Systems, devices and methods for applying Anti-VEGF compounds and using such compounds to treat skin conditions

Abstract

To provide methods for applying to the skin an anti-vascular endothelial growth factor (VEGF) to treat various skin conditions.SOLUTION: A therapeutically effective amount of at least one anti-VEGF-containing compound is topically applied to a target region of the skin by using a microneedle. The anti-VEGF-containing compound is selected from anti-VEGF antibodies such as bevacizumab and ranibizumab, or tyrosine kinase inhibitors such as pegaptanib, imatinib, vandetanib, sorafenib, pazopanib, erlotinib and gefitinib. Further, the compound may comprise at least one filler selected from NSAID, hyaluronic acid, collagens, elastin, proteoglycan, chondroitin sulfate, heparin sulfate, elastin, fibrillin and fibrin or a combination thereof.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to Provisional Application No. 62 / 721,656, filed August 23, 2018. No. 6,233,633, filed Sep. 11, 2017, which is a continuation-in-part of pending application Ser. No. 15 / 700,992, filed Sep. 11, 2017, which is a continuation-in-part of pending application Ser. No. 14 / 861,943, filed Sep. 22, 2015, which is now U.S. Patent No. 9,757,452, the entire contents of which are expressly incorporated by reference herein. This is a divisional application of application serial number 14 / 261,198, filed April 24, 2014, and is currently U.S. Pat. No. 9,161,978, which is a divisional application of application serial number 13 / 830,819, filed March 14, 2013, now U.S. Patent No. 8,747,852, which claims priority from provisional application serial number 61 / 746,778, filed December 28, 2012.

[0002] Technical Field The present disclosure generally relates to systems, devices and methods for applying anti-vascular endothelial growth factor (anti-VEGF) compounds to the skin to treat various skin conditions. The present disclosure also relates to delivery systems and methods of use for applying the disclosed compounds to the skin, including transdermal patches and bandages containing anti-VEGF, to treat various skin conditions.

[0003] background Anti-vascular endothelial growth factor therapy, also known as "anti-VEGF" therapy or anti-VEGF agents, is the use of drugs that block vascular endothelial growth factor. This is done in the treatment of certain cancers and in age-related macular degeneration. They may include monoclonal antibodies such as bevacizumab, antibody derivatives such as ranibizumab (Lucentis), or orally available small molecules that inhibit tyrosine kinases stimulated by VEGF: lapatinib, sunitinib, sorafenib, axitinib, and pazopanib. Some of these therapies target the VEGF receptor rather than VEGF. Both antibody-based compounds and the first three orally available compounds are commercialized with the latter two (axitinib and pazopanib) in clinical trials.

[0004] Bevacizumab: a new treatment for age-related macular degeneration (AMD) that involves angiogenesis and vasculogenesis Bevacizumab is a 149-kD humanized monoclonal antibody that inhibits vascular endothelial growth factor A (VEGF-A), a signaling protein that stimulates the vascular endothelial growth factor receptor (VAG) signaling. Bevacizumab has been approved by the FDA for use in the management of various cancers, but compounded bevacizumab has not been approved for the treatment of eye diseases, including AMD, since May 2005. Currently, bevacizumab is also used successfully to treat diabetic retinopathy, central retinal vein occlusion, neovascular glaucoma, and retinopathy of prematurity, in addition to many other less common eye diseases.

[0005] The application of AVEGF and other means to slow or prevent angiogenesis reduces excess blood vessels. Neoplasia may play a role in many diseases and injuries which can have undesirable effects including scarring, swelling, keloids, prolonged redness and many other conditions listed below.

[0006] The disclosed systems, devices and methods for treating inflammatory skin diseases and other skin conditions are directed to overcoming one or more of the above problems and / or other problems of the prior art. Summary of the Invention [Means for solving the problem]

[0007] Abstract In an embodiment, a method is disclosed for treating inflammation or a vascular condition by transdermal modulation of inflammation in a target area of ​​the body having the inflammation or vascular condition by topically applying to the skin of the target area a therapeutically effective amount of at least one anti-VEGF-containing compound.

[0008] In another embodiment, a device, such as a transdermal patch, bandage, paint, atomized spray, etc., for treating inflammation or a vascular condition is also disclosed, the device being configured to transdermally apply to the skin of a target area a therapeutically effective amount of at least one anti-VEGF-containing compound that modulates inflammation in the target area.

[0009] Apart from the subject matter discussed above, the present disclosure includes numerous other features as will be described hereinafter. Both the foregoing and the following description are merely exemplary. [Brief description of the drawings]

[0010] The accompanying drawings are incorporated in and constitute a part of this specification. [Figure 1] 1A-1D show various designs for transdermal patches, including matrix (FIG. 1A), reservoir (FIG. 1B), multi-laminate (FIG. 1C) and drug-in-adhesive (FIG. 1D) designs. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Detailed Description Definition: The term "subject" as used herein means any mammal, and particularly a human, and may also be referred to as, for example, an individual or a patient.

[0012] As used herein, "anti-VEGF agent" refers to an inhibitor of VEGF signal transduction. Anti-VEGF agents include antibodies (e.g., bevacizumab), antibody fragments (e.g., antibody light chains (VL), antibody heavy chains (VH)). , single chain antibodies (scFv), F(ab')2 fragments, Fab fragments, Fd fragments, Fv fragments, and single domain antibody fragments (DAb). For example, an intact antibody or a complete antibody or antibody chain, or by recombinant means), fusion Chemical or enzymatic treatments such as proteins, peptides, nucleic acids (e.g., siRNA, shRNA), and other small molecules that disrupt the interaction between VEGF (VEGF-A) and its receptors (VEGFR-1 / VEGFR-2). Other non-limiting examples of anti-VEGF agents encompassed by the present disclosure are provided herein below.

[0013] For example, the term "adjacent" as used herein in the context of applying or injecting an anti-VEGF adjacent or proximate to a site of neovascular growth means adjacent to the site of neovascular growth (e.g., the site of neovascular growth). "within about 0.1 mm, 0.2 mm, 0.3 mm, 0.4 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, or 5 mm from the

[0014] The terms "therapeutically effective" and "effective amount" as used herein, which are used interchangeably and which apply to dose or amount, refer to an amount of a composition, compound or pharmaceutical preparation sufficient to produce a desired activity upon administration to a subject in need thereof. Within the context of the present invention, the term "therapeutically effective" refers to an amount of a composition, compound or pharmaceutical preparation sufficient to reduce, eliminate or delay at least one symptom of a disease or condition identified herein. When a combination of active agents is administered, the effective amount of the combination, or of each agent, may or may not include the amount of each agent that would have been effective if administered individually. The dosage of the therapeutic formulation will vary depending on the nature of the disease or condition, the medical history of the patient, the frequency of administration, the mode of administration, clearance of the agent from the host, and the like. An initial dosage may be higher, followed by a lower maintenance dosage. Dosage may be administered, for example, weekly, biweekly, or weekly, to maintain an effective dosage level. , daily, twice weekly, etc.

[0015] The therapeutically effective dosage in the methods described herein can be determined by the treating physician. For example, the physician can begin treatment with the manufacturer's recommended dose for the anti-VEGF agent and adjust based on the physician's observation of the effectiveness of the treatment. Further guidance is provided herein and in the Examples. Additionally, clinical trials can be performed to determine the effective dose to produce a statistically significant therapeutic effect when a population of patients is treated.

[0016] As used herein, "combination therapy" refers to the treatment of a subject in need of treatment with a particular composition or drug, where the subject is treated or given one or more other compositions or drugs for a disease in combination with the first and / or in combination with one or more other therapies, such as surgery. Such combination therapy may be used when a patient is first treated with one treatment modality (e.g., drug or therapy) and then with another (e.g., drug or therapy). It may be a sequential therapy in which all drugs and / or In either case, the drugs and / or therapies may be referred to as "combined." "Combined" does not necessarily mean that the drugs and / or therapies are administered in a combined form (i.e., they may be administered simultaneously at the same or different sites). It should be understood that the two agents may be administered separately or together at the same or different times.

[0017] The expression "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the reasonable scope of medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0018] As used herein, "modulating inflammation" is intended to mean suppressing an unwanted inflammatory response, enhancing a beneficial inflammatory response, or otherwise altering an inflammatory response to beneficially treat the described disorder or condition.

[0019] As used herein, "treating" or "treatment" of a condition, disorder, or condition means: (1) treating a person who may be suffering from or susceptible to the condition, disorder, or condition; (1) to prevent or delay the onset of a clinical or subclinical symptom of a disease, disorder or condition in a mammal that has not yet experienced or exhibited a clinical or subclinical symptom of the disease, disorder or condition; and / or (2) to arrest, reduce or delay the onset of a disease or its recurrence (in the case of maintenance therapy) or at least one clinical or subclinical symptom thereof. (3) inhibiting a state, disorder, or condition, including preventing a disease; and / or (4) alleviating a disease (3) causing a reduction in the severity of one or more symptoms of a disease, i.e., causing a reduction in at least one of the symptoms, disorders, or conditions or their clinical or subclinical symptoms; and / or (4) causing a reduction in the severity of one or more symptoms of a disease. The benefit to a treated subject is either statistically significant or at least perceptible to the patient or to the physician.

[0020] As used herein, "target area" is intended to mean the area of ​​the body or skin to be treated as it is the location, adjacent to or in close proximity to a site of a vascular or inflammatory condition, such as new blood vessel growth, associated with one or more of the diseases / conditions described herein.

[0021] As used herein, "lipid-based nanocarriers" are intended to include liposomes and micelles, which are biocompatible.

[0022] As used herein, "liposome" refers to an FDA approved spherical structure comprising at least a phospholipid bilayer having an encapsulated aqueous phase capable of carrying an anti-VEGF compound as described herein. It is meant to be tasted.

[0023] As used herein, "micelle" is intended to mean an FDA approved spherical structure comprising a lipid monolayer having a hydrophilic shell surrounding a hydrophobic core.

[0024] As used herein, "FLT-1" refers to a high affinity tyrosine kinase receptor for VEGF. By way of example, the term is intended to describe vascular endothelial growth factor receptor 1 (VEGFR-1), which is a marker and is expressed almost exclusively on vascular endothelial cells.

[0025] inflammatory skin diseases In one embodiment, the treatment involves treating a condition in which increased or altered vasculature is an important component and which would therefore benefit from therapeutic treatment with an AVEGF compound as described herein. Thus, methods and devices are provided for treating inflammatory skin diseases, other skin conditions and lesions, abrasions, and for surgeries that may cause scarring and prolonged erythema, where increased or remodeled vasculature plays a role in the treatment of inflammatory skin diseases.

[0026] There are a variety of modulations of conditions in which increased or altered vasculature is an important component and which therefore would benefit from therapeutic treatment with the AVEGF compounds described herein. These include: (a) photoaging, (b) skin treated with dermal or subdermal fillers, (c) skin exposed to ionizing radiation, (d) skin exposed to UV radiation, (e) damaged skin (acute and chronic), (d) port wine stains, Other vascular conditions that may be treated include, but are not limited to, vascular conditions such as port wine stains (before and after treatment), which often grow or darken over time and may even recur or flourish without treatment. Other vascular conditions that may be treated include cherry angiomas, hemangiomas, spider angiomas (star-shaped blood vessels), and vascular ulcers. (e) congenital conditions where the blood vessels are the key, including but not limited to hereditary hemorrhagic telangiectasia also known as Osler-Rendu; (f) acquired conditions where the blood vessels are the key-CREST form of Scleroderma; (g) any connective tissue disease such as rheumatoid arthritis, lupus, scleroderma, Sjogren's syndrome, Raynaud's syndrome and disease, and others; and (h) acute and chronic wounds.

[0027] In one embodiment, the use of AVEGF in conjunction with one or more treatments for the skin is described. For example, in various embodiments, in conjunction or in combination with other skin treatments, such as in combination with post-filler administration; to prevent microvascular regeneration and hair follicle recovery. in combination with laser hair removal for dry eyes; in combination with melasma treatment; IPL for dry eyes in combination with laser and other treatments; and in combination with treatments for psoriasis, or Sturge-Weber syndrome, among others. Methods for treating

[0028] Non-limiting examples of inflammatory skin diseases and other skin conditions include, but are not limited to: rosacea, acne, atopic dermatitis, contact dermatitis, drug eruptions, psoriasis, seborrheic dermatitis, connective tissue diseases, autoimmune diseases, hives, photodamage, aging, sunburn, skin infections, radiation dermatitis, skin exposed to ionizing radiation, port wine stains, hemangiomas, wounds or any lesions, cherry hemangiomas, stellate hemangiomas, or skin or deeper tissue, acute or chronic wounds, photodamage, aging, sunburn, skin infections, radiation dermatitis, skin exposed to ionizing radiation.

[0029] Because the vasculature plays an important role in inflammation, and virtually any cytokine that affects blood vessel growth will also have the effect of modulating and controlling inflammation, rather than decreasing or increasing it.

[0030] Anti-VEGF agents The human VEGF-A gene is organized in eight exons. Alternative exon splicing results in the production of four major VEGF isoforms (VEGF121, VEGF165, VEGF189, and VEGF206) with 121, 165, 189, and 206 amino acids, respectively, after signal sequence cleavage. VEGF165 is considered to be the most physiologically relevant isoform. Overview For details, see Ferrara et al., Biochem. Biophys. Res. Commun., 2005, 333, 328-335. The amino acid sequence of VEGF-A is well known in the art, and due to splice variants, the sequences are numerous. By way of non-limiting example, the following are exemplary, non-limiting GenBank.RTM. Accession Numbers for human VEGF-A ("VEGF") amino acid sequences: AAP86646.1, P15692.2, NP_001191313.1, NP_001165101.1, NP_001165099.1, NP_001165097.1, NP_001165095.1, NP_001020539.2 ... 03367.4, NP_001165093.1, NP_001020541.2, NP_001191314.1, NP_001165100.1, NP_001165098.1, NP_001 165096.1, NP_001165094.1, NP_001028928.1, NP_001020540.2, NP_001020538.2, and NP_001020537.2.

[0031] The two VEGF receptors (VEGFRs), also known as VEGFR-1 and KDR, Flk-1, or VEGFR-2 VEGFR-2 mediates VEGF-induced mitogenesis, angiogenesis, and There is now agreement that VEGFR is the primary mediator of the permeability enhancing effect. For a detailed review of the biological and signaling properties of VEGFR, see Ferrara, Endocr. Rev. 2004, 25, 581-611. Amino acid sequences for VEGFR are known in the art. By way of a non-limiting example, the GenBank.RTM. Accession Number for the VEGFR-1 amino acid sequence is: NP_001153503.1 , NP_002010.2, NP_001153502.1, and NP_001153392.1. The amino acid sequence for VEGFR-2 is known in the art. By way of non-limiting example, the GenBank.RTM. Accession Numbers for the VEGFR-2 amino acid sequence are: NP_002244.1, AAC16450.1, and and NP_001153503.1.

[0032] Disclosed herein are methods for treating various skin conditions by administering an anti-VEGF agent to a subject. In one embodiment, the anti-VEGF antibody bevacizumab may be used in the methods. The antibody bevacizumab and its VEGF-binding activity are reviewed in detail in Ferrara et al., Biochem. Biophys. Res. Commun., 2005, 333, 328-335. Bevacizumab Mabs may be administered to the skin at doses of about 5-15 mg (e.g., to inhibit keloid recurrence) In one embodiment, the dose for administration to the site of keloid removal (eg, to inhibit keloid recurrence) is about 10 mg.

[0033] However, the therapeutic methods described herein also include, so long as the anti-VEGF agent has the ability to inhibit the action of VEGF (e.g., human VEGF) and / or VEGFR (e.g., VEGFR-1 and / or VEGFR-2) (e.g., human VEGFR-1 or human VEGFR-2) (i.e., inhibit VEGF signaling). Other anti-VEGF agents, either known in the art or to be discovered or designed in the future (e.g., other anti-VEGF antibodies, drugs, prodrugs, small molecules, peptides, nucleic acid inhibitors, It should be understood that this can be done using VEGF or VEGFR inhibitors, such as, but not limited to, agents (e.g., siRNA, shRNA, antisense oligonucleotides), fusion proteins, etc. It can be determined whether an antibody or other agent interferes with VEGF signaling (either by inhibiting VEGF or VEGFR, or by the interaction between VEGF and its receptor). Assays for determining, for example, whether an anti-VEGF agent interferes with VEGF signaling and therefore is encompassed by the methods disclosed herein are well known in the art and can be used to determine whether an anti-VEGF agent interferes with VEGF signaling and therefore is encompassed by the methods disclosed herein. Non-limiting examples of such assays are described in Vicari et al., J. Biol. Chem., 2011, 286(15), 13612-25 and Brekken et al. Cancer Res., 2000, 60, 5117-24. The VEGF inhibition assay described in

[0034] By way of non-limiting example, other anti-VEGF antibodies and inhibitors that are known in the art and can be used in the methods disclosed herein include: ranibizumab, pegaptanib, imatinib, vandetanib, sorafenib, pazopanib, varatanib, bevasiranib, and vevaciranib. vasiranib), aflibercept, etanercept, anecortave acetate (anti-angiogenic angiostatic steroid, VEGF-trap (fusion protein), squalamine Lactic acid, erlotinib, gefitinib (small molecule), combretastatin A4 prodrug (anti- tubulin / angiogenesis inhibitor), AdPEDF (adenovector pigment epithelium-derived factor), Cand5 (siRNA), protein tyrosine kinase 7 inhibitor (PTK7), lipolytic agent, TG100801, AG013958, AL39324, AGN211745 (VEGF receptor blocker), anti-angiogenic EGF-A(xxx)b family, VEGF trap ( receptor decoy), protein kinase antibodies against the tyrosine kinase inhibitor receptor SIM010603, kinase domain receptor antibodies (KDR1.3 and KDR2.6), GS101 aganirsen (antisense oligonucleotide against insulin receptor substrate aka IRS-1), picropoiesis Dofilin (PPP), tetrameric tripeptide, tissue kallikrein, KH906 (recombinant human VEGF receptor receptor protein fusion), beta-adrenergic receptor blockers, β.3-AR, nicotinic acetylcholine receptor antagonists, linomide analogs (Lin05), morpholino oligomers (VEGFR1_MOe13), decursin, prorenin, vasohibin and sirolimus. Because the amino acid sequences of VEGF and VEGFR (as well as the nucleic acid sequences encoding the amino acid sequences) are known in the art, it will be understood that one of skill in the art can readily design additional anti-VEGF agents for use in the methods of the present disclosure.

[0035] Dosage ranges for anti-VEGF agents, e.g., as disclosed above, can be readily determined by one of ordinary skill in the art, and can, for example, be initially determined in animal models to determine dosage, safety, and efficacy according to standard methods known in the art.

[0036] Anti-inflammatory steroids Anti-inflammatory steroids are steroid compounds that have anti-inflammatory activity and include corticosteroids, including glucocorticoids, which bind to glucocorticoid receptors in the cytoplasm and encode anti-inflammatory proteins, including lipocortin-1, interleukin-10, interleukin-1 receptor antagonist, and neutral endopeptidase. Glucocorticoids can increase the transcription of genes that promote inflammation. Glucocorticoids also inhibit the expression of several inflammatory genes, including genes for various cytokines, enzymes, receptors and adhesion molecules. Barnes et al., Clin. Sci., 1998, 94, 557-572.

[0037] Suitable steroids for application to the skin include, for example, alclometasone 0.05% cream (generic or Aclovate.RTM. 0.05% cream available from PharmaDerm Inc.), diclofenac, Suitable dosages for administration to humans include, for example, 0.05% to 0.1%. For use in the methods described herein, suitable dosages include, for example, 0.05% to 0.1%. Suitable additional commercially available topical ophthalmic steroids are listed in Table 3.

[0038] [Table 1]

[0039] Nonsteroidal anti-inflammatory drugs (NSAIDs) Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonsteroidal compounds that reduce inflammation. Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes, which catalyze the formation of prostaglandins. COX-1 inhibition is associated with gastrointestinal side effects of NSAIDs. Because it is believed to be associated with COX-2 activation, compounds that are selective COX-2 inhibitors have also been developed.

[0040] Non-limiting examples of NSAIDs that may be administered to the skin include, for example, diclofenac 1% (topical) (e.g., Voltaren gel 1% from Novartis Pharmaceuticals Corp. or Pennsaid 1.5% solution (topical) from Mallinckrodt Pharmaceuticals). Suitable dosages for administration to humans include, for example, 1% (topical) application to the skin (administered by injection of 1 mL into the skin) of up to 40 mg once daily.

[0041] Methods for transdermal administration / application of anti-VEGF compounds Transdermal delivery systems, such as transdermal patches, are useful for administering and administering the AVEGF-containing compounds described herein. One advantage of percutaneously treating the skin is the potential for increased pharmacological activity in the liver that may result from oral administration of the described AVEGF compounds. Therefore, the present invention provides a method for preventing the metabolism of AVEGF compounds via the transdermal delivery system described herein. The administration prevents unwanted hepatic and gastrointestinal side effects. A single dose usually requires less pharmacologic agent to have the same effect. Furthermore, studies have shown that the transdermal delivery system described herein provides a more constant blood concentration of the pharmacologic agent since the agent is immediately effective in a systemic manner by permeation through the skin.

[0042] Topically, via transdermal patches, lipid-based nanocarriers, such as liposomes and micelles, allow passage of the skin barrier. In one embodiment, transdermal patches are used to deliver dimethyl esters of NSAIDs, which have been shown to be effective penetration enhancers for topical administration of NSAIDs. It may include a sulfoxide.

[0043] In an embodiment, AVEGF is delivered to the target area in a matrix release osmotic patch. The AVEGF receptor may be included in a compound such as hyaluronic acid that allows for a slow release. The patch is specifically designed to be used to treat the skin conditions described herein.

[0044] In one embodiment, AVEGF is administered by skin peel or ablative fractional peel. It is applied to the target area via a transdermal patch after surfacing or microneedling. The described AVEGF can be mixed with other adjuvants for treating skin conditions, such as hyaluronic acid, vitamin C, hydroquinone, corticosteroids, tretinoin, etc.

[0045] Additionally, in an embodiment, AVEGF is administered in combination with at least one anti-inflammatory steroid, at least The active ingredient may be mixed with one or more nonsteroidal anti-inflammatory drugs, or any combination of these ingredients.

[0046] Various transdermal delivery systems A. Patch The AVEGF compounds described herein can be included in a transdermal patch. Typically, the transdermal patch The transdermal patch includes six components. Depending on the exact design, not all components may be required. With reference to FIGS. 1A-1D, in an embodiment, the transdermal patch described herein includes: The patch may take a variety of forms and include various layers and locations for the active ingredients. For example, in an embodiment, the patch may include an outermost layer that protects the formulation while the patch is placed on the skin. The patch may also include a membrane that controls the rate of drug release from the patch into the skin. The patches described herein also include an adhesive disposed in a layer that contacts the skin and adheres the patch to the skin. In another embodiment, the adhesive may include an adhesive that is capable of adhering the AVEGF-containing compound to the skin. Further included. The patches described herein also include an overlaminate tape, which is an outer protective cover or functional layer that can be directly incorporated into the patch design. Finally, the patches described herein also include a release liner that protects the adhesive that contacts the skin during storage and is removed prior to application of the patch.

[0047] Depending on different uses and desired therapeutic treatments, the transdermal patches described herein can be designed in a number of ways. Different designs are influenced by various factors including the properties of the drug, the dosage level, the treatment area and the time required to administer the drug.

[0048] Referring again to FIGS. 1A-1D, in one embodiment, the transdermal patch has an adhesive design. This design incorporates AVEGF, typically mixed with one or more of the above components, directly into the adhesive of the patch. This, referred to as drug-in-adhesive, or DIA, is the most common type of patch. Figure 1D.

[0049] In another embodiment, the transdermal patch described herein comprises a classical reservoir design. Figure 1B. In this embodiment, the AVEGF-containing compound is placed between a rate-limiting membrane on one side and a membrane on the other. The capsule is placed into a blister pouch having an impermeable backing on one side.

[0050] In another embodiment, the transdermal patch described herein comprises a polymer reservoir design. FIG. 1A. In this embodiment, the AVEGF-containing compound is in direct contact with the skin and is delivered to the matrix. The drug is placed in a semi-solid drug-containing polymer matrix that has an adhesive ring around the base for adhering to the skin.

[0051] In another embodiment, the transdermal patch described herein comprises a multilaminate solid reservoir design. FIG. 1C. In this embodiment, the AVEGF-containing compound is administered through the DIA The design is similar to that of the control (Figure 1D) and typically contains AVEGF mixed with one or more of the above components. The patch has multiple layers, including the AVEGF directly in the adhesive, where each layer is separated by a membrane. This design allows for the delivery of two drugs with different release times, which can be used, for example, when a bolus dose is required to initiate treatment, followed by a maintenance dose of a therapeutically active compound.

[0052] In one embodiment, AVEGF is administered as a treatment for skin or surgical procedures as described herein. The AVEGF strip is incorporated into a bandage strip specially designed for areas of the body exposed to surgical incisions. The surgical strip is permeable to promote healing and contains a concentration of AVEGF in an ointment that moderates migration to the treated area, such as a surgical incision, during healing. The AVEGF strip is provided to the patient for reapplication one or more times per day, or for 1-100 days, to maintain the desired concentration of AVEGF. The design of the strip is specific for use with straight incisions, such as incisions made during facial wrinkle removal, chin implants, blepharoplasty, breast implants, cosmetic procedures, and incisions from medical procedures such as sternotomy, which have a high incidence of hypertrophic scarring. The AVEGF surgical strip has a predetermined concentration of AVEGF in a medium, and the strip is specially designed to be consumed and reapplied by the patient.

[0053] In one embodiment, the gel or ointment and the adhesive region surrounding the region of AVEGF. Permeable bandage strips with a predetermined concentration of AVEGF are used to treat keratomileusis after surgery or injury. It is packaged as an adjunct to prevent or reduce inflammatory and scarring disorders. The bandage is designed to be packaged for application by the patient.

[0054] In one embodiment, the gel or ointment and the adhesive region surrounding the region of AVEGF. Permeable bandage strips with a predetermined concentration of AVEGF are used for Mohs surgery or mole removal. The concentration of AVEGF is preferably adjusted to prevent scarring and to prevent precancerous blood vessel growth. The AVEGF bandage is to be applied by the patient to the area of ​​mole removal or Mohs surgery. Designed to be packaged for application.

[0055] In an embodiment, the patch or bandage strip can be in the form of a sheet or roll. The sheet or roll can be pre-cut or perforated, thus containing the patch of pre-cut size and shape. For example, the pre-cut patch can be circular with a diameter ranging from 1 mm to 80 mm, such as 2 mm to 60 mm, or even 5 mm to 50 mm. In an embodiment, the pre-cut patch may have an oval shape with a major axis ranging from 5 mm to 100 mm, such as from 10 mm to 80 mm, or even from 15 mm to 60 mm.

[0056] In another embodiment, the patch or bandage strip may be in the form of a sheet or roll that is not pre-cut or perforated. Rather, in this embodiment, the patch or bandage strip is in the form of a sheet or roll that can be cut into the desired shape and size, for example, by a supplier or end user.

[0057] In one embodiment, AVEGF is administered to patients prone to keloid formation or other scarring. Piercings less than 1 inch in diameter used in ear piercing and body piercing for and is preferably assembled into a disk pad having a diameter of about 0.5 inches. The pad is disposable. Specially designed to be used in conjunction with body piercing as a pad.

[0058] In this embodiment, VEGF may be administered transdermally via body paint in a latex or aqueous solution. AVEGF paint may be applied to areas of skin suffering from keloid or scar formation. The treatment can be self-administered by the patient to the affected area, such as the peritoneal cavity. The advantage over patches is that treatment can be easily limited to the target area at a regular dose to maintain a predetermined concentration level in the target area. A patch that overlies a non-target area will release AVEGF to the non-target area, reducing the cost of dosage. The patch also loses migration rate as concentration decreases. Occlusive paints such as latex or other lipids, oils, or water-insoluble compounds can be peeled off and reapplied as concentration levels decrease.

[0059] In one embodiment, topical and mechanical methods that increase or enable skin penetration, including a combination of fractional ablative treatments, microneedling, etc., provide a porous tissue surface for enhanced penetration of AVEGF.

[0060] In one embodiment, the method and system enhances the penetration of the AVEGF solution by thinning or removing the stratum corneum using a laser or other method. Local Laser Ablation

[0061] Lasers, both fractionated and non-fractionated, in conjunction with devices such as microneedling with and without RF, laser micropeel or dermabrasion followed by ultrasound, and heating have been used to enhance penetration.

[0062] Methods and devices for ensuring delayed, sustained or timed release of anti-VEGF compounds - Patents.com By way of non-limiting example, anti-VEGF-containing compounds may be used in combination with hyaluronic acid fillers, collagen, elastin, proteoglycans (e.g., decorin, versican, chondroitin sulfate, heparin sulfate proteoglycans), elastin, fibrillin, fibulin (see attached filler specifics). Mix with fillers such as collagen (all types) It is used as a filler, etc.

[0063] In one embodiment, sustained release of anti-VEGF compounds, including but not limited to carrier molecules; extracellular matrix molecules; synthetic compounds, and the like, is provided.

[0064] In one embodiment, sustained or timed release of anti-VEGF compounds is provided that include albumin and similar carrier proteins. In an embodiment, sustained or timed release of anti-VEGF compounds includes the disclosed AVEGF with at least one corticosteroid, hydroquinone and other drugs.

[0065] Methods and devices utilizing sensors to monitor target areas - Patents.com In an embodiment, AVEGF is administered over a period of time providing more efficient use and more effectively. Determine the amount of AVEGF to be applied, such that it is applied at a concentration or level that provides effective use. An algorithm for, and a means for applying AVEGF are described.

[0066] In one embodiment, an oxygen sensor is used to monitor oxygen levels in the target tissue and the oxygen levels are used to regulate blood flow to the tissue such that angiogenesis is controlled. An algorithm is used to determine perfusion and adjust the application of AVEGF. can be used to non-invasively measure tissue oxygen levels for skin surface application. In one embodiment, fiber optics can be used to monitor deep wounds, conditions, tumors, or target areas where angiogenesis is to be monitored.

[0067] In an embodiment, pulse oximetry can be used to determine oxygen levels in tissue over an extended area by distributing pulse oximeters in an array. An array of pulse oximeters can be used that utilize red and infrared light overlaying an array of detectors. The light or signal array can be an array of LEDs and the light source can be a light flash. The detector can be an array of solid-state detectors or an array of light collectors, such as optical fibers and single or multiple detectors. In one embodiment, there is a red and infrared source connected via a microlens array or an array of optical fibers, and an array of optical fibers that collects the light reflected or passing through the target tissue and sends the light to a detector that averages the pulse oximetry signal over the target area. The algorithm determines the amount of AVEGF to apply, and AVEGF is applied to the area of ​​tissue that supplies the blood supply of the target area.

[0068] In an embodiment, reducing agents such as calcium, oxalic acid, ascorbic acid, carbon monoxide, etc. can be used to reduce the oxygen level in the target tissue to a level that is not beneficial to angiogenesis or slows down angiogenesis.For CO, application of less than 100 ppm in solution, most often less than 35 ppm, directly to the target tissue reduces O2 in the target tissue. The CO-oximeter measures angiogenesis, vascularization, and tissue growth in a target area. It may be used in conjunction with a pulse oximeter to determine the concentration of carboxyhemoglobin sufficient to reduce the progression of scars, keloids or tumors. CO is easily removed by the body so that small micro concentrations below 35 ppm are confined to the target area. I have found that localized micro concentrations of CO are not used to treat any disease. Levels of 26 ppm for 1 hour and 9 ppm for 8 hours are considered safe. CO levels CO declines rapidly except in the area of ​​application, so intermittent application can halt angiogenesis, neurogenesis, keloid formation, tumor growth in a very localized area at levels that safely decline in the surrounding tissue for a given safe time. Thus, similar to botulinum toxin, Botox, CO can be generated in very low concentrations and used safely in a localized area, a highly toxic toxin that can be used locally at very low local concentrations.

[0069] In embodiments, devices for monitoring CO, O2 or other indicators of scarring, keloids, angiogenesis, determining medication levels, and administering medications can be worn on a belt or attached to the patient so as to effectively apply AVEGF, AVEGF compounds, or other anti-angiogenic solutions at predetermined concentrations for predetermined periods of time.

[0070] In an embodiment, the sensor may be monitored wirelessly.

[0071] Specifically in combination with stem cell therapy, growth factors, and PRP to prevent stem cell stimulated angiogenesis Match In one embodiment, a method and system is provided for the effect of AVEGF in combination with stem cell therapy and platelet rich plasma (PRP) to control angiogenesis. In one embodiment, the method and device administers AVEGF directly using a multi-needle injector, a precision injector, or an air injector.

[0072] In one embodiment, a device and system is provided in which AVEGF is added to the PRP at a concentration that affects angiogenesis to a desired level. Although tissue growth factors are more concentrated in the prepared growth injection, PRP is not selective and inhibits the desired vascularization producing long-term redness and scarring. It can stimulate the body growth of new healthy cells, promoting levels not seen before. and promote healing. The device contains a predetermined amount of AVEGF that is added to and is stable in the patient's PRP. The device includes a means for adding AVEGF to the PRP in an occlusive, sterile manner so that the AVEGF may be safely applied or injected into the damaged or treated tissue.

[0073] In one embodiment, the device for adding AVEGF to PRP comprises a device for adding a predetermined amount of AVEGF to PRP. In another embodiment, the kit can be sterilized by autoclaving, immersion, or other methods, and can include a means for adding a predetermined amount of AVEGF. In one embodiment, the PRP is separated into a means for injection into tissue, and such means The tiers contain predetermined amounts of AVEGF.

[0074] For controlled release drug delivery of AVEGF solutions, including but not limited to, microencapsulation, Methods and devices for In an embodiment, the described AVEGF compounds are induced by light, laser, ultrasound. Alternatively, AVEGF may be encapsulated in liposomes that can degrade AVEGF over time. The described AVEGF compounds can be microencapsulated in a polymeric carrier, which can then be In this embodiment, the AVEGF can be released by applying ultrasound at a level sufficient to release the microencapsulated AVEGF. In this embodiment, the ultrasound can be administered using a high intensity focused ultrasound transducer to release a fraction of the AVEGF. The treatment can be applied in a fractional pattern by a high intensity facilitation (HIFU) laser, and subsequent treatments can be performed by treating a fractional array in the target area, e.g., a grid of treatment areas that constitute a predetermined percentage of the target area, thereby distributing AVEGF at predetermined intervals. The drug may be released non-invasively at .

[0075] In one embodiment, a subject is treated with an AVEGF-containing compound that is microencapsulated in a polymeric microcapsule carrier and injected into the target tissue. A non-invasive method of treating at regular intervals is described. In this embodiment, AVEGF is administered to myeloid leukemia cells. By applying ultrasound at a level sufficient to release the encapsulated AVEGF. The ultrasound was then delivered to the brain using a high intensity focused ultrasound transducer to release a fraction of AVEGF. The treatment can be administered in a fractional pattern by a sedative, and subsequent treatments can be non-invasively administered at predetermined intervals to administer AVEGF. It may be released automatically.

[0076] Use of colloidal or polymeric capsules for microencapsulation and nanoencapsulation of AVEGF solutions for controlled release of AVEGF and microencapsulated AVEGF solutions An injector for administering the compound is also described.

[0077] Photothermal-triggered delivery In one embodiment, a method of photothermal-triggered delivery of the anti-VEGF compounds described herein using various inorganic nanoparticles is described. Nanoparticles as used herein are intended to mean particles with dimensions generally ranging from 1 nm to hundreds of nanometers in at least one dimension. The nanoparticles described herein are used with or designed to carry anti-VEGF compounds. In one embodiment, the nanoparticles can include gold, silver, and iron oxide and have desirable photothermal properties. In one embodiment, anti-VEGF compounds are described that include gold and silver nanoparticles for mediating inhibition of angiogenesis. In one embodiment, anti-VEGF compounds are described that include gold nanoparticles for photothermally controlling the release of angiogenesis inhibitors using light or radio wave activation.

[0078] In one embodiment, the inhibition of angiogenesis in vivo is achieved in combination with visible laser irradiation. Metal nanoparticles, such as gold nanoparticles conjugated with antiangiogenic peptides, are described that can enhance inhibition. The combination of a green laser coupled with gold nanoparticles can achieve high local temperatures that can precisely cauterize blood vessels, which, when combined with VEGF pathway inhibition, such as transdermal application of anti-VEGF, can reduce FLT-1 expression.

[0079] In one embodiment, a method of photothermal triggered delivery using laser light is described. In one non-limiting embodiment, a 532 nm laser is used to stimulate the delivery of gold nanoparticles conjugated with anti-angiogenic peptides. It can be used in conjunction with particles. Lasers have been found to cause a significantly higher rise in temperature for long-term low-intensity exposure. This has the effect of increasing activity and simultaneously coagulating blood vessels. In another embodiment, RF or light interaction with other nanoparticles described herein is described. This has been shown to enhance activity by heating, or to release the bound antiangiogenic compound from the nanoparticles using thermal shock or pulse energy.

[0080] Anti-VEGF Implant Methods and Devices In one embodiment, AVEGF is incorporated onto the surface of a bodily implant to permit the above-mentioned benefits of AVEGF to be slowly released at the internal surgical site. For example, silicone breast implants are described that have the AVEGF compounds described herein incorporated onto their surface in a slow-release polymer or lipid film to prevent capsular contracture. The implants are constructed using a biocompatible layer containing a defined concentration of AVEGF in HA or other media. It is designed with this in mind.

[0081] In one embodiment, AVEGF helps prevent or reduce scar formation. The implants are then incorporated onto the surface of surgical implants, such as jaw implants, facial implants, etc., to promote cell proliferation and cell death. The implants contain a biocompatible material containing a predetermined concentration of AVEGF in hyaluronic acid or other medium. It is designed with a body conforming layer.

[0082] In one embodiment, sutures impregnated with the AVEGF compounds described herein are described that correct the progression of inflammation and neovascularization at the suture needle site reducing the progression of scar formation. do.

[0083] In one embodiment, AVEGF is incorporated into a stent to prevent restenosis, Alternatively, the stent may be coated with a polymer-like compound that contains an anti-VEGF that is released over a period of time sufficient to prevent restenosis.

[0084] Devices such as jet injectors, needles including arrays of microneedle injectors, and atomized sprayers

[0085] The device is configured to deliver AVEGF to a target tissue at a predetermined depth. AVEGF is applied directly to the area of ​​interest rather than being transported through a concentration gradient in tissues. In one embodiment, AVEGF is administered over a predetermined region and It is applied by the microneedles over a range of predetermined depths, where the area largely conforms to the area of ​​the target tissue and the range of depths extends through almost the entire depth of the target tissue, whereby the target tissue is an area exposed to scar or keloid formation.

[0086] The multiple needle device is spaced apart to allow complete dispersion of the anti-VEGF solution to the target area, such as a keloid, or an area prone to developing surgical scars.

[0087] Different inflammatory skin diseases treated The above delivery mechanisms are useful in treating a variety of inflammatory skin diseases, including those described above as well as the following different non-limiting inflammatory skin diseases: Each of the following diseases / conditions is either primarily inflammatory or has inflammation that at least partially causes the symptoms of the disease / condition. Thus, the systems, devices and methods disclosed herein are suitable for treating the following diseases / conditions:

[0088] Acne-like Skin Breakouts In one embodiment, systems, devices and methods are provided for treating acne-like skin breakouts caused by alterations in the pilosebaceous unit.

[0089] Autoinflammatory syndrome. In one embodiment, systems, devices and methods are provided for treating autoinflammatory syndrome, a group of genetic disorders characterized by inflammatory skin lesions and periodic bouts of fever.

[0090] Chronic Blisters. In one embodiment, systems, devices and methods are provided for treating chronic blisters. Chronic blistering skin conditions have a long course and exhibit vesicles and blisters.

[0091] Mucous Membranes.In one embodiment, systems, devices and methods are provided for treating conditions of the mucous membranes, including the moist linings of the eye, nose, mouth, genitals, and anus.

[0092] Glands. In one embodiment, systems, devices and methods are provided for treating skin appendage conditions, those affecting the skin, hair, nails, and arrector pili glands.

[0093] Subcutaneous Fat. In one embodiment, systems, devices and methods are provided for treating subcutaneous fat conditions that affect the layer of adipose tissue between the dermis and the underlying fascia.

[0094] Congenital anomalies. In one embodiment, systems, devices and methods are provided for treating congenital anomalies. Skin congenital anomalies are a diverse group of disorders resulting from defects in morphogenesis, the biological process that forms the shape of the human body.

[0095] Connective tissue diseases. In one embodiment, systems, devices and methods are provided for treating connective tissue diseases. Connective tissue diseases are caused by a complex array of autoimmune responses that target or affect collagen or matrix.

[0096] Dermal fibrous tissue and elastic tissue. In one embodiment, a system, device and method are provided for treating abnormalities of dermal fibrous tissue and elastic tissue. Abnormalities of dermal fibrous tissue and elastic tissue are caused by problems in regulating collagen synthesis or degradation.

[0097] Cutaneous and Subcutaneous Growths. In one embodiment, systems, devices and methods are provided for treating cutaneous and subcutaneous growths. Cutaneous and subcutaneous growths result from (1) reactive or neoplastic proliferation of cellular components of the dermis or subcutaneous tissue, or (2) tumors that invade or are abnormally present in the dermis.

[0098] Dermatitis. In one embodiment, systems, devices and methods are provided for treating various types of dermatitis. Dermatitis is a general term for "inflammation of the skin", including but not limited to granulomatous orifice dermatitis in children and essential dermatitis. This definition also includes atopic dermatitis, which is defined as a chronic dermatitis associated with a genetic predisposition to develop allergies to foods and inhalants. Non-limiting examples of atopic dermatitis include atopic eczema, disseminated neurodermatitis, flexural eczema, infantile eczema, and prurigo diathsique. Also included within this definition is contact dermatitis, which is defined as dermatitis caused by a substance that comes into contact with the skin.

[0099] Eczema. In one embodiment, systems, devices and methods are provided for treating eczema. Eczema refers to a wide range of conditions that begin as a spongiotic dermatitis and can progress to a lichenified stage.

[0100] Pustular dermatitis. In one embodiment, systems, devices and methods are provided for treating pustular dermatitis. Pustular dermatitis is an inflammation of the skin that shows pustular lesions. Non-limiting examples include: eosinophilic pustular folliculitis (Ofuji's disease, sterile eosinophilic pustulosis); reactive arthritis (formerly known as Reiter's syndrome); and subcorneal pustulosis (Sneddon-Wilkinson's disease).

[0101] Seborrheic Dermatitis In one embodiment, systems, devices and methods are provided for treating seborrheic dermatitis, a chronic, superficial inflammatory disease characterized by scaling on an erythematous base.

[0102] Pigmentation Disorders. In one embodiment, systems, devices and methods are provided for treating human pigmentation disorders. Human pigmentation disorders, either lost or reduced, can be associated with the loss of melanocytes or the inability of melanocytes to properly produce melanin or transport melanosomes.

[0103] Drug rash. In one embodiment, systems, devices and methods are provided for treating drug rash, defined as an adverse drug reaction that presents with cutaneous symptoms. Non-limiting examples include: adverse reactions to biological agents and cytokines; chemotherapy-induced acral erythema (palmoplantar erythematodysesthesia syndrome) and hyperpigmentation; drug-induced acne, angioedema, lupus erythematosus, nail changes, pigmentation, etc.; injection site reactions; vitamin K reactions; and warfarin necrosis.

[0104] Endocrine Conditions In one embodiment, systems, devices and methods are provided for treating endocrine conditions that often have cutaneous manifestations, as the skin interacts with the endocrine system in many ways.

[0105] Eosinophilic Skin Conditions In one embodiment, systems, devices and methods are provided for treating eosinophilic skin conditions, which include a wide variety of diseases characterized histologically by the presence of eosinophils in an inflammatory infiltrate or evidence of eosinophil degranulation.

[0106] Epidermal nevi, neoplasms, and cysts In one embodiment, systems, devices and methods are provided for treating epidermal nevi, neoplasms, and cysts, which are skin lesions that develop through the epidermal layer of the skin.

[0107] Erythema In one embodiment, systems, devices and methods are provided for treating erythema, a reactive skin condition in which there is a fadeable redness.

[0108] Genodermatoses. In one embodiment, systems, devices and methods are provided for treating genodermatoses, which are inherited genetic skin conditions that are often divided into three categories: chromosomal, monogenic, and multigenic.

[0109] Infection-related conditions. In one embodiment, the infection-related conditions are caused by bacteria, fungi, yeast, viruses, or parasites. Provided are systems, devices and methods for treating infection-associated skin conditions that may be caused by

[0110] In one embodiment, systems, devices and methods are provided for treating bacteria-associated skin conditions, which often have distinct morphological characteristics that may be manifestations of a systemic, generalized process or simply an isolated superficial infection.

[0111] Mycobacterium Associated In one embodiment, systems, devices and methods are provided for treating mycobacterium-associated skin conditions caused by mycobacterium infection.

[0112] Fungal Disease-Associated In one embodiment, systems, devices and methods are provided for treating fungal disease-associated skin conditions that are caused by fungi or yeast and can present as superficial or deep infections of the skin, hair, or nails.

[0113] Parasitic Infestation, Stings, and Bites. In one embodiment, systems, devices, and methods are provided for treating parasitic infestation, stings, and bites in humans caused by several groups of organisms belonging to various forms of animals and insects, including the following phyla: Annelida, Arthropoda, Bryozoa, Chordata, Cnidaria, Cyanobacteria, Echinodermata, Nematoda, Platyhelminthes, and Protozoa.

[0114] Virus-related. In one embodiment, two major groups of viruses - DNA and RNA types Systems, devices and methods are provided for treating virus-associated skin conditions caused by P. cerevisiae, both of which are obligate intracellular parasites.

[0115] Lichenoid rash. In one embodiment, systems, devices and methods are provided for treating lichenoid rash, a skin condition associated with lichen planus, a common inflammatory disease affecting the skin, mucous membranes, nails, and hair.

[0116] Lymphatic Associated. In one embodiment, systems, devices and methods are provided for treating lymphatic-associated skin conditions, a group of disorders characterized by the collection of lymphatic cells within the skin.

[0117] Melanocytic nevi and neoplasms. In one embodiment, systems, devices and methods are provided for treating melanocytic nevi and neoplasms caused by proliferation of either (1) melanocytes, or (2) nevus cells, a form of melanocyte that lacks dendrites.

[0118] Melanoma. In one embodiment, systems, devices and methods are provided for treating melanoma, which is a malignant proliferation of melanocytes and is the most aggressive form of skin cancer.

[0119] Monocyte- and Macrophage-Associated. In one embodiment, systems, devices and methods are provided for treating monocyte- and macrophage-associated skin conditions that are often divided into several categories and are histologically characterized by infiltration of the skin with monocyte or macrophage cells, including granulomatous diseases, histiocytosis, and sarcoidosis.

[0120] Mucinosis In one embodiment, systems, devices and methods are provided for treating mucinosis, which is classified as a group of conditions caused by skin fibroblasts abnormally producing large amounts of mucopolysaccharides.

[0121] Neurocutaneous In one embodiment, systems, devices and methods are provided for treating neurocutaneous conditions that are conditions caused by organic nervous system diseases or that are psychiatric in etiology.

[0122] Non-infectious immunodeficiency associated In one embodiment, systems, devices and methods are provided for treating non-infectious immunodeficiency associated skin conditions caused by T-cell or B-cell dysfunction.

[0123] Nutrition-related. In one embodiment, systems, devices and methods are provided for treating nutrition-related skin conditions caused by malnutrition due to improper or inadequate diet. Non-limiting examples include: biotin deficiency; carotenemia; essential fatty acid deficiency; folic acid deficiency; hypervitaminosis A; vitamin A deficiency (cat's skin disease); iron deficiency; kwashiorkor; lycopenemia; mersyrup urine disease; wasting disease; niacin deficiency (pellagra, vitamin B3 deficiency); Selenium deficiency; Vitamin B1 deficiency (beriberi, thiamine deficiency); Vitamin B 12 Deficiency (Cyanobala vitamin B2 deficiency (riboflavin deficiency, riboflavin deficiency); vitamin B6 deficiency (pyridoxine deficiency); vitamin B6 excess (pyridoxine excess); vitamin C deficiency (scurvy) disease); vitamin K deficiency; and zinc deficiency.

[0124] Papulosquamous Keratotic In one embodiment, systems, devices and methods are provided for treating papulosquamous keratotic skin condition, which is one that exhibits papules and scales caused by thickening of the stratum corneum.

[0125] Palmoplantar Keratodermas. In one embodiment, systems, devices and methods are provided for treating palmoplantar keratodermas, a diverse group of inherited and acquired keratodermas in which there is keratinization of the skin on the palms and soles.

[0126] Pregnancy Associated In one embodiment, systems, devices and methods are provided for treating pregnancy-associated skin conditions, which are a group of skin changes observed during pregnancy.

[0127] Pruritus In one embodiment, systems, devices and methods are provided for treating pruritus, commonly known as itch, a condition that is a sensation limited to the skin and is characteristic of many skin conditions.

[0128] Psoriasis. In one embodiment, systems, devices and methods are provided for treating psoriasis, a common chronic and recurrent inflammatory disease of the skin characterized by focal, erythematous, dry, scaly plaques.

[0129] Reactive Neutrophils. In one embodiment, systems, devices and methods are provided for treating reactive neutrophil skin conditions. These conditions constitute a spectrum of diseases mediated by neutrophils and are typically associated with underlying diseases such as inflammatory bowel disease and hematological malignancies.

[0130] Refractory Palmoplantar Rash In one embodiment, systems, devices and methods are provided for treating refractory palmoplantar rash, a skin condition of the palms and soles that is resistant to treatment.

[0131] In one embodiment, a system, device, or method for treating a skin condition resulting from metabolic errors caused by enzyme deficiencies that result in the accumulation or deficiency of various cellular components, including, but not limited to, amino acids, carbohydrates, and lipids, is provided. and methods are provided.

[0132] Resulting from physical factors. In one embodiment, systems, devices and methods are provided for treating skin conditions resulting from physical factors caused by a number of sources, including but not limited to high and low temperatures, friction, and humidity. Non-limiting examples include: scratches; calluses (calluses, corns, blisters, corns, hard corns, soft corns, refractory plantar keratosis, calluses); friction. chafing blisters; frostbite; jogger's nipple; photoaging (dermatoheliosis); sunburn; Includes burns; turf toe; and wrestler's ear (cauliflower ear, traumatic aural hematoma).

[0133] Ionizing radiation induced. In one embodiment, systems, devices and methods are provided for treating ionizing radiation induced skin conditions. Non-limiting examples include conditions resulting from exposure to radiation therapy, such as for cancer.

[0134] Urticaria and angioedema. In one embodiment, systems, devices and methods are provided for treating urticaria, a vascular reaction of the skin characterized by the appearance of wheals, which are firm, raised swellings of the skin. Angioedema, which can occur alone or together with urticaria, is characterized by a well-defined edematous swelling involving subcutaneous tissue, abdominal organs, or upper respiratory tract.

[0135] Vascular Associated In one embodiment, systems, devices and methods are provided for treating vascular associated skin conditions resulting from dysfunction of the blood or blood vessels in the dermis, or lymphatic vessels in the subcutaneous tissue.

[0136] It will be apparent to those skilled in the art that various modifications and variations can be made in the disclosed alloys and methods of forming the alloys into finished parts without departing from the scope of the disclosure. Other implementations will be apparent to those skilled in the art from consideration of the specification and practice disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope of the disclosure being indicated by the following claims and their equivalents.

Claims

1. 1. A method for treating an inflammatory or vascular condition comprising: A method of treatment comprising transdermally modulating inflammation in a target area of ​​the body having an inflammatory or vascular condition by topically applying to the skin in the target area a therapeutically effective amount of at least one anti-VEGF-containing compound.

2. Anti-VEGF, hyaluronic acid, vitamin C, hydroquinone, corticosteroids, tretinoin 10. The method of claim 1, wherein the composition is mixed with at least one adjuvant for treating a skin condition selected from the group consisting of phenylalanine, ...

3. 10. The method of claim 1, wherein topically applying at least one anti-VEGF-containing compound is performed using a transdermal patch, a bandage, a paint, a sprayer, or a combination thereof.

4. 10. The method of claim 1, further comprising pre-treating the target area to affect the surface of the skin prior to topically applying a therapeutically effective amount of at least one anti-VEGF-containing compound to the surface of the skin.

5. 5. The method of claim 4, wherein the pretreatment comprises dermabrasion, ablative fractional resurfacing, microneedling, or a combination thereof.

6. 10. The method of claim 1, wherein the anti-VEGF compound is encapsulated in a lipid-based nanocarrier or a polymeric carrier prior to topical application to the skin of the target area.

7. The liposomes are configured to cause sustained-release or time-release of at least one anti-VEGF compound by light, laser, ultrasound, or degradation over time. The method of claim 6, further comprising inducing a

8. 10. The method of claim 1, further comprising mixing the at least one anti-VEGF-containing compound with at least one filler selected from hyaluronic acid, collagen, elastin, proteoglycans, chondroitin sulfate, heparin sulfate, elastin, fibrillin, and fibulin.

9. 9. The method of claim 8, further comprising mixing at least one anti-VEGF compound with a sustained-release or timed-release compound selected from a carrier molecule, an extracellular matrix molecule, a water-soluble protein, a synthetic compound, or a combination thereof.

10. 10. The method of claim 9, wherein the water-soluble protein comprises albumin or a proteoglycan.

11. Targeted areas are treated with anti-inflammatory steroids, nonsteroidal anti-inflammatory drugs (NSAIDs), or both. The method of claim 1 , further comprising:

12. Anti-inflammatory steroids include alclometasone, diflorasone, fluocinonide, prednicarb, hydrocortisone, tramcinolone, and acetanide.

12. The method of claim 11, comprising administering to said patient an effective amount of serotonin, betamethasone, clobetasol, proprionate, or a combination thereof.

13. NSAIDs include diclofenac acetylsalicylic acid, ibuprofen, and naproxen sodium. The method of claim 11 , further comprising:

14. The method of claim 11 , wherein the anti-VEGF compound comprises a small molecule inhibitor of VEGF signaling.

15. 15. The method of claim 14, wherein the anti-VEGF compound is selected from the group consisting of bevacizumab, ranibizumab, pegaptanib, imatinib, vandetanib, sorafenib, pazopanib, varatanib, bevasiranib, aflibercept, etanercept, squalamine lactate, erlotinib, and gefitinib.

16. 2. The method of claim 1, wherein the inflammatory or vascular condition is selected from rosacea, acne, atopic dermatitis, contact dermatitis, drug rash, psoriasis, seborrheic dermatitis, connective tissue disease, autoimmune disease, urticaria, photodamage, aging, sunburn, skin infection, radiation dermatitis, skin exposed to ionizing radiation, port wine stain birthmarks, hemangiomas, cherry hemangiomas, stellate hemangiomas, acute or chronic wounds, photodamage, aging, sunburn, skin infection, radiation dermatitis, and skin exposed to ionizing radiation.

17. A device for treating inflammation or a vascular condition, the device being configured to transdermally apply a therapeutically effective amount of at least one anti-VEGF-containing compound to the skin of a target area, wherein the therapeutically effective amount of the at least one anti-VEGF-containing compound modulates inflammation in the target area.

18. 20. The device of claim 17, comprising a transdermal patch, a bandage, a paint, a sprayer, or a combination thereof.

19. Anti-VEGF, hyaluronic acid, vitamin C, hydroquinone, corticosteroids, tretinoin 20. The device of claim 18, wherein the device is mixed with at least one adjuvant for treating a skin condition selected from the group consisting of:

20. an outermost layer that protects the formulation while the patch is on the skin; a membrane comprising an anti-VEGF compound, wherein the membrane is configured to control the rate of drug release from the patch into the skin; An adhesive is disposed in the layer that contacts the skin and adheres the patch to the skin.

20. The device of claim 18, which is a transdermal patch comprising:

21. 21. The device of claim 20, wherein the membrane comprises a rate-controlling material on one side closest to the skin and an impermeable backing on an opposite side away from the skin.

22. 21. The device of claim 20, further comprising an overlaminate tape to provide an outer protective layer.

23. 21. The device of claim 20, further comprising a release liner that protects the skin-contacting adhesive during storage and that is removed prior to application of the patch.

24. 20. The device of claim 18, which is a transdermal patch comprising at least one pharma- ceutical active layer comprising a matrix of adhesive material mixed with an anti-VEGF compound.

25. 25. The device of claim 24, comprising a multi-laminate of at least two separate pharma- ceutical active layers with a membrane separating each active layer to allow separate release of the different pharma- ceutical active layers.

26. 26. The device of claim 25, wherein at least two distinct pharma- ceutical active layers comprise the same or different matrices.

27. Two separate pharma- ceutical active layers may be used in the following ways: with different anti-VEGF compounds; 27. The device of claim 26, which differs in at least one of: having an anti-VEGF concentration; being mixed with a different compound; or treating a different inflammatory or vascular condition.

28. 20. The device of claim 18, which is a transdermal patch comprising at least one polymer reservoir for holding an anti-VEGF-containing compound disposed in a semi-solid drug-containing polymer matrix, the polymer reservoir having an adhesive ring around the matrix for direct contact with the skin and for adhering to the skin.

29. an outer layer that is permeable to air and water vapor but impermeable to liquids or bacteria; a contact layer for contacting the target area, the contact layer comprising an anti-VEGF compound and configured to modulate delivery of the anti-VEGF compound to the area to be treated; and An adhesive surrounding the contact layer for adhering the bandage to the skin 20. The device of claim 18 which is a bandage comprising:

30. 30. The device of claim 29, which is a bandage strip containing a predetermined concentration of anti-VEGF in the form of a gel or ointment.

31. 30. The device of claim 29, wherein the bandage is in the form of a sheet or roll having precut or perforated sizes and shapes disposed thereon.

32. 30. The device of claim 29, wherein the bandage is not pre-cut or perforated, but is in the form of a sheet or roll that can be cut by the end user to the desired shape and size.

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