Natural polymer-based patch products

Abstract

The present invention relates to a patch product. [Solution] The patch product is composed of a membrane substrate based on a natural polymer suitable for absorption by the skin and at least one active ingredient, and can be packaged in a package consisting of a support for placing the patch product and a covering layer for protecting the patch product.

Description

Technical Field

[0001] The present invention relates to a product, more particularly a patch product that can be absorbed by the skin, which is based on a biocompatible polymer compound, obtained by fibers, particularly nanofibers, preferably by electrospinning, and packaged.

Background Art

[0002] Products applied directly to the skin, such as emulsions, creams, lotions, serums, gels, powders, oils, sun milks, etc., are widely known and are manufactured in various forms that are compatible with the skin and / or absorbed by the skin.

[0003] However, these products are difficult to apply to the skin, require long-term application or long-term massage to be completely absorbed by the dermis, and may leave cosmetic residues on the fingers, hands, or applicators used. There are also generally cosmetics applied by a fibrous physical support, which facilitates application to the skin, such as a makeup remover wipe impregnated with a special cleansing composition.

[0004] The disadvantages of this type of product are that after use, it has a fibrous physical support that has no function other than the function as a support, and the packaging must be discarded.

[0005] Furthermore, known fibrous physical supports have specific surfaces that do not allow for proper transport and release of the active ingredient. Also, generally, skin cosmetic compositions, such as those applied like creams, or general pastes, present the problem of providing the use of skin-functional compounds and compounds that function only with respect to the structure of the formulation.

[0006] Skin-functional compounds are those that are partially or completely absorbed by the skin and have an effect on the treatment site of the body. Generally, this type of compound represents a so-called active ingredient.

[0007] Compounds that function exclusively with respect to the structure of the formulation contribute to obtaining the applicable composition, whether it be an emulsion, serum, fluid, oleolite, water, or gel. The effects of compounds that are solely functional to the structure of a formulation may affect the storage method, or the texture of the composition before and / or during use, and therefore when spread on the skin being treated.

[0008] For example, compounds that function solely on the structure of a formulation can make the composition soft, fluid, or viscous; they can gel and prevent the separation of oily compounds from aqueous compounds in an emulsion. Furthermore, compounds that function solely on the structure of a formulation allow for the preservation of the composition, especially in the presence of water.

[0009] However, a problem arises because many of the compounds used function only in relation to the structure of the formulation, providing no benefit to the skin and, in fact, potentially even worsening the treated skin. Indeed, some compounds that function only in relation to the structure of the formulation remain irrelevant to the skin, or may even cause further dryness, clogged pores, or the development of allergies or dermatitis, for example.

[0010] Among the compounds that function exclusively on the structure of the formulation, for example, silicones, petrolatum (e.g., paraffin), alcohols, fragrances, stabilizers, preservatives, and emulsifiers have been identified. Their main functions are to give the formulation a "silky effect" texture upon contact with the skin and / or to provide stability to oily portions, or to increase the viscosity of gel formulations and / or to enhance the emollient and wetting effects of emulsions.

[0011] For example, one problem that arises with these compounds that function solely on the structure of a formulation is a lack of skin compatibility, which hinders skin respiration and can lead to, for example, progressive dryness, clogged pores, and / or greater sensitization.

[0012] Furthermore, the presence of alcohol and preservatives is known to, on the one hand, enable the preservation of the composition, and on the other hand, to increase skin sensitization in the development of dermatitis, allergies, or similar pathologies. [Overview of the Initiative] [Problems that the invention aims to solve]

[0013] Therefore, it is necessary to develop a product that can overcome at least one of the shortcomings of conventional technology. In particular, one objective of the present invention is to provide a product that can be applied to the skin easily and quickly.

[0014] Another object of the present invention is to provide a product that does not have a physical support that is discarded after use. Another object of the present invention is to provide a product having a specific surface that optimizes the transport and release of an active ingredient, if present. The applicant has devised, tested, and embodied the present invention in order to overcome the shortcomings of the prior art and to obtain these and other objectives and advantages.

[0015] The present invention is defined and characterized in the independent claims. Dependent claims describe other features of the present invention or variations on the main concept of the invention. In line with the above objectives, a patch was manufactured that overcomes the current limitations and eliminates existing defects.

[0016] According to several embodiments, a patch product is provided comprising a membrane substrate that is particularly suitable for preferential application to the skin and absorption by the skin. The membrane substrate is electrospinned. The electrospinned substrate (electrospinned substrate) is composed of at least one fiber, preferably a nanofiber, and in particular in the form of a nonwoven fabric.

[0017] Advantageously, the membrane substrate contains one or more active ingredients selected from cosmetic active ingredients, pharmaceutical active ingredients, and nutritional active ingredients. The term "active ingredient" as used herein means a compound that is functional to the body or a part thereof and is partially or completely absorbed by the skin, providing a benefit to the part of the body that is treated.

[0018] According to some embodiments, the substrate is based on a biocompatible polymer material suitable for electrospinning, selected from the group consisting of polysaccharides, collagen, gelatin, albumin, elastin, and their derivatives. Preferably, the polysaccharide is selected from the group consisting of xanthan gum, pectin, chitin, chitosan, dextran, carrageenan, guar gum, agar, cellulose derivatives, starch, gelatin, β-glucan, glycosaminoglycan, mucopolysaccharides, water-soluble polysaccharides, and their derivatives.

[0019] Preferably, the cellulose derivative can be selected from hydroxypropylmethylcellulose HPMC, hydroxypropylcellulose HPC, hydroxyethylcellulose HEC, and carboxymethylcellulose sodium Na-CMC. The glycosaminoglycan GAG or mucopolysaccharide can be selected from chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and hyaluronic acid HA. The water-soluble polysaccharide can be selected from galactomannan, xylan, acacia gum, ghati gum, glucomannan, acemannan, water-soluble dietary fiber, glycogen, amylose, and polysaccharides derived from plants, bacteria, and fungi.

[0020] According to some embodiments, the active ingredient is integrated into the membrane substrate. Alternatively, the active ingredient can be embedded in the three-dimensional structure of the membrane substrate.

[0021] According to some embodiments, the membrane substrate comprises linear and / or cross-linked hyaluronic acid. Advantageously, the membrane substrate can be made from both linear and cross-linked hyaluronic acid. Preferably, hyaluronic acid has a molecular weight of less than 10,000 Da. This molecular weight is advantageous for the complete absorbability of hyaluronic acid in the skin.

[0022] One advantage of the patch products according to the embodiments described herein is that they are completely absorbed by the skin together with the active ingredients present, such as those of cosmetics, pharmaceuticals or nutrition. In addition to being complete, the absorption is rapid, and it has been confirmed that the total absorption of the patch products according to the present invention occurs within a few minutes from the application to the skin.

[0023] Another advantage is that the form presented by the patch product is such that the active ingredient is carried and transmitted by the membrane substrate, which is completely biocompatible and absorbable by the skin and does not cause danger or damage to the skin itself, so it does not mean a form that requires the presence of a compound that functions only for the structure.

[0024] Another advantage of cosmetics, pharmaceuticals or nutritional products is that they can achieve a much higher local concentration of the target compound than the concentration obtained with conventional formulations. Even for polysaccharides, collagen, gelatin, albumin, elastin and their low molecular weight derivatives, it is substantially impossible to reach a high concentration because the viscosity of the product increases too much and it is impossible to exceed 5-10% by weight. Using the composition of the present invention, it is possible to obtain a cosmetic that can apply a target compound at a concentration of up to 50% by weight to the skin.

[0025] According to another aspect, the present invention also relates to an article comprising the patch product (adhesive) as shown above disposed on a support. Preferably, the article has a package, and this package has a support and the patch product is present inside it. Advantageously, the package also includes a coating layer that serves to protect the patch product present on the support. The coating layer and the support are joined to each other to form an internal space for accommodating the patch product. More preferably, the support and the coating layer are heat-sealed to each other.

[0026] Advantageously, the support and the coating layer are heat-sealable. Preferably, they are made of PBSA (polybutylene succinate adipate) or PLA (polylactic acid).

Embodiments for Carrying out the Invention

[0027] Here, as a non-limiting example, reference will be made in detail to possible embodiments of the present invention, in which one or more examples are shown in the accompanying drawings. The turns of phrase and technical terms used here are also for the purpose of providing non-limiting examples.

[0028] Unless otherwise defined, all technical and scientific terms used here and below have the same meaning as commonly understood by those of ordinary skill in the technical field to which the present invention pertains. Even if methods and materials similar or equivalent to those described here can be used in the implementation and testing of the present invention, the methods and materials are described below as an example. In case of conflict, the present invention including its definition shall prevail. The materials, methods, and examples are for purely illustrative purposes and should not be understood restrictively.

[0029] Unless otherwise specified, all measurements were carried out at 25°C (room temperature) and atmospheric pressure. Unless otherwise specified, all temperatures are expressed in degrees Celsius. It is understood that all percentages and ratios shown here refer to the weight (w / w) of the total composition, unless otherwise stated. All percentage intervals reported here are provided with the stipulation that, unless otherwise stated, the sum regarding the overall composition is 100%. All intervals (ranges) reported here are understood to include those that describe the interval "between" two values, including both ends, unless otherwise stated.

[0030] Also, in this description, unless otherwise stated, intervals derived by overlapping or integrating two or more described intervals are also included. Furthermore, unless otherwise specified, this explanation includes intervals derived from combinations of two or more values ​​obtained at different points. When "water" is mentioned, unless otherwise specified, it means distilled water.

[0031] The embodiments described herein relate to patch products preferably applied to the skin, comprising at least one electrospinned fiber (electrospinned fiber) in the form of a nonwoven fabric, preferably an electrospinned membrane substrate (electrospinned membrane substrate) consisting of nanofibers. This embodiment is obtained by gradually depositing the fibers onto a support during electrospinning. The fibers are gradually deposited on several gradually overlapping layers. It is possible to provide more fibers, for example, by supplying them simultaneously onto the same support.

[0032] Electrospinning is performed by supplying a specific composition under an electric field and passing it through an electrospinning head. The fibers exiting the electrospinning head are deposited on a support. The shape of the nonwoven fabric can be obtained by the relative movement between the electrospinning head and the support.

[0033] Preferably, the fibers are continuous, have a homogeneous composition, and have a substantially smooth surface. The fibers are also preferably defect-free, i.e., free from substrate accumulation or dripping that may form during electrospinning. Advantageously, the electrospinned fibers have diameters on the order of nanometers and micrometers, but in either case less than 100 μm, more preferably less than 50 μm, even more preferably less than 25 μm, and up to a maximum diameter of 10 μm. The substrate fibers can have diameters of several tens of nanometers, for example, starting from 50 nm. It should be noted that the diameter does not substantially change along the entire fiber. Substantially consistent diameter means that while the diameter may fluctuate, it will not exceed 30% of the measured average value.

[0034] Fibers with these diameters generally have a larger surface-to-volume ratio than known fibers with diameters of 100 μm or more, and possess superior mechanical and structural properties that provide higher efficiency and performance than industry standards. The large specific surface area of ​​the resulting fibers is particularly suitable for the transport and release of active ingredients. The resulting nanofibers are 1-30 m 2 This allows for a specific surface area of ​​2 to 20 m² / g, preferably 2 to 20 m² / g.

[0035] The membrane substrate is a biocompatible polymer material suitable for electrospinning, and is selected from xanthan gum, pectin, chitin, chitosan, dextran, carrageenan, guar gum, agar, hydroxypropyl methylcellulose HPMC, hydroxypropyl cellulose HPC, hydroxyethyl cellulose HEC, sodium carboxymethylcellulose (Na-CMC), albumin, starch, gelatin, collagen, elastin, β-glucan, chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, hyaluronic acid HA, galactomannan, xylan, acacia gum, ghati gum, glucomannan, acemannan, water-soluble dietary fiber, glycogen, amylose, polysaccharides derived from plants, bacteria, and fungi, and their derivatives.

[0036] These compounds or classes of compounds, by their properties, can alter the viscosity of liquids and are suitable for forming normal electrospinned fibers (electrospinned fibers) with good mechanical and absorbent properties. Furthermore, they are all biocompatible, naturally derived, and can be used in the food, pharmaceutical, and / or cosmetic fields.

[0037] In particular, xanthan gum, dextran, carrageenan, Na-CMC, starch, gelatin, and guatti gum are used in the food industry as thickeners, stabilizers, and sometimes gelling agents. Furthermore, xanthan gum is used as a stabilizer for suspensions and emulsions in the pharmaceutical and cosmetic industries, guar gum is also used as a thickener and gelling agent in the pharmaceutical and cosmetic industries, and carrageenan is used as an inactive excipient in the pharmaceutical industry. Dextran is also used as a thickener in the pharmaceutical industry.

[0038] Chitosan is used in the food industry as a low-calorie food ingredient and in the pharmaceutical industry as an excipient, particularly in inhalation products. Pectin, on the other hand, is used in the food industry as a gelling agent and in the pharmaceutical industry as a food ingredient and probiotic. Agar, galactomannan, and glucomannan are used as gelling agents in the nutrition field.

[0039] Among cellulose derivatives, HPMC is used in the food industry as a stabilizer and viscosity modifier, and in the pharmaceutical industry as an excipient for eyewashes and oral medications. HPC is used as a food additive and in the pharmaceutical industry as a binder for eyewashes and tablets. HEC is used as a thickener and gelling agent in the pharmaceutical and cosmetic industries.

[0040] Beta-glucan is used as a dietary fiber, and xylan is used similarly. Chondroitin sulfate is used as a food additive and as a treatment for osteoarthritis. Dermatan sulfate, heparin, and heparan sulfate are known as anticoagulants in the pharmaceutical field. Gum arabic is used in the food industry as a stabilizing excipient and viscosity modifier. On the other hand, acemannan is known in the pharmaceutical industry for its immunostimulatory properties.

[0041] It should be noted that some of these compounds, such as starch, elastin, hyaluronic acid, heparin, collagen, pectin, β-glucan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and their derivatives, have unique functions in the fields of cosmetics, pharmaceuticals, or food. Therefore, electrospinning these compounds is advantageous because, by applying the corresponding fibers, these compounds can be applied in higher doses than in known solutions, resulting in a greater effect.

[0042] It should be noted that electrospinned fibers may also contain pullulan and / or alginic acid, which are used as electrospinning promoters during the production of the fibers. If present, pullulan and / or alginic acid are present in a (electrospinning compound):promoter ratio of preferably 10:1 to 1:10 by weight, more preferably 4:1 to 1:7, and even more preferably 3:1 to 1:6. Pullulan is a preferred spinning promoter because it yields the best results in terms of the structure of the electrospinned fibers.

[0043] According to some embodiments, the membrane substrate is composed of hyaluronic acid. Preferably, the substrate is composed of linear and / or crosslinked hyaluronic acid. Advantageously, the substrate is made of both linear and crosslinked hyaluronic acid, with a linear HA:crosslinked HA ratio of 1:99 to 99:1. Such mixtures can be used to adjust the stiffness of the resulting yarn and the three-dimensional structure of the nonwoven film.

[0044] Hyaluronic acid can have a high mass, for example, on the order of 1 million Daltons or more, or alternatively, it can have a low mass, typically on the order of 10,000 Daltons or less. The latter form is preferred because hyaluronic acid with a molecular weight of 10,000 Da or less, in its electrospinned form, is completely absorbed once it comes into contact with the skin, penetrates the stratum corneum to reach the innermost layer, and, thanks to its properties such as hygroscopicity, viscoelasticity, and structural function, can regulate the hydration of (cellular) tissue, osmotic balance, and the physical properties of the ECM.

[0045] Advantageously, the absorption and penetration of the membrane substrate into the skin makes it possible to deliver the active ingredients related to the membrane support toward the skin. In particular, according to some embodiments, the patch product comprises at least one active ingredient associated with a membrane substrate, selected from cosmetic active ingredients, pharmaceutical active ingredients, and nutritional active ingredients. Furthermore, active ingredients can possess a variety of functions, regardless of their specific area of ​​action.

[0046] Cosmetic active ingredients can be of the following types: Anti-seborrheic agents (e.g., sebacic acid, azelaic acid), anti-sebum agents (e.g., charcoal powder), antibacterial agents (e.g., crimbazole, piroctone olamine), antioxidants (e.g., ascorbic acid, tocopherol, coenzyme Q10, resveratrol, glutathione), antiperspirants (e.g., aluminum chlorohydrate, aluminum sesquichlorohydrate), astringents (e.g., Citrus aurantifolia (lime) flower extract, calcium lactate), whitening agents (e.g., glabridin, ammonium persulfate), makeup removers (e.g., sodium cocoyl glutamate), deodorants (e.g., triethyl citrate, zinc ricinoleate), exfoliants (e.g., glycolic acid, malic acid, mandelic acid), flavorings (e.g., citral, honey), fragrances (e.g., d,l-limonene, coumarin), humectants (e.g., glycerin, Propanediol), keratolytic agents (e.g., chloroacetic acid, salicylic acid), moisturizers (e.g., aloe arborescens leaf extract), fragrances (e.g., geraniol, linalool), emollients (e.g., triolein, squalene), refreshing agents (e.g., menthol, menthyl lactate), skin moisturizers (e.g., panthenol, allantoin), skin protectants (e.g., sphingolipids, zinc oxide), smoothing agents (e.g., castor bean seed oil), soothing agents (e.g., witch hazel extract, chamomile extract, bisabolol), or tonic agents (e.g., Arnica montana, Capsicum arvensis extract), UV filters (e.g., methylenebis-benzotriazolyltetramethylbutylphenol, ethylhexyl methoxycinnamate, caffeine, theine, theobromine, theophylline).

[0047] The active ingredients in pharmaceuticals can be of the following types: 5α-reductase inhibitors (e.g., finasteride), 5-aminosalicylic acid (e.g., mesalamine), 5HT3 receptor antagonists (e.g., ondansetron), ACE inhibitors used in combination with calcium channel blockers (e.g., amlodipine / benazepril), ACE inhibitors used in combination with thiazides (e.g., hydrochlorothiazide), adamantane antiviral drugs (e.g., amantadine), corticosteroid inhibitors (e.g., aminoglutethimide), adrenaline bronchodilators (e.g., albuterol), antihypertensive drugs (e.g., antihypertensive drugs), pulmonary hypertension treatment Therapeutic drugs (e.g., treprostinil), aldosterone receptor antagonists (e.g., spironolactone), alkylating agents (e.g., cyclophosphamide), allergens (e.g., leucoma mites allergen extract), α-glucosidase inhibitors (e.g., miglitol), anti-amebic drugs (e.g., metronidazole), aminoglycosides (e.g., tobramycin), aminopenicillins (e.g., amoxicillin), aminosalicylic acids (e.g., aminosalicylic acid), AMPA receptor antagonists (e.g., perampanel), amylin analogs (e.g., Pramlinta) Analgesics (e.g., acetaminophen), androgens and anabolic steroids (e.g., testosterone), angiotensin-converting enzyme inhibitors (e.g., ramipril), combination of angiotensin II inhibitors and calcium channel blockers (e.g., amlodipine / olmesartan), combination of angiotensin II inhibitors and thiazides (e.g., hydrochlorothiazide / olmesartan), angiotensin receptor antagonists (e.g., valsartan), angiotensin and neprilysin receptor inhibitors (e.g., sacubitril / valsalta) ), rectal drugs (e.g., hydrocortisone / pramoxin), appetite suppressants (e.g., phentermine), antacids (e.g., magnesium hydroxide), anthelmintics (e.g., pyrantel), anti-angiogenic ophthalmic drugs (e.g., aflibercept), anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab), anti-PD-1 monoclonal antibodies (e.g., nivolumab), anti-adrenergic agonists used in combination with thiazides (central) (e.g., hydrochlorothiazide / methyldopa), anti-adrenergic agonists used in combination with thiazides (peripheral) (e.g., polythiazide / prazosin),Central antiadrenergic agonists (e.g., guanfacine), peripheral antiadrenergic agonists (e.g., tamsulosin), antiandrogens (e.g., enzalutamide), antianginal drugs (e.g., nitroglycerin, e.g., diphylline / guaifenesin), antibiotics (e.g., metronidazole), antibiotics / antineoplastic agents (e.g., doxorubicin), anticholinergic antiemetics (e.g., diphenhydramine) ), anticholinergic antiparkinsonian drugs (e.g., procyclidine), anticholinergic bronchodilators (e.g., tiotropium), anticholinergic / antispasmodics (e.g., hyoscyamine), anticoagulants (e.g., phytonadione), anticonvulsants (e.g., lacosamide), antidepressants (e.g., bupropion), antidiarrheals (e.g., loperamide), antidiuretic hormones (e.g., desmopressin), antidotes (e.g., naltrexone) Dronabinol), antifungal agents (e.g., griseofulvin), antigonadotropins (e.g., danazol), antigout agents (e.g., colchicine), antihistamines (e.g., cetirizine), antihyperlipidemic agents and combinations (e.g., ezetimibe / simvastatin), antiuricemia agents (e.g., febuxostat), antimalarial agents (e.g., doxycycline), antimalarial agents, antimalarial / quinoline combinations (e.g., hydroxychloroquine), antimanic agents (e.g., lithium), antimetabolites (e.g., capecitabine), antimigraine agents (e.g., rizatriptan), antitumor agents (e.g., isotretinoin), antitumor combinations (e.g., letrozole / ribociclib), antitumor antidotes (e.g., amifostine) ), antitumor interferons (e.g., interferon alpha-2b), anti-Pseudomonas penicillins (e.g., carbenicillin), antipsoriasis drugs (e.g., acitretin), antipsychotics (e.g., haloperidol), antirheumatic drugs (e.g., adalimumab), antiseptics and antibacterials (e.g., potassium iodide), antitoxins and antivirals (e.g., antibenin (crotariaceae) polyvalent), antitussives (e.g., dextromethorphan), antiviral boosters (e.g., ritonavir), antiviral interferons (e.g., pegylated interferon alpha-2a), aromatase inhibitors (e.g., anastrozole), atypical antipsychotics (e.g., aripiprazole), azole antifungals (e.g., fluconazole),Bacterial vaccines (e.g., 13-valent pneumococcal vaccine), barbiturate anticonvulsants (e.g., primidone), barbiturates (e.g., phenobarbital), BCR-ABL tyrosine kinase inhibitors (e.g., imatinib), anticonvulsant benzodiazepines (e.g., diazepam), benzodiazepines (e.g., clonazepam), combination therapy of β-blockers and thiazides (e.g., bisoprolol / hydrochlorothiazide), β-lactamase inhibitors (e.g., clavulanate), bile acid chelating agents (e.g., corseveram), bisphosphonates (e.g., zoledronic acid), BTK inhibitors (e.g., ibrutinib), calcium receptor agonists (e.g., cinacalcet), calcineurin inhibitors (e.g., tacrolimus), calcitonin, calcium channel blockers (e.g., Verapamil), anticonvulsant carbamates (e.g., felbamate), carbapenems (e.g., doripenem), carbapenem / β-lactamase inhibitors (e.g., meropenem / bavolbactam), anticonvulsant carbonic anhydrase inhibitors (e.g., topiramate), carbonic anhydrase inhibitors (e.g., acetazolamide), cardiac stress medications (e.g., regadenoson), cardiac-selective β-blockers (e.g., nebivolol), catecholamines (e.g., epinephrine), CD20 monoclonal antibodies (e.g., ocrelizumab), CD30 monoclonal antibodies (e.g., brentiximab), CD33 monoclonal antibodies (e.g., gemtuzumab), CD38 monoclonal antibodies (e.g., CD52 monoclonal), (e.g., alemtuzumab), CDK4 / 6 inhibitors (e.g., palbociclib) ), cephalosporins / β-lactamase inhibitors (e.g., avibactam / ceftazidime), earwax dissolving agents (e.g., carbamide peroxide), CFTR combination therapy (e.g., ibaftol / lumaftol), CFTR enhancers (e.g., ibaftol), CGRP inhibitors (e.g., erenumab), chelating agents (e.g., deferasirox), chemokine receptor inhibitors (e.g., maraviroc), chloride channel activators (e.g., lubiprostone), cholesterol absorption inhibitors (e.g., ezetimibe), cholinergic agonists (e.g., cevimeline), cholinergic muscle stimulants (e.g., pyridostigmine), cholinesterase inhibitors (e.g., donepezil), central nervous system stimulants (e.g.,Phentermine), colony-stimulating factors (e.g., filgrastim), contraceptives (e.g., levonorgestrel), corticotropins, coumarins and indanedions (e.g., warfarin), Cox-2 inhibitors (e.g., celecoxib), decongestants (e.g., pseudoephedrine), diarylquinolines (e.g.,), dibenzazepine antiepileptic drugs (e.g., carbamazepine), digestive enzymes (e.g., lactase), dipeptidyl peptidase 4 inhibitors (e.g., sitagliptin), dopaminergic antiparkinsonian drugs (e.g., ropinirole), drugs for alcohol dependence (e.g., acamprosate), echinocandin (e.g., caspofungin) inhibitors (e.g., erlotinib), estrogen receptor antagonists (e.g., fulvestrant), estrogen (e.g., estradiol), expectorants (e.g., guaifenesin), factor Xa inhibitors (e.g., rivaroxaban), fatty acid inducers Conductive anticonvulsants (e.g., divalproex sodium), fibric acid derivatives (e.g., fenofibrate), first-generation cephalosporins (e.g., cephalexin), fourth-generation cephalosporins (e.g., cefepime), gallstone dissolving agents (e.g., ursodiol), gamma-aminobutyric acid analogs (e.g., gabapentin), gamma-aminobutyric acid reuptake inhibitors (e.g., thiagabin), general anesthetics (e.g., propofol), GI stimulants (e.g., (e.g., metoclopramide), glucocorticoids (e.g., budesonide), glucose-raising agents (e.g., glucagon), glycopeptide antibiotics (e.g., vancomycin), glycoprotein platelet inhibitors (e.g., tyrofiban), glycylacrin (e.g., tigecycline), gonadotropin-releasing hormone (e.g., leuprolide), gonadotropin-releasing hormone antagonists (e.g., ellagolix), gonadotropins (e.g., chorionic gonadotropins) Class I antiarrhythmic drugs (e.g., phenytoin), Class II antiarrhythmic drugs (e.g., propranolol), Class III antiarrhythmic drugs (e.g., delonedarone), Class IV antiarrhythmic drugs (e.g., verapamil), Class V antiarrhythmic drugs (e.g., digoxin), growth hormone receptor blockers (e.g., pegvisomant), growth hormone (e.g., somatropin), guanylate cyclase C agonists (e.g., linaclotide), H. pylori eradication agents (e.g.,Bismuth potassium nitrite / metronidazole / tetracycline), H2 antagonists (e.g., ranitidine), Hedgehog pathway inhibitors (e.g., bismodegib), heparin antagonists (e.g., protamine), HER2 inhibitors (e.g., neratinib), herbal medicines (e.g., 5-hydroxytryptophan, aloe vera), histone deacetylase inhibitors (e.g., romidepsin), hormonal / antinomatous drugs (e.g., medroxyprogesterone), hydantoin anticonvulsants (e.g., phenytoin), hydrazide derivatives (e.g., isoniazid), immunoglobulins , impotence drugs (e.g., sildenafil), incretin mimetic drugs (e.g., liraglutide), cardiac stimulants (e.g., digoxin), insulin and derivatives (e.g., insulin glargine), insulin-like growth factors (e.g., mecasermin), interferon (e.g., interferon β-1a), interleukin inhibitors (e.g., dupilumab), interleukins (e.g., aldesleukin), iron drugs (e.g., ferrous sulfate), ketolides (e.g., telithromycin), laxatives (e.g., bisacodyl), anti-leprosy drugs (e.g., clofazimun) ), leukotriene modifiers (e.g., montelukast), lincomycin derivatives (e.g., clindamycin), loop diuretics (e.g., furosemide), lysosomal enzymes (e.g., imiglucerase), macrolides (e.g., azithromycin), mast cell stabilizers (e.g., cromolyn), meglitinide (e.g., repaglinide), melanocortin receptor agonists (e.g., bremelanotide), methylxanthines (e.g., theocorticoids), mineralocorticoids (e.g., fludrocortisone), minerals and electrolytes (e.g., citrate / citric acid) Potassium), various antiviral drugs (e.g., baloxavir marboxil), various anxiolytics, sedatives and hypnotics (e.g., zolpidem), various bone resorption inhibitors (e.g., denosumab), various cardiovascular drugs (e.g., midodrine), various central nervous system drugs (e.g., dalfampridine), various coagulation regulators (e.g., tranexamic acid), various diuretics (e.g., pamabrom), various urinary tract drugs (e.g., phenazopyridine), various gastrointestinal drugs (e.g., misoprostol), various metabolic drugs (e.g., burosumab), various respiratory drugs (e.g., α1-proteinase inhibitors),Various topical medications (e.g., sodium hyaluronate), various vaginal medications (e.g., estradiol), mitotic inhibitors (e.g., vincristine), monoamine oxidase inhibitors (e.g., phenelzine), oropharyngeal medications (e.g., fluoride), mTOR inhibitors (e.g., everolimus), mucolytics (e.g., acetylcysteine), Mar, Thikinase inhibitors (e.g., sorafenib), combinations of narcotic analgesics (e.g., buprenorphine / naloxone), narcotic analgesics (e.g., fentanyl), natural penicillin (e.g., penicillin V potassium), neuraminidase inhibitors (e.g., oseltamivir), neuronal potassium channel openers (e.g., ezogavine), new generation cephalosporins (e.g., ceftarolin), NHE3 inhibitors (e.g., ceftarolin), nicotinic acid derivatives (e.g., ethionamide), NK1 receptor antagonists (e.g., aprepitant), NNRTIs (e.g., efavirenz), noncardiac selective β-blockers (e.g., carvedilol), nonsulfonylureas (e.g., metformin), nonsteroidal anti-inflammatory drugs (e.g., diclofenac), NS5A inhibitors (e.g., daclata) Subir, nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., tenofovir), dietary supplements (e.g., omega-3 polyunsaturated fatty acids), oral dietary supplements (e.g., arginine), other immunostimulants (e.g., glatiramer), other immunosuppressants (e.g., omalizumab), oxazolidinedione anticonvulsants (e.g., trimethadione), oxazolidinedione antibacterial agents (e.g., linezolid), parathyroid hormone and analogs (e.g., teriparatide), PARP Inhibitors (e.g., niraparib), PCSK9 inhibitors (e.g., evolcumab), penicillinase-resistant penicillins (e.g., oxacillin), peripheral opioid receptor antagonists (e.g., naloxegol), mixed peripheral opioid receptor agonists (e.g., agonist / erxadrine antagonists), peripheral vasodilators (e.g., isoxuprine), peripheral-acting anti-obesity drugs (e.g., orlistat), phenothiazine antiemetics (e.g., promethazine), phenothiazine antipsychotics (e.g., For example, prochlorperazine), phenylpiperazine antidepressants (e.g., trazodone), potassium phosphate inhibitors (e.g., trazodone) (e.g., idelalisib), platelet aggregation inhibitors (e.g., aspirin), platelet stimulants (e.g., eltrombopag), polyenes (e.g., nystatin), potassium-sparing diuretics (e.g., spironolactone), probiotics (e.g., Lactobacillus acidophilus), progesterone receptor modulators (e.g., ulipristal),Progestins (levonorgestrel), prolactin inhibitors (e.g., cabergoline), protease inhibitors (e.g., telaprevir), protease-activated receptor-1 antagonists (e.g., borapaxal), proteasome inhibitors (e.g., bortezomib), proton pump inhibitors (e.g., omeprazole), psoralens (e.g., methoxsalen), purine nucleosides (e.g., valacyclovir), pyrrolidinedione anticonvulsants (e.g., levetiracetam), Human quinolones (e.g., ciprofloxacin), recombinant human erythropoietin (e.g., epoetin alfa), renin inhibitors (e.g., aliskiren), rifamycin derivatives (e.g., rifampicin), salicylic acid (e.g., aspirin), second-generation cephalosporins (e.g., selective cefuroxime receptors), modulators (e.g., ospemifene), selective immunosuppressants (e.g., natalizumab), selective phosphodiesterase 4 Inhibitors (e.g., roflumilast), selective serotonin reuptake inhibitors (e.g., escitalopram), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), serotonergic neurogutogenic modulators (e.g., tegaserodone), SGLT-2 inhibitors (e.g., empagliflozin), skeletal muscle relaxants (e.g., onabotulinum toxin A), smoking cessation drugs (e.g., nicotine analog somatostat) (e.g., octreotide), statins (e.g., lovastatin), streptogramin (e.g., dalfopristin / quinupristin), streptomyces derivatives (e.g., capreomycin), antiepileptic drugs succinimide (e.g., ethos Ximide), sulfonamides (e.g., sulfamethoxazole), sulfonylurea stimulants (e.g., glimepistol, clomiphene), tetracyclic antidepressants (e.g., mirtazapine), tetracyclines (e.g., minocycline), thiazide diuretics (e.g., hydrochlorothiazide), thiazolidinediones (e.g., pioglitazone), thioxanthene (e.g., thiothixen), third-generation cephalosporins (e.g., ceftriaxone), thrombin inhibitors (e.g., dabigatozone), streptolidine (e.g., levothyroxine), TNFα inhibitors (e.g., adalimumab), labor suppressants (e.g., terbutaline), topical acne medications (e.g.,Tretinoin), local anesthetics (e.g., lidocaine), topical anti-infection agents (e.g., malathion), topical anti-rosacea agents (e.g., ivermectin), topical antibiotics (e.g., silver sulfadiazine), topical antifungal agents (e.g., econazole), topical antihistamines (e.g., diphenhydramine), topical antitumor agents (e.g., imiquimod), topical antipsoriasis agents (e.g., tazarotene), topical antiviral agents (e.g., penciclovir), Topical astringents (e.g., hazelnut), topical debridement agents (e.g., collagenase), topical bleaching agents (e.g., hydroquinone), topical emollients, topical keratolytic agents (e.g., salicylic acid), topical nonsteroidal anti-inflammatory drugs (e.g., diclofenac), topical photochemicals (e.g., aminolevulinic acid), topical erythrocytes (e.g., menthol), topical steroids (e.g., betamethasone), anti-infective agents Concomitant topical steroids (e.g., acyclovir / hydrocortisone), transthyretin stabilizers (e.g., tafamidis), triazine anticonvulsants (e.g., lamotrigine), tricyclic antidepressants (e.g., amitriptyline), urea cycle inhibitors (e.g., sodium phenylbutyrate), urinary tract anti-infectives (e.g., nitrofurantoin), urinary tract antispasmodics (e.g., amitriptyline), modifiers (e.g., potassium citrate), uterine contraction agents (e.g., dinoprostone), vaginal anti-infectives (e.g., clindamycin), vasodilators (e.g., alprostadil), vasopressors (e.g., conivaptan), vasopressors (e.g., epinephrine), VEGF / VEGFR inhibitors (e.g., pazopan), viral vaccines, vitamin / mineral combination drugs, vitamins (e.g., cyanocobalamin), VMAT2 inhibitors (e.g., valbenazine).

[0048] Nutritional active ingredients can include the following types: Vitamins (e.g., vitamins A, B, C, D, E, K, folic acid, biotin), minerals (e.g., potassium, chlorine, sodium, calcium, phosphorus, magnesium, iron, zinc, manganese, copper, iodine, chromium, molybdenum, selenium, cobalt, fluoride), amino acids, peptides and proteins and their metabolites and derivatives (e.g., essential and branched amino acids, carnosine, enzymes and enzyme complexes, lactoferrin, N-acetylcysteine, proteins from animal or plant foods), fatty acids (e.g., o Natural products produced using substances extracted or derived from plants, animals, algae, fungi, lichens or bacteria, or unprocessed sources (e.g., phytosterols, echinacea, green tea extract, garlic, aloe vera, fish oil, spirulina, chlorella, mushroom-derived digestive enzymes), sugars and polysaccharides (e.g., mannose, ribose, trehalose, dextrose, glucuronolactone, dextrin), probiotics (e.g., Lactobacillus, Bifidobacterium, Sugars, Succulents, etc.) Live microorganisms such as Boudii, prebiotics (e.g., fructans such as fructooligosaccharides and inulin, galactans such as galactooligosaccharides and xylooligosaccharides), antioxidants (e.g., lipoic acid, coenzyme Q10, flavonoids, glutathione, resveratrol, catechins), and other substances with nutritional or physiological effects (e.g., betaine, caffeine, theobromine, theophylline, CDP-choline, choline, creatine, phospholipids, GABA, glucosamine, inositol, melatonin, methylsulfonylmethane, nucleotides, squalene).

[0049] In these embodiments, it is particularly advantageous to provide that the membrane substrate is composed of one or more biopolymers, and that electrospinning thereof generates a membrane having a three-dimensional structure that can accept particles of the active ingredient. For example, the three-dimensional structure of the nonwoven fabric may include cavities, also called cages, that are suitable for accommodating molecules of the active ingredient. An example of a compound for obtaining a nonwoven fabric having cavities is a mixture of linear hyaluronic acid and cross-linked hyaluronic acid.

[0050] According to some embodiments, regardless of the first electrospinning compound (the compound to be electrospinned), the active ingredient is a nonsteroidal anti-inflammatory agent, for example, for application to skin burns. It is also possible to provide the addition of one or more analgesics as additional active ingredients to alleviate the pain caused by burns. For this type of application, it is particularly advantageous that the first compound is of a skin-regenerating type, such as hyaluronic acid.

[0051] Since the active ingredient can already be added to the electrospinning film substrate, the molecules or particles of the active ingredient can be "trapped" within the three-dimensional structure of the substrate while it is still in the nonwoven fabric state. Alternatively, the active ingredient may be included in the composition that is subsequently electrospun. In other words, the active ingredient can be co-electrospun, i.e., electrospun together with the material constituting the substrate. In that case, the resulting patch product is composed of the active ingredient incorporated into the electrospun fibers.

[0052] The use of the patch product according to the present invention in the treatment of skin burns is advantageous because it ensures the rapid absorption of the active ingredient and the first compound in the wound. Furthermore, the product, which can be obtained by electrospinning the composition, can be applied directly to the burned zone (area). This improves the therapeutic effect.

[0053] It should be noted that, similar to the treatment of burns, the patch products according to the present invention can be used for any type of application to deliver active ingredients in the cosmetic, pharmaceutical, or food fields to the body. In particular, the patch products can be advantageously used to apply active ingredients that are currently administered by intramuscular injection. One example is an anticoagulant such as heparin. The patch products can also be used for the intake of food supplements.

[0054] For this purpose, hyaluronic acid as an electrospinned compound is a suitable candidate to be combined with each of the three different types of active ingredients mentioned above.

[0055] For example, the following are examples of active ingredients in cosmetics: anti-seborrheic agents (sebacic acid, azelaic acid), antioxidants (ascorbic acid, tocopherol, retinol, retinal), blemish inhibitors (glabridin, ammonium persulfate), softeners (witch hazel extract, bisabolol), and moisturizers (glycerin, propanediol, etc.).

[0056] Suitable nutritional active ingredients include natural products (phytosterols, echinacea, green tea extract, garlic, aloe vera, fish oil, spirulina, chlorella, fungal digestive enzymes), vitamins (e.g., vitamins A, B, C, D, E, K, folic acid, biotin), and antioxidants (e.g., lipoic acid, coenzyme Q10, flavonoids, glutathione, resveratrol, catechins) produced using substances extracted or derived from plants, animals, algae, fungi, lichens, or bacteria, or from unprocessed sources).

[0057] The most advantageous active pharmaceutical ingredients are androgens and anabolic steroids (e.g., testosterone), anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab), anti-PD-1 monoclonal antibodies (e.g., nivolumab), anti-angina agents (e.g., nitroglycerin), anti-asthma combination drugs (e.g., diphylline / guaifenesin), antibiotics (e.g., metronidazole), antibiotic / antineoplastic agents (e.g., doxorubicin), antineoplastic agents (e.g., isotretinoin), and antineoplastic combination drugs (e.g., letrozole / ribociclib).

[0058] It should be noted that these active ingredients can be advantageously combined with other electrospinned compounds, such as xanthan gum, guar gum, chondroitin sulfate, collagen, or starch. Other examples of patch products include supplying heparin as an electrospinning compound and a pharmacoactive ingredient, such as an allergen extract or a platelet stimulant like eltrombopag.

[0059] Furthermore, the patch product according to the present invention can replace existing patch products that provide a membrane substrate that is not absorbed by the skin and sometimes remains attached for several days in order to deliver the active ingredient into the body. In fact, according to the present invention, the membrane substrate is completely absorbed in a short time (typically a few minutes), and there is no need to leave the membrane attached to the skin.

[0060] The present invention also relates to an article having the above-described patch product disposed on a support. Preferably, the support, together with a covering layer disposed to cover the patch product, forms a package enclosing the patch product. For this purpose, the support and the covering layer are joined to each other to form an internal space intended to contain the patch product.

[0061] Preferably, the joining of the components is carried out by heat sealing, and more preferably, corresponding to the edges of the support and the coating layer. The packaging can protect the patch product, i.e., the film substrate and one or more active ingredients, and can isolate it from external factors that may damage it or alter its structure and / or chemical composition.

[0062] Advantageously, the support and coating layer can be made of the same material or two different materials, and obviously consist of at least one surface made of a material compatible with the patch product. Compatibility with the patch product, in the context of this specification, means that the patch product to which this surface comes into contact is not chemically or structurally altered. The surface made of the compatible material does not interact with the substrate or active ingredients and functions solely as an inert support.

[0063] Advantageously, the support and coating layers are made of heat-sealable materials, such as polybutylene succinate adipate (PBSA) or polylactic acid (PLA).

[0064] A preferred method for manufacturing an article provides depositing an electrospinning film substrate directly onto a support. The electrospinning film substrate is then covered with a coating layer, and subsequently the support and the coating layer are bonded together. Advantageously, the bonding of the support and the coating layer is carried out in such a manner that it forms an internal space between them for housing a patch product.

[0065] As described above, the inter-layer bonding is preferably achieved by heat sealing, and more preferably by heat sealing corresponding to the edges of the support and the coating layer.

[0066] example The following different compositions were electrospinned under the conditions indicated. In the example compositions, the first compound to be electrospinned, and thus constituting the film substrate of the cosmetic patch product, is selected from the compounds listed in the table below. TIFF2023513742000001.tif28121

[0067] These compounds were supplied from Esperis SpA, Milan, Evonik Degussa Italia, Cremona, and IRALAB SpA, Usmate Velate (MI). Molecular weights were determined by GPC (Gel Permeation Chromatography).

[0068] Electrospinning was performed using the NANON.01A instrument from Mecc, a Japanese company. The experimental conditions are shown in the following examples.

[0069] The fabricated fibers were evaluated using a scanning electron microscope. Specifically, they were coated with gold using an EMITECH K950x Turbo Evaporator sputter coater, EBSciences, East Granby, CT, and observed with a Cambridge Stereoscan 440 SEM, Cambridge, UK.

[0070] An example of electrospinning of a composition containing hyaluronic acid as the compound to be electrospinned and a PEO:alginate mixture as a spinning aid. The spinning aid was a mixture of a 5% by weight aqueous solution of alginic acid and a 5% by weight aqueous solution of PEO in a 1:1 ratio. To this aid, an aqueous solution of linear hyaluronic acid (HA1) with an average molecular weight of 1.2 MDa was added at a concentration of 0.5% by weight. The ratio of aid to (HA solution) was equal to 5.6:1. This composition was electrospinned under conditions of relative humidity (RH) of 24%-29%, temperature of 22°C, electric field of 20 kV, volumetric flow rate of the composition at the spinning head of 0.7 mL / h, distance between the spinning head and the support on which the fibers were deposited of 15 cm, and using a needle with a diameter of 22 G. The resulting fibers were normal and had few defects.

[0071] The same auxiliary agent was mixed with a 13% by weight aqueous solution of hyaluronic acid oligomer in a ratio of 1:3 for the auxiliary agent to the HA solution. When this second example composition was electrospinned under the same operating conditions as the first example, very normal, defect-free fibers with an average diameter of 250–350 nm were obtained. The resulting fibers completely covered the support used.

[0072] An example of electrospinning of a composition containing hyaluronic acid as the compound to be electrospinned and pullulan as a spinning aid. The pullulan used was food-grade from HAYASHIBARA Co., Ltd. 10%, 15%, and 20% by weight pullulan aqueous solutions were prepared, and these pullulan solutions (spinning aids) were mixed with hyaluronic acid aqueous solution to perform electrospinning.

[0073] The table below shows examples of electrospinned compositions and the corresponding electrospinning conditions. TIFF2023513742000002.tif84125

[0074] In Example 1, normal fibers with no defects and an average diameter of 400-700 nm were obtained. However, little deposition was observed during the experiment.

[0075] In Example 2, the viscosity of the electrospinning solution is high, resulting in thick fibers with an average diameter of 10 μm.

[0076] In Example 3, the obtained fibers have an average diameter of 50 nm to 2 μm. In this example, it is observed that the fibers were deposited on both aluminum and PBSA film.

[0077] The effect of the ratio of the adjuvant to hyaluronic acid was verified by two examples: one, Examples 4 and 7 (where the pullulan:HA ratio was equal to 1:2), and the other, Examples 6 and 8 (where the pullulan:HA ratio was equal to 1:3). In Example 4, the resulting solution had optimal properties for good electrospinning, and the resulting fibers had an average diameter ranging from 800 nm to 1 μm. For the composition of Example 4, which had an acidic pH, the pH was increased to 5.5 (by adding 1M NaOH), resulting in the solution of Example 7. In the latter case, electrospinning yielded normal, uniform fibers with an average diameter of 500-700 nm, which was smaller than that of Example 4.

[0078] By increasing the proportion of hyaluronic acid, in Example 6 (at an acidic pH), fibers with a uniform diameter equal to 1-3 μm on average were obtained, while in Example 8 (at pH 5.5), fibers with non-uniform diameters ranging from 700 nm to 3 μm were obtained.

[0079] In Example 5, alginic acid was added to pullulan as a stabilizer. With an auxiliary agent:HA ratio of 1:3, thick fibers with an average diameter on the order of several microns were obtained under the conditions shown in the table.

[0080] It is clear that modifications and / or additions to the patch products described herein can be made without departing from the field and scope of the invention as defined by the claims.

[0081] In the following claims, references in parentheses are for readability purposes only and should not be considered as limiting factors relating to the scope of protection claimed in any particular claim.

Claims

1. It comprises a film substrate that is absorbed into the skin and at least one active ingredient, the membrane substrate is formed by at least one electrospun fiber based on a compound selected from xanthan gum, pectin, chitin, chitosan, dextran, carrageenan, guar gum, agar, cellulose derivatives, albumin, starch, gelatin, collagen, elastin, β-glucan, glycosaminoglycan, mucopolysaccharide, water-soluble polysaccharide, and derivatives thereof; A patch product, wherein the active ingredient is selected from the group consisting of a cosmetic active ingredient, a pharmaceutical active ingredient, and a nutritional active ingredient.

2. the cellulose derivative is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose; the glycosaminoglycan is selected from chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and hyaluronic acid HA; The patch product according to claim 1, characterized in that the water-soluble polysaccharide is selected from galactomannan, xylan, gum arabic, gum ghatti, glucomannan, acemannan, water-soluble dietary fiber, glycogen, amylose and polysaccharides derived from plants, bacteria and fungi.

3. 3. The patch product according to claim 1 or 2, characterized in that the electrospinning compound is selected from starch, elastin, hyaluronic acid, heparin, collagen, pectin, β-glucan, chondroitin sulfate, dermatan sulfate, heparan sulfate and derivatives thereof.

4. 4. The patch product of claim 1, wherein the membrane substrate is in the form of a nonwoven fabric.

5. The patch product according to any one of claims 1 to 4, characterized in that the electrospun fibers have a diameter of less than 100 μm.

6. 6. A patch product according to any one of claims 1 to 5, characterized in that the active ingredient is integrated into the electrospun fibres.

7. The patch product according to any one of claims 1 to 6, wherein the active ingredient is incorporated into the three-dimensional structure of the membrane substrate.

8. 8. The patch product according to claim 1, wherein the active ingredient comprises a nonsteroidal anti-inflammatory agent and / or one or more analgesics.

9. An article comprising the patch product of any one of claims 1 to 8 disposed on a support.

10. a package containing the patch product; The packaging includes the support and a covering layer that serves as protection for the patch product; 10. The article of claim 9, wherein the covering layer and the support are bonded to each other to form an interior space that contains the patch product.

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