Permeation delivery patch via formed pathways

Abstract

The thin solid tablet composition containing the active permeant can be used in a method for administering the permeant to a subject. The thin solid tablet can be incorporated into a patch. The patch can be used to administer permeants such as drugs and excipients to a subject by transdermal microporation.

Description

[Technical Field]

[0001] Background technology FIELD OF THE INVENTION This application relates to compositions and methods for transdermal drug delivery, and in particular to thin solid tablet compositions containing an active permeant, and methods for administering the permeant to a subject by transdermal microporation.

[0002] explanation Passive transdermal drug delivery is a convenient and effective method for administering a variety of therapeutic agents. This route of administration is noninvasive and simultaneously provides stable drug delivery over long periods of time. While traditional transdermal systems (e.g., drug patches) demonstrate the advantages of delivering drugs through the skin, they only work for a very limited number of drugs. This is because millions of dead skin cells form a protective barrier (the stratum corneum) on the surface of the skin, which prevents most therapeutic molecules from entering the skin.

[0003] The stratum corneum is primarily responsible for the barrier properties of the skin. Therefore, it represents the greatest barrier to the transdermal flux of drugs or other molecules into the body and to the transdermal flux of analytes out of the body. The stratum corneum, the outer horny layer of the skin, is a complex structure of dense keratinized cell remnants separated by lipid domains. Compared to oral or gastric mucosa, the stratum corneum is much less permeable to molecules either external or internal to the body. The stratum corneum is formed from keratinocytes, the majority of epidermal cells that lose their nuclei to become corneocytes. These dead cells form the stratum corneum, which is only about 10–30 microns thick and protects the body from invasion by external substances and the outward movement of internal fluids and dissolved molecules. The stratum corneum is continuously renewed by shedding keratinocytes during desquamation and forming new keratinocytes in the process of keratinization.

[0004] Historically, most drugs have been delivered orally or by injection. However, neither oral nor injection routes are well suited to the continuous delivery of drugs over long periods of time. In addition, injection administration methods are inconvenient and uncomfortable, and needles continue to pose a risk even after their use. Therefore, transdermal drug delivery to the body is a common and effective method for delivering a limited number of permeants to living organisms.

[0005] Passive transdermal patches are typically limited to lipid-soluble drugs with molecular weights of less than 500 daltons.There are known methods for increasing the permeability of skin to drugs to enhance transdermal drug delivery.For example, US Patent No. 8,116,860 describes a transdermal permeant delivery system and method that painlessly forms aqueous micropores in the stratum corneum within milliseconds.These aqueous channels allow water-soluble drugs to flow from the transdermal patch, enter the viable epidermis, and then enter the systemic circulation.Patches can be formulated to achieve bolus or continuous transdermal delivery.

[0006] A transdermal permeant delivery system has been developed under the trade name PASSPORT. The PASSPORT system comprises a reusable handheld applicator and a disposable porator with a drug patch. Pressing the activation button on the applicator releases an energy pulse into the porator. This energy is rapidly conducted to the skin's surface, painlessly ablating the stratum corneum beneath each filament and creating microchannels. A simple transdermal patch is then applied to the ablated skin, initiating drug delivery.

[0007] However, despite the widespread availability of such systems and the significant advantages they offer, there remains a need for improved compositions and methods for transdermal drug delivery.

[0008] Summary of the Invention One embodiment is a composition for delivering a permeant through a pathway in a biological membrane of a subject, comprising: 30 mg / cm 2Over 400mg / cm 2 At least one thin solid tablet having an areal density of less than Including, The thin solid tablet comprises at least one permeant, At least a portion of the permeate is soluble in biological water received from at least one pathway formed through the biological membrane of the subject; A composition is provided.

[0009] Another embodiment provides a patch for delivering a pharmaceutical agent via at least one formed pathway through a biological membrane of a subject, the patch comprising a composition comprising a thin solid tablet as described elsewhere herein.

[0010] Another embodiment is creating at least one channel in the patient's skin; applying a patch as described elsewhere herein to the patient's skin, thereby contacting at least one thin tablet with the channel; At least one thin tablet, (a) at least partially dissolving the permeant in biological fluid received from the pathway; and (b) maintaining the resulting solution in contact with the patient's skin for a period of time effective to deliver a therapeutically effective amount of the dissolved permeant to the patient via this route; The present invention provides a method of treating a patient, comprising:

[0011] Another embodiment provides a method of delivering a permeant through a pathway in a biological membrane of a subject, comprising applying a patch as described elsewhere herein to the skin of a patient.

[0012] These and other embodiments are described in more detail below. [Brief explanation of the drawings]

[0013] [Figure 1A]1 shows a schematic representation of a patch configuration having a thin solid tablet within a tablet layer, a backing layer above the tablet layer, and a release liner layer below the tablet layer. The option of the thin solid tablet being positioned within a cavity formed in the backing layer is shown. The backing may include an adhesive (not shown) to maintain the position of the thin solid layer within the cavity. [Figure 1B] 1A and 1B show schematic diagrams of a patch configuration having a thin solid tablet within a tablet layer, a backing layer above the tablet layer, a release liner layer below the tablet layer, and a cover below the tablet layer and above the release liner layer. Optionally, the cover may be a drug-release-controlling membrane. As in FIG. 1A, an option is shown in which the thin solid tablet is disposed within a cavity formed in the backing layer. The backing may include an adhesive (not shown) to maintain the position of the thin solid layer within the cavity. [Figure 2] 1A and 1B , a patch configuration is shown schematically having a thin solid tablet within a tablet layer, a backing layer above the tablet layer, an optional cover 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 release liner layer disposed below the cover (or below the tablet layer if the optional cover is absent) in the manner shown in FIGS. 1A and 1B . The spacer layer is laterally adjacent to the tablet and is configured to maintain a separation distance between the backing layer and the cover and optional release liner layer. Optionally, the cover may be a drug-release-controlling membrane. [Figure 3] 4 shows a schematic representation of a patch configuration similar to that of FIG. 2, except that the tablet layer includes two thin solid tablets (or optionally, a thin solid tablet and a film coated thereon) vertically adjacent to one another. The cover is optional. As in FIG. 2, the patch may optionally further include a release liner layer (not shown) disposed beneath the cover in the manner shown in FIG. 4. Optionally, the cover may be a drug-release controlling membrane. [Figure 4] 4 shows a schematic representation of a patch configuration similar to that of Figure 3, except that two thin solid tablets within the tablet layer are laterally adjacent to each other. Optionally, the cover may be a drug release controlling membrane. [Figure 5] 4 shows the pharmacokinetic (PK) profile of methylnaltrexone bromide released from a first thin solid tablet within a patch having the configuration as shown in FIG. 3. [Figure 6] 5 shows comparative PK profiles of methylnaltrexone bromide released from the comparative dry patch (dispensing type). The amount of methylnaltrexone bromide released was much less than the amount released using the various configurations summarized in FIG. 5. [Figure 7] Figure 1 shows the PK profile of aripiprazole released from a film-coated first thin solid tablet in a patch having the configuration (with cover) shown in Figure 3. The first thin solid tablet contained solubilizers (pH control agent and cyclodextrin) in addition to aripiprazole. [Figure 8] Figure 3 shows the PK profiles of aripiprazole released from a film-coated first thin solid tablet in a patch having the configuration (with and without cover) as shown in Figure 3. The first thin solid tablet contained solubilizers (pH control agent and cyclodextrin) in addition to aripiprazole. [Figure 9] Figure 3 shows the PK profiles of aripiprazole released from a film-coated first thin solid tablet in a patch having the configuration (with and without cover) as shown in Figure 3. The first thin solid tablet contained solubilizers (pH control agent and cyclodextrin) in addition to aripiprazole. [Figure 10] Figure 1 shows the PK profile of aripiprazole released from a first thin solid tablet (Groups 2 and 5) compared to the release from a first thin solid tablet combined with a second thin solid tablet (Group 4) in a patch having the configuration (covered) as shown in Figure 3. The first thin solid tablet(s) contained solubilizers (pH control agent and cyclodextrin) in addition to aripiprazole. The pharmacokinetic profile shows sustained delivery. [Figure 11] The (partial) patch construction and components of the patch of Figure 10 are described. [Figure 12] 1 shows the PK profile of sumatriptan released from the comparative dry patch. A color change was observed to occur during storage, indicating an interaction between sumatriptan and ascorbic acid. [Figure 13] Figure 3 shows the PK profile of sumatriptan released from a film layer on a thin solid tablet in a patch configured as shown in Figure 3. The thin solid tablet contained ascorbic acid, but the film layer did not. Separating the ascorbic acid from the sumatriptan enhances the stability of the formulation.

[0014] Detailed Description The present invention may be more readily understood by reference to the following detailed description, examples, figures, and claims, as well as the preceding and following descriptions thereof. However, before the present devices, systems, and / or methods are disclosed and described, it is to be understood that the present invention is not limited to the particular devices, systems, and / or methods disclosed, unless specifically stated otherwise. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not necessarily intended to be limiting.

[0015] This specification is provided as an enabling teaching of the present invention. To that end, those skilled in the relevant art will recognize and understand that many changes can be made to the various aspects of the invention described herein while still obtaining beneficial results. It will also be apparent that some of the desired benefits can be obtained by selecting some of the features described herein without utilizing other features. Thus, those working in the art will recognize that many modifications and adaptations to the present specification are possible, and may even be desirable in certain circumstances, and are a part of the present invention. Accordingly, this specification is provided as an illustration of certain principles of the invention, not as a limitation thereof.

[0016] definition As used throughout, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "filament" may include two or more such filaments unless the context dictates otherwise.

[0017] 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 embodiment includes from the one particular value and / or to the other particular value. Similarly, when values ​​are expressed as approximations, by use of "about" immediately above, it will be understood that the particular value forms another embodiment. Moreover, the endpoints of each range will be understood to be significant both in relation to the other endpoint, and independently of the other endpoint.

[0018] As used herein, the term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur.

[0019] As used herein, a "tissue membrane" can refer to any one or more epidermal layers of a subject. For example, in one embodiment, the tissue membrane is a skin layer including the outermost layer of skin, i.e., the stratum corneum. In an alternative embodiment, the skin layer can include one or more backing layers of the epidermis, commonly identified as the stratum granulosum, stratum Malpighi, and stratum basale. Those skilled in the art will appreciate that there is essentially little or no resistance to transport or absorption of permeants through the backing layers of the epidermis. Thus, in one embodiment, at least one formed pathway in a subject's skin layer is a pathway in the subject's stratum corneum. Furthermore, as used herein, "stratum corneum" refers to the outermost layer of skin, typically comprising about 15 to about 20 layers of cells in various stages of dryness. The stratum corneum forms a barrier against water loss from the inside of the body to the external environment and against attack from the external environment to the inside of the body. Furthermore, as used herein, "tissue membrane" can refer to an assembly of specific types of cells that, together with their intercellular substance, form a structural material. In various embodiments, at least one surface of the tissue membrane is accessible to one or more perforation devices and / or permeable compositions described herein.As mentioned above, the preferred tissue membrane is skin.Other tissues suitable for use with such devices and compositions include mucosal tissues and soft organs.

[0020] As used herein, the term "subcutaneous fluid" may include, but is not limited to, water, plasma, blood, one or more proteins, interstitial fluid, and any combination thereof. In one aspect, a subcutaneous fluid according to this specification is a source of moisture that includes water.

[0021] As used herein, "perforation," "microporation," or any such similar term refers to the formation of small holes or gaps (hereinafter also referred to as "micropores") in or through the outer layer of a tissue or biological membrane or organism, such as skin or mucosa, to reduce the barrier properties of the biological membrane and allow at least one permeant to pass from one side of the biological membrane to the other for a selected purpose. Preferably, the holes or "micropores" so formed are approximately 1 to 1,000 microns in diameter and extend sufficiently into the biological membrane to disrupt the barrier properties of the stratum corneum without adversely affecting the underlying tissue. While the term "micropore" is used in the singular for simplicity, it should be understood that the microporation devices described herein can form multiple artificial openings. Perforation may reduce the barrier properties of a biological membrane to the body for a selected purpose or for a specific medical or surgical procedure. In this application, "perforation" and "microporation" are used interchangeably and mean the same thing.

[0022] A "microporator" or "porator" is a component of a microporation device capable of microporation. Examples of microporators or porators include, but are not limited to, filaments that can conductively deliver thermal energy through direct contact with a biological membrane to cause ablation of a portion of the membrane deep enough to form a micropore, optically heated localized dye / absorber layers, electromechanical actuators, microlancets, arrays of microneedles or lancets, acoustic energy ablators, laser ablation systems, high-pressure fluid jet lancing devices, etc. As used herein, "microporator" and "porator" are used interchangeably.

[0023] As used herein, "penetration enhancement" or "permeation enhancement" means increasing the permeability of a biological membrane to a drug, bioactive composition, or other chemical molecule, compound, particle, or substance (also called a "permeant") in order to increase the rate at which the drug, bioactive composition, or other chemical molecule, compound, or particle permeates the biological membrane.

[0024] As used herein, the terms "enhancer," "chemical enhancer," "penetration enhancer," "permeation enhancer," and the like include all enhancers that increase the flux of a permeant, analyte, or other molecule across a biological membrane, limited only by function. In other words, they are intended to include all cell envelope disordering compounds and solvents, as well as other chemical enhancers. Additionally, they include all active force enhancer techniques, such as application of acoustic energy, mechanical suction, pressure, or localized tissue deformation, iontophoresis, or electroporation. One or more enhancer techniques may be combined, either sequentially or simultaneously. For example, a chemical enhancer can be applied first to permeabilize the capillary wall, followed by application of an iontophoretic or acoustic energy field to actively propel the permeant into the tissue surrounding and containing the capillary bed.

[0025] As used herein, "transdermal" means that the permeant enters and passes through a biological membrane.

[0026] As used herein, the terms "permeant," "drug," "permeable composition," or "pharmacologically active agent," or any other similar term, are used interchangeably to 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 herein, which material or compound induces a desired biological or pharmacological effect, which may include, but is not limited to, (1) having a prophylactic effect on an organism and preventing undesirable biological effects such as infection, (2) alleviating symptoms caused by disease, e.g., reducing pain or inflammation, and / or (3) alleviating, reducing, or completely eliminating disease from an organism. This effect may be local, such as providing a local anesthetic effect, or may be systemic. Such substances include a wide class of compounds that are typically delivered to the body, including across body surfaces and membranes, including the skin. Generally, for example, but not meant to be limiting, such substances may include any bioactive agent, such as a drug, chemical, or biological material, that induces a desired biological or pharmacological effect. To this end, in one aspect, the permeant can be a small molecule drug, while in another aspect, the permeant can be a large molecule drug.Generally, without limitation, exemplary permeants include anti-infectives such as antibiotics and antivirals; analgesics and analgesic combinations; appetite suppressants; anthelmintics; anti-arthritics; anti-asthmatics; anticoagulants; anticonvulsants; antidepressants; antidiabetics; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antiemetics; antineoplastics; antiparkinsonian drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; potassium and calcium channel blockers. These include, but are not limited to, cardiovascular agents including anticoagulants, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators, including general coronary, peripheral nerve, and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold medications, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressants; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers.

[0027] The devices and methods herein can also be used to transdermally deliver peptides, polypeptides, proteins, or other macromolecules that are known to be difficult to transmit across the skin using existing conventional techniques due to their size. These macromolecular substances typically have a molecular weight of at least about 300 Daltons, more typically about 300 to 40,000 Daltons.Examples of polypeptides and proteins that can be delivered by the present description include antibodies, LHRH, LHRH analogs (such as goserelin, leuprolide, buserelin, triptorelin, gonadorelin, nafarelin, and leuprolide), GHRH, GHRF, insulin, insulinotropin, calcitonin, octreotide, endorphins, TRH, NT-36 (chemical name: N-[[(s)-4-oxo-2-azetidinyl]-carbonyl]-L-histidyl-L-prolinyl] mide), lypressin, pituitary hormones (e.g., HGH, HMG, HCG, desmopressin acetate, etc.), growth factors such as follicular luteoid, alpha-ANF, GFRF, beta-MSH, GH, somatostatin, bradykinin, somatotropin, platelet-derived growth factor, asparaginase, bleomycin sulfate, chymopapain, cholecystokinin, chorionic gonadotropin, corticotropin (ACTH), erythropoietin, epoprostenol (platelet aggregation inhibitor) inhibitors), glucagon, hirudin, and hirudin analogues such as hirulogs, hyaluronidase, interleukin-2, menotropins (urofollitropin (FSH) and LH), oxytocin, streptokinase, tissue plasminogen activator, urokinase, vasopressin, desmopressin, ACTH analogues, ANP, ANP clearance inhibitors, angiotensin II antagonists, antidiuretic hormone agonists, antidiuretic hormone antagonists, bradykinin Renin antagonists, CD4, ceredase, CSI, enkephalin, FAB fragments, IgE peptide suppressors, IGF-1, neurotrophic factors, colony-stimulating factors, parathyroid hormone and agonists, parathyroid hormone antagonists, prostaglandin antagonists, cytokines, lymphokines, pentagetide, protein C, protein S, renin inhibitors, thymosin alpha-1, thrombolytic agents, TNF, GCSF, EPO, PTH, 3000-12,These include, but are not limited to, heparin having a molecular weight of 10,000 daltons, vaccines, vasopressin antagonist analogs, interferon-alpha, -beta, and -gamma, alpha-1 antitrypsin (recombinant), and TGF-beta genes; peptides; polypeptides; proteins; oligonucleotides; nucleic acids; and polysaccharides.

[0028] Furthermore, as used herein, "peptide" refers to peptides of any length, including proteins. The terms "polypeptide" and "oligopeptide" are used herein without any intended size limitations, unless a specific size is otherwise specified. Exemplary peptides that can be utilized include, but are not limited to, oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, prolactin, lubricating hormone or luteinizing hormone-releasing hormone, growth hormone, growth hormone-releasing factor, insulin, somatostatin, glucagon, interferon, gastrin, tetragastrin, pentagastrin, urogastroin, secretin, calcitonin, enkephalin, endorphin, angiotensin, renin, bradykinin, bacitracin, polymyxin, colistin, tyrocidine, gramicidin, and their synthetic analogs, modifications, and pharmacologically active fragments, monoclonal antibodies, and soluble vaccines. The only limitation on peptide or protein drugs that can be utilized is believed to be one of functionality.

[0029] Examples of peptide and protein drugs containing one or more amino groups include, but are not limited to, anticancer drugs, antibiotics, antiemetics, antivirals, anti-inflammatory and analgesic drugs, anesthetics, antiulcer drugs, drugs for treating hypertension, drugs for treating hypercalcemia, drugs for treating hyperlipidemia, etc., each of which has at least one primary, secondary, or tertiary amine group in the molecule, and preferably peptides, proteins, or enzymes, such as 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. Further examples of protein drugs include, but are not limited to, insulin, alpha-, beta-, and gamma-interferon, human growth hormone, alpha- and beta-1 transforming growth factor, 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.

[0030] As used herein, an "effective" amount of a pharmacologically active agent means an amount sufficient to provide the desired local or systemic effect and performance at a reasonable benefit / risk ratio associated with any medical treatment. As used herein, an "effective" amount of a permeation or chemical enhancer means an amount selected to provide the desired increase in biological membrane permeability, the desired depth of penetration, rate of administration, and amount of drug delivered.

[0031] In various embodiments, transdermal permeant delivery systems and methods that may be used and / or 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, all of which are incorporated herein by reference in their entirety, particularly for purposes of describing such systems and methods. In various embodiments, a transdermal permeant delivery system commercially available from Nitto Denko Corporation under the tradename PASSPORT may be used or adapted for use in delivering the permeant compositions described herein.

[0032] composition Various embodiments are 2 Over 400mg / cm 2 The present invention provides a composition for delivering an active permeant through a pathway in a biological membrane of a subject, comprising at least one thin solid tablet having a surface density of less than 1000 nm. 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 pathway formed through the biological membrane of the subject. In the pharmaceutical field, tablets are typically defined as oral dosage forms of pharmaceuticals. However, it has surprisingly been found that the thin solid tablet as described herein is a safe, effective, and convenient form that can provide a permeant (e.g., a pharmacologically active agent) for administration to a subject using a transdermal permeant delivery system as described elsewhere herein.

[0033] Many drugs have been prepared in the form of tablets, but their size and shape have generally been selected to be a relatively compact pill or capsule configuration suitable for the safe and effective administration of the orally administrable drug contained therein.In contrast, drugs intended for transdermal administration have generally been prepared in the form of a gel or flowable liquid (e.g., 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 in the form of a powder printed on a backing liner (see, for example, U.S. Patent Publication No. 2004 / 0137044).Those skilled in the art have not attempted to prepare drugs in the form of thin solid tablets with a relatively high surface density as described herein.Because they have been considered inappropriate for oral administration and / or inferior to traditional compact pill and capsule forms. Furthermore, various embodiments of the thin solid tablet form as described herein have been considered undesirably prone to breakage, and therefore inferior from the standpoint of manufacturing, shipping, and / or patient acceptance, compared to the flowable liquid forms typically used in transdermal patches. Various embodiments of the thin solid tablet form as described herein have also been considered more difficult to administer orally, and therefore less desirable for patient acceptance and / or compliance, compared to the relatively compact pill or capsule forms.

[0034] As used herein in the context of describing a thin solid tablet suitable for delivering a permeant through a pathway in a biological membrane of interest, the term "tablet" refers to a form that would normally be considered a pharmaceutical oral dosage form consistent with the ordinary meaning of "tablet" as understood by those skilled in the pharmaceutical arts, but which has a greater areal density than would be desirable for oral administration. The thin solid tablet may be in a variety of wafer- or plate-like shapes, such as oval, round, triangular, rectangular, square, pentagonal, hexagonal, irregular, etc. In various embodiments, the thin solid tablet is substantially flat. In one embodiment, the substantially flat thin solid tablet is slightly bent or curved to facilitate handling, for example, compared to a flat thin solid tablet that is more difficult to pick up from a flat surface.

[0035] In various embodiments, thin solid tablets as described herein have a density of 30 mg / cm 2 Ultra, 40mg / cm 2 Ultra, 50mg / cm 2 Ultra, 60mg / cm 2 Ultra, 70mg / cm 2 Ultra, 80mg / cm 2 Ultra, 90mg / cm 2 Over or 100 mg / cm 2 and above 400 mg / cm 2 Less than 350 mg / cm 2 Less than 300 mg / cm 2 Less than 250 mg / cm 2 Less than or 200 mg / cm 2 For example, in various embodiments, a thin solid tablet has an areal density of less than 30 mg / cm or any range of endpoints defined by any two of the foregoing values. 2 Over 400mg / cm 2 Less than 40 mg / cm 2 Over 400mg / cm 2 Less than or equal to 30 mg / cm 2 Over 400mg / cm 2 has an areal density of less than

[0036] In various embodiments, a thin solid tablet as described herein has a thickness of about 0.01 mm or more, about 0.02 mm or more, about 0.03 mm or more, about 0.04 mm or more, about 0.05 mm or more, about 0.05 mm or more, about 0.1 mm or more, about 0.2 mm or more, about 0.5 mm or more, or about 1 mm or more, and about 10 mm or less, about 5 mm or less, about 2 mm or less, or about 1 mm or less, or any range of thicknesses (depending on areal density and areal area) having endpoints defined by any two of the foregoing values. For example, in various embodiments, a thin solid tablet has a thickness in the range of about 0.01 mm to about 10 mm or in the range of about 0.1 mm to about 5 mm.

[0037] In various embodiments, the thin solid tablet has a face in a format similar to the front or back of a coin. In various embodiments, the face of the thin solid tablet is about 0.01 cm 2 More than 0.05cm 2 More than 0.1cm 2 More than 0.25cm 2 More than 0.5cm 2 More than 0.75cm 2 More than 1cm, or about 1cm 2 More than or equal to 50cm 2 Below, approximately 25cm 2 Below, approximately 15cm 2 Below, approximately 10cm 2 Below, approximately 5cm 2 Less than or equal to 2cm 2 For example, in various embodiments, the face of a thin solid tablet has an area of ​​about 0.01 cm or less, or any range of areas having endpoints defined by any two of the foregoing values. 2 ~about 25cm 2 , about 0.1cm 2 ~about 10cm 2 , or approximately 0.15 cm 2 ~about 5cm 2 It has an area in the range of

[0038] The thin solid tablets described herein can be made using various tableting materials and methods known to those skilled in the art, as long as they are compatible with the tablet configurations described herein. Such adaptations can be easily made by those skilled in the art in light of the instructions provided herein. In various embodiments, the thin solid tablets contain one or more excipients selected from binders, disintegrants, lubricants, permeation enhancers, solubilizers, absorption control agents, osmotic agents, pH control agents, antibacterial agents, release control agents, and fillers. For example, in various embodiments, the excipient is 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.

[0039] The thin solid tablet also contains one or more permeants, as described elsewhere herein. For example, in one embodiment, the permeant is a hydrophobic drug. In one embodiment, the permeant has an aqueous solubility of less than 10 mg / mL. In one embodiment, the permeant includes a high-dose drug requiring a daily dose rate that is difficult to achieve with a typical transdermal patch in the absence of microporation. In one embodiment, the high-dose drug requires an intake of 20 mg / day or more. In various embodiments, the permeant is selected from methylnaltrexone bromide, aripiprazole, sumatriptan succinate, exenatide, salts thereof, and combinations thereof. The permeant may be distributed throughout the thin solid tablet or concentrated in specific regions. For example, in one embodiment, the thin solid tablet contains the permeant in the form of a layer on the tablet, in the form of a dispersion within the tablet, or a combination thereof. In one embodiment, the distribution is selected to control the release rate of the permeant from the tablet, thereby providing for delivery of the permeant through a pathway within the biological membrane of the subject in a controlled manner, e.g., delayed or sustained release.

[0040] 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 tablet can be selected based on the properties of the permeant and the desired tablet configuration using routine experimentation guided by the detailed teachings provided herein. For example, in one 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 tablet comprises a solubilizer. The solubilizer can be selected based on the properties of the permeant and the desired degree of enhanced solubilization. For example, in one 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.

[0041] Compositions for delivering permeants through pathways in biological membranes of a subject can be configured in a variety of ways, for example, in one embodiment, the composition comprises a single thin solid tablet, while in another embodiment, the composition comprises two or more thin solid tablets.

[0042] In one embodiment, a thin solid tablet(s) is / are incorporated into the patch. For example, one embodiment provides a patch for delivering a drug through at least one formed pathway through a biological membrane of a subject, the patch comprising a composition for delivering a permeant through a pathway in the biological membrane of a subject, the composition comprising a thin solid tablet as described herein. Thus, for example, the thin solid tablet in the patch can comprise a bioactive agent as described herein. Figures 1A, 1B, and 2-4 show various patch configurations.

[0043] In various embodiments, the patch is suitable for use in combination with a microporation device configured to form pathways in a subject's biological membrane. A transdermal permeant delivery system including a suitable microporation device is commercially available from Nitto Denko Corporation under the trade name PASSPORT. The PASSPORT system includes a reusable handheld applicator and a disposable porator that can be used in combination with the patch described herein. Pressing the activation button on the applicator releases an energy pulse into the porator. This energy is rapidly conducted to the surface of the skin, painlessly ablating the stratum corneum beneath each filament and forming microchannels. The patch can then be applied to the ablated skin. Biological moisture from the subject can enter the thin solid tablet(s) in the patch through the formed microchannels, solubilizing the drug and allowing it to pass through the skin and enter the subject's body via the microchannels.

[0044] In one embodiment, creating at least one channel in the patient's skin; applying a patch as described herein to the skin of a patient, thereby contacting at least one thin tablet with a channel; and (a) at least partially dissolving the permeant in biological fluid received from the pathway; and (b) maintaining the resulting solution in contact with the patient's skin for a period of time effective to deliver a therapeutically effective amount of the dissolved permeant to the patient via this route; The present invention provides a method of treating a patient, comprising:

[0045] Example Various embodiments and alternatives are disclosed in further detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0046] Example 1 A series of thin, solid tablets containing methylnaltrexone bromide (MNTX-Br) ​​as the active ingredient along with other ingredients listed in Table 1 were prepared using standard techniques for forming tablets. The tablets were 8 mm x 8 mm square with an axial area of ​​approximately 0.64 cm. 2 and the tablet weight is 34.3 mg / cm 2 (22mg / 0.64cm 2 ) Patches with the configuration shown in Figure 3 were fabricated using thin solid tablets and applied to rat skin using a PASSPORT reusable handheld applicator and disposable porator. PK data were collected in the usual 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.

[0047] A summary of the resulting PK data is provided in Table 3. Figure 5 shows the PK profile of methylnaltrexone bromide released from the thin solid tablet within the patch, and a comparative PK profile of methylnaltrexone bromide released from the dry patch is shown in Figure 6. The amount of methylnaltrexone bromide released from the comparative patch was much less than the amount released using a patch containing a thin solid tablet as summarized in Table 3.

[0048] [Table 1]

[0049] [Table 2]

[0050] [Table 3]

[0051] Example 2 A series of thin, solid tablets containing aripiprazole as the active ingredient along with other ingredients listed in Table 4 were prepared using standard techniques for forming tablets. The tablets were 9 mm x 9 mm square with an axial area of ​​approximately 0.81 cm. 2 and the tablet weight is 61.7 mg / cm 2 (50mg / 0.81cm 2 ) Patches with the configuration shown in Figure 3 were fabricated using thin solid tablets and applied to rat skin using a PASSPORT reusable handheld applicator and disposable porator. PK data were collected in the usual manner.

[0052] A summary of the PK data obtained is provided in Table 5, and Figures 7 and 8 show the PK profile of aripiprazole released from the patch.

[0053] [Table 4]

[0054] [Table 5]

[0055] Example 3 A series of thin, solid tablets containing aripiprazole as the active ingredient along with other ingredients listed in Table 6 were prepared using standard techniques for forming tablets. The tablets were 9 mm x 9 mm square with an axial area of ​​approximately 0.81 cm. 2 and the tablet weight is 61.7 mg / cm 2 and 98 mg / cm 2 (50mg / 0.81cm each) 2 and 80 mg / 0.81 cm 2) Patches with the configuration shown in Figure 3 were fabricated using thin solid tablets and applied to rat skin using a PASSPORT reusable handheld applicator and disposable porator. PK data were collected in the usual manner.

[0056] A summary of the PK data obtained is provided in Table 7, and Figure 9 shows the PK profile of aripiprazole released from the patch.

[0057] [Table 6]

[0058] [Table 7]

[0059] Example 4 A series of thin, solid tablets containing aripiprazole as the active ingredient along with other ingredients as listed in Figure 11 were prepared using standard techniques for forming tablets. The tablets were 9 mm x 9 mm square with an axial area of ​​approximately 0.81 cm. 2 and the tablet weight is 210.0 mg / cm 2 , 402.5 mg / cm 2 , and 395.1 mg / cm 2 (170mg / 0.81cm respectively) 2 , 326 mg / 0.81 cm 2 , and 320 mg / 0.81 cm 2 ) Patches with the configurations shown in Figures 3 and 11 were fabricated using thin solid tablets and applied to the skin of hairless guinea pigs using a PASSPORT reusable handheld applicator and a disposable porator. PK data were collected in the usual manner. Figure 10 shows the PK profile of aripiprazole released from these patches, demonstrating sustained release.

[0060] Example 5 (comparison) A series of immediate-release dry patches containing sumatriptan as the active ingredient along with other ingredients listed in Table 8 were prepared. The immediate-release dry patches were applied to the skin of hairless guinea pigs, and PK data were collected in the usual manner. A summary of the resulting PK data is listed in Table 9, and Figure 12 shows the PK profile of sumatriptan released from the patches. It was observed that a color change in the components of the immediate-release patches occurred during storage, indicating a stability issue due to an interaction between sumatriptan and ascorbic acid.

[0061] [Table 8]

[0062] [Table 9]

[0063] Example 6 A series of thin, solid tablets containing sumatriptan as the active ingredient along with other ingredients listed in Table 10 were prepared using standard techniques for forming tablets. The tablets were 9 mm x 9 mm square with an axial area of ​​approximately 0.81 cm. 2 and 56.44 mg / cm 2 (45.72mg / 0.81cm 2 The tablets had a tablet weight of 1000 mg / mL. Patches having the configuration shown in Figure 3 were fabricated using thin, solid tablets and applied to the skin of hairless guinea pigs using a PASSPORT reusable handheld applicator and disposable porator. PK data were collected in the usual manner. A summary of the PK data obtained is provided in Table 11, and Figure 13 shows the PK profile of sumatriptan released from the patch. Because sumatriptan and ascorbic acid separated, the stability issues observed with the comparative immediate-release patch of Example 5 were not observed.

[0064] [Table 10]

[0065] [Table 11]

[0066] Example 7 (comparison) Immediate release dry patches were prepared containing exenatide as the active ingredient along with other ingredients as listed in Table 12. It was observed that a change in color of the ingredients of the immediate release patch occurred during storage, indicating a stability issue due to an interaction between exenatide and ascorbic acid.

[0067] [Table 12]

[0068] Example 8 Thin solid tablets containing exenatide as the active ingredient along with other ingredients listed in Table 13 were prepared using standard techniques for forming tablets. The tablets were 9 mm x 9 mm square with an axial area of ​​approximately 0.81 cm. 2 and 56.44 mg / cm 2 (45.72mg / 0.81cm 2 ) tablet weight. A patch having the configuration shown in Figure 3 was made using the thin solid tablets. Because the exenatide and ascorbic acid were separated, the stability issues observed in the comparative immediate-release dry patch of Example 7 were not observed.

[0069] [Table 13]

[0070] The data from the above examples demonstrate that thin solid tablets as described herein are useful in a variety of demanding applications, particularly when used in combination with an appropriate microporation device, such as that commercially available from Nitto Denko Corporation under the PASSPORT trademark. For example, in one embodiment, a patch containing a thin solid tablet as described herein has a relatively high loading of a hydrophobic drug and can therefore be used in the methods described herein to deliver drugs to a subject at high doses of 20 mg / day or more. Relatively large amounts of solubilizing agents are typically used to increase the solubility of such drugs for use in conventional transdermal delivery patches, thus limiting the drug loading and resulting daily dose. In another embodiment, a patch containing two or more thin solid tablets as described herein (or thin solid tablets with coatings), such as those shown in Figures 3-4, enhances the patch's ability to provide a desirable PK profile (such as controlled release) and / or enhances stability by allowing for the separation of components that might otherwise interact in undesirable ways. In another embodiment, a patch containing two or more thin solid tablets (or thin solid tablets with coatings) as described herein, such as those shown in Figures 3-4, allows for the delivery of multiple active ingredients (e.g., drugs) from a single patch, thereby facilitating the administration of combination therapies.

Claims

1. 1. A composition for delivering a permeant through one or more formed micropores in the skin of a subject, comprising: 30 mg / cm ２ Over 400 mg / cm ２ At least one thin solid tablet having an areal density of less than Including, The at least one thin solid tablet comprises: a backing layer disposed over said at least one thin solid tablet; a release liner layer disposed beneath the at least one thin solid tablet; and surrounded by a spacer layer disposed between the backing layer and the release liner layer; The thin solid tablet comprises at least one permeant in the form of a layer, at least a portion of the permeant is soluble in biological water received from one or more formed pores in the skin of the subject; composition.

2. 10. The composition of claim 1, wherein the thin solid tablet further comprises one or more excipients selected from the group consisting of binders, disintegrants, lubricants, permeation enhancers, solubilizers, absorption control agents, osmotic agents, pH control agents, antibacterial agents, release control agents, and fillers.

3. 3. The composition of claim 1 or 2, wherein the at least one permeant is one or more selected from the group consisting of a small molecule drug, a peptide, a protein, an oligonucleotide, an antibody, a polysaccharide, and a vaccine.

4. 4. The composition of claim 3, wherein the at least one permeant has a water solubility of less than 10 mg / mL.

5. 10. The composition of claim 1, wherein the at least one permeant requires an intake of more than 20 mg / day.

6. 6. The composition of claim 2, wherein the solubilizing agent is selected from the group consisting of polyethylene glycol, surfactants, pH control agents, cyclodextrins, fatty acids, and salts of fatty acids.

7. 7. The composition of any one of claims 1 to 6, wherein the thin solid tablet has a thickness ranging from about 0.01 mm to about 10 mm.

8. 8. The composition of claim 1, wherein the thin solid tablet further comprises a second permeant.

9. 9. The composition of claim 1, wherein the at least one permeant is on the surface of the thin solid tablet.

10. 10. The composition of any one of claims 1 to 9, wherein the at least one permeant is selected from the group consisting of methylnaltrexone bromide, aripiprazole, sumatriptan succinate, exenatide, salts thereof, and combinations thereof.

11. 11. The composition of any one of claims 2 to 10, wherein the excipient is selected from the group consisting of sucrose, lactose, HP-β-CD, citric acid monohydrate, SBE-β-CD, ascorbic acid, urea, magnesium stearate, methylparaben, and propylparaben.

12. 10. The composition of claim 1, comprising at least two thin solid tablets.

13. A patch for delivering a drug through one or more formed micropores in the skin of a subject, the patch comprising a composition according to any one of claims 1 to 12.

14. 14. The patch of claim 13, wherein at least one thin solid tablet comprises a bioactive agent.

15. 15. The patch of claim 14, wherein the patch provides an immediate release profile and a sustained release profile of the permeant from the at least one thin solid tablet through one or more formed micropores in the skin of the subject.

16. A patch described in any one of claims 13 to 15, further comprising a cover below at least one thin solid tablet and above the release liner layer, said cover configured to reduce contact between said at least one thin solid tablet and said release liner layer.

17. 17. The patch of claim 16, wherein the spacer layer is laterally adjacent to the at least one thin solid tablet and is configured to maintain a separation distance between the backing layer and the release liner layer, the separation distance being in the range of about 50% to about 150% of the thickness of the thin solid tablet.

18. 18. The patch of any one of claims 15 to 17, further comprising an adhesive layer below the backing layer and above the release liner layer.

19. A transdermal drug delivery system for delivering a drug, comprising: a transdermal microporation device configured to form one or more micropores through the skin of a subject; A patch according to any one of claims 13 to 18. A transdermal drug delivery system comprising:

20. A transdermal drug delivery system for delivering a drug as described in claim 19, wherein at least one thin solid tablet is configured to contact the skin of the subject for a period of time effective to at least partially dissolve the permeant in biological moisture received through the one or more formed micropores, and the at least one thin solid tablet is configured to deliver the resulting dissolved therapeutically effective amount of the permeant to the subject through the one or more formed micropores.

21. 20. A patch according to any one of claims 13 to 18 for use in delivering a therapeutically effective amount of at least one partially dissolved permeant through one or more formed micropores in the skin of a subject, wherein the patch is configured to be in contact with the skin of the subject for a period of time effective to at least partially dissolve the permeant in biological moisture received from the one or more formed micropores in the skin of the subject.

22. 20. A patch according to any one of claims 13 to 18 for use in delivering a permeant through one or more formed micropores in the skin of a subject, the patch being configured to be applied to the skin of the subject.

23. 13. The composition of claim 1, wherein the micropores are micropores formed by transdermal microporation.

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