Composition comprising anti-VEGF and nanoparticles for the treatment of abnormal or excessive angiogenesis, and method of using the same.

Abstract

The present invention provides a composition and method for treating abnormal or excessive angiogenesis, such as pyogenic granulomas. [Solution] A composition for treating abnormal or excessive angiogenesis, such as pyogenic granuloma, comprising an anti-vascular endothelial growth factor (anti-VEGF) agent (e.g., an antibody or small molecule inhibitor of VEGF signaling) and a carrier containing nanoparticles. A method for treating abnormal or excessive angiogenesis by administering the composition containing the anti-VEGF agent and nanoparticles to a subject, either alone or in combination with the administration of anti-inflammatory steroids and non-steroidal anti-inflammatory drugs (NSAIDs). A device for administering the composition for treating pyogenic granuloma is also disclosed.

Description

Technical Field

[0001] Priority data This application claims the benefit of priority to Provisional Application No. 63 / 018,786, filed May 1, 2020, the entire contents of which are hereby incorporated by reference in their entirety.

[0002] Technical field The present disclosure generally relates to compositions comprising anti-VEGF and nanoparticle delivery systems for the treatment of eye and / or skin disorders such as pyogenic granuloma. The present disclosure provides for the treatment of such eye and / or skin conditions by applying the described compositions to the affected skin area or around and / or in the orbital region of the eye.

Background Art

[0003] background Anti-vascular endothelial growth factor therapy, known as anti-VEGF therapy or anti-VEGF pharmacotherapy, involves using drugs that block vascular endothelial growth factors, including but not limited to vascular endothelial growth factor receptors 1, 2, and 3. Conventionally, this method has been used for the treatment of certain cancers and age-related macular degeneration.

[0004] Anti-VEGF drugs have shown therapeutic efficacy in mouse models of cancer and in increasing human cancers. Such drugs can include monoclonal antibodies such as bevacizumab (sold as Avastin®), antibody derivatives such as ranibizumab (sold as Lucentis®), or orally available small molecules that inhibit tyrosine kinases stimulated by VEGF.

[0005] The off-label use of intravitreal bevacizumab has become widespread as a treatment for neovascular age-related macular degeneration (AMD). Some studies have suggested that bevacizumab is effective in increasing vision with a low rate of ocular side effects. ​

[0006] Bevacizumab is a drug that stimulates angiogenesis and vascularization in age-related macular degeneration (AMD). It is a 149-kD humanized monoclonal antibody that inhibits vascular endothelial growth factor (VEGF), a monoclonal protein. Bevacizumab has received FDA approval for use in various specialized cancer therapies. However, the bevacizumab included in the formulation has been used off-label since May 2005 for the treatment of ophthalmic conditions such as AMD. Currently, bevacizumab is being successfully used to treat a variety of conditions, including diabetic retinopathy, central retinal vein occlusion, neovascular glaucoma, and retinopathy of prematurity, as well as many other less common eye diseases. [Overview of the project]

[0007] The abnormal or abnormal condition described in Example 1, such as the development of suppurative granuloma of the eyeball after pterygium removal surgery. A composition is needed for the treatment of excessive angiogenesis. The disclosed composition, comprising an anti-VEGF and a nanoparticle delivery system, addresses one of the above problems and / or other problems of the prior art. Regarding overcoming superiors.

[0008] overview In one embodiment, the present disclosure relates to a composition for the treatment of abnormal or excessive angiogenesis. The composition comprises at least one anti-vascular endothelial growth factor (anti-VEGF) antibody; and nanoparticles. The nanoparticles, which include a support, are organic, inorganic, or a combination thereof.

[0009] In another embodiment, the disclosure relates to a method for treating abnormal or excessive angiogenesis. In one embodiment, the method comprises a composition containing at least one anti-VEGF antibody and nanoparticles. The method comprises administering to a region containing normal or excessive angiogenesis, wherein the nanoparticles are organic, inorganic, or a combination thereof. The method further comprises administering additional pharmaceutical compounds such as one or more anti-inflammatory steroids and one or more nonsteroidal anti-inflammatory drugs (NSAIDs). But that's fine.

[0010] In another embodiment, the disclosure relates to a device for administering the disclosed composition. In one embodiment, the device is configured to administer the composition by at least one method selected from intravenous, subconjunctival, subtenon's capsule, episcleral, intrascleral, subscleral, intraperitoneal, epidural, subarachnoid, intramuscular, intracavitary, intratracheal, epidermal, intradermal, subdermal, or subcutaneous.

[0011] Brief explanation of the drawing The attached figures are incorporated herein and constitute part of this specification. [Brief explanation of the drawing]

[0012] [Figure 1] Figure 1 is a pre-operative photograph of the eye of the patient described in Example 1. [Figure 2] Figure 2 is a postoperative photograph of the eye of a patient exhibiting a suppurative granulomatous lesion as described in Example 1. [Figure 3] Figure 3 shows a photograph of the patient's eye after injection of an anti-inflammatory steroid (Kenalog) and before injection of an anti-VEGF agent, demonstrating a reduction in pyogenic granulomatous lesions as described in Example 1. [Figure 4] Figure 4 shows a photograph of the eye of a patient 18 days after injection of both an anti-inflammatory steroid (Kenalog) and an anti-VEGF agent (bevacizumab), demonstrating a significant reduction in the pyogenic granulomatous lesions described in Example 1. [Figure 5]Figures 5A, 5B, 5C, and 5D are photographs showing the effect of anti-VEGF use according to the present disclosure on hypertrophic scars at various intervals after treatment with bevacizumab injection, such as before surgery (Figure 5A), 2 weeks after surgery (Figure 5B), 4 weeks after surgery (Figure 5C), and about 7 months after surgery (Figure 5D). Figures 5E, 5F, 5G, and 5H are photographs showing the effect of anti-VEGF use according to the present disclosure on hypertrophic scars at various intervals after surgery, such as before surgery (Figure 5E), 1 week after surgery (Figure 5F), 3 weeks after surgery (Figure 5G), and about 7 months after surgery (Figure 5H). [Figure 6] Figures 6A, 6B, and 6C are photographs showing a keloid on the left ear of a patient before laser surgery (Figure 6A), 3 weeks after laser surgery (Figure 6B), and 2 weeks after local bevacizumab injection (Figure 6C). Figures 6D, 6E, and 6F are photographs showing a keloid on the right ear of a patient before treatment with local bevacizumab injection (Figure 6D); and 2 weeks after local bevacizumab injection (Figures 6E and 6F). Detailed Description of the Invention

[0013] Detailed explanation of disclosure Definition: As used herein, the term "ocular pyogenic granuloma" is the manifestation of a pterygium in the eye after pterygium removal surgery.

[0014] As used herein, the term "subject" means any mammal, particularly a human, and can also be referred to, for example, as an individual or a patient.

[0015] A "subject in need of treatment" for ocular pyogenic granuloma by the methods disclosed herein is a subject at risk of ocular pyogenic granuloma, such as a subject who is about to undergo, or has recently (e.g., within about 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 month, within about 2 weeks or 1 week or less) undergone surgery to remove a pterygium, keloid, or scar, or is about to undergo surgery to remove a pterygium, keloid, or scar (e.g., within about 1 month, within about 1 week or less) patient.

[0016] As used herein, "anti-VEGF agent" means an inhibitor of VEGF signaling. Anti-VEGF agents include antibodies (e.g., bevacizumab), antibody fragments (e.g., antibody light chain (VL), antibody heavy chain (VH), single-chain antibody (scFv), F(ab’)2 fragment, Fab fragment, Fd fragment, Fv fragment and single-domain antibody fragments (DAb). Fragments can be obtained, for example, from intact or full antibodies or by chemical or enzymatic treatment of antibody chains, or by recombinant means, fusion proteins, peptides, nucleic acids (e.g., siRNA, shRNA), and other small molecules that inhibit the interaction between VEGF (VEGF-A or VEGF-C / VEGF-D) and its receptors (VEGFR-1, / VEGFR-2 or VEGFR-3), respectively. Other non-limiting examples of anti-VEGF agents encompassed by the present disclosure are provided hereinbelow.

[0017] As used herein, for example, in the context of injecting an anti-VEGF adjacent to or near a site of new blood vessel growth, the term "adjacent" means proximal (e.g., 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 site of blood vessel growth).

[0018] As used herein, the terms "therapeutically effective" and "effective amount", which are used interchangeably and applied to a dosage or amount, refer to an amount of a composition, compound or pharmaceutical formulation sufficient to produce the desired activity upon administration to a subject that requires it. In the context of the present invention, the term "therapeutically effective" refers to a composition, compound or This refers to the quantity of the pharmaceutical preparation. When a combination of active agents is administered, the effective dose of the combination or individual agents may or may not include the amount of each agent that would have been effective if administered individually. The dosage of a therapeutic preparation varies depending on the nature of the disease or condition, the patient's medical history, the frequency of administration, the method of administration, the clearance of the agent from the host, etc. The initial dose may be large, and then the retention dose may be small. The dose may be administered, for example, weekly, every other week, daily, or bi-weekly, to maintain an effective dose level.

[0019] The therapeutically effective dose in the methods described herein may be determined by the treating physician. For example, the physician may manufacture anti-VEGF agents, anti-inflammatory steroids and / or NSAIDs. Treatment can be initiated using the dose recommended by the physician and adjusted based on the physician's observation of the treatment's effectiveness. Further guidance is provided in this specification and in the examples. In addition, clinical trials can be conducted to determine the dose that is effective in producing a statistically significant therapeutic effect when treating a population of patients.

[0020] As used herein, “combination therapy” means that a subject requiring treatment with a certain composition or drug receives treatment in combination with the initial therapy and / or one or more other therapies, such as surgery. In combination with the therapy, one or more other compositions or drugs for the disease can cure the subject This refers to a treatment or therapy administered. Such combination therapy is when the patient initially undergoes one treatment method. For example, treatment may be sequential, with one drug or therapy followed by another treatment (e.g., another drug or therapy), or all drugs and / or therapies may be administered simultaneously. In either case, these drugs and / or therapies are said to be “co-administered.” It should be understood that “co-administered” does not necessarily mean that the drugs and / or therapies are administered in a combined form (i.e., they may be administered separately or together at the same or different times, to the same or different sites).

[0021] The phrase "medically acceptable" means that, within the bounds of sound medical judgment, a compound, material, or composition is suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit-to-risk ratio. And / or as used herein to refer to dosage forms.

[0022] As used herein, “treating” or “treatment” of a condition, disorder or state (e.g., recurrence of pterygium or keloid) includes: (1) preventing or delaying the onset of clinical or subclinical symptoms of a condition, disorder or state in mammals that are susceptible to or predisposed to the condition but have not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder or state; and / or (2) suppressing a condition, disorder or symptom, such as preventing, reducing or delaying the onset of the disease or its recurrence (in the case of maintenance treatment) or at least one clinical or subclinical symptom; and / or (3) alleviating the disease, i.e., the condition, disorder or To cause a regression of a condition, or at least one of its clinical or subclinical symptoms. ; and / or (4) causing a reduction in the severity of one or more symptoms of the disease. The benefit to the person being treated is statistically significant or at least recognizable to the patient or physician.

[0023] Explanation of abnormal or excessive angiogenesis The disclosed compositions, devices, and methods can be used to treat abnormal or excessive angiogenesis that forms in the skin or eyes. Angiogenesis is a physiological process in which new blood vessels form existing ones by continuing the growth of the vascular system by sprouting or dividing from existing blood vessels. Normal angiogenesis is a process necessary for the growth and development of the human body, such as wound healing and granulation tissue formation. Angiogenesis is controlled by a very delicate interaction of growth factors and inhibitors, and its instability can lead to disease. One of the growth factors is a chemical stimulant such as VEGF. VEGF is a hair follicle in a given network. It has been demonstrated that this increases the number of small vessels and significantly contributes to angiogenesis. Instability in this interaction may lead to abnormal or excessive angiogenesis, which can worsen other health factors.

[0024] For example, abnormal or excessive angiogenesis can lead to excessive growth of the vascular system, potentially resulting in cancer, skin diseases, age-related blindness, diabetic ulcers, cardiovascular disease, stroke, and many other debilitating conditions. Specifically, excessive expression of VEGF may not only stimulate angiogenesis but also increase vascular permeability. In wet macular degeneration, VEGF causes the proliferation of capillaries in the retina. Increased angiogenesis also causes edema, leading to leakage of blood and other retinal fluids into the retina and causing vision loss.

[0025] In some embodiments, complications of abnormal or excessive angiogenesis may result in one or more of the following conditions: suppurative granuloma, pediatric hemangioma, infantile hemangioma, congenital hemangioma, Aquiline hemangioma, spindle cell hemangioma, epithelioid cell hemangioma, Kaposi's hemangioendothelioma, reticular hemangioendothelioma, papillary lymphangioendothelioma, Dabska tumor, complex hemangioendothelioma, Kaposi's sarcoma, angiosarcoma, epithelioid hemangioendothelioma, capillary malformation, lymphatic malformation, venous malformation, arteriovenous malformation, arteriovenous fistula, capillary-lymphatic malformation, capillary-arteriovenous malformation, capillary-lymphatic-arteriovenous malformation, capillary-vein-arteriovenous malformation, capillary-lymphatic-vein-arteriovenous malformation.

[0026] Explanation of anti-VEGF agents The human VEGF-A gene consists of eight exons. Alternative exon splicing is , after signal sequence cleavage, four molecules having 121, 165, 189, and 206 amino acids respectively. This leads to the generation of the major VEGF isoforms (VEGF121, VEGF165, VEGF189, and VEGF206). VEGF165 is considered to be the most physiologically relevant isoform. For the review, see Ferrara et al., Biochem. Biophys. Res. Commun., 2005, 333. See pages 328-335. The amino acid sequence of VEGF-A is well known in the art, and there are many sequences due to splice mutations. As a non-limiting example, the following is an illustrative and non-limiting example from GenBank. This is RTM. Accession numbers for the human VEGF-A amino acid sequence: AAP86646.1, P15692.2, NP_001191313.1, NP_001165101.1, NP_001165099.1, NP_001165097.1, NP_001165095.1, NP_001020539.2, NP_003367.4, NP _001165093.1, NP_001020541.2, NP_001191314.1, NP_001165100.1, NP_001165098.1, NP_001165096.1, NP_001165094.1, NP_001028928.1, NP_001020540.2, NP_001020538.2, and NP_001020537.2. Other VEGF family members include VEGF-C and VEGF-D.

[0027] Disclosed herein is a method for treating pyogenic granuloma by administering an anti-VEGF agent to a subject. In one embodiment, the anti-VEGF antibody bevacizumab can be used in the disclosed method. The antibody bevacizumab and its VEGF-binding activity have been reviewed in detail in Ferrara et al., Biochem. Biophys. Res. Commun., 2005, 333, 328-335. Bevacizumab may be administered to the skin or eyes (for example, for the treatment of pyogenic granuloma) in a dose determined by a physician. In one embodiment, the dose for administration to the site of pyogenic granuloma (for example, for the treatment of a granulomatous lesion) is about 1.25 mg.

[0028] However, the therapeutic methods described herein do not involve other anti-VEGF agents (e.g., other anti-VEGF antibodies, drugs, prodrugs, small molecules, peptides, nucleic acid inhibitors (e.g., siRNA, shRNA, antisense oligonucleotides), fusion proteins, etc., such as VEGF or VEGFR. This can also be carried out using inhibitors, in which anti-VEGF agents inhibit the action of VEGF (e.g., human VEGF) and / or VEGFR (e.g., VEGFR-1, VEGFR-2, and / or VEGFR-3) (e.g., human VEGFR-1, human VEGFR-2, or human VEGFR-3) (i.e., VEGF signaling). It should be understood that, insofar as they possess the ability to inhibit VEGF and VEGFR inhibitors, they are either well-known in the art or will be discovered or designed in the future. This is discussed in detail in Masabumi Shibuya, Genes & Cancer, 2(12), 1097-1105 (2011). This has been done and is incorporated herein by reference.

[0029] Other anti-VEGF antibodies and inhibitors known in the art and usable in the manner disclosed herein include, but are not limited to, ranibizumab, pegaptanib, imatinib, vandetanib, sorafenib, pazopanib, baratanib, bevacilanib, aflibercept, etanercept, anecolta acetate (an angiogenesis-inhibiting steroid), VEGF-trap (a fusion protein), Squalamine lactate, erlotinib, gefitinib (low molecular weight), combretastatin A4 prodrug (anti-tubulin / anti-angiogenic agent), AdPEDF (adenovector pigment derived from epithelium) Factors), Cand5 (siRNA), Protein Tyrosine Kinase 7 Inhibitor (PTK7), Lipid-degrading agents, TG100801, AG013958, AL39324, AGN211745 (VEGF receptor blocker), Anti-angiogenic VEGF-A(xxx)b Family, VEGF-trap (receptor decoy), tyrosine kinase inhibitor receptor SIM010603 Protein kinase antibodies and kinase domain receptor antibodies (KDR1.3 and KDR2.6) against [the target protein kinase] GS101 aganilsen (an antisense oligonucleotide for insulin receptor substrate aka IRS-1) Rheotide), picropodophyllin (PPP), tetrameric tripeptide, tissue kallikrein, KH906 (recombinant human VEGF receptor protein fusion), beta-adrenoreceptor blocker beta.3-AR, nicotinic acetylcholine receptor antagonist, linamide analog (Lin05), morpho Rhinoligomer (VEGFR1_MOe13), decalcin, prorenin, vasohibin, and sirolimus. The amino acid sequences of VEGF and VEGFR (and the nucleic acid sequences encoding the amino acid sequences) are as follows: As is known in the art, those skilled in the art will understand that additional anti-VEGF agents for use in the currently disclosed methods can be readily designed.

[0030] The dosage range of anti-VEGF agents disclosed above can be readily determined by those skilled in the art and can be first determined in animal models for determining dosage, safety, and efficacy according to standard methods known in the art.

[0031] Explanation of nanoparticles As used herein, nanoparticles generally mean particles with a cross-section ranging from 1 nm to approximately 100 microns. The nanoparticles described herein are used in conjunction with anti-VEGF compounds or are designed to support anti-VEGF compounds. More generally, nanoparticle therapeutics are particles typically composed of therapeutic entities such as small molecule drugs, peptides, proteins, and nucleic acids, as well as components that, when constructed with therapeutic entities such as lipids and polymers, form nanoparticles.

[0032] Nanoparticles are described herein as part of a smart drug delivery system. The inventors have found that nanoparticles have tremendous potential for delivering therapeutic agents to areas of abnormal or excessive angiogenesis in the disclosed compositions. These novel delivery systems can enhance efficacy and simultaneously reduce side effects due to properties such as more targeted localization and active cellular uptake in tumors. Nanoparticles that are candidates for use in drug delivery systems can be classified into two classes: inorganic nanoparticles and organic nanoparticles. In some embodiments, the compositions disclosed herein include inorganic nanoparticles. In other embodiments, the compositions disclosed herein include organic nanoparticles. In further embodiments, the compositions disclosed herein also include both inorganic and organic nanoparticles.

[0033] In some embodiments, inorganic nanoparticles may include those having physicochemical properties that can be used for both diagnostic purposes such as imaging and therapeutic purposes such as targeted destruction. In certain embodiments, inorganic particles may include semiconductor quantum dots, superparamagnetic iron oxide, and gold-based and / or silver-based particles. In certain embodiments, inorganic nanoparticles made of a composition such as silicon may be coated with gold and / or silver.

[0034] In some embodiments, the organic nanoparticles may include soft types (e.g., paclitaxel-borne polymer micelles, liposomal doxorubicin, and paclitaxel-borne human serum albumin nanoaggregates), porphysomal nanovesicles, and conductive polymer nanoparticles.

[0035] In some embodiments, the nanoparticles may include, in addition to any of the above combinations, "all-in-one" type nanoparticles such as porphyrin-based organic nanoparticles and porphyrin / cholic acid hybrid polymers.

[0036] In one embodiment, a method for photothermally triggering the delivery of the anti-VEGF compounds described herein using various organic or inorganic nanoparticles is described.

[0037] In one embodiment, the nanoparticles may include gold, silver, and / or iron oxide having specific photothermal properties.

[0038] In one embodiment, an anti-VEGF compound comprising gold and silver nanoparticles for mediating the inhibition of angiogenesis is described.

[0039] In one embodiment, an anti-VEGF compound comprising gold nanoparticles is described for photothermally controlling the release of angiogenesis inhibitors by light or radio wave activation.

[0040] In one embodiment, metal nanoparticles, such as gold nanoparticles, conjugated to an anti-angiogenic peptide can be combined with visible laser irradiation to enhance in vivo angiogenesis arrest. The combination of gold nanoparticles and a green laser can achieve high local temperatures that allow for precise ablation of blood vessels and, when combined with VEGF pathway inhibition such as transdermal application of anti-VEGF, may reduce FLT-1 expression.

[0041] In one embodiment, a method is described in which delivery is triggered photothermally using laser light. In one non-limiting embodiment, a 532 nm laser is used to deliver a gold nanoparticle conjugated with an anti-angiogenic peptide. It may be used in combination with nanoparticles. Lasers have been found to cause a significantly higher temperature rise in response to prolonged, low-intensity exposure. This has the effect of increasing activity while simultaneously coagulating blood vessels. In another embodiment, RF or photo-interaction with other nanoparticles described herein is described. This has been shown to increase activity by heating or to release bound anti-angiogenic compounds from the nanoparticles by thermal shock or pulsed energy.

[0042] Explanation of anti-inflammatory steroids Anti-inflammatory steroids are steroid compounds that have anti-inflammatory activity, and examples include corticosteroids such as glucocorticoids. Glucocorticoids bind to glucocorticoid receptors in the cytoplasm, and affect lipocortin-1, interleukin-10, and interleukin Anti-inflammatory proteins such as N-1 receptor antagonists and neutral endopeptidases They can increase the transcription of the genes they encode. Glucocorticoids also suppress the expression of multiple inflammatory genes, including genes for various cytokines, enzymes, receptors, and adhesion molecules. See, for example, Barnes et al., Clin. Sci., 1998, 94, 557-572, which is incorporated herein by reference.

[0043] The anti-inflammatory steroids described herein are (1) mixtures of water and oil and usually contain preservatives. (1) Creams; (2) Ointments made of oil and a small amount of water or anhydrous water, usually without preservatives; (3) Gels made of water and propylene glycol; and (4) Typically oil and water, and others It can be used in various forms, such as solutions, foams, and lotions containing these chemicals.

[0044] In some embodiments, the compositions described herein may contain any known anti-inflammatory steroid. Non-limiting examples of such steroids include triamcinolone acetonide (TAC) suspension, typically administered by injection at concentrations ranging from 2 mg / ml to 40 mg / ml, prednisolone acetate 1% and / or difluprednate 0.05% (for ophthalmic use), and Examples include alclomethasone 0.005% cream, ointment, gel, or solution.

[0045] Other anti-inflammatory steroids that may be used in the described compositions include Class IV, moderate-potency topical steroids in the form of creams, ointments, gels, or lotions. Non-exclusive examples of such steroids include: flulandrenolide 0.05%, triamcinolone acetonide 0.1%, mometasone furoate 0.1%, and propionate. Fluticasone acid 0.05%, triamcinolone acetonide 0.1 or 0.025%, clobetasol propionate 0.05%, diflorasone 0.005% cream, fluocinonide cream 0.1%, and or prednicarbate 0.1% topical cream or ointment (for skin use), and NSAIDs ( For example, diclofenac 1% gel, diclofenac 1.5% solution (for external use).

[0046] Generally, triamcinolone acetonide and triamcinolone diacetate are the most widely used topical corticosteroids, although dexamethasone, betamethasone, or methylprednisolone acetate are used by some clinicians. Triamcinolone drugs are available as microparticle suspensions. Preferred features of microparticle suspensions for topical administration include the small size of the corticosteroid particles, stability at room temperature, and ease of resuspending the corticosteroid particles due to gentle mixing. Smaller corticosteroid crystals are delivered more efficiently to the treatment site, thus reducing the total dose of the drug and decreasing the risk of systemic side effects and skin atrophy. Furthermore, because microparticle crystals of corticosteroids are in depot form, the active ingredient is stored in the tissue and released over several weeks. Therefore, this type of corticosteroid delivery system is very suitable for the treatment of chronic inflammatory skin diseases. Examples of chronic inflammatory skin diseases that are particularly suitable for this type of sedative action include psoriasis, chronic lichen simplex, cutaneous lupus erythematosus, and nodular prurigo. In preferred embodiments, the anti-inflammatory steroid may be alclometasone, diflorasone, fluocinonide, triamcinolone, prednicarbate, or prednisolone.

[0047] Explanation of nonsteroidal anti-inflammatory drugs (NSAIDs) Nonsteroidal anti-inflammatory drugs (NSAIDs) are nonsteroidal compounds that suppress inflammation. Most NSAIDs act as non-selective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isozymes. COX catalyzes the production of prostaglandins. COX-1 inhibition is an NSAID Since it is thought to be associated with gastrointestinal side effects, compounds that are selective COX-2 inhibitors are also considered. It has been developed.

[0048] In some embodiments, the compositions described herein contain any known NSAID It may also be included. In a preferred embodiment, the NSAID may be diclofenac.

[0049] Treatment method In some embodiments, a form of treating excessive or abnormal angiogenesis involves applying, independently or with at least one or more anti-inflammatory steroids, to the skin or eyes of the affected patient. This includes the use of anti-VEGF agents, either as a drug or in combination with NSAIDs.

[0050] In some embodiments, the anti-VEGF agent is at least one organic, inorganic, or hybrid Combined with rhizoid nanoparticles, a composition is formed that can be injected into or around a region containing abnormal or excessive angiogenesis. In a particular embodiment, this composition comprises one or more Inject before, after, or both before and after the application of anti-inflammatory steroids or NSAIDs. It is possible.

[0051] In one embodiment, anti-inflammatory steroids or NSAIDs include abnormal or excessive angiogenesis. It can also be applied via injection to the area or its vicinity. In another embodiment, an anti-inflammatory steroid or NSAID may be administered as eye drops or by any other delivery mechanism known in the art. It can be applied via [a specific method / tool].

[0052] In certain embodiments, when the area of ​​treatment is the eyeball, eyelid, and orbital lesion, the area in which excessive or abnormal neovascularization is formed may be selected from: cavernous hemangioma, cavernous malformation, arteriovenous malformation, arteriovenous fistula, aneurysm, lymphangioma, hemangioendothelioma, malignant hemangioendothelioma (angiosarcoma), angiolympholympia with eosinophilia (Kimura's disease), vine-like hemangioma of Wyburn-Mason syndrome, hemangioblastoma, orbital varicose veins, venous lymphatic malformation, choroidal plexus hemangioma, choroidal plexus melanoma, and Coats' disease.

[0053] Carrier As described above, the compositions described herein include at least one anti-vascular endothelial growth factor (anti-VEGF) antibody and a carrier such as nanoparticles. The carrier is collagen, elastic fiber components, hyaluronic acid Extracellular matrix components such as proteoglycans including rosinic acid, glycosaminoglycans, decorin and versican, PMMA (polymethyl methacrylate beads), triamcinolone acetonide suspension (TAC / Kenalog - typically 10 or 40 mg / ml), human recombinant or This includes albumin such as animal albumin, mitomycin C, beta-blockers, and triamin. Nolon acetonide (TAC), or other carriers known to those skilled in the art that can be released with sustained release. It may contain protein or steroids.

[0054] Delivery device In some embodiments, a delivery device for administering the disclosed composition may be configured to administer the composition by at least one method selected from: vein Internal, subconjunctival, subtenon's capsule, episclera, intrascleral, subscleral, intraperitoneal, epidural, subarachnoid, intramuscular, intracavitary, intratracheal, epidermal, intradermal, subdermal or subcutaneous.

[0055] In one embodiment, the drug delivery device includes a microneedle array. For example, such an array includes a patch of multiple microneedles that deliver the described composition to the skin. This delivery system is particularly useful when there is an area of ​​excessive or abnormal angiogenesis in the skin. In this embodiment, the patch can be applied like a bandage, such as a Band-Aid®. In this embodiment, the needles, made exclusively from sugar and protein pieces, dissolve readily in the skin.

[0056] In another embodiment, if the disorder to be treated is located in the periorbital and / or orbital region of the eye, such as a suppurative granuloma, the delivery system delivers a therapeutic protective contact lens (BCL). They may include protective lenses. These types of therapeutic lenses are scleral contact lenses. A contact lens is defined as any contact lens used to promote healing, relieve pain, and protect the surface of the eyeball. Scleral contact lenses cover a larger area, covering the entire surface of the cornea and resting on the "white" (sclera) of the eye, rather than just a portion of the cornea (like conventional lenses). The placement of these therapeutic lenses is part of a medical procedure or process to deliver the compositions described herein to a pyogenic granuloma, whether temporary or part of a long-term treatment plan. Thus, in one embodiment, the VEGF antibody-containing composition described herein is applied as a coating on a BCL and the disclosed composition to the site of the pyogenic granuloma. Long-term and direct releases will be provided.

[0057] In another embodiment, the drug delivery device includes a punctal plug, defined as a small medical device positioned in the lacrimal duct of the eye to help prevent tear leakage. In one embodiment, a scleral contact lens and / or punctal plug bound to anti-VEGF and nanoparticles is a device that can be placed in the periorbital and periorbital regions near the eyeball to treat suppurative granulomas and other tumors mentioned herein on the eyeball.

[0058] In some embodiments, a delivery device for administering the disclosed composition may be configured to deliver the composition and carrier to the affected tissue at high speed. For example, the composition and carrier may be injected supersonic into the subsurface tissue. In these embodiments, the delivery device may include a computer-controlled application station, an applicator, and a therapeutic cartridge. In certain embodiments, the computer-controlled application station may be operated via a touchscreen, allowing the user to select a program according to the indication and active ingredient. Without being bound by theory, it is believed that preset programs ensure standardized and efficient operation of the application system.

[0059] In some embodiments, the delivery device is at least one syringe, vial, or applicator pre-loaded with a predetermined amount of pharmaceutical composition, as will be described in more detail below. It can be part of a kit consisting of the following:

[0060] kit In certain embodiments, the Disclosure provides a kit for treating excessive or abnormal angiogenesis in a subject. The kit comprises an anti-VEGF antibody (e.g., bevacizumab, ranibizumab, pegaptanib) or an anti-VEGF agent (e.g., anecoltab acetate, an angiogenesis-inhibiting steroid), as well as a crystalline, small needle-shaped drug applied by a bandage. The means of administration may include a patch, a single multi-needle injector, or any other device for administering the compound subcutaneously.

[0061] The kit may further contain one or more of the anti-inflammatory steroids described herein. The person concerned may not consider the above-mentioned dosages of anti-inflammatory steroids and NSAIDs to be outside the scope of this disclosure. Those skilled in the art will understand that the dosage may vary and therefore other dosages are also included in this disclosure. The dosage can be administered safely and effectively to the subject in accordance with standard care and knowledge in the art, and may include anti-inflammatory steroids and NSAIDs as described herein. You will understand that.

[0062] The kit may further include the smart drug delivery system described herein. In particular, the kit may include inorganic or organic nanoparticles dispersed in a suitable carrier, such as a cream or gel, which can encapsulate the described active ingredients and deliver them to the site of treatment. In one embodiment, the carrier includes extracellular matrix components such as collagen, elastic fiber components, hyaluronic acid, glycosaminoglycans, proteoglycans such as decorin and versican, PMMA (polymethyl methacrylate beads), triamcinolone acetonide suspension (TAC / Kenalog - typically 10 or 40 mg / ml), and albumin. Other carriers for nanoparticles The body is disclosed in Li et al., Nat. Commun., 5, 4712 (2014), which is referenced herein. It will be incorporated into the book.

[0063] In certain embodiments, the kit includes bevacizumab; prednisolone acetate 1% and Diflu. Prednate 0.05% and one or more triamcinolone acetonides, and a nanoparticle carrier. Includes.

[0064] In another specific embodiment, the kit includes at least one sterile therapeutic ophthalmople for the eyeball. Includes protective lenses. In this embodiment, the therapeutic protective lens is a composition comprising one or more of the following: Placing on the surface: anti-VEGF antibodies (e.g., bevacizumab, ranibizumab, pegaptanib) or anti-VEGF agents (e.g., anecoltab acetate, angiogenesis-inhibiting steroids); anti-inflammatory steroids as specified herein; NSAIDs as specified herein; all of these are collagen, elastic These may be contained in carriers such as those containing fibrous components, hyaluronic acid, glycosaminoglycans, extracellular matrix components such as proteoglycans like decorin and versican, triamcinolone acetonide suspension, and albumin.

[0065] In certain embodiments, the kit is intended for treating excessive or abnormal angiogenesis in subjects such as pyogenic granulomas. The kit may optionally further include instructions for use.

[0066] In one embodiment, the kit may include a syringe or applicator pre-loaded with the above-mentioned drug, and / or vials containing one or more of the drugs.

[0067] Measurement / Inspection Technology Slit-lamp examination: A slit-lamp examination uses a device equipped with a low-power microscope and a slit lamp to examine a patient's eye. The slit lamp emits high-intensity light, allowing for a more detailed examination of the eye. To enable a more accurate eye examination, eye drops containing dyes or dilating infusions may be used. Slit lamps have different filters to obtain different fields of view of the eye, and the device can be used to examine various parts of the eye, such as the eyelids, conjunctiva, iris, lens, sclera, cornea, retina, and optic nerve.

[0068] In some embodiments, known diagnostic methods are used to locate lesions within the body. These examination techniques include: optical coherent tomography, positron emission tomography, dual-mode positron emission tomography-magnetic resonance imaging, magnetic resonance imaging, or a combination of the disclosed methods.

[0069] The therapeutic effects of drugs used to treat specific conditions such as tumors include severe destabilization of blood circulation, the blood-brain barrier / blood-brain tumor barrier (BBB / BBTB), and limited tumor uptake. Multiple barriers to delivery are present. Therefore, in one embodiment, a sequentially targeted crosslinking (STICK) nanodelivery system is disclosed to overcome these significant physiological barriers and improve drug delivery to specific lesions in or on the body, such as excessive or abnormal angiogenesis in subjects like pyogenic granulomas or various tumors. In one embodiment, Contrast agents comprising a STICK nano-delivery system having oily, lipophilic, and pH-sensitive properties are used in blood They are used to penetrate the fluid-brain barrier, the blood-oncological barrier, and other organ or tissue barriers. In certain embodiments, the disclosed nanoparticles may be coupled with an anti-VEGF contrast agent to enhance the visibility of any lesion and activate the anti-VEGF agent. In these embodiments, the nanoparticles may be introduced into the body in two applications. In the first application, the nanoparticles paired with the contrast agent may be used to identify any lesion. In the second application, the nanoparticles may be used to modify the configuration of the receptors. Protein-carrying nanoparticles may be introduced into the lesion site. This allows the anti-VEGF agent to reach the cells.

[0070] Antitumor agents and nanoparticle delivery systems In various embodiments, the compositions described herein may contain at least one antitumor agent, such as mitomycin or fluorouracil (5 FU). Fluorouracil is It is an anti-cancer ("antitumor" or "cytotoxic") chemotherapy drug, and is an "antimetabolite". They are classified as follows. These drugs can be used to prevent the formation of pyogenic granulomas. Therefore, in one embodiment, the composition can be used in specialized chemotherapy and / or chemoradiotherapy to deliver high doses of antitumor agents directly to the tumor in order to kill more tumor cells and cause less damage to normal tissue. These drugs used in chemotherapy, for example, fluorouracil and mitomycin C, kill cells or necrotic cells by killing them or by necrotic cells. By stopping cell division, tumor cells act in different ways to halt their growth.

[0071] As those skilled in the art will understand, antitumor agents are highly toxic and, if not administered in precise doses, can have undesirable, often dangerous, side effects. As mentioned above, a further advantage of the nanoparticle delivery systems disclosed herein is that they enable the precise delivery of the described therapeutic agents to the precise site of treatment, thereby mitigating or eliminating toxic side effects to surrounding tissues.

[0072] Devices such as jet injectors, microneedle injector arrays, needles, and atomizers. AVEGF-containing composition and its compounds are configured to deliver them to a predetermined depth within target tissue. A lower concentration of AVEGF may be used when applied directly to the area of ​​interest rather than moving through a concentration gradient within the tissue. In one embodiment, AVEGF is applied by a microneedle over a predetermined area and a predetermined depth range, where the area mainly coincides with an area of ​​target tissue, and the depth range extends almost throughout the entire depth of the target tissue, so that the target tissue is an area subject to scarring or keloid formation.

[0073] A device having multiple needles spaced apart to ensure that an anti-VEGF solution is completely dispersed in target areas such as areas prone to keloid formation or surgical scars.

[0074] In one embodiment, the following description refers to injection, multi-needle injector, or jet This means it is used by a power injector. The method and device are used to ensure the slow, sustained, or temporal release of the anti-VEGF compound, as described below:

[0075] a) Physiological saline, hyaluronic acid (HA), collagen, elastin, decorin, proteoglycans such as versican, chondroitin sulfate, herparin sulfate To bind with fillers such as proteoglycans, elastin, fibrillin, fibrin (see attached abandoned filler patent), and collagens (all types);

[0076] b) To bind to albumin and similar carrier proteins;

[0077] c) Liposomes, and liposomes that can be triggered by light, laser, ultrasound or decay over time;

[0078] d) Use of colloidal or polymer capsules for microencapsulation and nanoencapsulation of AVEGF solutions for controlled release of AVEGF, and microencapsulated AVEGF solutions An injector for administration;

[0079] e) Compounds containing AVEGF, corticosteroids, hydroquinone, and other drugs;

[0080] f) In combination with stem cell therapy, growth factors, and PRP, particularly stem cell-stimulated angiogenesis. To prevent this.

[0081] A mixture of physiological saline, sterile water, one of the above, or a combination thereof. A method of injecting a substance. A pre-filled cartridge for injecting one of the listed compounds. A device for the dodge is also disclosed. In one embodiment, the concentration of the AVEGF-containing compound, such as bevacizumab, used in the embodiments of the disclosed invention is in the range of 0.025 to 250 mg / ml, e.g., 1.0 to 100 mg / ml, 10 to 50 mg / ml, 20 to 30 mg / ml, e.g., 25 mg / ml. These endpoints can be used in any combination, such as 30 to 100 mg / ml.

[0082] In one embodiment, a pre-filled device such as a cartridge, syringe, vial, applicator, patch, or other delivery device containing bevacizumab in an amount of 2.5 mg / 0.1 mL (25 mg / mL) is described.

[0083] Therefore, in various aspects of this disclosure, nanoparticle delivery achieves one or more of the following advantages. The system is described as: highly specific drug targeting and delivery; reduced toxicity while maintaining therapeutic efficacy; greater safety and biocompatibility; and faster delivery of the compositions described herein to the therapeutic area. [Examples]

[0084] Example - Treatment of pyogenic granuloma with bevacizumab in combination therapy The following non-limiting embodiments, intended as illustrative examples, further clarify this disclosure.

[0085] Treatment protocol Local anesthetic (Proparacaine 0.5% eye drops or Alcaine manufactured by Alcon Laboratories, Inc.) The ) was applied to the eye after recent pterygium excision and amniotic membrane transplantation. Patients were examined to check for any abnormal growth in the eye. If abnormal growth was found during examination, patients were treated with a combination of anti-inflammatory steroids such as bevacizumab (Avastin) (Genentech / Roche) and triamcinolone (Kenalog) (Bristol-Myers Squibb), and / or NSAIDs such as ketrolac injection (Tradol) (Roche) or ketrolac eye drops (Acra) (Allergan). It was done.

[0086] Insert a syringe containing approximately 0.05 mL of bevacizumab (1.25 mL / 0.05 mL) into the eye, and then insert the plunger. The plunger was withdrawn to check for the presence of blood in the syringe hub. If blood was present (indicating the presence of blood vessels), the needle was withdrawn and the plunger was withdrawn again until no more blood was observed in the syringe hub. Bevacizumab was then injected into the suppurative granulomatous lesion and / or the area adjacent to the lesion where numerous dilated blood vessels were present. If bleeding occurred (e.g., in the form of a subconjunctival or subcutaneous hematoma), tamponade was performed with a Q-tip until the bleeding stopped. Then, the injections were resumed.

[0087] Anti-inflammatory steroids and / or NSAIDs may be taken either before or after bevacizumab injection. It was administered by injection and / or It was administered by eye drops. Anti-inflammatory steroids and / or NSAIDs were administered by injection. If so, it was done following a similar process to that described above for bevacizumab injection. A syringe containing approximately 0.03 mL of triamcinolone injection (40 mg / mL) was injected into the suppurative granuloma lesion. The needle was inserted, and the plunger was withdrawn to measure whether blood was present in the hub of the syringe. If blood was present (indicating the presence of a blood vessel), the needle was withdrawn, and this procedure was repeated until no more blood was observed in the hub of the syringe. Anti-inflammatory steroids or NSAIDs were administered. The medication was injected into the pyogenic granulomatous lesion and / or the area adjacent to the lesion where numerous dilated blood vessels were present. If bleeding occurred (e.g., in the form of subconjunctival or subcutaneous hematoma), tamponade was performed with a Q-tip until the bleeding stopped, after which injection was resumed. When anti-inflammatory steroids or NSAIDs were delivered as eye drops, steroid eye drops were administered 1 to 4 times a day (every 6 hours) or once every hour (24 drops / day) for approximately 6 weeks. NSAID eye drops were administered 4 times a day, every 6 hours, for 3 to 6 months.

[0088] Patients were followed up to monitor for the emergence of new pyogenic granulomas. The presence of new pyogenic granulomas was an indication for further treatment (e.g., by injection and / or eye drops). In some cases, the pterygium was only partially removed during the initial surgery to remove it (e.g., to prevent necrosis). Consequently, in some patients, additional surgery was subsequently performed to remove the remaining portion of the pterygium, resulting in additional pyogenic granulomas.

[0089] Two patients (Patient 1 and Patient 2) underwent manual surgery to remove primary pterygium from the cornea of ​​one or both eyes. I underwent surgery (pterygium excision), followed by an amniotic membrane transplant, and was treated as described below.

[0090] Patient 1 - Right eye An 88-year-old patient presented with occasional bilateral eyelid lacerations without pain or discomfort. Slit-lamp examination revealed a 4.2 mm alar tumor in the right eye. The patient underwent pterygium resection and amniotic membrane grafting. He underwent surgery and had a good recovery with no complications. At a follow-up 60 days after surgery, a newly growing, red, raised lesion identified as a pyogenic granuloma was found in his right eye.

[0091] Following pterygium resection and amniotic membrane transplantation, the following drug treatments were administered for the prescribed number of days:

[0092] Day 90: Inject 0.03 mL of triamcinolone (40 mg / mL) into the lesion.

[0093] Day 97: 0.05 mL of bevacizumab (1.25 mg / mL) was injected into the lesion.

[0094] 104 days after the patient's surgery, the pyogenic granuloma had shrunk considerably and showed no signs of congestion. The pyogenic granuloma completely disappeared after 30 days.

[0095] The results above demonstrate that when patients received combination therapy including bevacizumab and anti-inflammatory steroids (injections), suppurative granulomatous lesions were suppressed.

[0096] Patient 2 - Left eye A 77-year-old male presented with a 6-month history of bilateral pterygium, measuring 4.6 mm in the right eye and 4.8 mm in the left eye. Relapse The patient had undergone multiple pterygium resections and amniotic membrane grafts in both eyes for the pterygium. The patient had a good postoperative course, and the graft remained in the right eye for three months. Several months after completing the series of pterygium resections (pyerygiectomy), a suppurative granuloma developed in the patient's left eye.

[0097] The following drug treatments were administered 98 days after pterygium resection and amniotic membrane transplantation.

[0098] Day 98: 0.03 mL of triamcinolone (40 mg / mL) was injected into the lesion.

[0099] Day 100: 0.05 mL of bevacizumab (1.25 mg / mL) was injected into the lesion.

[0100] A significant improvement was observed within two weeks after bevacizumab injection. The pyogenic granuloma is still present in the left eye. Although present, its size had significantly decreased, and the redness had also lessened. At the follow-up visit several months later, the pyogenic granuloma had completely disappeared, and there was no evidence of recurrence.

[0101] The results above demonstrate that when patients receive combination therapy including bevacizumab and anti-inflammatory steroids (injection or topical), suppurative granulomatous lesions are suppressed.

[0102] Patient 3 - Right eye A 55-year-old male with a 6.4 mm pterygium in his right eye. Figure 1 shows the patient's eye before pterygium resection and amniotic grafting. The patient's right eye after pterygium resection and amniotic grafting, as shown in Figure 2. I developed a pyogenic granuloma in my eye and, 60 days after pterygium excision and amniotic membrane transplantation, received the following treatments:

[0103] Day 60: Inject 0.03 mL of triamcinolone (40 mg / mL) into the lesion. Figure 3 shows triamcinolone. The patient's eye after the injection is shown.

[0104] Day 68: 0.05 mL of bevacizumab (1.25 mg / mL) is injected into the lesion.

[0105] Day 86: As shown in Figure 4, the suppurative granuloma in the right eye has completely disappeared.

[0106] The results above demonstrate that when patients received combination therapy including bevacizumab, anti-inflammatory steroids (injection or topical), and topical NSAIDs, suppurative granulomatous lesions disappeared, and that combination therapy is superior to bevacizumab monotherapy.

[0107] Other embodiments of the present invention will be apparent to those skilled in the art from the specification and practical examination of the invention disclosed herein. This specification and examples are illustrative only, and the true scope of the invention is intended to be indicated by the following claims.

Claims

1. At least one anti-vascular endothelial growth factor (anti-VEGF) antibody; and Nanoparticle-containing carrier, Includes, Nanoparticles are organic, inorganic, or a combination thereof. A composition for the treatment of abnormal or excessive angiogenesis.

2. The composition of claim 1, wherein the anti-VEGF antibody comprises bevacizumab, ranibizumab, lapatinib, sunitinib, sorafenib, axitinib, pazopanib, or a combination thereof.

3. The composition according to claim 2, wherein the anti-VEGF antibody is bevacizumab.

4. The composition according to claim 3, wherein the concentration of bevacizumab in the administration solution is 1.25 mg / 0.05 mL.

5. The composition according to claim 1, wherein the nanoparticles are organic.

6. The composition according to claim 5, wherein the organic nanoparticles comprise porphysome nanovesicles or conductive polymer nanoparticles.

7. Claim 6, wherein the organic nanoparticles comprise at least one of a paclitaxel-borne polymer micelle, liposomal doxorubicin, or paclitaxel-borne human serum albumin nanoaggregates. The composition of.

8. The composition according to claim 1, wherein the nanoparticles are inorganic.

9. The composition according to claim 8, wherein the inorganic nanoparticles include semiconductor quantum dots, superparamagnetic iron oxide, and a gold-based compound.

10. The composition according to claim 1, wherein the nanoparticles are a combination of porphyrin-based organic nanoparticles and a porphyrin / cholic acid hybrid polymer.

11. Furthermore, claims include anti-inflammatory steroids, non-steroidal anti-inflammatory drugs (NSAIDs), or both. The composition of item 1.

12. The composition of claim 11, wherein the anti-inflammatory steroid is alclometason, diflorasone, fluocinonide, triamcinolone, prednicarbate, or prednisolone.

13. NSAIDs are diclofenac, ketrolac, neparenac, or bromfenac. The composition according to claim 11.

14. The composition according to claim 1, wherein a suppurative granuloma is present in the periorbital region and / or orbital region of the eye.

15. The composition according to claim 1, wherein suppurative granulomas are present in the skin.

16. Areas containing abnormal or excessive angiogenesis include pyogenic granuloma, pediatric hemangioma, infantile hemangioma, congenital hemangioma, tufted hemangioma, spindle cell hemangioma, epithelioid cell hemangioma, Kaposi's hemangioendothelioma, reticular hemangioendothelioma, papillary lymphangioendothelioma, Dabska tumor, complex hemangioendothelioma, and Kaposi's tumor. The composition of claim 1, comprising sarcoma, angiosarcoma, epithelioid hemangioendothelioma, capillary malformation, lymphatic malformation, venous malformation, arteriovenous malformation, arteriovenous fistula, capillary-lymphatic malformation, capillary-arteriovenous malformation, capillary-lymphatic vessel-arteriovenous malformation, capillary-vein-arteriovenous malformation, and capillary-lymphatic vessel-vein-arteriovenous malformation.

17. Areas containing abnormal or excessive angiogenesis include cavernous hemangiomas, cavernous malformations, arteriovenous malformations, arteriovenous fistulas, aneurysms, lymphangiomas, hemangioectocytomas, malignant hemangioendotheliomas (angiosarcomas), and eosinophilia. The composition of claim 16, comprising lesions of at least one eye, eyelid and orbit, selected from angiolymphatic hypertrophy with multiple lesions (Kimura's disease), vine-like hemangiomas, hemangioblastomas, orbital varicose veins, venous lymphatic malformations, choroidal plexus hemangiomas, choroidal plexus melanomas, and Coats' disease.

18. A composition containing at least one anti-VEGF antibody and nanoparticles is used to treat abnormal or excessive blood vessels. To administer to a region containing the formation, where the nanoparticles are organic, inorganic, or a combination thereof; Administer anti-inflammatory steroids; and Administer nonsteroidal anti-inflammatory drugs (NSAIDs). A treatment method for abnormal or excessive angiogenesis, including [specific example].

19. The method of claim 18, wherein the steps can be carried out in any order or simultaneously.

20. The method of claim 18, wherein the anti-VEGF antibody is bevacizumab.

21. The method of claim 20, wherein bevacizumab is administered in a dose of 1.25 mg.

22. The method of claim 18, wherein the nanoparticles are organic and comprise porphysome nanovesicles or conductive polymer nanoparticles.

23. Claim 1, wherein the organic nanoparticles comprise at least one of a paclitaxel-borne polymer micelle, liposomal doxorubicin, or paclitaxel-borne human serum albumin nanoaggregates. 8 methods.

24. The method of claim 18, wherein the nanoparticles are inorganic.

25. The method of claim 24, wherein the inorganic nanoparticles include semiconductor quantum dots, superparamagnetic iron oxide, and a gold-based compound.

26. The method of claim 18, wherein the nanoparticles are a combination of porphyrin-based organic nanoparticles and porphyrin / cholic acid hybrid polymers.

27. The method of claim 18, wherein the composition is administered by injection or topically.

28. The composition, anti-inflammatory steroids, and NSAIDs should all be taken on the same day, or individually on separate days. The method of claim 18, wherein the agent is administered to the patient.

29. The composition, anti-inflammatory steroid, and NSAID are all administered at least once, according to the claim. 28 methods.

30. The anti-inflammatory steroid is one or more of the following: alclometason, diflorasone, fluocinonide, triamcinolone, prednicarbate, or prednisolone. The method according to claim 18.

31. The method of claim 30, wherein the anti-inflammatory steroid is triamcinolone.

32. The method of claim 30, wherein triamcinolone is administered in a dose of 12 mg.

33. The method of claim 18, wherein the NSAID is one or more of diclofenac, ketrolac, neparenac, or bromfenac.

34. The method of claim 18, wherein a region containing abnormal or excessive angiogenesis is present in the eye.

35. The method of claim 18, wherein a region containing abnormal or excessive angiogenesis is present in the skin.

36. Areas containing abnormal or excessive angiogenesis include pyogenic granuloma, pediatric hemangioma, infantile hemangioma, congenital hemangioma, tufted hemangioma, spindle cell hemangioma, epithelioid cell hemangioma, Kaposi's hemangioendothelioma, reticular hemangiendothelioma, papillary lymphangioendothelioma, Dabska tumor, complex hemangioendothelioma, and Kaposi's tumor. The method of claim 18, comprising di sarcoma, angiosarcoma, epithelioid hemangioendothelioma, capillary malformation, lymphatic malformation, venous malformation, arteriovenous malformation, arteriovenous fistula, capillary-lymphatic malformation, capillary-arteriovenous malformation, capillary-lymphatic vessel-arteriovenous malformation, capillary-vein-arteriovenous malformation, and capillary-lymphatic vessel-vein-arteriovenous malformation.

37. The method of claim 18, wherein the region containing abnormal or excessive angiogenesis comprises a lesion of at least one eye, eyelid and orbit, selected from cavernous hemangioma, cavernous malformation, arteriovenous malformation, arteriovenous fistula, aneurysm, lymphangioma, hemangioendothelioma (angiosarcoma), angiolympholympia with eosinophilia (Kimura's disease), vine-like hemangioma of Wyburn-Mason syndrome, hemangioblastoma, orbital varicose veins, venous lymphatic malformation, choroidal plexus hemangioma, choroidal plexus melanoma, and Coats' disease.

38. A device for administering the composition of claim 1, wherein the composition is administered by at least one method selected from intravenous, subconjunctival, subtenon's capsule, episclera, intrasclera, subsclera, intraperitoneal, epidural, subarachnoid, intramuscular, intracavitary, intratracheal, epidermal, intradermal, subdermal, or subcutaneous. A device configured in such a way.

39. The device of claim 38, wherein the device comprises one part of a kit.

40. The kit includes at least one cartridge pre-loaded with a predetermined amount of pharmaceutical composition, and an injection. The device according to claim 39, comprising a container, vial, or applicator.

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