the transdermal flux is 3.4. mu.g/cm2The target dose is 5 mg/day, and the selected area is about 43cm2The transdermal composition of (1). Or, for example, if the transdermal flux is 3.4. mu.g/cm2For a target dose of 10 mg/day, an area of about 87cm is selected2The transdermal patch of (1). In certain embodiments, when applied in the range of 10 to 200cm2E.g. 20 to 150cm2Including 40 to 140cm2The size of the composition is selected to cover an area of skin.
The thickness of the active agent layer and the conversion layer of the composition may be different. In some examples, the combined thickness of the layers ranges from 25 to 250 micrometers, such as from 50 to 200 micrometers, including from 100 to 150 micrometers. The different layers of the composition may have the same thickness or different thicknesses, as desired.
In some embodiments, the active agent layer and the conversion layer may be insoluble in water. By water-insoluble it is meant that the layers can be immersed in water for 1 day or more, such as 1 week or more, including 1 month or more, while showing little, such as no, visible dissolution.
The transdermal composition according to an embodiment of the present invention is characterized in that it is storage-stable. By storage stable is meant that the composition can be stored for extended periods of time without significant degradation and/or significant reduction in the activity of the active agent. In certain embodiments, the composition is stable for 6 months or more, such as 1 year or more, including 2 years or more, such as 3 years or more, and the like, when maintained under sterile conditions and at 25 ℃. In some cases, the ratio of the amount of active agent in the composition to the initial amount of active agent in the composition after storage at about 60 ℃ for at least one month is 92% or more, 93% or more, e.g., 94% or more, including 95% or more, or more.
In some embodiments, such as shown in fig. 1A, the compositions of the present invention comprise an active agent layer 4, a conversion layer 2, a backing layer 1, and a release liner (or release liner, release paper) 5. In some embodiments, such as that shown in fig. 1B, the compositions of the present invention include an active agent layer 4, a conversion layer 2, a support/rate control membrane 3 separating the active agent layer and the conversion layer, a backing layer 1, and a release liner 5. Each of these layers will be described in more detail below.
Active agent layer
As noted above, the transdermal compositions described herein include an active agent layer. The active agent layer of interest includes an amount of active agent present in the matrix. A plurality of active agents may be present in the active agent layer. Of interest are active agents in the free base form that exhibit reduced storage stability. Such active agents may include agents that have a lower melting temperature (Tm) when in base form, e.g., agents with a Tm of 120 ℃ or less, e.g., 90 ℃ or less. Agents of interest include agents that have a higher vapor pressure when in base form, e.g., agents with a vapor pressure of 0.01mmHg (25 ℃) or higher, e.g., 0.05mmHg or higher. A variety of different active agents may be present in the composition, such agents including, but not limited to: propynylaminoindan, for example, rasagiline; rivastigmine; memantine; amino esters, for example, benzocaine, chloroprocaine, cyclomecaine, dicaine/larocaine, perocaine, propoxycaine, procaine/novocaine, proparacaine, tetracaine/amethocaine; aminoamides such as articaine, bupivacaine, cinchocaine/dibucaine, etidocaine, levobupivacaine, lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, trimetaine, and the like.
In some examples, the active agent present in the active agent layer is propynylaminoindan (or propargylaminoindan). Propynylaminoindan of interest includes compounds as described above having the formula:
wherein R is1Is H, -OR2,or
Wherein R is2Is C1-C4Alkyl, and R3Is H or C1-C4An alkyl group. In some examples, the propynylaminoindan is N-propargyl-1-aminoindan (i.e., rasagiline).
The active agent in the active agent layer, e.g., a propynylaminoindan active agent, can be present in the matrix as a free base or a salt, where in some instances the active agent is present as a salt. Pharmaceutically acceptable salts include, but are not limited to, the mesylate, maleate, fumarate, tartrate, hydrochloride, hydrobromide, esylate, p-toluenesulfonate, benzoate, acetate, phosphate and sulfate salts. Additionally, the active agent (e.g., propynylaminoindan) may exist as a racemic mixture or as a pure enantiomer (e.g., the R or L enantiomer of the active agent). For example, when the active agent is a propynylaminoindan, the propynylaminoindan in the matrix may be the only R (+) -N-propargyl-1-aminoindan free base, and in some examples, the propynylaminoindan may be the only R (+) -N-propargyl-1-aminoindan mesylate salt.
The amount of active agent (e.g., propynylaminoindan) present in the active agent layer can vary. In some examples, the amount of active agent can range from 5mg to 50mg, such as 10mg to 40mg and including 15mg to 30 mg. In some examples, the wt% of active agent in the active agent layer ranges from 5% to 25%, e.g., 10% to 20%.
As outlined above, the active agent layer comprises an amount of active agent (e.g., as described above) in the matrix. The matrix can vary as desired, wherein the matrix can be tacky or non-tacky. Examples of matrix materials of interest include polymeric materials, where the polymeric materials can vary widely and can include, but are not limited to: a polyurethane; ethylene/vinyl acetate copolymers (EVA), polyacrylates, styrenic block copolymers, cellulosic polymers, and the like. Suitable matrix materials can include, but are not limited to, polyacrylates, polysiloxanes, Polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, blends and combinations of the foregoing, and the like. Suitable styrenic block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene copolymer (SBS), styrene-ethylene butylene-styrene copolymer (SEBS), and diblock analogs thereof. Suitable acrylic polymers are composed of copolymer terpolymers comprising at least two or more exemplary components selected from acrylic acid, alkyl acrylates, methacrylates, copolymerizable second monomers, or monomers having functional groups. Examples of monomers include, but are not limited to, acrylic acid, methacrylic acid, methoxyethyl acrylate, ethyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, methyl methacrylate, ethyl acrylate, t-butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, and the like.
The active agent layer matrix may include a pressure sensitive adhesive (or pressure sensitive adhesive, pressure sensitive adhesive) as desired (e.g., in configurations where the composition is configured to contact the skin in use with the active agent layer). The terms "pressure sensitive adhesive", "self-adhesive" and "self-adhesive" mean an adhesive that forms a bond when pressure is applied to cause the adhesive to adhere to a surface. In some examples, the adhesive is an adhesive that does not require solvents, water, or heat to achieve adhesion. For pressure sensitive adhesives, the degree of bond strength is directly proportional to the amount of pressure used to apply the adhesive to the surface.
Pressure sensitive adhesives of interest for the active agent layer include, but are not limited to, acrylate copolymers. Acrylate copolymers of interest include copolymers of various monomers, which may be "soft" monomers, "hard" monomers, and optionally "functional" monomers. Also of interest are blends comprising such copolymers. The acrylate copolymer may consist of a copolymer comprising a dimer (i.e., made from two monomers), a trimer (i.e., made from three monomers), or a tetramer (i.e., made from four monomers), or a copolymer made from an even greater number of monomers. The acrylate copolymer may comprise a crosslinked or non-crosslinked polymer. The polymer may be crosslinked by known methods to provide the desired polymer.
The monomers used to make the acrylate copolymer include at least two or more exemplary components selected from acrylic acid, alkyl acrylates, methacrylates, copolymerizable second monomers, or monomers having functional groups. Monomers of interest ("soft" and "hard" monomers) include, but are not limited to, methoxyethyl acrylate, ethyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Other examples of Acrylic binder monomers are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive adhesive technology, 2 nd edition, page 396-456 (D. Satas.), Van Nostrand Reinhold, New York (1989). Acrylic adhesives available from a variety of commercial sources are sold under the trade names AROSET, DUROTAK, EUDRAGIT, GELVA, and NEOCRYL.
In some examples, the active agent layer may include a pressure sensitive adhesive containing a non-carboxylated polymer (e.g., Gelva 7883) and a carboxylated polymer. Of particular interest for carboxylated polymers are monomer residues that provide the-COOH functionality. Carboxylic acid monomers useful for providing the-COOH functionality may contain from about 3 to about 6 carbon atoms and include acrylic acid, methacrylic acid, itaconic acid, and the like, among other functional groups. Acrylic acid, methacrylic acid, and mixtures thereof may be employed in certain embodiments. In certain embodiments, the functional monomer(s) are present in the copolymer in an amount of 2wt% or more, for example between 3 and 10 wt%.
In some embodiments, the active agent adhesive may comprise a pressure sensitive adhesive that is or is substantially the same as a composition selected from the group consisting of:87-2100（Henkel）、87-2852 (Henkel), and the like. The term "substantially the same" as used herein means that the composition is an acrylate-vinyl acetate copolymer in organic solvent solution and has functionality as described herein. In some embodiments, the acrylic pressure sensitive adhesive is selected from87-2100、87-2852, and the like. The active agent layer may comprise a single pressure sensitive adhesive, or a combination of two or more pressure sensitive adhesives.
In some examples, the pressure sensitive adhesive can be made from 50 to 95wt%, such as 60 to 90wt% of the matrix, including 65 to 85wt% of the matrix.
Conversion layer
The conversion layer (i.e., conversion layer, conversion substrate, or active agent conversion layer) is a layer used to convert the active agent salt in the active agent layer to the free base form after the composition is applied to the skin. The conversion layer is characterized by having substantially less active agent than the active agent layer (e.g., 5wt% or less, such as 2.5wt% or less, including 1wt% or less), at least during storage and prior to contact with the skin or use, wherein in some examples, the conversion layer includes substantially no active agent (e.g., 0.9wt% or less, such as 0.5wt% or less, including no detectable active agent)). The conversion layer includes a conversion agent, which can be any agent (alone or in combination with one or more other components) capable of mediating the conversion of an active agent from a salt form to a free base form. The conversion agent of interest that may be present in the conversion agent layer comprises a weak base. Weak base means the alkaline dissociation constant (K)b) A base of 10 or less, for example 9 or less. Any convenient weak base may be employed, for example polymeric weak bases such as cationic acrylic copolymers (or cationic acrylic copolymers), inorganic bases such as calcium hydroxide and the like. Cationic acrylic copolymers of interest are polymers having two or more different monomer residues, wherein at least one residue is an acrylic acid residue, such as an acrylate or methacrylate, and wherein at least one residue includes a cationic side group, such as an amino side group, wherein these features may be included in the same or different monomer residues making up the polymer. The cationic acrylic copolymer may be an aminated methacrylate copolymer, as desired. The aminated methacrylate copolymer may be a copolymer of diethylaminoethyl methacrylate, butyl methacrylate and methyl methacrylate. Of interest areE100 aminated methacrylate copolymer substantially the same aminated methacrylate copolymer. As used herein, the term "substantially the same" means that the aminated methacrylate copolymer is copolymerized withThe E100 aminated methacrylate copolymer has the same functional impact on the composition. If present, the cationic acrylic copolymer is present in an amount ranging from 1 to 15wt%, such as 2 to 10wt%, and including 4 to 8wt%, of the conversion layer.
The conversion layer comprises, in addition to the conversion agent (e.g. a weak base), a matrix. In some examples, the matrix is a polymer matrix, e.g., a matrix described above in connection with the active agent layer.
The conversion layer includes a pressure sensitive adhesive, e.g., as described above, as desired (e.g., in configurations where the composition is configured to contact the skin in use. Pressure sensitive adhesives of interest include, but are not limited to, carboxylated polymers, such as carboxylated acrylate copolymers. Acrylate copolymers of interest include copolymers of different monomers, which may be "soft" monomers, "hard" monomers, and optionally "functional" monomers. Also of interest are blends comprising such copolymers. The acrylate copolymer may consist of a copolymer comprising a dimer (i.e., made from two monomers), a trimer (i.e., made from three monomers), or a tetramer (i.e., made from four monomers), or a copolymer made from an even greater number of monomers. The acrylate copolymer may comprise a crosslinked or non-crosslinked polymer. The polymer may be crosslinked by known methods to provide the desired polymer. The monomers used to make the acrylate copolymer include at least two or more exemplary components selected from acrylic acid, alkyl acrylates, methacrylates, copolymerizable second monomers, or monomers having functional groups. Monomers of interest ("soft" and "hard" monomers) include, but are not limited to, methoxyethyl acrylate, ethyl acrylate, butyl methacrylate, hexyl acrylate, hexyl methacrylate, 2-ethylbutyl acrylate, 2-ethylbutyl methacrylate, isooctyl acrylate, isooctyl methacrylate, 2-ethylhexyl acrylate, 2-ethylhexyl methacrylate, decyl acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl methacrylate, acrylonitrile, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of Acrylic binder monomers are described in Satas, "Acrylic Adhesives," Handbook of Pressure-Sensitive adhesive technology, 2 nd edition, page 396-456 (D. Satas eds.), Van Nostrand Reinhold, New York (1989).
The acrylate copolymers of interest include polar functional monomer residues. The monomer residues of particular interest have a-COOH functional group. The carboxylic acid monomers used to provide the-COOH functional group can contain from about 3 to about 6 carbon atoms and include, among others, acrylic acid, methacrylic acid, itaconic acid, and the like. In certain embodiments, acrylic acid, methacrylic acid, and mixtures thereof may be employed. In certain embodiments, the functional monomer(s) are present in the copolymer in an amount of 2wt% or more, such as between 3 and 10 wt%.
In some embodiments, the adhesive may have a composition that is or is substantially the same as a composition selected from the group consisting of:87-2100（Henkel）、87-2852 (Henkel), and the like. The term "substantially the same" as used herein means that the composition is an acrylate-vinyl acetate copolymer in organic solvent solution and has functionality as described herein. In some embodiments, the acrylic pressure sensitive adhesive is selected from the group consisting of87-2100、87-2852, and the like. The conversion layer may comprise a single pressure sensitive adhesive, or a combination of two or more pressure sensitive adhesives. The pressure sensitive adhesive may be the same or different than the pressure sensitive adhesive present in the active agent.
In some examples, the pressure sensitive adhesive can be made from 50 to 95wt%, such as 60 to 90wt% (including 65 to 85 wt%) of the substrate.
In addition to the weak base, the conversion layer may optionally include a carboxylated component. By carboxylated component is meant a layer component (e.g. a matrix or another compound in a matrix) having carboxyl moieties. Thus, in some examples, the carboxylated component is a polymeric component, such as a matrix component, e.g., a carboxylated polymer of a pressure sensitive adhesive, such as described above. Additionally or alternatively, the carboxylated component may be some other compound present in the conversion layer, such as a small molecule compound, for example, an organic acid, such as ascorbic acid.
Penetration enhancer
As described herein, at least one of the active agent layer and the conversion layer may contain a percutaneous absorption enhancer (or enhancer). The transdermal absorption enhancer can promote absorption of the active agent by the skin of a subject. The transdermal absorption enhancers are also referred to as transdermal penetration enhancers because they not only enhance transdermal absorption of the active agent, but also enhance transdermal penetration of the active agent through the skin of the subject.
The percutaneous absorption enhancer may include, but is not limited to, the following: aliphatic alcohols such as, but not limited to, saturated or unsaturated higher alcohols having 12 to 22 carbon atoms, such as oleyl alcohol and lauryl alcohol; fatty acids such as, but not limited to, linoleic acid, oleic acid, linolenic acid, stearic acid, isostearic acid, and palmitic acid; fatty acid esters such as, but not limited to, isopropyl myristate, diisopropyl adipate, and isopropyl palmitate; alcohol amines such as, but not limited to, triethanolamine hydrochloride, and diisopropanolamine; polyhydric alcohol alkyl ethers, such as, but not limited to, e.g., glycerol, ethylene glycol, propylene glycol, 1, 3-butylene glycol, diglycerol (digl)ycerol), polyethylene glycol, diethylene glycol, polyethylene glycol, dipropylene glycol, polypropylene glycol, sorbitan, sorbitol, isosorbide, methyl glucoside, oligosaccharide, and alkyl ether of a polyol of a reduced oligosaccharide, wherein the number of carbon atoms of the alkyl moiety in the alkyl ether of the polyol is preferably 6 to 20; polyoxyethylene alkyl ethers, such as but not limited to those wherein the number of carbon atoms in the alkyl moiety is from 6 to 20 and the polyoxyethylene chain has repeating units (-O-CH)2CH2-) polyoxyethylene alkyl ethers having a number of 1 to 9,such as but not limited to polyoxyethylene lauryl ether, polyoxyethylene cetyl ether, polyoxyethylene stearyl ether, and polyoxyethylene oleyl ether; glycerides (i.e., fatty acid esters of glycerol), such as, but not limited to, glycerides of fatty acids having from 6 to 18 carbon atoms, where the glycerides can be monoglycerides (i.e., a glycerol molecule is covalently bonded to one fatty acid chain through an ester linkage), diglycerides (i.e., a glycerol molecule is covalently bonded to two fatty acid chains through an ester linkage), triglycerides (i.e., a glycerol molecule is covalently bonded to three fatty acid chains through an ester linkage), or combinations thereof, where the fatty acid components forming the glycerides include, but are not limited to, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid (i.e., stearic acid), and oleic acid; medium chain fatty acid esters of polyhydric alcohols; an alkyl lactate; a dibasic acid alkyl ester; an acylated amino acid; a pyrrolidone; a pyrrolidone derivative; and combinations thereof.
Other types of transdermal absorption enhancers include, but are not limited to, lactic acid, tartaric acid, 1,2, 6-hexanetriol, benzyl alcohol, lanolin, potassium hydroxide (KOH), and tris (hydroxymethyl) aminomethane.
Specific examples of the percutaneous absorption enhancers include, but are not limited to, Glycerol Monooleate (GMO), Sorbitan Monolaurate (SML), Sorbitan Monooleate (SMO), laureth-4 (LTH), and combinations thereof.
In some cases, the matrix of at least one of the active agent layer and the conversion layer contains a percutaneous absorption enhancer in an amount ranging from 2% to 25% (w/w), such as from 5% to 20% (w/w), and including from 5% to 15% (w/w). In some cases, the matrix contains the percutaneous absorption enhancer in an amount of about 5% (w/w), about 10% (w/w), about 15% (w/w), or about 20% (w/w).
If necessary, an antioxidant (e.g., BHA, BHT), propyl gallate, pyrogallol, tocopherol, or the like may be incorporated in any or all of the layers.
Structural support/rate controlling membrane
In some embodiments, the transdermal formulation includes an intermediate layer, such as non-woven PET, microporous polypropylene, or the like, between the active agent layer and the conversion layer. In some embodiments, the intermediate layer may be a rate controlling membrane. The rate controlling membrane meters the amount of active agent that is administered through the skin over an extended period of time such that the active agent is released from the transdermal formulation at a substantially constant rate until the desired total amount of active agent (i.e., the target dose) is administered.
In certain embodiments, the rate controlling membrane may be a microporous membrane having pores that allow penetration of the active agent. In these embodiments, the flux or release rate of the active agent through the membrane is controlled by the rate at which the active agent can diffuse through the pores of the membrane. The rate controlling membrane may be any porous material that allows for permeation of the active agent, such as, but not limited to, polypropylene, polyethylene, polyacrylonitrile, polytetrafluoroethylene, polydimethylsilane, polymethylmethacrylate, and combinations thereof. In addition, the rate controlling membrane may be a single layer or multiple layers (i.e., having one or more porous membrane layers made up of the same or different materials laminated together). In certain embodiments, the rate controlling membrane is a single layer polypropylene membrane.
The porosity, pore size, and thickness of the rate controlling membrane depend on physicochemical properties such as the molecular weight of the active agent, the desired flux, and the like. For example, the rate controlling membrane may generally have the following properties: porosity ranges from about 10% to 85%, including from about 20% to 75%, such as from 30% to 50%; pore sizes in the range of 0.03 to 0.25. mu. m.times.μ m, including 0.03 to 0.2. mu. m.times.μ m, such as 0.04 to 0.12. mu. m.times.μ m; and has a thickness in the range of 10 μm to 70 μm, including 15 μm to 60 μm, for example 20 μm to 50 μm. In certain embodiments, the rate controlling membrane may have a porosity of 37%, a pore size of 0.04 to 0.12 μm × μm, and a thickness of 25 μm.
In some embodiments, the rate controlling membrane may have a ph of2400 (Celgard LLC, Charlotte, NC) groupTo substantially the same composition. The term "substantially the same" as used herein means that the composition is a monolayer polypropylene film and has functionality as described herein. In some embodiments, the rate controlling membrane is2400。
Multilayer structure
In summary, the transdermal compositions described herein have a multilayer structure. By multi-layer structure is meant that the composition, in addition to a backing (e.g., as described below), comprises two or more different layers that differ in composition, wherein the total number of different layers in the composition can be two or more layers, e.g., 3 or more layers, including 4 or more layers, e.g., 5 or more layers. In some examples, the number of different layers ranges from 2 to 5, such as 2 to 4, including 2 to 3. For example, it may have a configuration in which the conversion layer is located between the first and second conversion layers. As noted above, the thickness of each layer in the composition may be the same or different, as desired.
Back lining
In summary, the transdermal compositions of interest may include a backing (i.e., a support layer). The backing may be flexible to some extent so that it can be brought into intimate contact with a desired localized area of the subject. The backing may be made of a material that does not absorb the active agent and that does not allow the active agent to be released from the sides of the support layer. The backing may include, but is not limited to, a nonwoven fabric, a woven fabric, a film (including a sheet), a porous body, a foam, a paper, a composite obtained by laminating a film to a nonwoven fabric or a fabric, and combinations thereof.
The nonwoven fabric may include, but is not limited to, the following materials: polyolefin resins such as polyethylene and polypropylene; polyester resins such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; rayon (rayon), polyamide, polyester ether, polyurethane, polyacrylic resin, polyvinyl alcohol, styrene-isoprene-styrene copolymer, and styrene-ethylene-propylene-styrene copolymer; and combinations thereof. The fabric may include, but is not limited to: cotton, rayon, polyacrylic resins, polyester resins, polyvinyl alcohol, and combinations thereof. The film may include, but is not limited to, the following materials: polyolefin resins such as polyethylene and polypropylene; polyacrylic resins such as polymethyl methacrylate and polyethyl methacrylate; polyester resins such as polyethylene terephthalate, polybutylene terephthalate, and polyethylene naphthalate; and cellophane, polyvinyl alcohol, ethylene-vinyl alcohol copolymer, polyvinyl chloride, polystyrene, polyurethane, polyacrylonitrile, fluororesin, styrene-isoprene-styrene copolymer, styrene-butadiene rubber, polybutadiene, ethylene-vinyl acetate copolymer, polyamide, and polysulfone; and combinations thereof. Paper may include, but is not limited to, impregnated paper, coated paper, wooded paper (offset paper), Kraft paper (Kraft paper), japanese paper, glassine paper, synthetic paper, and combinations thereof. The composite material may include, but is not limited to, a composite material obtained by laminating the above-described film on the above-described nonwoven fabric or textile.
The backing may vary in size, and in some instances, is sized to cover the desired localized target site. In some embodiments, the backing has a length ranging from 2 to 100cm, such as 4 to 60cm, and a width ranging from 2 to 100cm, such as 4 to 60 cm.
In some embodiments, the backing layer is insoluble in water. By water-insoluble it is meant that the layers can be immersed in water for 1 day or more, for example 1 week or more, including 1 month or more, while showing little, for example no, visible dissolution.
The backing layer may be in contact with the surface of the conversion layer or active agent layer, as desired, for example, depending on whether the composition is configured to contact the conversion layer or active agent layer to the skin after application to a subject. For example, when the composition is configured such that the active agent layer contacts the skin after application, the backing will be in contact with the surface of the active agent layer. Alternatively, when the composition is configured to contact the conversion layer to the skin after application, the backing will be in contact with the surface of the conversion layer.
Release liner
In some embodiments, the release liner is disposed on the active agent layer (i.e., the matrix), and in particular on the surface of the active agent layer that is distal (i.e., opposite) from the backing layer (if present). The release liner helps protect the active agent layer. The release liner may be prepared by treating polyethylene coated forest paper, polyolefin coated glassine paper, polyethylene terephthalate (polyester) film, polypropylene film, etc. with a silicone treatment. The release liner may be in contact with the surface of the conversion layer or active agent layer, as desired, for example, depending on whether the composition is configured to contact the conversion layer or active agent layer with the skin after application to a subject. For example, when the composition is configured to contact the active agent layer with the skin after application, the release liner will contact the surface of the active agent layer. Alternatively, when the composition is configured to contact the conversion layer with the skin after application, the release liner will be in contact with the surface of the conversion layer.
Application method
Methods of using the transdermal compositions of the products include administering to a patient an effective amount of an active agent to treat a patient suffering from a target condition of interest, such as described in the utility section below. By "treating" is meant at least inhibiting or alleviating the symptoms associated with the condition in the subject, where inhibiting or alleviating is used in a broad sense to mean at least reducing the magnitude of a parameter, such as the symptoms associated with the condition being treated. Thus, treatment also includes situations where the condition is completely inhibited, e.g., prevented from occurring or halted, e.g., terminated, such that the subject no longer experiences the condition. Thus, treatment includes both prevention and control of the condition.
In the practice of this method, the subject can be topically administered with the present disclosureThe transdermal composition disclosed in (1), i.e., the transdermal composition can be applied to any convenient topical location (e.g., skin site). Application may include contacting the active agent layer or the conversion layer with a skin site of the subject, depending on the configuration of the transdermal composition. The local sites of interest include mucosal sites and keratinized skin sites, and thus include, but are not limited to: mouth, nose, eye, rectum, vagina, arm, leg, torso, head, etc. The surface area covered by the topical composition after application is sufficient to provide the desired amount of agent administration, and in some embodiments, ranges from 1 to 200cm2E.g. 10 to 180cm2And comprises 100 to 150cm2E.g. 140cm2。
For example, the transdermal composition may be maintained at the topical site to which it is applied for a desired period of time to deliver the desired amount of active agent delivery. In some examples, the composition is held at the site of application for a period of 24 hours or more, such as 48 hours or more, such as 72 hours or more, such as 96 hours or more.
In the practice of the subject methods, a given dose of the transdermal composition can be applied in a single or multiple applications over a given period of time (e.g., the course of the disease to be treated), wherein when multiple compositions are administered over a given period of time, the dosage regimen can be daily, weekly, biweekly, monthly, etc.
The area of skin covered by the topical composition when applied may be different. In some examples, the area of skin covered by the topical composition after application may range from 1 to 200cm2E.g. 10 to 180cm2And comprises 100 to 150cm2。
After the transdermal active agent composition is applied to the skin site for a desired period of time (i.e., a period of time sufficient to deliver a target dose of the active agent to the subject over a period of time), the composition can be removed from the skin site. The new transdermal composition may be applied to the same or different skin sites. The new transdermal compositions may be applied to different skin sites to reduce skin irritation and/or skin sensitivity that may occur at the site of prior application.
In certain embodiments, the method comprises a diagnostic step. An individual may be diagnosed as in need of such a method using any convenient method. In addition, the individual may be one for whom the method is known to be desirable, e.g., an individual suffering from Parkinson's disease. Diagnosis and assessment of the target condition may be performed using any convenient diagnostic method.
The methods of the invention further comprise assessing the efficacy of a treatment regimen comprising administration of a local anesthetic emulsion composition. Assessment of the efficacy of the treatment can be performed using convenient (suitable) methods.
In some examples, the transdermal composition may be administered with one or more additional therapeutic agents specific for the target condition of interest. Thus, the transdermal composition may be used alone to treat a target disease or, alternatively, in the case of, for example, parkinson's disease, the transdermal composition may be used to assist conventional L-DOPA treatment.
The transdermal compositions of the present invention can be administered to a variety of different types of subjects. Subjects of interest include, but are not limited to: human and non-human mammals, including carnivores (e.g., dogs and cats), rodents (e.g., mice, guinea pigs, and rats), animals of the order rabbit (e.g., rabbits), and primates (e.g., humans, chimpanzees, and monkeys). In certain embodiments, the subject (e.g., patient) is a human.
Practicality of use
The transdermal compositions of the present invention can be used in any application where a subject may benefit from transdermal administration of an active agent (e.g., a propynylaminoindan, e.g., rasagiline). Rasagiline and/or a salt thereof finds use in the treatment of a variety of different disease conditions, such as, but not limited to: parkinson's disease, alzheimer's disease, memory impairment, stroke and other diseases, for example, U.S. patent No. 5,387,612; 5,453,446 No; 5,457,133 No; 5,668,181 No; 5,576,353 No; U.S. Pat. No. 5,532,415; 5,599,991 No; 5,786,390 No; 5,519,061 No; 5,891,923 No; 5,744,500 and 6,316,504, the contents of which are incorporated herein by reference. Treatment means at least achieving an improvement in the symptoms associated with the condition the patient is suffering from, wherein improvement is used in a broad sense which means at least reducing the magnitude of a parameter such as the symptoms associated with the condition to be treated. Thus, treatment also includes the case where the pathological condition, or at least the symptoms associated therewith, are completely inhibited, e.g., prevented from occurring or from being halted, e.g., terminated, so that the subject is no longer afflicted with the condition, or at least is no longer afflicted with the symptoms of the condition.
Reagent kit
Kits for performing some of the methods described herein are also provided. In certain embodiments, the kit comprises one or more transdermal compositions as described above. In certain embodiments, the kit comprises an adhesive cover layer as described above. In some embodiments, the kit comprises multiple layers, such as a drug-containing layer and a layer with or without any drugs or other excipients. In a given kit comprising two or more compositions, the compositions may be packaged separately or present in a common container.
In certain embodiments, the kit may further comprise instructions for performing the method or means/devices for obtaining the method (e.g., a URL directing the user to a web page providing the instructions), which may be printed on an object, which may be one or more of the following: package instructions (package insert), packaging, reagent containers, and the like. In the kit, the one or more components are contained in the same or different containers, as convenient or as desired.
The following examples are offered by way of illustration and not by way of limitation. Specifically, the following examples are specific embodiments for carrying out the present invention. This example is for illustrative purposes only and is not intended to limit the scope of the present invention in any way.