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 through the skin, based on biocompatible polymeric compounds and packaged in fibres, in particular nanofibers, preferably obtained by electrospinning. [Background technology]

[0002] Products for direct application to the skin, such as emulsions, creams, lotions, serums, gels, powders, oils, sun milks, etc., are widely known and are manufactured in a variety of forms that are compatible with and / or absorbed by the skin.

[0003] However, these products can be difficult to apply to the skin, require prolonged application or prolonged massage to ensure complete absorption into the dermis, and can leave cosmetic residue on fingers, hands, and applicators. There are also cosmetic products that are generally applied by a fibrous physical support, which facilitates application to the skin, such as makeup remover wipes impregnated with special cleansing compositions.

[0004] A drawback of this type of product is that after use, the fibrous physical support, which has no other function than to provide support, and the packaging must be discarded.

[0005] Furthermore, known fibrous physical supports have certain surfaces that do not allow proper transport and release of the active ingredients. Furthermore, cosmetic compositions for the skin, such as topical applications such as creams or general pastes, generally present the problem of providing for the use of functional compounds for the skin and compounds that function exclusively for the structure of the formulation.

[0006] Skin functional compounds are those that are partially or totally absorbed by the skin and exert a beneficial effect on the treated area of ​​the body. Generally, compounds of this type represent so-called active ingredients.

[0007] The compounds which are exclusively functional for the structure of the formulation are those which contribute to obtaining the composition to be applied, whether it be an emulsion, serum or fluid, oleolite, water or gel. The effect of solely functional compounds on the structure of the formulation may affect the storage method or the texture of the composition before and / or during use and therefore when spread on the skin to be treated.

[0008] For example, compounds that function exclusively in the structure of a formulation can make the composition soft, fluid, or viscous; can gel and prevent the separation of oily compounds from aqueous compounds in emulsions; and can also allow the composition to be preserved, especially in the presence of water.

[0009] However, the problem arises that many of the compounds used act on the structure of the formulation, and therefore do not bring any benefit to the skin, and may even cause further deterioration of the treated skin.In fact, some compounds that act only on the structure of the formulation remain irrelevant to the skin, or may cause, for example, further dryness, clogged pores, or the development of allergies, dermatitis, etc.

[0010] Among the compounds that have an exclusive function in the structure of the formulation, for example silicones, petrolatum (e.g. paraffin), alcohols, fragrances, stabilizers, preservatives, emulsifiers have been identified, whose main function is to give the formulation of the composition a "silk effect" texture in contact with the skin and / or to provide stability to the oily part, or to increase the viscosity of a gel formulation and / or to increase the emollient and moisturizing effect of an emulsion.

[0011] For example, one problem that arises with these compounds that function exclusively in the structure of the formulation is a lack of skin compatibility, which prevents the skin from breathing and leads, for example, to its progressive drying, pore closure and / or greater sensitization.

[0012] It is also known that the presence of alcohol and preservatives, on the one hand, allows the composition to be preserved, but on the other hand, increases the sensitization of the skin in the development of dermatitis, allergies or similar pathologies. Summary of the Invention [Problem to be solved by the invention]

[0013] Therefore, there is a need to perfect a product that can overcome at least one of the drawbacks of the prior art. In particular, it is an object of the present invention to provide a product that can be easily and quickly applied to the skin.

[0014] Another object of the present invention is to provide a product that has no physical support that is discarded after use. Another object of the present invention is to provide a product with a specific surface that optimizes the transport and release of active ingredients, if any. Applicant has conceived, tested and embodied the present invention to overcome the shortcomings of the prior art and to obtain these and other objects and advantages.

[0015] The invention is defined and characterized in the independent claims. The dependent claims describe other features of the invention or variants to the main inventive idea. In accordance with the above objectives, a patch has been produced that overcomes the limitations of the current state of the art and eliminates the existing defects.

[0016] In some embodiments, a patch product is provided, which is composed of a membrane substrate suitable for preferential application to and absorption by the skin. The membrane substrate is electrospun. The electrospun substrate (electrospun substrate) is composed of at least one fiber, preferably nanofiber, in the form of a nonwoven fabric.

[0017] Advantageously, the film substrate comprises one or more active ingredients selected from cosmetic active ingredients, pharmaceutical active ingredients and nutritional active ingredients. The expression "active ingredient" means herein a compound that is functional for the body or a part thereof and that is absorbed partially or completely by the skin and provides a benefit to the part of the body that is treated.

[0018] According to some embodiments, the substrate is based on a biocompatible polymeric material suitable for electrospinning selected from the group consisting of polysaccharides, collagen, gelatin, albumin, elastin and derivatives thereof. 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, glycosaminoglycans, mucopolysaccharides, water-soluble polysaccharides and derivatives thereof.

[0019] Preferably, the cellulose derivative may be selected from hydroxypropylmethylcellulose HPMC, hydroxypropylcellulose HPC, hydroxyethylcellulose HEC, and sodium carboxymethylcellulose Na-CMC. The glycosaminoglycan GAG or mucopolysaccharide may be selected from chondroitin sulfate, dermatan sulfate, heparin, heparan sulfate, and hyaluronic acid HA. The water-soluble polysaccharide may be selected from galactomannan, xylan, gum arabic, gum ghatti, 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 is made of both linear and cross-linked hyaluronic acid. Preferably, the hyaluronic acid has a molecular weight of less than 10,000 Da, which is advantageous for the complete absorption of the hyaluronic acid in the skin.

[0022] One advantage of the patch products according to the embodiments described herein is that they are completely absorbed into the skin along with any active ingredients present, such as cosmetic, pharmaceutical or nutritional active ingredients. In addition to being complete, absorption is fast, with full absorption of the patch products according to the invention being observed to occur within just a few minutes of application to the skin.

[0023] Another advantage is that the form that the patch product presents does not imply a form that requires the presence of compounds that function exclusively in the structure, since the active ingredient is carried and transmitted by the membrane substrate, which is completely biocompatible and can be absorbed by the skin, without posing any danger or damage to the skin itself.

[0024] Another advantage of cosmetic, pharmaceutical, or nutritional products is that they can achieve much higher local concentrations of the target compound than those achieved with conventional formulations. Even with polysaccharides, collagen, gelatin, albumin, elastin, and their low molecular weight derivatives, achieving high concentrations is virtually impossible because the viscosity of the product increases too much, making it impossible to exceed 5-10% by weight. Using the compositions of the present invention, it is possible to obtain cosmetic products that can be applied to the skin with a target compound concentration of up to 50% by weight.

[0025] According to another aspect, the present invention also relates to an article comprising a patch product (tissue patch) as described above disposed on a support. Preferably, the article comprises a package having a support within which the patch product resides. Advantageously, the package also includes a covering layer that serves to protect the patch product present on the support. The covering layer and the support are joined to each other to form an interior space for containing the patch product. More preferably, the support and the covering layer are heat-sealed to each other.

[0026] Advantageously, the support and the covering layer are heat-sealable and are preferably made of PBSA (polybutylene succinate adipate) or PLA (polylactic acid). DETAILED DESCRIPTION OF THE INVENTION

[0027] Reference will now be made in detail to possible embodiments of the invention, one or more examples of which are illustrated by way of non-limiting example in the accompanying drawings. The phraseology and terminology used herein is also for the purposes of providing a non-limiting example.

[0028] Unless otherwise defined, all technical and scientific terms used herein and hereinafter have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice and testing of the present invention, the methods and materials are described below by way of example. In case of conflict, the present invention, including its definitions, will control. The materials, methods, and examples are purely illustrative and should not be construed as limiting.

[0029] All measurements were performed at 25°C (room temperature) and atmospheric pressure unless otherwise noted. All temperatures are in degrees Celsius unless otherwise noted. All percentages and ratios given herein are understood to refer to weight (w / w) of the total composition unless otherwise specified. All percentage intervals reported herein are provided in terms of total sum of 100% for the entire composition unless otherwise noted. All intervals reported herein are to be understood as inclusive, including those describing an interval "between" two values, unless otherwise specified.

[0030] In addition, unless otherwise specified, this description also includes sections derived by overlapping or integrating two or more sections described. In addition, unless otherwise specified, the present description also includes intervals derived from a combination of two or more values ​​obtained at different points. When water is mentioned, it means distilled water unless otherwise specified.

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

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

[0033] Preferably, the fibers are continuous, have a homogeneous composition, and have a substantially smooth surface. The fibers are also preferably free of defects, i.e., no accumulations or drips of the substrate that may form during electrospinning. Advantageously, the electrospun fibers have diameters on the order of nanometers and micrometers, but in any case smaller than 100 μm, more preferably smaller than 50 μm, even more preferably smaller than 25 μm, and at most on the order 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 vary substantially along the entire fiber. By substantially unchanged diameter, it is meant that the diameter may vary, but does not exceed 30% of the measured average value.

[0034] Fibers with these diameters have a larger surface / volume ratio than known fibers, typically with diameters of 100 μm or greater, and also possess significant mechanical and structural properties that provide greater efficiency and performance than industry standards. The large specific surface of the resulting fibers is particularly suitable for the transport and release of active ingredients. The resulting nanofibers have diameters ranging from 1 to 30 m. 2 / g, preferably 2 to 20 m2 / g.

[0035] The membrane substrate is a biocompatible polymeric material suitable for electrospinning and is selected from the group consisting of 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, gum arabic, gum ghatti, 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 have the properties of being able to modify the viscosity of a liquid, making them suitable for forming normal electrospun fibers with good mechanical and absorption properties. Furthermore, they are all biocompatible, naturally occurring, and can be used in the food, pharmaceutical, and / or cosmetic industries.

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

[0038] Chitosan is used in the food sector in low-calorie diets and in the pharmaceutical sector as an excipient, especially in inhalation products, while pectin is used in the food sector as a gelling agent and in the pharmaceutical sector as a food and probiotic. Agar, galactomannan, and glucomannan are used as gelling agents in the nutritional field.

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

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

[0041] It should be noted that some of these compounds have unique functions in the cosmetic, pharmaceutical or food fields, such as, for example, starch, elastin, hyaluronic acid, heparin, collagen, pectin, β-glucan, chondroitin sulfate, dermatan sulfate, heparan sulfate and their derivatives. It is therefore advantageous to electrospin these compounds, since by applying the corresponding fibers it is possible to apply these compounds in higher doses than known solutions, with the advantage that their effectiveness is greater.

[0042] Electrospun fibers are made from pullulan and / or alginate, which are used as electrospinning promoters during the production of the fibers. salt It should be noted that the present invention may also include pullulan and / or alginic acid, if present. salt is preferably present in a weight ratio of (electrospinning compound (compound to be electrospun)):adjuvant of 10:1 to 1:10, more preferably 4:1 to 1:7, and even more preferably 3:1 to 1:6. Pullulan is the preferred spinning adjuvant as it gives the best results in terms of the structure of the electrospun fibers.

[0043] According to some embodiments, the membrane substrate is composed of hyaluronic acid. Preferably, the substrate is composed of linear and / or cross-linked hyaluronic acid. Advantageously, the substrate is made of both linear and cross-linked hyaluronic acid, with the ratio of linear HA:cross-linked HA being 1:99 to 99:1. Such a mixture allows for adjustment of 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, a low mass, typically on the order of 10,000 Daltons or less. The latter form is preferred, since hyaluronic acid with a molecular weight of 10,000 Da or less, in electrospun form, is completely absorbed once in contact with the skin, penetrates the stratum corneum to the innermost layer, and, thanks to its properties such as hygroscopicity, viscoelasticity, and structural function, is able to regulate the hydration of (cellular) tissues, the osmotic balance, and the physical properties of the ECM.

[0045] Advantageously, the absorption and penetration of the membrane substrate into the skin also allows the active ingredient associated with the membrane support to be delivered towards the skin. In particular, according to some embodiments, the patch product comprises at least one active ingredient selected from cosmetic active ingredients, pharmaceutical active ingredients, and nutritional active ingredients, associated with a film substrate. It should be noted that an active ingredient, regardless of its field of action, can have various types of functions.

[0046] Cosmetic active ingredients can be of the following types: Antiseborrheic agents (e.g., sebacic acid, azelaic acid), antisebum agents (e.g., charcoal powder), antibacterial agents (e.g., climbazole, 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), skin lightening 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 oil), soothing agents (e.g., Hamamelis virginiana extract, chamomile extract, bisabolol), or tonic agents (e.g., Arnica montana, Capsicum annuum extract), UV filters (e.g., methylenebis-benzotriazolyltetramethylbutylphenol, ethylhexyl methoxycinnamate, caffeine, theine, theobromine, theophylline).

[0047] The active pharmaceutical ingredient can be of the following types: 5α-reductase inhibitors (e.g., finasteride), 5-aminosalicylic acids (e.g., mesalamine), 5HT3 receptor antagonists (e.g., ondansetron), ACE inhibitors in combination with calcium channel blockers (e.g., amlodipine / benazepril), ACE inhibitors in combination with thiazides (e.g., hydrochlorothiazide), adamantane antivirals (e.g., amantadine), corticosteroid inhibitors (e.g., aminoglutethimide), adrenergic bronchodilators (e.g., albuterol), antihypertensives (e.g., hypertension drugs), and pulmonary hypertension treatments. These include: antihistamines (e.g., treprostinil), aldosterone receptor antagonists (e.g., spironolactone), alkylating agents (e.g., cyclophosphamide), allergens (e.g., dust mite allergen extract), α-glucosidase inhibitors (e.g., miglitol), amoebic drugs (e.g., metronidazole), aminoglycosides (e.g., tobramycin), aminopenicillins (e.g., amoxicillin), aminosalicylates (e.g., aminosalicylic acid), AMPA receptor antagonists (e.g., perampanel), amylin analogs (e.g., pramlint), steroids), analgesics (e.g., acetaminophen), androgens and anabolic steroids (e.g., testosterone), angiotensin-converting enzyme inhibitors (e.g., ramipril), angiotensin II inhibitor and calcium channel blocker combinations (e.g., amlodipine / olmesartan), angiotensin II inhibitor and thiazide combinations (e.g., hydrochlorothiazide / olmesartan), angiotensin receptor blockers (e.g., valsartan), angiotensin and neprilysin receptor inhibitors (e.g., sacubitril / valsartan), steroids (e.g., phentermine), rectal medications (e.g., hydrocortisone / pramoxine), appetite suppressants (e.g., phentermine), antacids (e.g., magnesium hydroxide), anthelmintics (e.g., pyrantel), anti-angiogenic ophthalmic medications (e.g., aflibercept), anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab), anti-PD-1 monoclonal antibodies (e.g., nivolumab), anti-adrenergic agonists (central) in combination with thiazides (e.g., hydrochlorothiazide / methyldopa), anti-adrenergic agonists (peripheral) in combination with thiazides (e.g., polythiazide / prazosin),Central antiadrenergics (e.g., guanfacine), peripheral antiadrenergics (e.g., tamsulosin), antiandrogens (e.g., enzalutamide), antianginals (e.g., nitroglycerin, e.g., dyphylline / guaifenesin), antibiotics (e.g., metronidazole), antibiotics / antineoplastics (e.g., doxorubicin), anticholinergic antiemetics (e.g., diphenhydramine ), anticholinergic antiparkinsonian drugs (e.g., procyclidine), anticholinergic bronchodilators (e.g., tiotropium), anticholinergic / antispasmodic drugs (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), antifungals (e.g., griseofulvin), antigonadotropins (e.g., danazol), antigout agents (e.g., colchicine), antihistamines (e.g., cetirizine), antihyperlipidemic agents and combinations (e.g., ezetimibe / simvastatin), antihyperuricemia agents (e.g., febuxostat), antimalarials (e.g., doxycycline), antimalarials, antimalarial / quinoline combinations (e.g., hydroxychloroquine), antimanic agents (e.g., lithium), antimetabolites (e.g., capecitabine), antimigraine agents (e.g., rizatriptan), antineoplastic agents (e.g., isotretinoin), antineoplastic combinations (e.g., letrozole / ribociclib), antineoplastic antidotes (e.g., amifostine), ), antitumor interferons (e.g., interferon alpha-2b), antipseudomonal penicillins (e.g., carbenicillin), antipsoriatics (e.g., acitretin), antipsychotics (e.g., haloperidol), antirheumatic drugs (e.g., adalimumab), antiseptics and disinfectants (e.g., potassium iodide), antitoxins and antivirals (e.g., antivenin (Crotariidae) 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), barbiturates (e.g., primidone), barbiturates (e.g., phenobarbital), BCR-ABL tyrosine kinase inhibitors (e.g., imatinib), anticonvulsant benzodiazepines (e.g., diazepam), benzodiazepines (e.g., clonazepam), beta-blocker and thiazide combinations (e.g., bisoprolol / hydrochlorothiazide), beta-lactamase inhibitors (e.g., clavulanic acid), bile acid sequestrants (e.g., colsevelam), 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 / beta-lactamase inhibitors (e.g., meropenem / vaborbactam), anticonvulsant carbonic anhydrase inhibitors (e.g., topiramate), carbonic anhydrase inhibitors (e.g., acetazolamide), cardiac stress medications (e.g., regadenoson), cardioselective beta-blockers (e.g., nebivolol), catecholamines (e.g., epinephrine), CD20 monoclonal antibodies (e.g., ocrelizumab), CD30 monoclonal antibodies (e.g., brentuximab), CD33 monoclonal antibodies (e.g., gemtuzumab), CD38 monoclonal antibodies (e.g., CD52 monoclonal), (e.g., alemtuzumab), CDK4 / 6 inhibitors (e.g., palbociclib) ), cephalosporins / beta-lactamase inhibitors (e.g., avibactam / ceftazidime), ceruminoleptics (e.g., carbamide peroxide), CFTR combinations (e.g., ivacaftor / lumacaftor), CFTR potentiators (e.g., ivacaftor), 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), corticotropin, coumarins and indanediones (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), estrogens (e.g., estradiol), expectorants (e.g., guaifenesin), factor Xa inhibitors (e.g., rivaroxaban), fatty acid derivatives 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., tiagabine), general anesthetics (e.g., propofol), GI stimulants (e.g., , metoclopramide), glucocorticoids (e.g., budesonide), glucose-elevating drugs (e.g., glucagon), glycopeptide antibiotics (e.g., vancomycin), glycoprotein platelet inhibitors (e.g., tirofiban), glycylureas (e.g., tigecycline), gonadotropin-releasing hormones (e.g., leuprolide), gonadotropin-releasing hormone antagonists (e.g., elagolix), gonadotropins (e.g., chorionic gonadotropin) Class I antiarrhythmic drugs (e.g., phenytoin), Class II antiarrhythmic drugs (e.g., propranolol), Class III antiarrhythmic drugs (e.g., dronedarone), Class IV antiarrhythmic drugs (e.g., verapamil), Class V antiarrhythmic drugs (e.g., digoxin), growth hormone receptor blockers (e.g., pegvisomant), growth hormones (e.g., somatropin), guanylate cyclase C agonists (e.g., linaclotide), H. pylori eradication drugs (e.g.,bismuth potassium nitrite / metronidazole / tetracycline), H2 antagonists (e.g., ranitidine), hedgehog pathway inhibitors (e.g., vismodegib), heparin antagonists (e.g., protamine), HER2 inhibitors (e.g., neratinib), herbal medicines (e.g., 5-hydroxytryptophan, aloe vera), histone deacetylase inhibitors (e.g., romidepsin), hormones / antineoplastic agents (e.g., medroxyprogesterone), hydantoin anticonvulsants (e.g., phenytoin), hydrazide derivatives (e.g., isoniazid), immunoglobulins anti-leprosy drugs (e.g., bisacodyl), anti-impotence drugs (e.g., sildenafil), incretin mimetics (e.g., liraglutide), cardiac inotropes (e.g., digoxin), insulin and derivatives (e.g., insulin glargine), insulin-like growth factors (e.g., mecasermin), interferons (e.g., interferon beta-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., clofazimine), 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), meglitinides (e.g., repaglinide), melanocortin receptor agonists (e.g., bremelanotide), methylxanthines (e.g., teocorticoids), 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 circulatory system 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 system drugs (e.g., phenazopyridine), various gastrointestinal system drugs (e.g., misoprostol), various metabolic system drugs (e.g., burosumab), various respiratory system 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), mal, These include: kinase inhibitors (e.g., sorafenib), narcotic analgesic combinations (e.g., buprenorphine-naloxone), narcotic analgesics (e.g., fentanyl), natural penicillins (e.g., penicillin V potassium), neuraminidase inhibitors (e.g., oseltamivir), neuronal potassium channel openers (e.g., ezogabine), new-generation cephalosporins (e.g., ceftaroline), NHE3 inhibitors (e.g., ceftaroline), nicotinic acid derivatives (e.g., ethionamide), NK1 receptor antagonists (e.g., aprepitant), NNRTIs (e.g., efavirenz), non-cardioselective beta-blockers (e.g., carvedilol), non-sulfonylureas (e.g., metformin), nonsteroidal anti-inflammatory drugs (e.g., diclofenac), NS5A inhibitors (e.g., daclata). subvir), nucleoside reverse transcriptase inhibitors (NRTIs) (e.g., tenofovir), dietary supplements (e.g., omega-3 polyunsaturated fatty acids), oral nutritional supplements (e.g., arginine), other immunostimulants (e.g., glatiramer), other immunosuppressants (e.g., omalizumab), oxazolidinedione anticonvulsants (e.g., trimethadione), oxazolidinedione antibiotics (e.g., linezolid), parathyroid hormone and analogs (e.g., teriparatide), PARP inhibitors (e.g., niraparib), PCSK9 inhibitors (e.g., evolocumab), penicillinase-resistant penicillins (e.g., oxacillin), peripheral opioid receptor antagonists (e.g., naloxegol), mixed peripheral opioid receptor agonists (e.g., agonist / eluxadoline antagonists), peripheral vasodilators (e.g., isoxsuprine), peripherally acting antiobesity drugs (e.g., orlistat), phenothiazine antiemetics (e.g., promethazine), phenothiazine antipsychotics (e.g., prochlorperazine), phenylpiperazine antidepressants (e.g., trazodone), potassium phosphate inhibitors (e.g., trazodone) (e.g., idelalisib), platelet aggregation inhibitors (e.g., aspirin), platelet stimulating agents (e.g., eltrombopag), polyenes (e.g., nystatin), potassium-sparing diuretics (e.g., spironolactone), probiotics (e.g., Lactobacillus acidophilus), progesterone receptor modulators (e.g., ulipristal),progestin levonorgestrel, prolactin inhibitors (e.g., cabergoline), protease inhibitors (e.g., telaprevir), protease-activated receptor-1 antagonists (e.g., vorapaxar), proteasome inhibitors (e.g., bortezomib), proton pump inhibitors (e.g., omeprazole), psoralens (e.g., methoxsalen), purine nucleosides (e.g., valacyclovir), pyrrolidine 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), salicylates (e.g., aspirin), second-generation cephalosporins (e.g., cefuroxime receptor modulators), modulators (e.g., ospemifene), selective immunosuppressants (e.g., natalizumab), selective phosphodiesterase 4 inhibitors inhibitors (e.g., roflumilast), selective serotonin reuptake inhibitors (e.g., escitalopram), serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine), serotonergic neuroenteric modulators (e.g., tegaserod), SGLT-2 inhibitors (e.g., empagliflozin), skeletal muscle relaxants (e.g., onabotulinumtoxinA), smoking cessation medications (e.g., nicotine analogues somatostats) (e.g., octreotide), statins (e.g., lovastatin), streptogramins (e.g., dalfopristin / quinupristin), streptomycin derivatives (e.g., capreomycin), antiepileptic succinimides (e.g., ethos ximid), 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), thioxanthenes (e.g., thiothixene), third-generation cephalosporins (e.g., ceftriaxone), thrombin inhibitors (e.g., dabigatozone), streptolysins (e.g., levothyroxine), TNF-α inhibitors (e.g., adalimumab), labor-inhibiting drugs (e.g., terbutaline), topical acne medications (e.g.,tretinoin), local anesthetics (e.g., lidocaine), topical anti-infectives (e.g., malathion), topical anti-rosacea medications (e.g., ivermectin), topical antibiotics (e.g., silver sulfadiazine), topical antifungals (e.g., econazole), topical antihistamines (e.g., diphenhydramine), topical antineoplastics (e.g., imiquimod), topical antipsoriatics (e.g., tazarotene), topical antivirals (e.g., penciclovir), Topical astringents (e.g., hazelnut), topical debridement agents (e.g., collagenase), topical depigmenting agents (e.g., hydroquinone), topical emollients (e.g., emollients), topical keratolytic agents (e.g., salicylic acid), topical nonsteroidal anti-inflammatory agents (e.g., diclofenac), topical photochemical agents (e.g., aminolevulinic acid), topical rubefacients (e.g., menthol), topical steroids (e.g., betamethasone), anti-infective 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 antiinfectives (e.g., nitrofurantoin), urinary tract antispasmodics (e.g., amitriptyline), modifiers (e.g., potassium citrate), uterotonics (e.g., dinoprostone), vaginal antiinfectives (e.g., clindamycin), vasodilators (e.g., alprostadil), vasopressin antagonists (e.g., conivaptan), hypertensives (e.g., epinephrine), VEGF / VEGFR inhibitors (e.g., pazopan), viral vaccines, vitamin-mineral combinations, vitamins (e.g., cyanocobalamin), VMAT2 inhibitors (e.g., valbenazine).

[0048] Nutritional active ingredients can be of 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., oleic acid, niacin ... Omega-3, Omega-6, Omega-9 fatty acids), natural products extracted or derived from plants, animals, algae, fungi, lichens, or bacteria or produced using unprocessed sources (e.g., phytosterols, echinacea, green tea extract, garlic, aloe vera, fish oil, spirulina, chlorella, digestive enzymes from mushrooms), sugars and polysaccharides (e.g., mannose, ribose, trehalose, dextrose, glucuronolactone, dextrin), probiotics (e.g., Lactobacillus, Bifidobacterium, saccharin, etc.), live microorganisms such as Proteus boulardii), 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), 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 the electrospinning produces a membrane with a three-dimensional structure that accommodates particles of the active ingredient. For example, the three-dimensional structure of the nonwoven fabric can include cavities, also called cages, suitable for accommodating molecules of the active ingredient. An example of a compound for obtaining a nonwoven fabric with cavities is a mixture of linear hyaluronic acid and cross-linked hyaluronic acid.

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

[0051] The active ingredient can be added already to the electrospun membrane substrate, allowing the active ingredient molecules or particles to be "trapped" within the three-dimensional structure of the substrate while in the nonwoven state. Alternatively, the active ingredient can be included in the composition that is subsequently electrospun. In other words, the active ingredient can be co-electrospun, i.e., electrospun with the material that constitutes the substrate. In that case, the resulting patch product will consist 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.In addition, the product obtainable by electrospinning the composition can be applied directly to the burned zone (area), which improves the effectiveness of treatment.

[0053] It should be noted that the patch product according to the present invention can be used for any type of application, such as for the treatment of burns, to supply the body with active ingredients in the fields of cosmetics, medicines, or food.In particular, the patch product 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 product can also be used for the intake of food supplements.

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

[0055] For example, cosmetic active ingredients include: antiseborrheic agents (sebacic acid, azelaic acid), antioxidants (ascorbic acid, tocopherol, retinol, retinal), pigmentation inhibitors (glabridin, ammonium persulfate), emollients (witch hazel extract, bisabolol), moisturizers (glycerin, propanediol, etc.).

[0056] Among the suitable nutritional active ingredients are 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, catechin), which are extracted or derived from plants, animals, algae, fungi, lichens, or bacteria or are produced using intact sources.

[0057] The most preferred 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), antianginal drugs (e.g., nitroglycerin), antiasthmatic combination drugs (e.g., dyphylline / guaifenesin), antibiotics (e.g., metronidazole), antibiotic / antineoplastic drugs (e.g., doxorubicin), antineoplastic drugs (e.g., isotretinoin), and antineoplastic drug combination drugs (e.g., letrozole / ribociclib).

[0058] It should be noted that these active ingredients can be advantageously combined with other compounds to be electrospun, such as, for example, xanthan gum, guar gum, chondroitin sulfate, collagen or starch. Another example of a patch product provides heparin as the electrospun compound and an active pharmaceutical ingredient, such as an allergen extract or a platelet stimulating agent such as eltrombopag.

[0059] Furthermore, the patch product of 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 to deliver the active ingredient into the body. Indeed, according to the present invention, the membrane substrate is completely absorbed in a short period of time (typically within a few minutes), eliminating the need for the membrane to remain attached to the skin.

[0060] The present invention also relates to an article having the above-mentioned patch product disposed on a support. Preferably, the support, together with a covering layer disposed so as 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 so as to form an internal space intended to accommodate the patch product.

[0061] Preferably, the joining is performed by heat sealing, more preferably along the edges of the support and the coating layer. The packaging can protect the patch product, i.e., the membrane substrate and one or more active ingredients, and isolate them from external factors that may damage them or alter their structure and / or chemical composition.

[0062] Advantageously, the support and the covering layer can be made of the same material or two different materials, and obviously, at least one surface is made of a material that is compatible with the patch product. Compatibility with the patch product in the present context means that the patch product that is brought into contact with this surface is not chemically or structurally modified. A surface made of a compatible material does not interact with the substrate or the active ingredient, and only functions as an inert support.

[0063] Advantageously, the support and the covering layer are made of a heat-sealable type of material, for example polybutylene succinate adipate PBSA or polylactic acid PLA.

[0064] A preferred method for producing the article involves depositing the electrospun film substrate directly onto a support. The electrospun film substrate is then covered with a coating layer, and the support and the coating layer are then bonded together. Advantageously, the support and the coating layer are bonded together in such a way that an internal space for accommodating the patch product is formed therebetween.

[0065] As mentioned above, the joining of the layers to one another preferably occurs by heat sealing, more preferably by heat sealing corresponding edges of the support and the covering layer.

[0066] example The different compositions listed below were electrospun under the conditions indicated. In the example compositions, the first compound that is electrospun, and therefore constitutes the membrane substrate of the cosmetic patch product, is selected from the compounds listed in the table below. TIFF0007762154000001.tif28121

[0067] These compounds are supplied by 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 carried out in a NANON.01A device from the Japanese company Mecc Co. The experimental conditions are given in each example below.

[0069] The fabricated fibers were characterized by scanning electron microscopy: they were gold coated using an EMITECH K950x Turbo Evaporator sputter coater (EB Sciences, East Granby, CT) and observed with a Cambridge Stereoscan 440 SEM (Cambridge, UK).

[0070] Hyaluronic acid as the compound to be electrospun and PEO:alginate as the spinning aid salt Examples of electrospinning of compositions comprising mixtures of The spinning aid was 5% by weight of alginic acid. salt The composition was prepared by mixing an aqueous solution of 5 wt% PEO in a 1:1 ratio. This adjuvant was then mixed with a 0.5 wt% aqueous solution of linear hyaluronic acid (HA1) with an average molecular weight of 1.2 MDa. The adjuvant:(HA solution) ratio was equal to 5.6:1. This composition was electrospun at a relative humidity (RH) of 24%-29%, a temperature of 22°C, an electric field of 20 kV, a volumetric flow rate of the composition at the spinning head equal to 0.7 mL / h, a distance between the spinning head and the support on which the fibers were deposited equal to 15 cm, and a needle with a diameter of 22 G. The resulting fibers were normal and had few defects.

[0071] The same adjuvant was mixed with a 13% by weight aqueous solution of hyaluronic acid oligomers in an adjuvant:(HA solution) ratio of 1:3. When this composition of Example 2 was electrospun under the same operating conditions as Example 1 above, very normal, defect-free fibers with an average diameter of 250-350 nm were obtained. The resulting fibers completely covered the substrate used.

[0072] Example of electrospinning of a composition containing hyaluronic acid as the compound to be electrospun and pullulan as a spinning aid The pullulan used was food-grade pullulan from HAYASHIBARA Co., Ltd. Aqueous solutions of 10 wt%, 15 wt%, and 20 wt% pullulan were prepared, and these pullulan solutions (spinning aids) were mixed with aqueous hyaluronic acid solutions and electrospinning was performed.

[0073] The table below lists examples of electrospun compositions and the corresponding electrospinning operating conditions. TIFF0007762154000002.tif84125

[0074] In Example 1, defect-free, normal fibers with an average diameter of 400-700 nm were obtained, but little deposition was observed during the test.

[0075] In Example 2, the obtained fibers were thick with an average diameter of 10 μm due to the high viscosity of the electrospinning solution.

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

[0077] The influence of the ratio of adjuvant to hyaluronic acid was investigated using Examples 4 and 7 (pullulan:HA ratio equal to 1:2) on the one hand, and Examples 6 and 8 (pullulan:HA ratio equal to 1:3) on the other hand. In Example 4, the resulting solution had optimal properties for good electrospinning, with the resulting fibers having an average diameter ranging from 800 nm to 1 μm. For the composition of Example 4, which had an acidic pH, increasing the pH to 5.5 (by adding 1M NaOH) resulted in the solution of Example 7. In the latter case, electrospinning yielded regular, uniform fibers with an average diameter of 500-700 nm, smaller than those of Example 4.

[0078] By increasing the proportion of hyaluronic acid, in example 6 (at acidic pH) fibers with a uniform diameter were obtained, with a mean value equal to 1-3 μm, whereas in example 8 (at pH 5.5) fibers with a non-uniform diameter ranging from 700 nm to 3 μm were obtained.

[0079] In Example 5, pullulan was stabilized with alginate. salt At a ratio of 1:3 between adjuvant and HA, thick fibers with an average diameter on the order of several microns were obtained under the conditions shown in the table.

[0080] It will be apparent that modifications and / or additions may be made to the patch product as hereinbefore described without departing from the field and scope of the present invention as defined by the claims.

[0081] In the claims that follow, references in parentheses are for ease of reading only and should not be considered as limiting factors with respect 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 made of an electrospun 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 (excluding pullulan and alginate), and derivatives thereof; the active ingredient is selected from a cosmetic active ingredient, a pharmaceutical active ingredient, and a nutritional active ingredient; A patch product, characterized in that the electrospun fibers contain hyaluronic acid as the electrospinning compound and pullulan and / or alginate as electrospinning aids.

2. the cellulose derivative is selected from hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and sodium carboxymethylcellulose; the glycosaminoglycan is selected from chondroitin sulfate, dermatan sulfate, heparin, and heparan sulfate; 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. A patch product as described in claim 1 or 2, characterized in that the electrospinning compound other than hyaluronic acid is selected from starch, elastin, 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. The patch product according to any one of claims 1 to 5, wherein the active ingredient is electrospun together with the electrospinning compound and is integrated into the electrospun fibers.

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 cover layer and the support are bonded to each other to form an interior space that contains the patch product.

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