Permeate Delivery Patch via Formed Pathway

Abstract

A thin solid tablet composition containing an active permeant can be used in a method of administering the permeant to an individual. The thin solid tablet can be incorporated into a patch. The patch can be used to administer a permeant (such as a drug) and an excipient to an individual by percutaneous microperforation.

Description

Background Art Technical Field

[0001] This application relates to compositions and methods for transdermal drug delivery, and particularly to thin solid tablet compositions containing active permeants and methods of administering the permeants to an individual by transdermal microperforation.

[0002] Description

[0003] Passive transdermal drug delivery is a convenient and effective way to administer various therapeutic agents. This route of administration is non-invasive and provides a steady drug delivery over an extended period of time. Although conventional transdermal systems (such as drug patches) have demonstrated the benefits of delivering drugs via the skin, they are only suitable for an extremely limited number of drugs. This is because millions of dead skin cells form a protective barrier (stratum corneum) on the skin surface, preventing most therapeutic molecules from entering the skin.

[0004] The stratum corneum is primarily responsible for the barrier properties of the skin. Thus, it is this layer that provides the greatest barrier to the transdermal flux of drugs or other molecules into the body and the excretion of analytes out of the body. The stratum corneum (the outermost keratinized layer of the skin) is a complex structure of densely keratinized cell remnants separated by lipid domains. Compared to oral or gastric mucosa, the stratum corneum is much less permeable to molecules from either the external or internal body. The stratum corneum is formed by keratinocytes, which include epidermal cells that have mostly lost their nuclei and become corneocytes. These dead cells make up the stratum corneum, which is only about 10 to 30 micrometers thick and protects the body from the invasion of exogenous substances and the outward migration of endogenous fluids and dissolved molecules. The stratum corneum is constantly renewed by the shedding of stratum corneum cells during desquamation and the formation of new stratum corneum cells during the keratinization process.

[0005] Historically, most drugs have been delivered orally or by injection. However, neither the oral nor the injection route is well-suited for continuous drug delivery over an extended period of time. In addition, the injection administration method is neither convenient nor comfortable; furthermore, needles continue to pose a danger after their use. Therefore, transdermal drug delivery to the body has been a popular and effective method for delivering a limited number of permeants to a living organism.

[0006] Passive transdermal patches are generally limited to lipophilic drugs with a molecular weight less than 500 daltons. To enhance transdermal drug delivery, there are known methods for increasing the skin's permeability to drugs. For example, U.S. Patent No. 8,116,860 describes a transdermal permeant delivery system and method that painlessly creates aqueous micropores in the stratum corneum within a few milliseconds. These aqueous channels enable water-soluble drugs to flow out of the transdermal patch, enter the viable epidermis, and then enter the systemic circulation. The patch can be formulated to provide a bolus or continuous transdermal delivery.

[0007] A transdermal permeant delivery system is being developed under the PASSPORT trade name. The PASSPORT system includes a reusable hand-held applicator and a disposable porator with a drug patch. Pressing the activation button of the applicator releases an energy pulse to the porator. The energy is rapidly conducted to the skin surface, painlessly ablating the stratum corneum under each filament to create microchannels. A simple transdermal patch is then applied to the ablated skin and drug delivery begins.

[0008] However, despite the widespread availability of such systems and the significant benefits they provide, there remains a need for improved compositions and methods for transdermal drug delivery. SUMMARY OF THE INVENTION

[0009] Embodiments provide a composition for delivering a permeant through a pathway in an individual's biological membrane, comprising:

[0010] at least one thin solid tablet having an areal density greater than 30 mg / cm 2 and less than 400 mg / cm 2 ;

[0011] wherein the thin solid tablet comprises at least one permeant; and

[0012] wherein at least a portion of the permeant is soluble in biological moisture received from at least one pathway formed through the individual's biological membrane.

[0013] Another embodiment provides a patch for delivering an agent via at least one pathway formed through an individual's biological membrane, the patch comprising a composition comprising a thin solid tablet as described elsewhere herein.

[0014] Another embodiment provides a method of treating a patient, comprising:

[0015] opening at least one channel in the skin of the patient;

[0016] applying a patch as described elsewhere herein to the skin of the patient such that at least one thin tablet is in contact with the channel; and

[0017] maintaining the at least one thin tablet in contact with the skin of the patient for a period of time effective to:

[0018] (a) dissolve at least a portion of the permeant in biological moisture received from the pathway; and

[0019] (b) deliver a therapeutically effective amount of the resulting dissolved permeant to the patient via the pathway.

[0020] Another embodiment provides a method of delivering a permeant through a pathway in a biofilm of an individual, which comprises applying a patch as described elsewhere herein to the skin of a patient.

[0021] These and other embodiments will be described in more detail below. Brief Description of the Drawings

[0023] Figure 1A A patch configuration is schematically shown, which has a thin solid tablet in a tablet layer, a backing layer above the tablet layer, and a release liner layer below the tablet layer. An option is shown where the thin solid tablet is located in a cavity formed in the backing layer. The backing may contain an adhesive (not shown) to hold the thin solid layer in place within the cavity.

[0024] Figure 1B A patch configuration is schematically shown, which has a thin solid tablet in a tablet layer, a backing layer above the tablet layer, a release liner layer below the tablet layer, and a cover layer below the tablet layer and above the release liner layer. Optionally, the cover layer may be a drug release control membrane. As Figure 1A shown, an option is shown where the thin solid tablet is located in a cavity formed in the backing layer. The backing may contain an adhesive (not shown) to hold the thin solid layer in place within the cavity.

[0025] Figure 2 A patch configuration is schematically shown, which has a thin solid tablet in a tablet layer, a backing layer above the tablet layer, an optional cover layer below the tablet layer, and a spacer layer between the backing layer and the cover layer. Optionally (not shown), the patch may further include a Figure 1A and Figure 1B release liner layer disposed below the cover layer (or below the tablet layer when there is no optional cover layer) in the manner shown in. The spacer layer is laterally adjacent to the tablet and configured to maintain a spaced distance between the backing layer and the cover layer and the optional release liner layer. Optionally, the cover layer may be a drug release control membrane.

[0026] Figure 3 A patch configuration similar to Figure 2 is schematically shown, but the tablet layer contains two thin solid tablets (or, optionally, a thin solid tablet and a film-coated tablet) adjacent to each other vertically. The cover layer is optional. As Figure 2 shown, the patch may optionally further include a Figure 4 release liner layer (not shown) disposed below the cover layer in the manner shown in. Optionally, the cover layer may be a drug release control membrane.

[0027] Figure 4 A patch configuration similar to Figure 3A similar patch construction, but two thin solid tablets in the tablet layer are adjacent to each other horizontally. Optionally, the covering can be a drug release control membrane.

[0028] Figure 5 Shows the pharmacokinetics (PK) curve of methylnaltrexone bromide released from the first thin solid tablet in a patch having the construction as Figure 3 shown.

[0029] Figure 6 Shows the comparative PK curve of methylnaltrexone bromide released from a comparative dry patch (dispensing type). The amount of methylnaltrexone bromide released is much less than the amount released using Figure 5 the various constructions outlined.

[0030] Figure 7 Shows the PK curve of aripiprazole released from a film-coated first thin solid tablet in a patch (with covering) having the construction as Figure 3 shown. In addition to aripiprazole, the first thin solid tablet also contains solubilizers (pH control agent and cyclodextrin).

[0031] Figure 8 Shows the PK curve of aripiprazole released from a film-coated first thin solid tablet in a patch (with and without covering) having the construction as Figure 3 shown. In addition to aripiprazole, the first thin solid tablet also contains solubilizers (pH control agent and cyclodextrin).

[0032] Figure 9 Shows the PK curve of aripiprazole released from a film-coated first thin solid tablet in a patch (with and without covering) having the construction as Figure 3 shown. In addition to aripiprazole, the first thin solid tablet also contains solubilizers (pH control agent and cyclodextrin).

[0033] Figure 10 Shows the PK curve of aripiprazole released from a film-coated first thin solid tablet in a patch (with covering) compared to aripiprazole released from a combination of the first thin solid tablet and the second thin solid tablet (Group 4). In addition to aripiprazole, the first thin solid tablet also contains solubilizers (pH control agent and cyclodextrin). The pharmacokinetic curve illustrates sustained delivery. Figure 3 shown.

[0034] Figure 11 Describes the (partial) patch construction and composition for a patch for Figure 10 ...

[0035] Figure 12The PK curve of sumatriptan released from a relatively dry patch is shown. A color change was observed during storage, indicating an interaction between sumatriptan and ascorbic acid.

[0036] Figure 13 The PK curve of sumatriptan released from a film layer on a thin solid tablet in a patch having the structure shown in Figure 3 is shown. The thin solid tablet contains ascorbic acid; the film layer does not. The separation of ascorbic acid from sumatriptan enhances the stability of the formulation. DETAILED DESCRIPTION

[0037] The present invention can be more readily understood by reference to the following detailed description, examples, drawings, and claims, and their prior and subsequent descriptions. However, prior to the disclosure and description of the apparatus, system, and / or method of the present application, it should be understood that the present invention is not limited to the specific apparatus, system, and / or method disclosed, unless otherwise stated. It should also be understood that the terms used herein are for the purpose of describing particular aspects only and are not necessarily intended to be limiting.

[0038] This description is provided as an enabling teaching of the present invention. To this end, those skilled in the relevant art will recognize and understand that many changes can be made to the various aspects of the present invention described herein while still obtaining beneficial results. It will also be apparent that some desired benefits can be obtained by selecting some of the features described herein and not utilizing other features. Accordingly, those skilled in the art will recognize that many modifications and adaptations to this specification are possible and even desirable in some cases and are part of the present invention. Accordingly, this description is provided to illustrate certain principles of the present invention and not to limit the present invention.

[0039] Definition

[0040] As used throughout the specification, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a filament" can include two or more such filaments unless the context otherwise indicates.

[0041] Ranges may be expressed herein as from "about" one particular value, and / or to "about" another particular value. When such a range is expressed, another aspect includes from one particular value and / or to another particular value. Similarly, when values are expressed as approximations by use of the antecedent "about", it should be understood that the particular value forms another aspect. It should also be understood that each end point of each range is both related to and meaningful independently of the other end point.

[0042] As used herein, the term "optional" or "optionally" means that the subsequent described event or circumstance may or may not occur, and this description includes examples where the event or circumstance occurs and examples where the event or circumstance does not occur.

[0043] As used herein, "tissue membrane" can be any one or more epidermal layers of an individual. For example, in one aspect, the tissue membrane is the skin layer, which includes the outermost layer of the skin, i.e., the stratum corneum. In an alternative aspect, the skin layer can include one or more backing layers of the epidermis, generally recognized as the stratum granulosum, stratum spinosum, and stratum germinativum. Those of ordinary skill in the art will understand that there is little or no resistance to the transport or absorption of permeants through the backing layers of the epidermis. Thus, in one aspect, at least one pathway formed in the skin layer of an individual is a pathway in the stratum corneum of the individual. Additionally, as used herein, "stratum corneum" refers to the outermost layer of the skin, typically composed of about 15 to about 20 layers of cells in different stages of drying. The stratum corneum provides a barrier against water loss from the body interior to the external environment and against damage to the body interior from the external environment. Further, as used herein, "tissue membrane" can refer to an aggregate of a specific type of cells together with their intercellular material forming a structural material. In various embodiments, at least one surface of the tissue membrane is accessible to one or more of the perforation devices and / or permeant compositions described herein. As described above, the preferred tissue membrane is the skin. Other tissues suitable for use with such devices and compositions include mucosal tissue and soft organs.

[0044] As used herein, the term "subcutaneous fluid" can include, but is not limited to, water, plasma, blood, one or more proteins, interstitial fluid, and any combination thereof. In one aspect, the subcutaneous fluid according to this specification is a water source containing water.

[0045] As used herein, "perforation", "microperforation", or any such similar term means forming small holes or slits (subsequently also referred to as "micropores") in or through the outer layer of a tissue or biological membrane (such as skin or mucosa) or an organism, for the purpose of reducing the barrier properties of the biological membrane for a selected purpose to allow at least one permeant to pass from one side of the biological membrane to the other side. Preferably, the diameter of the holes or "micropores" so formed is approximately 1 micron to 1000 microns and extends into the biological membrane far enough to disrupt the barrier properties of the stratum corneum without adversely affecting the underlying tissue. It should be understood that for simplicity, the term "micropore" is used in the singular form, but the microperforation devices described herein can form multiple artificial openings. For a selected purpose or for certain medical or surgical purposes, perforation can reduce the barrier properties of the biological membrane to the interior of the body. For the purposes of this application, "perforation" and "microperforation" are used interchangeably and mean the same thing.

[0046] A "micropuncturer" or "puncturer" is a component of a micropuncturing device capable of performing micropunctures. Examples of micropuncturers or puncturers include, but are not limited to, filaments capable of conductively delivering thermal energy via direct contact with a biological membrane to ablate a portion of the membrane to a depth sufficient to form micropores, optically heated local dye / absorbing layers, electromechanical actuators, microlancets, micro needles or arrays of lancets, acoustic energy ablators, laser ablation systems, high-pressure fluid jet puncturers, and the like. As used herein, "micropuncturer" and "puncturer" may be used interchangeably.

[0047] As used herein, "penetration enhancement" or "permeation enhancement" refers to an increase in the permeability of a biological membrane to a drug, bioactive composition, or other chemical molecule, compound, particle, or substance (also referred to as a "permeate"), thereby increasing the rate at which the drug, bioactive composition, or other chemical molecule, compound, or particle permeates the biological membrane.

[0048] As used herein, "enhancers", "chemical enhancers", "penetration enhancers", "permeation enhancers", etc. include all enhancers that increase the flux of a permeate, analyte, or other molecule across a biological membrane and are limited only by function. In other words, it is intended to include all cell envelope-disrupting compounds and solvents as well as any other chemical enhancers. Additionally, it includes all active force enhancement techniques such as the application of acoustic energy, mechanical aspiration, pressure, or local deformation of tissue, iontophoresis, or electroporation. One or more enhancer techniques may be combined sequentially or simultaneously. For example, a chemical enhancer may first be applied to render the capillary wall permeable, and then iontophoresis or an acoustic energy field may be applied to actively drive the permeate into those tissues surrounding and including the capillary bed.

[0049] As used herein, "transdermal" refers to the entry and passage of a permeate through a biological membrane.

[0050] As used herein, the terms "penetrant", "drug", "penetrant composition", or "pharmacological active agent" or any other similar terms are used interchangeably and refer to any chemical or biological material or compound suitable for transdermal administration by methods previously known in the art and / or by methods taught in this specification, which induces the desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on an organism and preventing undesired biological effects, such as infection, (2) alleviating a condition caused by a disease, such as alleviating pain or inflammation, and / or (3) alleviating, reducing, or completely eliminating a disease in an organism. The effect may be local, such as providing a local anesthetic effect, or may be systemic. Such substances include a variety of compounds that are typically delivered (including through body surfaces and membranes, including the skin) into the body. Generally, by way of example and not limitation, such substances may include any bioactive agent that induces the desired biological or pharmacological effect, such as a drug, chemical, or biological material. For this purpose, in one aspect, the penetrant may be a small molecule agent. In another aspect, the penetrant may be a macromolecule agent. Generally, but not limited to, exemplary penetrants include but are not limited to anti-infective agents, such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorectics; anthelmintics; anti-arthritis agents; anti-asthma agents; anticoagulants; anticonvulsants; antidepressants; anti-diabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; anti-migraine preparations; antiemetics; antineoplastic agents; anti-Parkinson agents; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations, including potassium and calcium channel blockers, β-blockers, α-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators, including general coronary, peripheral, and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones, such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympathetic inhibitors; psychostimulants; sedatives; and tranquilizers.

[0051] The devices and methods of the present specification can also be used for transdermal delivery of peptides, polypeptides, proteins, or other macromolecules known to be difficult to transport across the skin due to their size by existing conventional techniques. These macromolecular substances typically have a molecular weight of at least about 300 Daltons, more typically about 300 Daltons to 40,000 Daltons. Examples of polypeptides and proteins that can be delivered according to the present specification include, but are not limited to, antibodies, LHRH, LHRH analogs (such as goserelin, leuprorelin, buserelin, triptorelin, gonadorelin, napharelin, and leuprorelin), GHRH, GHRF, insulin, proinsulin, calcitonin, octreotide, endorphin, TRH, NT-36 (chemical name: N-[[(s)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinamide), liprecin, pituitary hormones (such as, HGH, HMG, HCG, desmopressin acetate, etc.), follicle lutein, α-ANF, growth factors such as growth factor releasing factor (GFRF), β-MSH, GH, somatostatin, bradykinin, growth hormone, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymotrypsin, cholecystokinin, chorionic gonadotropin, adrenocorticotropic hormone (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor), glucagon, hirudin and hirudin analogs such as lepirudin, hyaluronidase, interleukin-2, menotropins (follicle stimulating hormone (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analogs, ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin antagonists, CD4, cereedase, CSI, enkephalin, FAB fragments, IgE peptide inhibitors, IGF-1, neurotrophic factors, colony stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, cytokines, lymphokines, pentigetide, protein C, protein S, renin inhibitors, thymosin α-1, thrombolytics, TNF, GCSF, EPO, PTH, heparin with a molecular weight of 3000 Daltons to 12,000 Daltons, vaccines, vasopressin antagonist analogs, interferon-α, -β, and -γ, α-1 antitrypsin (recombinant), and TGF-β gene; peptides; polypeptides; proteins; oligonucleotides; nucleic acids; and polysaccharides.

[0052] In addition, as used herein, "peptide" refers to peptides of any length, including proteins. The terms "polypeptide" and "oligopeptide" are used herein without any specific intended size limitations, unless a specific size is otherwise specified. Exemplary peptides that can be used include, but are not limited to, oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, prolactin, luteinizing hormone releasing hormone or luteinizing hormone-releasing hormone, growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagon, interferon, gastrin, tetrapeptide gastrin, pentapeptide gastrin, urogastroine, secretin, calcitonin, enkephalin, endorphin, angiotensin, renin, bradykinin, bacitracin, polymyxin, colistin, tyrocidin, gramicidines, and their synthetic analogs, modifications, and pharmacologically active fragments, monoclonal antibodies, and soluble vaccines. The only limitation on the peptides or protein drugs that are expected to be utilized is function.

[0053] Examples of peptide and protein drugs containing one or more amino groups include, but are not limited to, anticancer agents, antibiotics, antiemetics, antiviral agents, anti-inflammatory and analgesic agents, anesthetics, antiulcer agents, agents for treating hypertension, agents for treating hypercalcemia, agents for treating hyperlipidemia, etc., each of which has at least one primary, secondary, or tertiary amine group in the molecule, preferably a peptide, protein, or enzyme. For example, insulin, calcitonin, growth hormone, granulocyte colony-stimulating factor (G-CSF), erythropoietin (EPO), bone morphogenetic protein (BMP), interferon, interleukin, platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), nerve growth factor (NGF), urokinase, etc. can be mentioned. Other examples of protein drugs include, but are not limited to, insulin, α-, β-, and γ-interferons, human growth hormone, α- and β-1-transforming growth factors, granulocyte colony-stimulating factor (G-CSF), granulocyte macrophage colony-stimulating factor (G-MCSF), parathyroid hormone (PTH), human or salmon calcitonin, glucagon, somatostatin, vasoactive intestinal peptide (VIP), and LHRH analogs.

[0054] As used herein, an "effective" amount of a pharmacologically active agent refers to an amount sufficient to provide the desired local or systemic effects and properties at a reasonable benefit / risk ratio when participating in any medical treatment. An "effective" amount of a penetration enhancer or chemical enhancer as used herein means an amount selected to provide the desired increase in biofilm permeability, desired penetration depth, application rate, and amount of drug delivered.

[0055] In various embodiments, transdermal permeant delivery systems and methods that can be used in conjunction with and / or are adapted for use with the compositions and methods described herein are described in one or more of U.S. Patent Nos. 6,022,316; 6,142,939; 6,173,202; 6,183,434; 6,508,785; 6,527,716; 6,692,456; 6,730,028; 7,141,034; 7,392,080; 7,758,561; 8,016,811; 8,116,860; and / or 9,498,609, which are hereby incorporated by reference in their entirety, and in particular for the purpose of describing such systems and methods. In various embodiments, a transdermal permeant delivery system commercially available under the trade name PASSPORT from Nitto Denko Corporation can be used or is adapted for delivering the permeant compositions described herein.

[0056] Composition

[0057] Various embodiments provide a composition for delivering an active permeant through a pathway in an individual's biological membrane, the composition comprising at least one thin solid tablet having an areal density greater than 30 mg / cm 2 and less than 400 mg / cm 2 The thin solid tablet comprises at least one permeant, and at least a portion of the permeant is soluble in the biological moisture received from at least one formed pathway through the individual's biological membrane. In the pharmaceutical field, tablets are generally defined as oral dosage forms of drugs. However, surprisingly, it has now been found that the thin solid tablets as described herein are a safe, effective, and convenient form through which the provided permeant (e.g., a pharmacological active agent) can be administered to an individual using a transdermal permeant delivery system as described elsewhere herein.

[0058] A large number of drugs have been formulated into tablet form, but their size and shape are usually selected to be relatively compact pill or capsule configurations suitable for the safe and effective administration of the orally administrable drugs contained therein. In contrast, drugs intended for transdermal administration are typically formulated into a gel or flowable liquid form (e.g., as a solution or dispersion) suitable for inclusion in a patch, such as those described in U.S. Patent No. 9,498,609 and U.S. Patent Publication No. 2012 / 0238942, or are formulated into a powder form printed on a backing liner (see, e.g., U.S. Patent Publication No. 2004 / 0137044). Those skilled in the art have no incentive to formulate drugs into the form of thin solid tablets having a relatively large areal density as described herein, as they are considered unsuitable and / or inferior to the traditional dense pill and capsule forms for oral administration. Additionally, compared to the flowable liquid forms commonly used in transdermal patches, the various embodiments of the thin solid tablet form described herein would be considered undesirably prone to breakage and thus inferior from the perspectives of manufacturing, transportation, and / or patient acceptance. The various embodiments of the thin solid tablet form described herein are also considered more difficult to administer orally and thus are not ideal for achieving patient acceptance and / or compliance compared to the relatively dense pill or capsule form.

[0059] As used herein in the context of describing thin solid tablets adapted to deliver permeants through pathways in an individual's biological membrane, the term "tablet" refers to a form of an oral dosage form of a drug that would otherwise be considered to conform to the general meaning of "tablet" as understood by those skilled in the pharmaceutical arts, but having an areal density greater than that considered desirable for oral administration. The thin solid tablet can be of various sheet-like or plate-like shapes, such as oval, circular, triangular, rectangular, square, pentagonal, hexagonal, irregular, etc. In various embodiments, the thin solid tablet is substantially flat. In an embodiment, the substantially flat thin solid tablet is slightly curved or bent to an extent that facilitates handling, e.g., compared to a flat thin solid tablet that is more difficult to pick up from a flat surface.

[0060] In various embodiments, the areal density of the thin solid tablet as described herein is greater than 30 mg / cm 2 、greater than 40 mg / cm 2 、greater than 50 mg / cm 2 、greater than 60 mg / cm 2 、greater than 70 mg / cm 2 、greater than 80 mg / cm 2 、greater than 90 mg / cm 2 or greater than 100 mg / cm 2 ; less than 400 mg / cm 2 、less than 350 mg / cm2 and less than 300 mg / cm 2 and less than 250 mg / cm 2 or less than 200 mg / cm 2 ; or within any range having endpoints defined by any two of the above values. For example, in various embodiments, the areal density of the thin solid tablet is greater than 30 mg / cm 2 and less than 400 mg / cm 2 ; greater than 40 mg / cm 2 and less than 400 mg / cm 2 ; or greater than 30 mg / cm 2 and less than 400 mg / cm 2 .

[0061] In various embodiments, the thickness of the thin solid tablet as described herein (depending on the areal density and area of the face) is about 0.01 mm or greater, about 0.02 mm or greater, about 0.03 mm or greater, about 0.04 mm or greater, about 0.05 mm or greater, about 0.05 mm or greater, about 0.1 mm or greater, about 0.2 mm or greater, about 0.5 mm or greater, or about 1 mm or greater; about 10 mm or less, about 5 mm or less; about 2 mm or less; or about 1 mm or less; or within any range having endpoints defined by any two of the above values. For example, in various embodiments, the thin solid tablet has a thickness of about 0.01 mm to about 10 mm or about 0.1 mm to about 5 mm.

[0062] In various embodiments, the thin solid tablet has a face in a manner similar to the front or back of a coin. In various embodiments, the area of the face of the thin solid tablet is about 0.01 cm 2 or greater, about 0.05 cm 2 or greater, about 0.1 cm 2 or greater, about 0.25 cm 2 or greater, about 0.5 cm 2 or greater, about 0.75 cm 2 or greater, or about 1 cm 2 or greater; or about 50 cm 2 or less, about 25 cm 2 or less, about 15 cm 2 or less, about 10 cm 2 or less, about 5 cm 2 or less, or about 2 cm 2 or less, or within any range having endpoints defined by any two of the above values. For example, in various embodiments, the area of the face of the thin solid tablet is about 0.01 cm 2 to about 25 cm2 , about 0.1 cm 2 to about 10 cm 2 , or about 0.15 cm 2 to about 5 cm 2 .

[0063] The described thin solid tablets can be prepared using various tablet-making materials and methods known to those skilled in the art as being suitable for the tablet configurations described herein. Given the guidance provided herein, those skilled in the art can readily make such adaptations. In various embodiments, the thin solid tablets comprise one or more excipients selected from the group consisting of: binders, disintegrants, lubricants, permeation enhancers, solubilizers, absorption control agents, permeants, pH control agents, antimicrobial agents, release control agents, and fillers. For example, in various embodiments, the excipients are selected from one or more of sucrose, lactose, HP-β-CD, citric acid monohydrate, SBE-β-CD, ascorbic acid, urea, magnesium stearate, methylparaben, propylparaben, and Tween 80.

[0064] The thin solid tablets also comprise one or more permeants as described elsewhere herein. For example, in an embodiment, the permeant is a hydrophobic drug. In an embodiment, the permeant has a water solubility of less than 10 mg / mL. In an embodiment, the permeant comprises a high-dose drug that requires a daily dose that is difficult to achieve with a typical transdermal patch without microperforations. In an embodiment, the high-dose drug requires an intake of more than 20 mg / day. In various embodiments, the permeant is selected from methylnaltrexone bromide, aripiprazole, sumatriptan succinate, exenatide, salts thereof, and combinations thereof. The permeant can be curved throughout the thin solid tablet or concentrated in one or more specific regions. For example, in an embodiment, the thin solid tablet comprises the permeant in the form of a layer on the tablet, a dispersion within the tablet, or a combination thereof. In an embodiment, the distribution is selected to control the release rate of the permeant from the tablet, thereby providing delivery of the permeant through the pathway in the biological membrane of an individual in a controlled manner (e.g., delayed release or sustained release).

[0065] In various embodiments, the permeant is one or more of a small molecule drug, a peptide, a protein, an oligonucleotide, an antibody, a polysaccharide, and a vaccine. One or more excipients in the thin solid tablets can be selected using routine experimentation guided by the detailed teachings provided herein based on the properties of the permeant and the desired tablet configuration. For example, in an embodiment, the permeant is a hydrophobic drug and the excipient comprises an effective amount of a permeation enhancer for the hydrophobic drug. In various embodiments, the thin solid tablets comprise a solubilizer. The solubilizer can be selected based on the properties of the permeant and the desired degree of solubilization. For example, in an embodiment, the solubilizer is one or more of polyethylene glycol, a surfactant, a pH control agent, a cyclodextrin, a fatty acid, and a salt of a fatty acid.

[0066] The composition for delivering a permeate through a pathway in a biological membrane of an individual can be configured in various ways. For example, in an embodiment, the composition comprises a single thin solid tablet; in an alternative embodiment, it comprises two or more thin solid tablets.

[0067] In embodiments, a thin solid tablet is incorporated into a patch. For example, embodiments provide a patch for delivering a medicament via at least one formed pathway through a biological membrane of an individual, the patch comprising a composition for delivering a permeate through a pathway in a biological membrane of an individual, the composition comprising a thin solid tablet as described herein. Thus, for example, the thin solid tablet in the patch may comprise a bioactive agent as described herein. Figure 1A , Figure 1B as well as Figures 2 to 4 Various patch configurations are shown.

[0068] In various embodiments, the patch is suitable for use in combination with a micro-perforation device, which is configured to form a pathway in an individual's biofilm. A transdermal permeate delivery system comprising a suitable micro-perforation device can be purchased from Nitto Denko Corporation under the trade name PASSPORT. The PASSPORT system includes a reusable handheld applicator and a disposable perforator that can be used in combination with a patch as described herein. Press the activation button of the applicator to release an energy pulse to the perforator. The energy is quickly conducted to the skin surface, painlessly ablating the stratum corneum under each filament to produce microchannels. The patch can then be applied to the ablated skin. From the individual's biological moisture, the microchannels formed are passed through the thin solid tablet in the patch, dissolving the drug and allowing it to pass through the skin via the microchannels and enter the individual body.

[0069] Embodiments provide a method of treating a patient, the method comprising:

[0070] opening at least one channel in the patient's skin;

[0071] applying a patch as described herein to the patient's skin so that at least one wafer is in contact with the channel; and maintaining at least one wafer in contact with the patient's skin for a period of time effective to:

[0072] (a) causing the permeate to at least partially dissolve in biological water received from the pathway; and

[0073] (b) delivering a therapeutically effective amount of the resulting dissolved permeate to a patient via a pathway.

[0074] Example

[0075] In the following examples, various embodiments and alternatives are disclosed in further detail, and these embodiments and alternatives are not intended to limit the scope of the claims in any way.

[0076] Example 1

[0077] A series of thin solid tablets containing methylnaltrexone bromide (MNTX-Br) as the active ingredient and the other ingredients described in Table 1 were prepared using standard techniques for forming tablets. The tablets were 8 mm × 8 mm squares with an axial area of approximately 0.64 cm 2 and a tablet weight of 34.3 mg / cm 2 (22 mg / 0.64 cm 2 ). Patches having the configuration shown in Figure 3 were prepared using the thin solid tablets and applied to the skin of rats using a PASSPORT reusable hand-held applicator and a disposable perforator. PK data were collected in a conventional manner. A dry patch (dispensing type) containing the same amount of MNTX-Br and the ingredients listed in Table 2 below was used for comparison.

[0078] An overview of the resulting PK data is provided in Table 3. Figure 5 The PK curve of methylnaltrexone bromide released from the thin solid tablets in the patch is shown, and the comparative PK curve of methylnaltrexone bromide released from the dry patch is shown in Figure 6 . The amount of methylnaltrexone bromide released from the comparative patch is much less than the amount released using the patch containing the thin solid tablets, as outlined in Table 3.

[0079] Table 1

[0080]

[0081] Table 2

[0082]

[0083]

[0084] Table 3

[0085]

[0086] *Penetrant: sucrose, lactose, SBECD, HPBCD

[0087] Example 2

[0088] A series of thin solid tablets containing aripiprazole as the active ingredient and the other ingredients described in Table 4 were prepared using standard techniques for forming tablets. The tablets were 8 mm × 8 mm squares with an axial area of approximately 0.81 cm2 with an axial area of 61.7 mg / cm 2 (50 mg / 0.81 cm 2 ) of the tablet weight for a 9 mm × 9 mm square. A patch having the structure shown in Figure 3 was prepared using the thin solid tablets and applied to the skin of rats using a PASSPORT reusable hand-held applicator and a disposable perforator. PK data were collected in a conventional manner.

[0089] An overview of the obtained PK data is provided in Table 5, and Figure 7 and Figure 8 shows the PK curve of aripiprazole released from the patch.

[0090] Table 4

[0091]

[0092]

[0093] *Penetrant: lactose, SBECD, HPCD

[0094] **Solubilizer: SBECD, HPCD, and CA

[0095] Table 5

[0096] Group AUC (ng / ml*hr) Cmax (ng / mL) Tmax (hours) 004_#1 0.0 0.0 0.0 004_#2 0.0 0.0 0.0 004_#3 27.2 8.6 0.7 004_#4 367.2 42.2 2.0 004_#5 2046.4 200.9 4.7 005_#1 47.1 6.4 4.7 005_#2 510.6 46.7 2.7 005_#3 76.7 13.7 1.3 005_#4 97.1 13.5 1.7 005_#5 51.6 4.9 4.0

[0097] Example 3

[0098] A series of thin solid tablets containing aripiprazole as the active ingredient and the other ingredients described in Table 6 were prepared using standard techniques for forming tablets. The tablets were 9 mm × 9 mm squares with an axial area of approximately 0.81 cm 2 and a tablet weight of 61.7 mg / cm 2 and 98 mg / cm 2 (50 mg / 0.81 cm 2 and 80 mg / 0.81 cm 2 ) respectively. A patch having the structure shown in Figure 3 was prepared using the thin solid tablets and applied to the skin of rats using a PASSPORT reusable hand-held applicator and a disposable perforator. PK data were collected in a conventional manner.

[0099] An overview of the obtained PK data is provided in Table 7, and Figure 9 shows the PK curve of aripiprazole released from the patch.

[0100] Table 6

[0101]

[0102] Table 7

[0103] Group AUC (ng / ml*hr) Cmax (ng / mL) Tmax (hours) 1 1003.7 113.7 5.0 2 2829.3 204.2 6.0 3 1527.9 162.4 5.3 4 1181.1 94.8 5.0 5 19.1 3.7 11.3

[0104] Example 4

[0105] A series of thin solid tablets containing aripiprazole as the active ingredient and the other ingredients described in Figure 11 are prepared using standard techniques for forming tablets. The tablets are 9 mm × 9 mm squares with a tablet weight of approximately 0.81 cm 2 axial area and 210.0 mg / cm 2 , 402.5 mg / cm 2 and 395.1 mg / cm 2 (170 mg / 0.81 cm 2 , 326 mg / 0.81 cm 2 and 320 mg / 0.81 cm 2 ), respectively). Patches with the configurations shown in Figure 3 and Figure 11 are prepared using the thin solid tablets and applied to the skin of hairless guinea pigs using a PASSPORT reusable hand-held applicator and a disposable punch. PK data are collected in a conventional manner. Figure 10 The PK curve of aripiprazole released from the patch is shown, indicating sustained release.

[0106] Example 5 (Comparison)

[0107] A series of immediate-release dry patches containing sumatriptan as the active ingredient and the other ingredients described in Table 8 are prepared. The immediate-release dry patches are applied to the skin of hairless guinea pigs, and PK data are collected in a conventional manner. An overview of the resulting PK data is provided in Table 9, and Figure 12 the PK curve of sumatriptan released from the patch is shown. A color change of the components of the immediate-release patch was observed during storage, indicating a stability problem caused by the interaction between sumatriptan and ascorbic acid.

[0108] Table 8

[0109]

[0110] *Penetrant: sucrose

[0111] **Enhancer: ascorbic acid

[0112] Table 9

[0113]

[0114] Example 6

[0115] A series of thin solid tablets containing sumatriptan as the active ingredient and the other ingredients described in Table 10 are prepared using standard techniques for forming tablets. The tablets are 9 mm × 9 mm squares having an axial area of about 0.81 cm 2 and having a tablet weight of 56.44 mg / cm 2 (45.72 mg / 0.81 cm 2 ). Patches having the configuration shown in Figure 3 are prepared using the thin solid tablets and are applied to the skin of hairless guinea pigs using a PASSPORT reusable hand-held applicator and a disposable punch. PK data are collected in a conventional manner. An overview of the resulting PK data is provided in Table 11, and Figure 13 the PK curve of sumatriptan released from the patch is shown. No stability issues were observed as were observed in the comparative immediate-release patch of Example 5 because sumatriptan and ascorbic acid were separated.

[0116] Table 10

[0117] Membrane layer (distribution layer)

[0118] L1: API Preparation #1,2,3 Sumatriptan Succinate (mg) 14 Active Pharmaceutical Ingredient (API) Sucrose (mg) 1 Penetrant Total (mg) 15 -

[0119] Tablet layer

[0120]

[0121] Table 11

[0122]

[0123] Example 7 (Comparison)

[0124] An immediate-release dry patch containing exenatide as the active ingredient and the other ingredients described in Table 12 is prepared. A color change of the components of the immediate-release patch was observed during storage, indicating a stability issue caused by the interaction between exenatide and ascorbic acid.

[0125] Table 12

[0126] Excipient #6 Exenatide (mg) 0.4 API Sucrose (mg) 8 Penetrant Urea (mg) 8 Enhancer Ascorbic Acid (mg) 2 Enhancer / Prolonger Tween 80 (mg) 0.07 Surfactant Total (mg) 18.47 -

[0127] Example 8

[0128] A series of thin solid tablets containing exenatide as the active ingredient and the other ingredients described in Table 13 are prepared using standard techniques for forming tablets. The tablets are 9 mm × 9 mm squares having an axial area of about 0.81 cm 2 and having a tablet weight of 56.44 mg / cm2 (45.72 mg / 0.81 cm 2 ) of the tablet weight in a 9 mm x 9 mm square. A patch having the configuration shown in Figure 3 was prepared using a thin solid tablet. No stability issues observed in the comparative immediate release dry patch of Example 7 were observed because exenatide and ascorbic acid were separated.

[0129] Table 10

[0130] Membrane layer (distribution layer)

[0131] L1: API Preparation #6 Exenatide (mg) 1 API Sucrose (mg) 1 Penetrant Total (mg) 2 -

[0132] Tablet layer

[0133] Granule - Excipient #6 Anhydrous Lactose (mg) 5.00 Binder / Penetrant Urea (mg) 24.00 Enhancer Ascorbic Acid (mg) 16.00 Enhancer / Prolonger Magnesium Stearate (mg) 0.50 Lubricant Methylparaben (mg) 0.20 Antimicrobial Agent Propylparaben (mg) 0.02 Antimicrobial Agent Total (mg) 45.72 -

[0134] The data in the above examples indicate that thin solid tablets as described herein can be used for applications with various requirements, particularly when used in combination with a suitable microperforated device (such as those commercially available under the name PASSPORT from Nitto Denko Corporation). For example, in an embodiment, a patch containing a thin solid tablet as described herein has a relatively high hydrophobic drug loading and can thus be used to deliver a drug at a high dose of 20 mg / day or higher to an individual in the manner described herein. Relatively large amounts of solubilizers are typically used to increase the solubility of such drugs for conventional transdermal delivery patches, thereby limiting the drug loading and the resulting daily dose. In another embodiment, a patch containing two or more thin solid tablets as described herein (or thin solid tablets with coatings), for example, as shown in Figures 3 to 4 , enhances the ability of the patch to provide a desired PK profile (such as controlled release) and / or enhances stability by enabling the components to be separated (otherwise they would interact in an undesirable manner). In another embodiment, a patch containing two or more thin solid tablets as described herein (or thin solid tablets with coatings), for example, as shown in Figures 3 to 4 , enables the delivery of multiple active ingredients (such as drugs) from a single patch, thus facilitating the administration of combination therapies.

Claims

1. A composition for delivering a permeate through a pathway in an individual's dermal membrane, comprising: with an areal density greater than 30 mg / cm 2 and less than 400 mg / cm 2 and at least one thin solid tablet having a thickness of from 0.01 mm to 10 mm; wherein the at least one thin solid tablet is surrounded by the following layers: a backing layer disposed above the at least one thin solid tablet; a release liner layer disposed below the at least one thin solid tablet; and a spacer layer configured between the backing layer and the release liner layer, the spacer layer being laterally adjacent to the at least one thin solid tablet and configured to maintain a spacing distance between the backing layer and the release liner layer, the spacing distance being 50% to 150% of the thickness of the thin solid tablet; wherein the thin solid tablet comprises at least one permeate in the form of a permeate layer, and the permeate is one or more selected from the following: small molecule drugs, peptides, proteins, oligonucleotides, antibodies, polysaccharides, and vaccines; wherein the thin solid tablet comprises: a permeation enhancer; and a permeant, wherein the permeant is selected from: sucrose, lactose, HP-β-CD, and SBE-β-CD; wherein at least a portion of the permeate is soluble in the biological moisture received from at least one pathway formed through the individual's dermal membrane, and the permeate has a water solubility of less than 10 mg / mL.

2. The composition according to claim 1, wherein the thin solid tablet further comprises one or more excipients selected from the following: binders, disintegrants, lubricants, solubilizers, absorption control agents, pH control agents, antimicrobial agents, release control agents, and fillers.

3. The composition according to claim 1, wherein said at least one thin solid tablet has an areal density greater than 30 mg / cm 2 and less than 250 mg / cm 2 .

4. The composition according to claim 2, wherein the solubilizer is selected from: polyethylene glycol, surfactants, pH control agents, cyclodextrins, fatty acids, and salts of fatty acids.

5. The composition according to any one of claims 1 to 4, wherein the thin solid tablet has a thickness of 0.1 mm to 5 mm.

6. The composition according to any one of claims 1 to 4, wherein the surface of the thin solid tablet has an area of from 0.01 cm 2 to 25 cm 2 .

7. The composition according to any one of claims 1 to 4, wherein the surface of the thin solid tablet has an area of 0.1 cm 2 to 10 cm 2 .

8. The composition according to any one of claims 1 to 4, wherein the surface of the solid tablet has an area of 0.15 cm 2 to 5 cm 2 in area.

9. The composition according to any one of claims 1 to 4, wherein the thin solid tablet further comprises a second permeate.

10. The composition according to any one of claims 1 to 4, wherein the permeate layer is on the surface of the thin solid tablet.

11. The composition according to any one of claims 1 to 4, wherein the permeate is selected from methylnaltrexone bromide, aripiprazole, sumatriptan succinate, exenatide, salts thereof, and combinations thereof.

12. The composition according to claim 1, wherein the permeation enhancer is ascorbic acid or urea.

13. The composition according to any one of claims 1 to 4, which comprises at least two thin solid tablets.

14. A patch for delivering a medicament via at least one pathway formed through an individual's dermal membrane, the patch comprising the composition according to any one of claims 1 to 13.

15. The patch according to claim 14, wherein the at least one thin solid tablet comprises a bioactive agent.

16. The patch according to claim 15, wherein the patch provides an immediate release profile and a sustained release profile of the permeate from the at least one thin solid tablet through the at least one pathway formed through the individual's dermal membrane.

17. The patch according to claim 14, wherein: the at least one thin solid tablet is a tablet layer.

18. The patch according to claim 17, further comprising a cover below the tablet layer and above the release liner, the cover being configured to reduce the contact between the at least one thin solid tablet and the release liner.

19. The patch according to claim 17, wherein the tablet layer comprises two or more thin solid tablets.

20. The patch according to any one of claims 14 to 19, further comprising an adhesive layer below the backing layer and above the release liner.

21. The patch according to claim 20, wherein the adhesive layer is below the spacer layer.

22. Use of the patch according to any one of claims 14 - 21 in the preparation of an antipsychotic drug, wherein the permeate comprises aripiprazole.

23. Use of the patch according to any one of claims 14 - 21 in the preparation of an anti - migraine drug, wherein the permeate comprises sumatriptan succinate.

24. Use of the patch according to any one of claims 14 - 21 in the preparation of an anti - diabetic drug, wherein the permeate comprises exenatide.

25. A transdermal drug delivery system for delivering a drug, comprising: a transdermal micro - perforation device configured to form a pathway through the skin of an individual; and the patch according to any one of claims 14 to 21.

26. The transdermal drug delivery system for delivering a drug according to claim 25, wherein the at least one thin tablet is configured to be in contact with the skin of the individual for a period of time effective to at least partially dissolve the permeate in the biological moisture received from the pathway, and the at least one thin tablet is configured to deliver a therapeutically effective amount of the resulting dissolved permeate through the pathway to the individual.

27. The transdermal drug delivery system for delivering a drug according to claim 25, wherein the patch is configured to be applied to the dermal surface of the individual.

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