This invention relates to a multilayer drug delivery system. More particularly, the invention relates to a multilayer system that includes a barrier that separates layers in the system used in transdermal drug delivery.
Transdermal devices for the delivery of biologically active agents have been used for maintaining health and treating therapeutically a wide variety of ailments. For example, analgesics, steroids, etc., have been delivered with such devices. Such transdermal devices include patches in which a biologically active agent is delivered to the body tissue passively without the use of an additional energy source. Many such devices have been described, for example, in U.S. Pat. Nos. 3,598,122, 3,598,123, 4,379,454, 4,286,592, 4,314,557, 4,568,343, and U.S. Publication No. 20030026829, all of which are incorporated herein by reference.
A transdermal patch is typically a small adhesive bandage that contains the drug to be delivered. A simple type of such transdermal patches is an adhesive monolith including a drug-containing reservoir disposed on a backing. The reservoir is typically formed from a pharmaceutically acceptable pressure sensitive adhesive. In some cases, the reservoir can be formed from a non-adhesive material, with the skin-contacting surface having a thin layer of a suitable adhesive. The rate at which the drug is administered to the patient from these patches can vary due to normal person-to-person and skin site-to-skin site variations in the permeability of skin to the drug.
More complex patches can be a multilaminate or can include drug reservoir layers in the patches. Exemplary transdermal drug delivery systems are illustrated by the embodiments shown in
In the embodiment shown in
In an alternative prior device shown in
Although the transdermal delivery of therapeutic agents has been the subject of intense research and development for over 30 years, only a relatively small number of drug molecules are suitable for transdermal delivery. For effective delivery, a delivery rate that is therapeutically effective is needed. Many factors affect the delivery rate. The thickness and concentration of the drug reservoir and the layers adjacent to the drug reservoir, as well as the rheological properties of the layers are some of these factors.
Often, due to the chemical as well as physical characteristics (e.g., rheological parameters), a system may change over time, e.g., during a period of storage. For example, the matrix formulations typically cold flow over time. The extent of cold flow can be affected by the fluid characteristics of the reservoir matrix, as well as physical forces that may be applied on the device, for example, by the protective pouch pressing on the reservoir. Typically, the drug delivery patches are made by cutting multiple layers simultaneously, resulting in the layers having the same planer size and their edges being flush on the side of the patch. Thus, for typical patch devices like those shown in
Galantamine, also called galanthamine, has the structure C17H21NO3, and is chemically named 4a,5,9,10,11,12-Hexahydro-3-methoxy-11-methyl-6H-benzofuro(3a,3,2-ef)(2)benzazepin-6-ol. The preparation and pharmacological activity of galantamine have been described in U.S. Pat. Nos. 5,877,172; 6,194,404; 6,335,328; 6,573,376; and 6,617,452. Further, transdermal delivery of galantamine has been mentioned in U.S. Pat. Nos. 5,700,480; 5,932,238; as well as U.S. Patent Publication No. 20040192683. Galantamine is one of the reversibly acting cholinesterase inhibitors. It is reported to have effects similar to those of physostigmine and neostigmine but presents a lower risk of toxicity as physostigmine or neostigmine. Galantamine has been reported to be useful for treatment of the narrow-angle glaucoma and, as antidote after curare applications, treatment of dementia, Alzheimer's disease and the treatment of alcohol dependence.
However, to be effective in a multiple day patch, galantamine content needs to be high. For example, a drug loading of 10 wt % cannot support a multi-day system without the introduction of a secondary drug reservoir or very thick adhesive layer. Prior art references on transdermal galantamine delivery do not teach systems that permits high galantamine solubility and flux rates. For example, U.S. Pat. No. 5,700,480 describes a flux that if delivered from a reasonably small patch would be low for effective therapy of Alzheimer's disease. The flux reported there was on mice skin, which tends to have higher permeability than human skin. For delivery to human, better design to improve galantamine loading and permeation will be required. High galantamine and enhancer contents tend to tackify and soften the reservoir, respectively, thereby increasing the risk of cold flow.
Thus, a transdermal galantamine delivery device with good drug loading and sufficient flux is needed for effective therapy of Alzheimer's disease from a reasonably sized patch. Similarly, there is a need for galantamine delivery device for therapy of other ailments since galantamine has been reported to be effective in therapy on dementia, smoking, alcoholism, etc. There continues to be a need for improved delivery of galantamine, especially sustained delivery over a period of time. What is needed is a multilayer galantamine delivery system that is more stable overtime, thus ensuring reliable, predictable delivery of the drug, even for systems that may have been stored for a long period of time.
The present invention provides a method and a device for delivery of galantamine for therapeutic effects, especially delivery of galantamine to a subject transdermally through the skin or other body surfaces. An individual can wear the device adhesively over an extended period of time.
In one aspect, the present invention provides a device for administration of galantamine to an individual at a therapeutically effective rate through a body surface. The device has a reservoir having a matrix including galantamine in the matrix; a backing layer attached to the reservoir and is substantially impermeable to galantamine. There is also a second matrix in which galantamine is diffusible and a barrier layer disposed between the reservoir and at least part of the second matrix. The barrier layer has a barrier outer perimeter and the reservoir has a reservoir outer perimeter such that the barrier layer outer perimeter is larger than the reservoir outer perimeter. The barrier layer is made of a material that is substantially impermeable, preferably completely impermeable, to galantamine.
The barrier layer, having an outer perimeter larger than the outer perimeter of a drug reservoir attached to it, advantageously prevents any migration of the drug reservoir from crossing over to anther matrix layer.
The present invention is particularly useful in transdermal systems in which the reservoir material (matrix) is a highly viscous fluid i.e. will deform under stress as may occur during processing or extended storage, and it may flow when pinched or pressed. In a method of making a patch with the reservoir matrix on the backing layer in which the two are cut to a desired size and shape (e.g., by die cutting), in which at least one (sometimes all) edge of the backing is flush with at least one edge of the reservoir matrix, some of the reservoir matrix material may adhere to the edges of the backing layer. The edges of the reservoir and the backing layer are flush in
In an aspect, the barrier layer is a frame-shaped layer. The frame-shaped layer has a window through which a matrix layer having some adhesive property can attach to a different layer, for example, the backing layer of another matrix layer. Since the reservoir material is fluid, this window enables the reservoir layer to be smaller in outer perimeter than the barrier frame and still be transferable and processed in the manufacturing process. In this way, a mechanized production line in which rolls (or webs) of materials are processed into final products can be implemented.
The present invention is illustrated by way of example in embodiments and not limitation in the figures of the accompanying drawings in which like references indicate similar elements. The figures are not shown to scale unless indicated otherwise in context.
The present invention relates to delivery of one or more pharmaceutical agents, including galantamine, through a body surface (e.g. skin) involving the use of an reservoir that incorporates the drug galantamine and optionally other ingredients such as other pharmaceutical agents and enhancers and having an adhesive layer to maintain the delivery system on a body surface of an individual. In the present invention, a barrier layer is used to prevent the reservoir material with drug in its matrix to come into contact with another matrix in the device.
In describing the present invention, the following terms are to be used as indicated below. As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural references unless the content clearly dictates otherwise.
As used herein, the term “transdermal” refers to the use of skin, mucosa, and/or other body surfaces as a portal for the administration of drugs by topical application of the drug thereto for passage into the systemic circulation. Such passage can take place through intact surface (such as skin) without wounds or punctures.
“Biologically active agent” is to be construed in its broadest sense to mean any material that is intended to produce some biological, beneficial, therapeutic, or other intended effect, such as enhancing permeation, relief of pain, or symptoms of Alzheimer disease or dementia, etc.
As used herein, the term “drug” refers to any material that is intended to produce some biological, beneficial, therapeutic, or other intended effect, such as improve symptoms of Alzheimer's disease or dementia.
As used herein, the term “therapeutically effective” refers to the amount of drug or the rate of drug administration needed to produce the desired therapeutic result.
For the sake of clarity and illustration the following will refer to the matrix layer 6 as an adhesive layer. A barrier frame 14 is disposed between the adhesive layer 6 and the backing layer 2 of the reservoir 3.
The overlay adhesive layer 6 is larger in area and in outer perimeter than the barrier frame 14. Thus, the overhang portion 8 outside of the frame 14 will provide adhesion to the body surface. The backing layer 10 is hidden by the overlay adhesive layer 6 and is therefore not shown. The figures are not shown to scale. In fact, the thicknesses of the various layers are relatively thin such that the device is flexible and generally flat when laid on a flat surface. Therefore, when pressure is applied to the flat surface of the device, either during manufacture or in use, the void area in the window is substantially filled so that the adhesive layer 6 attaches to the backing layer 2 within the window.
In
The second reservoir layer 28 has a ring of exposed area 40 encircling the outer perimeters of the first barrier frame 34 and the first reservoir layer 23 such that upon application to the body surface at least a portion of the ring of exposed area 40 will contact the body surface for delivery of an agent from the second reservoir layer 28 to the tissue through the body surface. The agent will migrate from the more central part of the second reservoir layer 28 to the exposed area as the drug concentration changes upon delivery of the agent.
A second barrier frame 42 is disposed between and attached to the backing layer 30 of the second reservoir layer 28 and the overlay adhesive layer 6. Again, the perimeters of theses layers have a cascading relationship similar to the cascading relationship between the second reservoir layer 28, the first barrier frame 34 and the first reservoir layer 23. The overlay adhesive layer 6 has the largest outer perimeter among the matrixes and adhesives.
A method of manufacture and construction for a system containing an occluded counter acting agent (antagonist) as shown in
Fentanyl base would be completely dissolved and mixed in a solution of solvent (such as ethyl acetate) and polyacrylate adhesive such as National Starch DURO-TACK 87-4287. The solution would be formulated so that the concentration of fentanyl would not exceed the solubility of fentanyl in the polymer (about 10%) once the solvent is removed. The solution would be coated to a uniform thickness on a 1-5 mil (0.025 mm-0.125 mm) thick silicone coated polyethylene terapthalate film (PET release coated liner) or similar. The liner and fentanyl polymer solution are passed through a series of ovens to remove the solvent forming a dry uniform film, typically less than 5 mils (0.125 mm) thick. The dried film would then be laminated to a second non-coated PET liner for further processing.
The antagonist layer would be produced by melting a polymer such as ethylene vinyl acetate (EVA-9, EVA-22, EVA-40, etc.), ethylene octene (ENGAGE), or similar elastomeric polymer, and blending in naltrexone-HCl at a concentration of 50-90%. The blend would be mixed to uniformity and extruded between two films such as PET liners, one of which would be release coated.
The two component films would be die cut and assembled on another polyisobutylene (PIB), polyacrylate, or similar adhesive (78) on a EVA/PET, polymer fiber woven, (80) or similar overlay film in a converting operation as follows: Barrier frames (84) would be die cut from a 0.5-5 mil (0.0125 mm-0.125 mm) thick PET film such that the inner (18) and outer edges (16) were respectively slightly larger and smaller than the target matrix area (23,26) and uniformly spaced on the overlay adhesive (78). The naltrexone-EVA (52) on PET film (54) would be die cut to the target size and placed on the adhesive (6) within the inner boundary of the frames (34). The release coated liner would be removed in this assembly step.
The matrix film would be cut to the appropriate length and width (23,26) and placed on top of the barrier frames (34), completely isolating the naltrexone component (52).
If desired, an additional barrier frame can be disposed between the second reservoir layer and the overlay adhesive layer. This is shown in
The drug (pharmaceutical agent) reservoir can be either a single phase polymeric composition or a multiple phase polymeric composition, as discussed earlier. In some embodiments, more than one component, e.g., a drug and a permeation enhancer, is present, and may be in amounts above saturation concentration. Preferably, the whole matrix, with drugs and other optional ingredients, is a material that has the desired adhesive properties, in which case, the reservoir 3 is formed using a pharmaceutically acceptable polymeric material that can provide adhesive property for application to the body surface.
The backing layers may be formed from any material suitable for making transdermal delivery patches, such as a breathable or occlusive material including fabric, polyvinyl acetate, polyvinylidene chloride, polyethylene, polypropylene, polyurethane, polyester, ethylene vinyl acetate (EVA), polyethylene terephthalate (PET), polybutylene terephthalate, coated paper products, aluminum sheet and the like, and a combination thereof. In preferred embodiments, the backing layer includes low density polyethylene (LDPE) materials, medium density polyethylene (MDPE) materials or high density polyethylene (HDPE) materials, e.g., SARANEX (Dow Chemical, Midland, Mich.). The backing layer may be a monolithic or a multilaminate layer. In preferred embodiments, the backing layer is a multilaminate layer including nonlinear LDPE layer/linear LDPE layer/nonlinear LDPE layer. The backing layer preferably has a thickness of about 0.012 mm (0.5 mil) to about 0.125 mm (5 mil); more preferably 0.025 mm (1 mil) to about 0.1 mm (4 mil); even more preferably 0.0625 mm (1.5 mil) to about 0.0875 mm (3.5 mil).
The purpose of the barrier frame is to separate materials, therefore the active compounds, excipients, and polymers within the system should have negligible solubility or permeability in the barrier material. It is desirable for the barrier material to serve as a processing web during assembly, thus mechanical strength (i.e. inelastic) in the web direction may be desirable. Further, the barrier frame may be used as a separating point in some system designs, therefore it may be release coated on one or both sides of the barrier frame. Materials that can be used for making a barrier frame include, for example, polyethylene terephthalate (PET) film, polyvinyl acetate, polyvinylidene chloride, polyethylene, polypropylene, polyurethane, polyester, polybutylene terephthalate, coated paper products, aluminum sheet and the like, and any combination thereof. The barrier material can be used with another layer (e.g., as a laminate) of a material that is a less effective barrier without the barrier material. The thickness of the barrier layer (e.g., barrier frame) preferably ranges between 0.012 mm (0.5 mil) and 0.125 mm (5.0 mil), with or without release coating on either side. Other materials can be used, as long as the active agent or permeation enhancers are insoluble in them.
The reservoir or matrix may be formed from drug (or biological active agent) reservoir materials as known in the art. For example, the drug reservoir is formed from a polymeric material in which the drug has reasonable solubility for the drug to be delivered within the desired range, such as, a polyurethane, ethylene/vinyl acetate copolymer (EVA), acrylate, styrenic block copolymer, and the like. In preferred embodiments, the reservoir 3 is formed from a pharmaceutically acceptable pressure sensitive adhesive, preferably an acrylate copolymer-based adhesive, as described in greater detail below.
The adhesive reservoir 3 may be formed from standard pressure sensitive adhesives. Examples of known pressure sensitive adhesives include, but are not limited to, acrylates, polysiloxanes, polyisobutylene (PIB), polyisoprene, polybutadiene, styrenic block polymers, and the like. Examples of styrenic block copolymer-based adhesives include, but are not limited to, styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene copolymer (SBS), styrene-ethylenebutene-styrene copolymers (SEBS), and di-block analogs thereof. PIB generally has poorer solubility for drugs than acrylate adhesives. Thus, acrylate polymers are preferred as the matrix for drug reservoirs but either PIB or acrylates are preferred as an overlay adhesive layer. The drug reservoir or the matrix layer can have a thickness of 0.025-0.25 mm (1-10 mils), preferably 0.05-0.12 mm (2-5 mils), more preferably 0.05-0.075 mm (2-3 mils).
It is desired that the material for the matrix in the reservoir has a high solubility for the agent to be delivered through the body surface, either for therapeutic drug agents or permeation enhancers to facilitate the delivery. If the reservoir material does not provide adequate adhesiveness for multiple day use, the overlay adhesive layer should be made with an adhesive material that has stronger and sufficient adhesive and cohesive properties for multiple day application.
Preferred materials for making the reservoir or overlay adhesive coating according to the present invention include acrylates, which can be a copolymer of various monomers (“soft” monomer, “hard” monomer, and “functional” monomer) or blends of copolymers. Acrylic polymers provide good solubility for many agents. The acrylic polymers can be composed of a copolymer or terpolymer including at least two or more exemplary components selected from the group including acrylic acids, alkyl acrylates, methacrylates, copolymerizable secondary monomers or monomers with functional groups. Functional monomers are often used to either provide needed functionality or improve cohesive properties through grafting or cross-linking. Examples of functional monomers are acids, e.g. acrylic acid, methacrylic acid and hydroxy-containing monomers such as hydroxyethyl acrylate, hydroxypropyl acrylate, acrylamides or methacrylamides that contain amino group and amino alcohols with amino group protected. Functional groups, such as acid and hydroxyl moieties can also help to increase the solubility of basic ingredients (e.g., drugs) in the polymeric material. Additional useful “soft” and “hard” monomers include, but are not limited to, methoxyethyl acrylate, ethyl acrylate, butyl 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, vinyl acetate, acrylamide, dimethylacrylamide, acrylonitrile, dimethylaminoethyl acrylate, dimethylaminoethyl methacrylate, tert-butylaminoethyl acrylate, tert-butylaminoethyl methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, and the like. Additional examples of appropriate acrylic adhesives suitable in the practice of the invention are described in Satas, “Acrylic Adhesives,” Handbook of pressure-Sensitive Adhesive Technology, 2nd ed., pp. 396-456 (D. Satas, ed.), Van Nostrand Reinhold, New York (1989). The acrylic adhesives are commercially available (National Starch and Chemical Corporation, Bridgewater, N.J.; Solutia, Mass.). Further examples of acrylate-based adhesives are as follows, identified as product numbers, manufactured by National Starch (Product Bulletin, 2000): DURO-TAK® 87-4098, 87-2287, 87-4287, 87-2051, 87-2052, 87-2054, 87-2196, 87-9259, 87-9261, 87-2979, 87-2510, 87-2353, 87-2100, 87-2852, 87-2074, 87-2258, 87-9085, 87-2525, 87-2825, 87-200A, 87-201A, 87-2194, 87-2677, 87-900A, and 87-9301. DURO-TAK® 87-2287 and 87-4287 both are polymeric adhesive having similar monomer compositions: 5.2 wt % 2-hydroxyethyl acrylate monomer, about 20-40 wt % vinyl acetate, and about 55-75 wt % 2-ethylhexyl acrylate; and these two polymeric adhesives are provided solubilized in ethyl acetate in solids content of about 40-50 wt %. The DURO-TAK® 87-2287 adhesive is also mentioned in U.S. Pat. No. 5,693,335.
The acrylic polymers can include cross-linked and non-cross-linked polymers. The polymers can be cross-linked by known methods to provide the desired polymers. In some typical embodiments, the adhesive at the stage of application to the skin is a acrylate adhesive having a glass transition temperature (Tg) less than −10° C., preferably −10° C. to about −30° C., more preferably having a Tg of about −20° C. to about −40° C. The molecular weight of the acrylate adhesive, expressed as weight average (MW), preferably ranges from 25,000 to 10,000,000, further preferably from 50,000 to about 3,000,000 and more preferably from 100,000 to 1,000,000 prior to any cross-linking reactions. Upon cross-linking the MW can further increase, as known to those involved in the art of polymer chemistry.
As aforementioned, the reservoir(s) can include a multiple phase composition or a single phase polymeric composition, free of undissolved components, containing an amount of the drug sufficient to induce and maintain the desired therapeutic effect in a human for at least three days. The present invention has utility in connection with the delivery of wide variety of drugs (such as those mentioned in U.S. Publication No. 20030026829), in addition to galantamine, delivered through body surfaces and membranes, including skin.
The dissolved galantamine content in the drug reservoir matrix can be above 5 wt % on solids. However galantamine content above 10 wt % is preferred, prefereably above 15 wt %, more preferably from 15 wt % to 35 wt %, more preferably above 20 wt %, even more preferably from 20 wt % to 30 wt %. Such galantamine contents are suitable for effecting flux of therapeutic effect for ailments such as Alzheimer's disease or dementia, with a flux of, e.g., greater than 10 μg/cm2-hr, preferably about 12.5 to 18.8 μg/cm2-hr for a 3 day patch, more preferably a 7 day patch. It is noted that galantamine base, salts or esters thereof, or analogs thereof, as known by those skilled in the art, can also be delivered with devices of the present invention having barrier(s), since the advantage of having the barrier in a device is not limited to galantamine base alone. The galantamine can be in any reservoir that has a flow path for the galantamine to migrate to a body surface of the user individual. As used herein, when the term “galantamine” is used, it can mean galantamine base, salt, ester, or analog unless specified to be otherwise in the content.
As indicated in the above, in some embodiments, the reservoir or the adhesive may contain additional components such as, additives, permeation enhancers, stabilizers, dyes, diluents, plasticizer, tackifying agent, pigments, carriers, inert fillers, antioxidants, excipients, gelling agents, anti-irritants, vasoconstrictors and other materials as are generally known to the transdermal art. Typically, such materials are present below saturation concentration in the reservoir.
The protective layer (or release liner) can be made of a polymeric material that may be optionally metallized. Examples of the polymeric materials include polyurethane, polyvinyl acetate, polyvinylidene chloride, polypropylene, polycarbonate, polystyrene, polyethylene, polyethylene terephthalate, polybutylene terephthalate, paper, and the like, and a combination thereof. In preferred embodiments, the protective layer includes a siliconized polyester sheet.
As mentioned, many adhesives are useful polymeric materials for forming drug-containing pressure sensitive adhesive (PSA). One preferred adhesive for galantamine is polyacrylate (acrylate polymers). After formulating into a transdermal system with drugs, permeation enhancers, and the like, which produce plasticizing effect as well as tackifying effect, adhesive polymers (such as polyacrylates) plasticized with permeation enhancers and drug would have storage modulus and creep compliance ranges that can be used with the systems of the present invention. For example, the plasticized material could have a resulting creep compliance that is about 1×10−3 cm2/dyn or less, preferably more than about 7×10−5 cm2/dyn, preferably from about 7×10−5 cm2/dyn to 6×10−4 cm2/dyn, more preferably about 1×10−4 cm2/dyn to 6×10−4 cm2/dyn. The preferred storage modulus of the plasticized acrylate polymer is about 1×105 dyn/cm2 to 8×105 dyn/cm2, preferably about 1.2×105 dyn/cm2 to 6×105 dyn/cm2, more preferably about 1.4×105 dyn/cm2 to 5×105 dyn/cm2. However, even with stiff adhesives, after incorporating high drug content, it is beneficial to have barrier layers to prevent possible flow of drug reservoir material into other adhesive layers. Contact between different matrix and adhesive layers results in drug diffusion between such layers, resulting in undesirable changes over a prolonged period.
For rheology parameters, modulus G′ is storage modulus measured at 25° C. and 1 rad/s frequency (Frequency sweep experiment was conducted using AR-2000 rheometer from TA Instruments (TA Instruments, 109 Lukens Drive, New Castle, Del. 19720). The test conditions are: strain 1%, temperature 25° C., frequency range 0.1 to 100 rad/s, gap around 1000 micron). Creep compliance tests are conducted using AR-2000 r heometer from TA Instruments. The test conditions are: stress 1000 dyn/cm2, temperature 30° C., time 3600 seconds, gap around 1000 microns, as would be understood by those skilled in the art.
Less stiff polymer adhesives can also be used, but such adhesives would have a higher tendency to cold flow, for example, adhesives after incorporation of ingredients (such as galantamine and permeation enhancers) with creep compliance of from greater than about 1×10−3 cm2/dyn, as well as those with storage modulus of less than about 1×105 dyn/cm2. The implementation of barrier films according to the present invention protects against undesired mixing of adhesives from different layers.
One can select the ingredients and the appropriate amounts thereof to result in an effective transdermal drug delivery system with the right adhesive properties for the desirable length of time, such as 24 hours, 3 day, or even 7 day application on a body surface. When the drug reservoir tends to be a little soft due to the presence of a large amount of drug or enhancer, the barrier frames of the present invention is useful for preventing drug reservoir material from cold-flowing to undesirable positions.
Permeation enhancers can be useful for increasing the skin permeability of the drug galantamine or drug combinations to achieve delivery at therapeutically effective rates. Such permeation enhancers can be applied the skin by pretreatment or currently with the drug, for example, by incorporation in the reservoir. A permeation enhancer should have the ability to enhance the permeability of the skin for one, or more drugs or other biologically active agents. A useful permeation enhancer would enhance permeability of the desired drug or biologically active agent at a rate adequate for therapeutic level from a reasonably sized patch (e.g., about 20 to 80 cm2). Some useful permeation enhancers include non-ionic surfactant, one or more can be selected from the group including glyceryl mono-oleate, glyceryl mono-laurate, sorbitan mono-oleate, glyceryl tri-oleate, and isopropyl myristate. The non-ionic surfactant can be used in the amount of 0.1 about 20 wt % solids to the total composition of the matrix layer. Examples of permeation enhancers include, but are not limited to, fatty acid esters of alcohols, including fatty acid esters of glycerin, such as capric, caprylic, dodecyl, oleic acids; fatty acid esters of isosorbide, sucrose, polyethylene glycol; caproyl lactylic acid; laureth-2; laureth-2 acetate; laureth-2 benzoate; laureth-3 carboxylic acid; laureth-4; laureth-5 carboxylic acid; oleth-2; glyceryl pyroglutamate oleate; glyceryl oleate; N-lauroyl sarcosine; N-myristoyl sarcosine; N-octyl-2-pyrrolidone; lauraminopropionic acid; polypropylene glycol-4-laureth-2; polypropylene glycol-4-laureth-5dimethy-1 lauramide; lauramide diethanolamine (DEA). Preferred enhancers include, but are not limited to, pyroglutamate (such as octyl-, ethyl-, lauryl pyroglutamate (LP)), glyceryl monolaurate (GML), glyceryl monocaprylate, glyceryl monocaprate, glyceryl monooleate (GMO) and sorbitan monolaurate. Other permeation enhancers that could improve drug permeability include: isosorbide, oleth-4, ethoxydiglycol, and lauryl pyrrolidone. Additional examples of suitable permeation enhancers are described, for example, in U.S. Pat. Nos. 5,785,991; 5,843,468; 5,882,676; and 6,004,578. As used herein, “permeation enhancers” is meant to include dissolution assistants, unless specified otherwise in context.
As already mentioned, the formulations can contain various types of enhancers. One type is acidic, including, e.g., fatty acids, e.g., oleic acid, linoleic acid, linolenic acid, arachidonic acid, lauric acid, myristic acid serve as solubilizers for the polar galantamine, increasing the concentration of drug that can be loaded into the adhesive. A second type of useful enhancers are fatty acid esters, alcohol, or fatty acid/base reaction products, such as isopropyl myristate (a fatty ester), lauryl pyrrolidone (amide), laureth-2 (fatty alcohol ether), glycerol monooleate (fatty acid ester), lauryl lactate (fatter acid ester), 1,2-dihydroxydodecane (fatty alcohol), ethyl palmitate (fatty ester). These can also serve as cosolvents for galantamine in skin, enabling high flux. Other than the above, an nonexhaustive list of useful permeation enhancers that enable high flux rate include selachyl alcohol, laureth-4 (fatty alcohol ether), oleth-2 (fatty alcohol ether), and N-lauroyl sarcosine (fatty acid).
In some embodiments, a large amount of permeation enhancer may be needed to aid the drug in transdermal delivery. The present invention is especially suitable for such transdermal delivery systems. Permeation enhancers in the polymer composition can be 10 wt % or high, 15 wt % and higher, greater than 20 wt %, or even greater than 30 dry weight % (or solids wt %). The permeation enhancers and the galantamine can constitute more than 25 wt % of the matrix reservoir, preferably more than 30 wt %, more preferably about 30 wt % to 50 wt %, in some embodiments even about 40 wt % to 50 wt % of the matrix reservoir.
In certain embodiments, polyvinylpyrrolidone (PVP) can be incorporated into the acrylate polymer matrix to increase cohesive strength and to affect the adhesive properties of the galantamine transdermal system. The incorporation of PVP resulted in an increase in modulus and decrease in creep compliance. PVP works particularly well with acrylate polymer adhesives that contain hydroxyl or acid functionalities, or both. Both of these functionalities have the capability to interact with PVP. More than 5 wt %, preferably from 5 wt % to 20 wt % of PVP on matrix solids can be used to increase modulus, decrease creep compliance, and improve the adhesive properties of the transdermal formulation without reducing galantamine solubility significantly.
As aforementioned, the drug reservoir contains galantamine, preferably totally dissolved in the matrix of the reservoir, or present as a crystalline dispersion in the reservoir. It is understood that the reservoir can also contain other drugs, preferably in a single phase polymeric composition. Other drugs that can be contained in the drug reservoir include, for example, those disclosed in U.S. Pat. No. 6,004,578. One skilled in the art will be able to incorporate such drugs based on the disclosure of the present invention.
A wide variety of materials that can be used for fabricating the various layers of the drug delivery patches according to this invention have been described above. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions.
Transdermal flux can be measured with a standard procedure using Franz cells or using an array of formulations. Flux experiments were done on isolated human cadaver epidermis. With Franz cells, in each Franz diffusion cell a disc of epidermis is placed on the receptor compartment. A transdermal delivery system is placed over the diffusion area (1.98 cm2) in the center of the receptor. The donor compartment is then added and clamped to the assembly. At time 0, receptor medium solution (between 21 and 24 ml, exactly measured) is added into the receptor compartment and the cell maintained at 35° C. This temperature yields a skin surface temperature of 30-32° C. Samples of the receptor compartment are taken periodically to determine the skin flux and analyzed by HPLC. In testing flux with an array of transdermal miniature patches, formulations are prepared by mixing stock solutions of each of the mixture components of formulation in organic solvents (about 15 wt % solids), followed by a mixing process. The mixtures are then aliquoted onto arrays as 4-mm diameter drops and allowed to dry, leaving behind solid samples or “dots.” (i.e., mini-patches). The miniature patches in the arrays are then tested individually for skin flux using a permeation array, whose principle of drug flux from a formulation patch through epidermis to a compartment of receptor medium is similar to that of Franz cells (an array of miniature cells). The test array has a plurality of cells, a piece of isolated human epidermis large enough to cover the whole array, and a multiple well plate with wells acting as the receptor compartments filled with receptor medium. The assembled permeation arrays are stored at 32° C. and 60% relative humidity for the duration of the permeation experiments. Receptor fluid is auto-sampled from each of the permeation wells at regular intervals and then measured by HPLC for flux of the drug.
Administration of the Drug
On application to the skin, the drug in the drug reservoir of the transdermal patch diffuses into the skin where it is absorbed into the bloodstream to produce a systemic therapeutic effect. The onset of the therapeutic depends on various factors, such as, potency of the drug, the solubility and diffusivity of the drug in the skin, thickness of the skin, concentration of the drug within the skin application site, concentration of the drug in the drug reservoir, and the like. Typically, it is preferable that a patient experiences an adequate effect within a few hours (e.g., 3-6 hours) of initial application. However, this is significant only on the initial application. On repeated sequential application, the residual drug in the application site of the patch is absorbed by the body at approximately the same rate as the drug from the new patch is absorbed into the new application area. Thus the patient should not experience any interruption of the therapeutic effect, such as analgesia.
When continuous therapeutic effect is desired the depleted patch would be removed and a fresh patch is applied to a new location. For example, the patch would be sequentially removed and replaced with a fresh patch at the end of the administration period to provide continual therapeutic effect. Since absorption of the drug from the fresh patch into the new application area usually occurs at substantially the same rate as absorption by the body of the residual drug within the previous application site of the patch, blood levels will remain substantially constant. Additionally, it is contemplated that doses may be increased over time and that concurrent use of other drugs may occur to deal with a need for increased relief.
Methods of Manufacture
The transdermal devices are made from laminates which are manufactured according to known methodology. In general, in an embodiment, a solution of the polymeric reservoir material, as described above, is added to a mixer, with the desired amounts of the drug, permeation enhancers, and other ingredients that may be needed. Preferably, the polymeric reservoir material is an acrylate material to provide adhesive property to the transdermal delivery device. Typically, the acrylate material is solubilized in an organic solvent, e.g., ethanol, ethyl acetate, hexane, and the like. The mixer is then activated for a period of time to achieve acceptable uniformity of the ingredients. The mixer is attached by means of connectors to a suitable casting die located at one end of a casting/film drying line. The mixer is pressurized using nitrogen to feed solution to the casting die. Optionally the solution is transferred to a pressurizable tank. Solution is cast as a wet film onto a moving siliconized polyester web. The web is drawn through a series of ovens to evaporate the casting solvent to acceptable residual limits. The dried reservoir film is then laminated to a selected backing membrane and the laminate is wound into rolls. However, the materials may also be dry blended and extruded to produce a similar laminate. In subsequent operations, the laminate is further processes in conjunction with other laminate(s) to result in individual patches that are die-cut, separated and unit-packaged using suitable pouchstock. Laminates of other reservoir materials can be made by people skilled in the art.
The present invention is particularly adapted for mass manufacturing practices using mechanized automated machineries. In such manufacture practices, long rolls (can be considered to be long strips) or webs of laminate materials are fed through roller nips for further lamination to complete the assembly and dies for cutting and alignment. For practical mechanical handling, such webs can be considered to be continuous. Thus, a reservoir, or matrix material needs to have a backing or some kind of flexible but strong (tough and not easily torn) material attached to it for ease of transfer. In this way, rolls of materials can be processed without tearing.
FIGS. 11 to 14 illustrate how mass production by machines involving repetitive mechanical die-cutting and pressing processes are used to make exemplary patches such as those of
Typically, the manufacture of a product of an embodiment similar to that shown in
An adhesive laminate (which includes siliconized PET temporary liner protecting an adhesive on a backing layer) is paid out from payout #2 and the temporary release liner is stripped to result in just a continuous strip of adhesive on a backing. The scrap release liner is removed by take up #2 (not shown).
As shown in
A lamination roller 98 applies the drug reservoir units on the final liner 100 to the adhesive overlay 86. The system webs (i.e., the webs with the drug reservoir) and overlay web are joined such that the system edges fall within the center of the “frames” on the overlay. Since the barrier frames 84 are discrete units spaced apart on the adhesive overlay 86 the slit strip 94 has to similarly space the drug reservoirs on the final liner 100 from payout #4. This is accomplished by having only intermittent contact between the slit strip and the final liner at die 96. The final liner web is accelerated when not in contact with the die 96, and decelerated to match the die speed for the duration of the contact, creating the spacing. This results in a web 102 with discrete units 103 of drug reservoirs 3 attached to backing layers 2 and barrier frames 84, which are shown in
The patches can be made such that only one reservoir matrix island in on a patch, similar to the patch of
Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only, and are not intended to limit the scope of the present invention in any way. Modulus G′ was storage modulus at 25° C. and 1 rad/s frequency (Frequency sweep experiment was conducted using AR-2000 rheometer from TA Instruments (TA Instruments, 109 Lukens Drive, New Castle, Del. 19720). The test conditions were: strain 1%, temperature 25° C., frequency range 0.1 to 100 rad/s, gap around 1000 micron). Creep compliance tests were conducted using AR-2000 rheometer from TA Instruments. The test conditions were: stress 1000 dyn/cm2, temperature 30° C., time 3600 seconds, gap around 1000 microns, as would be understood by those skilled in the art. In the following examples, galantamine base is used, although it is understood that salts, esters, and analog may also be used in similar fashion by one skilled in the art.
A galantamine-containing polyacrylate adhesive solution is mixed with flux enhancing agents such as lauryl pyrollidone, oleic acid, lauryl lactate. The adhesive is a National Starch DURO-TAK® 87-4287 adhesive which is a polymerization product of vinyl acetate, 2-ethylhexyl acrylate, and hydroxyethyl acrylate. The solution is film cast to approximately 9 mils (0.225 mm) thick on a 2 mil (0.05 mm) or 3 mil (0.075 mm) siliconized polyethelene terepathalate (Si-PET) film (also known as release liner) and dried according to conventional technology. Once the solvents are removed, the resulting film is approximately 5 mils (0.125 mm) thick and has approximately 14 wt % galantamine. The adhesive film is then laminated to the PET side of a 2 mil PET/EVA (ethylene vinyl acetate) backing film. The drug adhesive is referred to as a matrix.
A PIB adhesive film is prepared separately in similar fashion by mixing 2 grades of poly isobutylene, with polybutene, and crospovidone in heptane. The solution is film cast at approximately 6 mils (0.15 mm) onto a 3 mil (0.075 mm) Si-PET (silicone coated PET) film, dried to 3 mils (0.075 mm) as above, and laminated to a polyester interlock fabric.
Both the drug matrix film and the PIB adhesive films are simultaneously mounted on a web converting machine along with an uncoated 1-2 mil (0.025 mm-0.05 mm) PET film from which the barrier frames are cut and a 3 mil (0.075 mm) Si-PET film which will be used as the final system liner.
The following steps describe the order of assembly of an individual system. However, all steps occur continuously in various locations throughout the machine in a web converting process. The individual product system assembled in this example has an active area of 48 cm2, centered on a barrier frame, centered on a PIB adhesive of 60 cm2 all covered by a release liner.
The individual product system assembled in this example has two active areas (islands) of 20 cm2, centered on barrier frames, evenly spaced on a PIB adhesive of 60 cm2, all covered by a release liner.
A transdermal galantamine system is to be made through a construction showed in
Galantamine is mixed into solution of solvent (ethyl acetate) and polyacrylate adhesive such as National Starch DURO-TAK 87-4287 with permeation enhancers. The solution is formulated so that the concentration of galantamine is about 5 wt % and does not exceed its solubility in the polymer once the solvent is removed. The solution is coated to a uniform thickness on a 5 mil (0.125 mm) thick silicone coated polyethylene terephthalate film (PET release coated liner) or similar. The liner and galantamine polymer solution are passed through a series of ovens to remove the solvent forming a dry uniform film, to less than 5 mil (0.125 mm) thick. The dried film is then laminated to a second non-coated PET liner for further processing. The active component film is die cut and assembled on another polyisobutylene (PIB) adhesive (although other adhesives, e.g., polyacrylate, or similar adhesive can be used) (78) on a EVA/PET overlay film (80) in a converting operation as follows:
Barrier frames (84) is die cut from a 1 mil (0.025 mm) thick PET film such that the inner (18) and outer edges (16) are 0.15 cm larger and smaller than the target matrix area (3) and spaced according to adhesion requirements on the overlay adhesive (78) 5.15 cm apart in this example.
The matrix film is cut to the appropriate length and width 4.5×4.5 cm and placed on top of the barrier frames (84). The matrix layer release coated liner is removed in this assembly step and replaced with a larger final system release liner (not shown in the figure), covering all the system components. The assembled system is then die cut to the appropriate size with two separate skin-contacting reservoirs on a single patch applicable to a patient.
Galantamine is mixed into solution of solvent (ethyl acetate) and polyacrylate adhesive such as National Starch DURO-TAK 87-4287 with permeation enhancers. The solution is formulated so that the concentration of galantamine is about 24 wt % and above 10 wt % permeation enhancers.
The solution is coated to a uniform thickness on a 5 mil (0.125 mm) thick silicone coated polyethylene terephthalate film (PET release coated liner) or similar. The liner and galantamine polymer solution are passed through a series of ovens to remove the solvent forming a dry uniform film, to less than 5 mil (0.125 mm) thick. The dried film is then laminated to a second non-coated PET liner for further processing. The active component film is die cut and assembled on another polyisobutylene (PIB) adhesive (although other adhesives, e.g., polyacrylate, or similar adhesive can be used) (78) on an EVA/PET overlay film (80) in a converting operation as follows:
Barrier frames (84) is die cut from a 1 mil (0.025 mm) thick PET film such that the inner (18) and outer edges (16) are slightly larger and smaller than the target matrix area (3) and spaced according to adhesion requirements on the overlay adhesive (78).
The matrix film is cut to the appropriate length and width 4.5×4.5 cm and placed on top of the barrier frames (84). The matrix layer release coated liner is removed in this assembly step and replaced with a larger final system release liner (not shown in the figure), covering all the system components. The assembled system is then die cut to the appropriate size with one skin-contacting reservoirs on a single patch applicable to a patient.
Table 1 as follows shows the storage modulus and creep compliance values of a number of compositions with galantamine contents of 20 wt % and above with permeation enhancers. The percentages are the amount of the specific respective ingredients in the composition. The balance is the adhesive in the formulation. For example, the first sample had 20 wt % galantamine, the balance (i.e., 80 wt %) was adhesive A. The storage modulus and creep compliance values indicated that such compositions would tend to cold flow over a period of storage time, for example, several weeks.
In Table 1, Adhesive A is a polyacrylate adhesive with monomer components including about 3% acrylic acid, and 30% hydroxyethyl acrylate. Adhesvie B is a noncross-linked polyacrylate adhesive with monomer components of 59% butyl acrylate, 6% acrylic acid, 9.5% t-OA (N-t-pctylacrylamide), and 25.5% hydroxyethyl acrylate. GAL is galantamine. For the permeation enhancers, GMO is glycerol monooleate; IPM is isopropyl myristate; LAU is Laureth-2; LPY is lauryl pyrrolidone; LrA is lauric acid; OA is oleic acid; and PVP is polyvinyl pyrrolidone.
Casting solutions with solids content of the compositions of Table 1 were made into using ethyl acetate as solvent. A small amount of methanol may also be used in addition to ethyl acetate to help solublize the solids in the casting solution.
The casting solutions are used for casting and making patches with the method similar to that in Example 1 and Example 3. The barrier layer would prevent the migration of adhesive with galantamine to migrate to an adhesive near by.
The present invention has utility in connection with the delivery of galantamine or analogs or derivatives thereof through body surfaces and membranes, including skin. Galantamine derivatives and analogs are known in the art. It is noted that galantamine equivalents (analogs and derivatives), including salts and esters, can be incorporated into the device with or in place of galantamine base. Galantamine derivative and analogs have been disclosed in for example, the following, U.S. Pat. Nos. 5,958,903; 6,018,043; 6,093,815; 6,184,004; 6,316,439; 6,323,195; 6,323,196; US Publication 20050065338, and European Patent Application No. EP1458724A, which are incorporated by reference in their entireties herein.
The practice of the present invention will employ, unless otherwise indicated, conventional methods used by those in pharmaceutical product development within the knowledge of those skilled in the art. Embodiments of the present invention have been described with specificity. The embodiments are intended to be illustrative in all respects, rather than restrictive, of the present invention. It is to be understood that various combinations and permutations of various parts and components of the schemes disclosed herein can be implemented by one skilled in the art without departing from the scope of the present invention. All U.S. patents and U.S. patent publications cited herein are incorporated by reference herein in their entireties.
The present application claims the benefit of provisional application 60/680,905 filed May 13, 2005 and provisional application 60/790,236 filed Apr. 7, 2006, both of which are incorporated by reference herein.
Number | Date | Country | |
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60680905 | May 2005 | US | |
60790236 | Apr 2006 | US |