Rehydratable films for topical drug delivery

Abstract

The use of compositions in solid anhydrous form and in the form of a film, which can be reconstituted into semi-solid form at the time of topical application, as well as delivery systems for active ingredients or drugs, the related pharmaceutical compositions, the method for obtaining them and their use are described.

Description

[0001] REHYDRATABLE FILMS FOR TOPICAL DRUG DELIVERY

[0002] FIELD OF THE INVENTION

[0003] The present invention falls within the pharmaceutical sector and concerns the use of compositions in solid or waterless form as a delivery system for active ingredients or drugs or mixtures thereof. Said compositions are anhydrous and in the form of a film and can be reconstituted into semi-solid form at the time of topical application.

[0004] TECHNICAL BACKGROUND

[0005] Pharmaceutical research for topical formulations is aimed at improving the efficacy, tolerability, compliance and personalisation of pharmaceutical products. In addition, the growing attention to sustainability, short production chains and based on excipients of eco-sustainable natural origin, the need to reduce the carbon footprint has led to the development of a pharmaceutical formulation for topical use that meets these needs.

[0006] The market for topical pharmaceutical formulations is expected to expand due to several factors such as the increase in the prevalence of skin diseases, the increase in the elderly population, the growing awareness of consumers regarding the prevention and care of the skin and skin adnexa. The development of innovative techniques such as the use of encapsulation techniques for drugs and gelling polymers has led to an improvement in the absorption of drugs and therefore to greater therapeutic effectiveness and a reduction in side effects. Further improvement in both efficacy and tolerability research is still a goal of pharmaceutical research. In addition, new needs are emerging such as the improvement of patient compliance, the personalization of therapies, the sustainability of products in the production, transport, use and disposal phases. Patient compliance can be favoured by formulations based on natural ingredients, which are saferand more personalized, and by products that are easier to transport and store. The preparation of the pharmaceutical product in specific doses satisfies the demand for personalization of therapies. The sustainability of the entire life cycle of the pharmaceutical product can be increased by choosing excipients of natural origin and anhydrous formulations that reduce the use of preservatives, packaging and energy for transport and the consequent disposal of any surpluses or waste. Numerous reconstitutable formulations for topical use have been described but these, however, do not have the characteristics of personalized dose, ease of transport and storage (1-3).

[0007] Different encapsulation technologies are also known for both hydrophilic and lipophilic drugs, highlighting the possibility of using different types of nanocarriers with different drug release times and the possibility of penetration of the different layers of the skin to obtain the differenttherapeutic activities (4-6). The use of polymers to favour the application and absorption of the active ingredients (7- 9) is also known.

[0008] In the patent literature, Italian patent no. IT201900002623 describes a composition for the prevention and / or treatment of disorders of the oropharyngeal mucosa. U.S. Patent No. US20120141565 describes glycerosomes employed in pharmaceutical and cosmetic preparations for topical application.

[0009] The Italian patent no. IT202100022253A1 describes liposomes coated with hyaluronic acid which may contain in the core an active ingredient as a tyrosine kinase inhibitor, compositions containing them and their use in the treatment of respiratory diseases, preferably pulmonary fibrotic diseases. Said liposomes are prepared by means of a process that provides for a first step of solubilizing the phospholipid in a halogenated solvent then evaporating the solvent to obtain a phospholipid film, hydrating the phospholipid film in a buffer solution comprising at least one salt, obtaining a second suspension, subjecting the second suspension to extrusion and obtaining a suspension comprising liposomes, adding to said suspension comprising liposomes at least one active ingredient and obtaining liposomes containing said active ingredient.

[0010] Canadian Patent Application No. CA2289041 describes gel formulations for the topical application of active ingredients.

[0011] European Patent No. EP3025732 discloses liposome-like nanometric vesicles (hyalurosomes) for topical pharmaceutical or cosmetic applications comprising or consisting of: a) hyaluronate, preferably sodium hyaluronate, b) at least one phospholipid and c) at least one active pharmacological or cosmetic ingredient. The phospholipid is selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), etc. The vesicles are intended for the treatment of skin disorders such as dehydration, oxidative aging, cicatricia l / keloid alterations, atopic and seborrheic dermatitis, psoriasis. Liposomes were prepared using the conventional method of the phospholipid film, obtained by dissolving the lipophilic components in a solvent (chloroform or ethanol) and then removing the solvent by a rotary evaporator.

[0012] Chinese Patent CN103462895 describes a preparation method for liposomes that is based on microfluidization technology for high-pressure thin-film dispersion to prepare nanoliposomes together with layer-by-layer self-assembly technology.

[0013] Chinese Patent No. CN112006288 describes a method for preparing double layered modified reduced glutathione nanoliposomes which provides for dissolving a certain amount of soy lecithin, cholesterol and Tween 80 in anhydrous ethanol, then transferring to a round bottomed flask andevaporating under reduced pressure to remove the organic phase. Next, eluting and hydrating with a glutathione-containing buffer, slowly adding the glutathione nanoliposomes dropwise into the chitosan solution, stirring while adding, and letting it stand for a certain period. After the chitosan-modified glutathione liposomes are added dropwise to a solution of sodium alginate at a certain concentration, while continuing to mix, the solution is then allowed to stand for a certain period of time to obtain a solution of double-layered modified reduced glutathione nanoliposomes.

[0014] SUMMARY OF THE INVENTION

[0015] The present invention provides a solution to the aforementioned technical problem by making available a delivery system for active ingredients or drugs, called FiReFa (acronym for Rehydratable Films for the delivery of Drugs) characterized by being in solid form and without water (anhydrous). In fact, the absence of water does not allow microbial growth and for this reason it is possible to predict the reduction of the use of synthetic preservatives often responsible for the appearance of sensitizations and allergies. On the other hand, a waterless product is a much lighter product than a similar product that contains water, and this implies a considerable reduction in costs and environmental impact due to transport. Another reduction in environmental impact derives from the possibility of using much more eco-sustainable packaging since, being free of water, FiReFa can be packaged in paper avoiding bottles and jars and zeroing the use of plastic.

[0016] The invention also relates to anhydrous pharmaceutical compositions for topical use comprising a FiReFa delivery system and at least one active ingredient or drug, and are packable in single doses which are reconstituted into semi-solid formulations at the time of use.

[0017] These pharmaceutical compositions have numerous advantages: versatility of use and possibility of functionalisation for different therapeutic needs, reduction of the need to add preservatives and antimicrobial substances, they can be packaged in a sustainable way and in a single dose, they favour a drastic reduction in packaging, packaging, storage and transport costs, and they are easily scalable at an industrial level.

[0018] Therefore, the formulations subject-matter of the present invention offer the possibility of having much safer products, as they can be pre-dosed and personalized; they are also highly tolerable products based on few excipients and with a limited need for preservatives.

[0019] The FiReFa formulation technology of the present invention can be applied to drugs intended for the treatment the skin, mucous membranes and skin adnexa and transdermally administered drugs.The advantage for the consumer is the possibility of having a formulation for topical use dispensed in single doses, with greater safety due to the indication of the correct amount to be used and greater possibility of personalization of the care.

[0020] In comparison with conventional semi-solid pharmaceutical formulations for topical use such as gels, creams, ointments, the FiReFa formulations of the present invention are more sustainable in all steps of the product life cycle: excipients and / or bases of predominantly natural origin and from short supply chains, reduction of preservatives, elimination of bottles, jars, tubes for packaging for the benefit of paper packaging, reduction of energy use for storage and transport and easier disposal of packaging.

[0021] The compositions described in the prior art are all phospholipid particles in which a phospholipid double layer film is assembled by closing, generally in an aqueous environment thanks to hydrophobic interactions, and then incorporating the active ingredient.

[0022] In the present invention the phospholipid particles, possibly containing the active ingredient, are one of the elements that constitute a delivery system that is an anhydrous and solid polymer-based film, which is then reconstituted into a semi-solid form with the addition of water, only at the time of administration.

[0023] The invention therefore relates to a delivery system for active ingredients or drugs or mixtures thereof comprising:

[0024] a. Phospholipid nanoparticles;

[0025] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally

[0026] c. a plasticizing agent, preferably glycerin;

[0027] characterized by being anhydrous, in solid form, and in the form of a film

[0028] wherein the phospholipid nanoparticles are loadable with at least one active ingredient or a drug or mixtures thereof.

[0029] A further object of the present invention is a pharmaceutical composition for topical use comprising:a. Phospholipid nanoparticles containing at least one active ingredient or a drug or mixtures thereof;

[0030] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally

[0031] c. a plasticizing agent, preferably glycerin;

[0032] d. pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives;

[0033] characterised in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application.

[0034] The pharmaceutical composition of the present invention is reconstitutable into semi-solid form by adding water, in a volume amount of less than or equal to 0.15 mL per cm2of film.

[0035] The film composition is reconstituted into semi-solid form in a time of less than 30" from the time of addition of water.

[0036] Preferably the phospholipid nanoparticles are ethosomes, phytosomes, liposomes.

[0037] Preferably the phospholipid nanoparticles comprise phospholipids in the outer coating, preferably said nanoparticles are nanovesicles whose outer coating comprises soya lecithin.

[0038] Preferably the film has a thickness comprised between 10 and 90 pm, more preferably comprised between 10 and 50 pm, even more preferably comprised between 10 and 20 pm.

[0039] Preferably, the pharmaceutical composition of the invention can be reconstituted into a pharmaceutical composition in semi-solid / liquid form, preferably in the form of a gel, nanoemulgel, emulsion, lotion.

[0040] A further object of the invention is a method for obtaining a solid and anhydrous pharmaceutical composition for topical use comprising the following steps:

[0041] a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v;

[0042] c) Optionally adding glycerin in a concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;

[0043] e) Dehydrating the gel obtained from step d) to obtain a solid film.

[0044] Preferably in the method object of the invention the solution of soy lecithin in ethanol is added to the aqueous solution at a rate comprised between 1 mL / min and 2 mL / min.

[0045] Preferably in step e) the dehydration is performed by: drying, lyophilization.

[0046] More preferably in step e) the dehydration is performed by drying at a temperature comprised between 35 and 50 °C, even more preferably at 40 °C.

[0047] Preferably, the drying is carried out in heated air or on a heated surface.

[0048] A further object of the invention is a pharmaceutical composition comprising: phospholipid nanoparticles which contain at least one active ingredient or drug or mixtures thereof; a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol;

[0049] and optionally a plasticizing agent, preferably glycerin; pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives; characterized in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application, obtained by means of a method comprising the following steps:

[0050] a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v;

[0051] c) Optionally adding glycerin in a concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;

[0052] e) Dehydrating the gel obtained from step d) to obtain a solid film.

[0053] A further object of the invention is the pharmaceutical composition as defined above or obtainable by the method defined above for use as a medicament.

[0054] Further object of the present invention is a pharmaceutical composition as defined above or obtainable by the method defined above for use for the treatment of dermatological diseases. Preferably said dermatological diseases are selected from the group consisting of: acne, rosacea, dermatitis, erythema, mycosis, skin infections, burns and insect bites.

[0055] DETAILED DESCRIPTION OF THE INVENTION

[0056] Main object of the present invention is a system for the delivery of active ingredients or drugs or mixtures thereof comprising:

[0057] a. Phospholipid nanoparticles;

[0058] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally c. a plasticizing agent, preferably glycerin;

[0059] characterized in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application, wherein said phospholipid nanoparticles are loadable with at least one active ingredient or a drug or mixtures thereof.

[0060] A further object of the present invention is a pharmaceutical composition for topical use comprising:a. Phospholipid nanoparticles containing at least one active ingredient or drug or mixtures thereof;

[0061] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally c. a plasticizing agent, preferably glycerin;

[0062] d. pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives;

[0063] characterised in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application.

[0064] Preferably the phospholipid nanoparticles are for example ethosomes, phytosomes, liposomes. In a preferred embodiment the delivery system and the pharmaceutical composition object of the invention are in the form of a solid film preferably of thickness comprised between 10 and 90 pm, more preferably comprised between 10 and 50 pm, still more preferably comprised between 10 and 20 pm.

[0065] Both are reconstitutable into a semi-solid / liquid form preferably gel, nanoemulgel, emulsion, lotion.

[0066] The phospholipids that can be used in the nanoparticles according to the present invention are for example one or more natural or synthetic phospholipids, pure or in a mixture, such as for example soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), sphingomyelin and others. Preferably, soybean lecithin was employed in the invention. The fundamental characteristics of the phospholipids for the invention are the ability to form nanovesicles, the high biological compatibility and the absence of toxicity.

[0067] The composition may further comprise a specific plasticizing agent, in a preferred embodiment said plasticizing agent is glycerin.

[0068] The pharmaceutical composition is reconstitutable into semi-solid form by adding water in a volume amount of less than or equal to 0.15 mL per cm2of film, preferably the amount of water expressed in Volume (mL) per cm2of film is comprised between 0.10 mL of H2O / cm2film and 0.15 mL H2O / cm2of film, which corresponds to 2-3 drops.The pharmaceutical film composition is reconstituted into semi-solid form in a time less than 30 seconds from the time of addition of water, preferably in a time comprised between 20 and 30 seconds, preferably between 21 and 28 seconds.

[0069] Pharmacologically acceptable excipients are those known in the art, for example, hydrophilic and lipophilic bases, emulsifiers, humectants, rheological modifiers, provided they are not preservatives, preferably synthesis preservatives.

[0070] A further object of the present invention is a method for obtaining a solid, anhydrous and film-form pharmaceutical composition for topical use comprising the following steps:

[0071] a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;

[0072] b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v;

[0073] c) Optionally adding glycerin in a concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;

[0074] e) Dehydrating the gel obtained from step d) to obtain a solid film.

[0075] Preferably in the method object of the invention the solution of soy lecithin in ethanol is added to the aqueous phase at a rate comprised between 1 mL / min and 2 mL / min.

[0076] Preferably in the method object of the invention the solution of soy lecithin in ethanol is added in a controlled manner to the aqueous phase, preferably at a rate comprised between 1 mL / min and 2 mL / min.

[0077] Preferably in step e) the dehydration is carried out by: drying, lyophilization.

[0078] Preferably the drying is in hot air or heated plates.

[0079] In a preferred form in step e) the dehydration is carried out by drying at a temperature comprised between 35 and 50 °C, preferably at 40 °C to obtain a solid film.A further object of the invention is a pharmaceutical composition comprising: phospholipid nanoparticles which contain at least one active ingredient or drug or mixtures thereof; a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally a plasticizing agent, preferably glycerin; pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservative; characterized in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application, obtained by means of a method comprising the steps of:

[0080] a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin; b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v;

[0081] c) Optionally adding glycerin in concentration comprised between 1% and 3% w / v;

[0082] d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;

[0083] e) Dehydrating the gel obtained from step d) to obtain a solid film.

[0084] It is an object of the present invention the pharmaceutical composition for topical use comprising:

[0085] a. Phospholipid nanoparticles containing at least one active ingredient or drug or mixtures thereof;

[0086] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally

[0087] c. a plasticizing agent, preferably glycerin;d. pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives;

[0088] characterised in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application, for use as a medicament.

[0089] It is an object of the present invention the pharmaceutical composition for topical use comprising: a. Phospholipid nanoparticles containing at least one active ingredient or drug or mixtures thereof;

[0090] b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally c. a plasticizing agent, preferably glycerin;

[0091] d. pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives;

[0092] characterised in that it is anhydrous, in solid form, and in the form of a film and in that said composition is reconstitutable into semi-solid form by adding water at the time of topical application,

[0093] for use for the treatment of dermatological disorders preferably selected from the group consisting of: acne, rosacea, dermatitis, erythema, mycosis, skin infections, burns and insect bites.

[0094] In a further embodiment the pharmaceutical composition is in the form of a multilayer film, anhydrous and solid, of at least three layers which is reconstitutable into semi-solid form by adding water and which comprises

[0095] at least two layers of a first solid and anhydrous film comprising phospholipid nanoparticles which contain at least one active ingredient or drug or mixtures thereof; a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol;

[0096] and optionally a plasticizing agent, preferably glycerin;at least a second layer of solid and anhydrous film containing at least one oleolite of medicinal plants or a vegetable oil, at least one lipophilic vitamin and at least one wax of natural origin wherein the second layer is arranged between two layers of a first film,

[0097] and pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives.

[0098] Preferably the oleolite from a medicinal plant is selected from the group consisting of calendula oleolite, chamomile oleolite, hypericum oleolite, arnica oleolite, lavender oleolite, helichrysum oleolite, rose oleolite, lime oleolite, yarrow oleolite.

[0099] Preferably, the vegetable oil is selected from the group consisting of: sweet almond oil, jojoba oil, olive oil, sunflower oil, avocado oil, macadamia oil, grape seed oil, coconut oil. Preferably the lipophilic vitamin is vitamin A or vitamin E.

[0100] Preferably the wax of natural origin is selected from the group consisting of beeswax, lanolin, carnauba wax, candelilla wax, jojoba wax, rice wax, sunflower wax.

[0101] In a preferred embodiment the multilayer film consists of two films of sodium hyaluronate -ethosomes and lecithin (HA-ET-LC) and of one film consisting of calendula oleolite, soy lecithin, vitamin and beeswax.

[0102] In the multilayer embodiment, the first film is prepared according to the method already described, while the second layer is prepared by adding the components and melting the mixture at a temperature not higher than 60°C. To form the multilayer on the first film, a small amount of the mixture is placed and then another first film is placed and by applying a pressure assembly into the multilayer form is favoured.

[0103] Definitions

[0104] Within the scope of the present invention, by film is meant a composition, anhydrous therefore free of water, capable of being reconstituted and transformed into a semi-solid formulation at the time of skin application. The film is obtained by drying a fluid formulation, for example a gel, a gelled emulsion, a gelled micro / nanoemulsion or in general an emulgel. As used herein, the acronym FiReFa indicates Rehydratable Film for topical delivery of Drugs

[0105] Alternatively, the term "film" is used in the invention to mean the water-free composition formulated into a solid thin layer.Within the scope of the present invention, by "waterless" product is meant an anhydrous product that is free of water.

[0106] Within the scope of the present invention, by "ethosomes" are meant the phospholipid nanovesicles, mainly composed of one or more concentric layers of phospholipids, with a relatively high concentration of ethanol (20-45%), glycols and water, for the cutaneous and transdermal delivery of bioactive substances.

[0107] Within the scope of the present invention, by "an ethosomal suspension" is meant a suspension containing ethosomes dispersed in an aqueous and / or hydroalcoholic matrix.

[0108] Within the scope of the present invention, by "phytosomes (PHY)" are meant vesicular systems for the release of bioactive substances consisting of phospholipids, in particular lecithin, and functional ingredients of natural origin. Phytosomes are vesicles in which the active ingredient / bioactive substance is anchored to the polar head of the phospholipid and becomes an integral part of the phospholipid membrane, unlike liposomes, in which the active ingredient / bioactive substance is generally contained either within the aqueous core or between the hydrophobic tails of the phospholipids of the liposome.

[0109] Within the scope of the present invention, by "nanoemulsions (NE)" are meant oil-in-water emulsions in which the average diameters of the dispersed droplets are of nanometric scale (from 50 to 1000 nm).

[0110] Within the scope of the present invention, by "nanoemulgel (NEG)" are meant gelled nanoemulsions with the addition of natural or semi-synthetic or synthetic polymers.

[0111] Within the scope of the present invention, by "a gelling polymer" is meant a macromolecule of natural, synthetic or semi-synthetic origin, designed to be applied to the skin, where it forms a stable gel when combined with water or other appropriate solvents. Said polymer is chosen e.g. from sodium hyaluronate (HA), Solagum-AX ® (SG; commercial product consisting of a mixture of gum arabic and xanthan gum), sodium alginate (AL), pectin, chitosan (PA), carrageenan-l (CA), chitosan (CH), hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC), carbopol. Said polymer upon drying imparts mechanical strength to the formulation, thus it is also referred to as a filming polymer.

[0112] Within the scope of the present invention, preservatives are preferably synthetic preservatives or artificially produced chemical substances that are added to the pharmaceutical formulations to prevent or slow down the growth of microorganisms such as bacteria, fungi and yeasts, guaranteeing the safety, efficacy and stability of the product during its shelf life.Within the scope of the present invention, by "a plasticizing agent" is meant a substance that, when added to a polymeric material, implements certain characteristics, such as flexibility, workability and deformability. Said plasticizing agent may be e.g. glycerin (Gly) and lecithin (LC).

[0113] Within the scope of the present invention, by "dry substance" is meant the residual part of the ethosomal gel or phyto-nanoemulgel after removal of water at 40°C until a constant weight is reached.

[0114] Within the scope of the present invention, by dehydration stage is meant any process aimed at removing water from the composition such as for example hot air or heated plate drying, freeze-drying.

[0115] The invention will now be illustrated with the aid of experimental examples.

[0116] EXAMPLES

[0117] EXAMPLE 1

[0118] Rehydratable films for topical delivery of ascorbic acid / tocopherol / diclofenac / hydrocortisone / lidocaine

[0119] By way of example of FiReFA formulations, some formulations containing active ingredients commonly used for the treatment of inflammation, pain or itching of the skin are reported. Compared to conventional formulations currently on the market, for the preparation of said films, ethosomes have been selected in particular as nanocarriers; in fact, as widely reported in the literature (12-14), they improve the bioavailability of the active ingredients at the topical level. The choice of the gelling polymer fell on hyaluronic acid for its well-documented regenerating and moisturizing activities on the skin.

[0120] 1. Materials

[0121] Ethanol (EtOH), lecithin (LC), ascorbic acid (AA), tocopherol (TC), diclofenac (DF), hydrocortisone (IC), lidocaine (LD), and glycerin (Gly) were purchased from Sigma-Aldrich (Milan, Italy). Sodium hyaluronate (HA) (CAS: 9067-32-7) was purchased from Farmalabor (Canosa di Puglia, Italy). All other chemicals were purchased from Sigma-Aldrich (Milan, Italy). Ultrapure water (18.2 MQ cm) was obtained with a MilliQ apparatus from Millipore (Milford, MA, USA).

[0122] 2. Methods

[0123] 2.1. Preparation of the ethosomal suspensions

[0124] The ethosomes were prepared using the ethanol injection-sonication method. In particular, soy lecithin (300 mg) was dispersed in ethanol (9 mL) in a covered becker to prevent ethanol evaporation. For the preparation of ethosomal suspensions designated as ET-LC-TC, ET-LC-DF, ET-LC-IC, ET-LC-LD, tocopherol (30 mg) or diclofenac (150 mg) or hydrocortisone (150 mg) or lidocaine (150 mg) is added in the ethanol solution. For the preparation of the ethosomal suspension designated as ET-LC-AA, ascorbic acid (30 mg) was solubilized in bidistilled water (21 mL). Ethanol lecithin solution was added slowly (1 mL / min) to the aqueous solution with a syringe under constant stirring at 700 rpm. Unloaded ethosomal suspension (ET-LC), without the addition of active ingredients, was prepared as a control.

[0125] All ethosomal suspensions (ET-LC-TC, ET-LC-DF, ET-LC-IC, ET-LC-LD, ET-LC-AA, ET-LC) were characterized from a chemical-physical point of view (see Sallustio, V.; Chiocchio, I.; Mandrone, M.; Cirrincione, M.; Protti, M.; Farruggia, G.; Abruzzo, A.; Luppi, B.; Bigucci, F.; Mercolini, L.; et al. Extraction, Encapsulation into Lipid Vesicular Systems, and Biological Activity of Rosa canina L. Bioactive Compounds for Dermocosmetic Use. Molecules 2022, 27, 3025. https: / / doi. org / 10.3390 / molecules27093025).

[0126] 2.3. Preparation of gelling polymer-based gels

[0127] To 30 mL of each type of ethosomal suspension was added glycerin (Gly; O.lmL) as a plasticizing agent and the mixture was homogenized for 60 seconds. Subsequently, sodium hyaluronate (HA) was added in an amount equal to 2% w / v. Preliminary studies were performed to select the optimal percentage of polymer and glycerin for film preparation.

[0128] The polymers were slowly added to the ethosomal suspensions. The mixtures were stirred for 24 hours at 300 rpm and stored for 24 hours at room temperature to facilitate gel formation.

[0129] 2.4. Chemical-physical characterization of gels

[0130] The macroscopic characteristics of the gels (colour, homogeneity, transparency) were observed by visual inspection. Determination of nanoparticle sizes and their polydispersity (PDI) was performed by PCS (photon correlation spectroscopy) using the Brookhaven 90-PLUS instrument (Brookhaven Instruments Corp., Holtsville, NY, USA) with a He-Ne laser beam at a wavelength of 532 nm (diffusion angle of 90°). The samples were diluted (1:800 v / v) in ultrapure water. The measurements were performed at room temperature with five runs for each determination.

[0131] 2.5. Film preparation

[0132] Approximately 1.5 mL of each mixture was poured into a circular-shaped silicone support of diameter 3.5 cm and height 5 mm and oven-dried at 40°C for 4 hours (FD series oven, Binder, Tuttlingen, Germany). Preliminary tests were carried out to determine the optimal drying time by taking the films from the support and weighing them until a constant weight was reached. The films were then gently removed from the supports and stored in a polyethylene bag and maintained in a silica gel desiccator to prevent moisture absorption until further analysis.

[0133] 2.6. Chemical-physical characterization of the filmsAfter removal from the support, the films were visually inspected for roughness and cuts and evaluated for homogeneity and transparency.

[0134] The films obtained by drying to constant weight were weighed on an analytical balance to determine their dry substance. The measurements were performed in triplicate.

[0135] The thickness of the films was measured at five different positions taken randomly with a digital gauge with an accuracy of 0.01 mm. Three films were measured for each type of formulation.

[0136] 2.7. Determination of the minimum amount of water for hydration and minimum dissolution time of the films

[0137] Since rapid gel formation with a minimum amount of water is crucial for this type of film formulation, the following additional tests were performed for the most promising films. A sample of the selected films of square shape and surface of 1 cm2was placed on a glass surface and distilled water was added dropwise until a homogeneous transparent or translucent gel was obtained, thereby determining the minimum amount of water necessary for gelation.

[0138] Subsequently a similar sample was placed on a glass surface, the minimum amount of water necessary for gelation was added and the time for complete rehydration of the film and the formation of the homogeneous gel was timed. Verification of the formation of a homogeneous gel was obtained by macroscopic visual observation of transparency / translucency. The tests were performed at a temperature of 20±l°C and in triplicate.

[0139] 2.8. Preservation of nanoparticle structures in gels obtained from rehydrated films

[0140] Then 5 pL of the gels, obtained from the films thus redispersed, were diluted 1:800 (v / v) with ultrapure water and the size and polydispersity index of the vesicular systems were measured by pcs (photon correlation spectroscopy) as reported in paragraph 2.4.

[0141] 3. Results

[0142] 3.1. Chemical-physical characterization of ethosomal suspensions

[0143] Drug encapsulation techniques in nanovesicles have been widely studied, highlighting advantages such as the controlled release of the active ingredient and the improvement of transdermal bioavailability. Ascorbic acid (AA) was used as the hydrophilic drug model in this preparation, and tocopherol (TC) was used as the lipophilic drug model (10,11). To confirm that the proposed formulations with model molecules can also be effectively prepared with other active ingredients, formulations containing other drugs such as diclofenac, or hydrocortisone or lidocaine named respectively HA-ET-LC-DF, HA-ET-LC-IC, HA-ET-LC-LD were made.

[0144] The chemical-physical characterization of the unloaded ethosomal suspensions used as a control and those containing active ingredient is reported in Table 1.Table 1.

[0145] Size (nm) and polydispersity index (PDI) of the unloaded ethosomal suspensions (ET-LC), containing ascorbic acid (ET-LC-AA), tocopherol (ET-LC-TC), diclofenac (ET-LC-DF), hydrocortisone (ET-LC-IC), or lidocaine (ET-LC-LD).

[0146] Sample Size (nm) PDI

[0147] ET-LC 260.0±4.0 0.1141.0024 ET-LC-AA 216.2±2.2 0.077±0.009 ET-LC-TC 272.6±2.2 0.127±0.037 ET-LC-DF 229.9±2.6 0.224±0.010 ET-LC-IC 272.2±5.7 0.261±0.016 ET-LC-LD

[0148]

[0149] 295.6±4.4 0.262±0.046 *Values expressed as the average ± standard deviation (n=3)

[0150] As reported in Table 1, the analysed sample sizes are less than 300 nm and the polydispersity indices are less than 0.3; these values are optimal for topical drug delivery and indicate good homogeneity of nanoparticle sizes.

[0151] 3.2. Characterization of ethosomal gel for film preparation

[0152] The pH of the ethosomal gels, the size, the PDI and the zeta potential of the ethosomal vesicles were evaluated after 24 hours from their preparation. The data are reported in Table 2.

[0153] Table 2.

[0154] Macroscopic appearance, size (nm) and PDI of the ethosomal gels Sample appearance size (nm) PDI

[0155] HA ET-LC Homogeneous, whitish, translucent 238.7±35.3 0.155±0.094 HA ET-LC-AA Homogeneous, whitish, translucent 259.9±8.9 0.237±0.013 HA ET-LC-TC Homogeneous, milky white, 267.2±8.1 0.296±0.030

[0156] opalescent

[0157] HA ET-LC-DF Homogeneous, whitish, translucent 330.0±7.9 0.241±0.032 HA ET-LC-IC Homogeneous, whitish, opalescent 394.7±4.1 0.305±0.014 HA ET-LC-LD Homogeneous, whitish, translucent 305.8±5.1 0,276±0,013

[0158]

[0159] *Values are expressed as the average ± SD, (n = 3)

[0160] 3.3. Chemical-physical characterization of the films

[0161] 3.3.1. Macroscopic appearance

[0162] The films were obtained from the ethosomal gels following the procedure described in paragraph 2.3. After preparation, the films were removed from the Petri dishes and observed prior to storagein the dryer. The films were observed macroscopically by visual and tactile inspection. All films exhibit optimal macroscopic characteristics, i.e. homogeneity, absence of rips and are relatively transparent, indicating that the vesicles are uniformly incorporated into the polymer matrix.

[0163] 3.3.2. Determination of the weight and thickness of the loaded and unloaded films

[0164] The values of the dry substance and the thickness of the films are reported in Table 3.

[0165] Table 3.

[0166] Value of the dry substance (g) and thickness (mm) for loaded and unloaded films (HA-ET-LC f; HA-ET-LC-AA f; HA-ET-LC-TC f ; HA-ET-LC-DF f ; HA-ET-LC-IC f ; HA-ET-LC-LD f) Sample Weight (g)* Thickness (mm)*

[0167] HA-ET-LC f 0.0684±0.007 0.157±0.067 HA-ET-LC-AA f 0.0738±0.004 0.143±0.044 HA-ET-LC-TC f 0.0757±0.005 0.159±0.025 HA-ET-LC-DF f 0.0641±0.003 0.107±0.035 HA-ET-LC-IC f 0.0584±0.003 0.083±0.015 HA-ET-LC-LD f 0.0613±0.001 0.090±0.020

[0168]

[0169] *Values are expressed as the average ± SD, (n = 3) The thickness of the films (HA-ET-LC f; HA-ET-LC-AA f; HA-ET-LC-TC f; HA-ET-LC-DF f; HA-ET-LC-IC f; HA-ET-LC-LD f) depends on the method of preparation, the amount of gel used and the flatness of the drying surface (9). The average thicknesses of the films are reported in Table 3.

[0170] 3.4. Film rehydration

[0171] FiReFa was designed as a waterless formulation to be rehydrated when applied to the skin. In particular, the minimum amount of water and the minimum value of time necessary for rehydration to obtain a homogeneous gel were determined.

[0172] The results are shown in Table 4.

[0173] Table 4.

[0174] Minimum amount of water and minimum rehydration time Sample Volume H2O (mL) / cm2film* Rehydration time (seconds) HA-ET-LC f 0.10 (2 drops) 21.66±2.89

[0175] HA-ET-LC-AA f 0.15 (3 drops) 26.67±2.89

[0176] HA-ET-LC-TC f 0.15 (3 drops) 28.85±2.89

[0177]

[0178] HA-ET-LC-DF f 0.15 (3 drops) 23.45±2.89HA-ET-LC-IC f 0.20 (4 drops) 26.48±2.89

[0179]

[0180] HA-ET-LC-LD f 0.20 (4 drops) 25.52±2.89

[0181] *Minimum amount of water for the formation of a homogeneous gel

[0182] ** Minimum time required for rehydration of 1 cm2of film with the optimal volume of H2O

[0183] 3.5. Chemical-physical characterization of rehydrated films

[0184] After redispersion of the films, the size and PDI of the nanoparticles were measured to verify that their nanometric structures and homogeneity were maintained. The results are reported in Table 5.

[0185] Table 5.

[0186] Size of the vesicles (nm) and PDI of loaded and unloaded films

[0187] after rehydration with water

[0188] Sample Size (nm)* PDI*

[0189] HA-ET-LC (fr) 271.0±14.2 0.005±0.001

[0190] HA-ET-LC-AA (fr) 280.8±18.3 0.337±0.013

[0191] HA-ET-LC-TC (fr) 197.0±6.6 0.279±0.013

[0192] HA-ET-LC-DF (fr) 748.4±40.0 0.385±0.025

[0193] HA-ET-LC-IC (fr) 995.8±62.3 0.375±0.037

[0194] HA-ET-LC-LD (fr) 723.7±68.4 0.218±0.123

[0195]

[0196] *Values are expressed as the average ± SD, (n = 3) The data reported in Table 5 confirm the presence of the nanoparticles after rehydration and gelation of the films. In conclusion, the results confirm that rehydratable films containing liposomal nanoparticles loaded with hydrophilic drugs and / or lipophilic drugs lend themselves to topical application.

[0197] EXAMPLE 2

[0198] Multilayer rehydratable films for topical delivery of hydrocortisone / tocopherol / lidocaine for the treatment of burns and insect bites

[0199] Starting from the previous example 1, in the following example 2 the description of a formulation derived from the previous one that is called "multilayer film" is reported; this offers further advantages with respect to the already described FiReFa films and to the conventional formulations existing on the market for the treatment of similar pathologies.

[0200] The multilayer film consists of an overlap of films in which each layer contains a different active ingredient, thus making the coexistence of possibly incompatible active ingredients in the sameformulation compatible. In addition, this layering allows the integration of a completely lipophilic layer for the delivery of non-water-soluble active ingredients.

[0201] In the specific example, a multilayer film for the treatment of burns or insect bites was prepared by laminating a film containing lidocaine as a local anaesthetic, a lipophilic thin layer containing vitamin E and calendula oleolite for the antioxidant and soothing action, and finally an additional layer containing hydrocortisone for an anti-inflammatory action. The multilayer film reconstituted with the addition of a few mL of emulgel water stands as an innovation compared to the conventional formulations as well as for the practicality of use also for the possibility of effectively and stably combining more active ingredients; in addition, it ensures the best delivery of the different active ingredients thanks to their preliminary encapsulation in nanocarriers.

[0202] 4. Materials

[0203] Ethanol (EtOH), lecithin (LC), tocopherol (TC), hydrocortisone (IC), lidocaine (LD), glycerin (Gly), and beeswax (CA) were purchased from Sigma-Aldrich (Milan, Italy). Sodium hyaluronate (HA) (CAS: 9067-32-7) and fat-soluble calendula oil extract (CAL) were purchased from Farmalabor (Canosa di Puglia, Italy). All other chemicals were purchased from Sigma-Aldrich (Milan, Italy). Ultrapure water (18.2 MQ cm) was obtained with a MilliQ apparatus from Millipore (Milford, MA, USA).

[0204] 5. Methods

[0205] 5.1. Preparation of HA-ET-LC-IC and HA-ET-LC-LD films

[0206] A film containing as active ingredient hydrocortisone called HA-ET-LC-IC and a film containing as active ingredient lidocaine called HA-ET-LC-LD are prepared according to the procedures described in paragraphs 2.1 to 2.8 of EXAMPLE 1.

[0207] 5.2 Preparation of the lipophilic mixture CA-LC-TC-CAL

[0208] 5 mL of calendula oleolite (CAL) are added with 5 mg of soybean lecithin (LC), 0.5 mg of vitamin E (TC) and 0.5 g of beeswax (CA). The mixture is melted at 60±2°C.

[0209] 5.3 Preparation of the multilayer film

[0210] A film of HA-ET-LC-IC is placed on a glass plate; a drop of the lipophilic mixture CA-LC-TC-CAL is gently deposited in the centre and a film of HA-ET-LC-LD is superimposed. Light pressure is exerted on the films thus assembled to favour adhesion of the layers, thus obtaining a single multilayer film. The new formulation - multilayer film - is stable and has layers adhered to each other thanks to the particular chemical composition and technological function of the selected substances. In particular, lecithin acts as an emulsifier, favouring adhesion between hydrophilic and lipophilic layers, and glycerin contributes to the better adhesion of the hydrophilic layers. In addition, the lecithin present in all three layers is essential in order to obtain a stable emulsion after rehydration of the films.Finally, all the formulations proposed are made with a minimum number of ingredients which in addition to the technological function also have a specific beneficial action for the skin (for example Vitamin E, Lecithin and Calendula Oleolite have antioxidant action, Hyaluronic Acid has a regenerative and moisturising action). This formulation strategy is also an advantage for producers who can prepare the films with a minimum number of ingredients that are all functional, simplifying the supply chain.

[0211] 5.4 Determination of minimum amount of water for hydration and minimum time for emulgel formation from multilayer film

[0212] A sample of the multilayer films was placed on a glass surface and distilled water was added dropwise until a homogeneous translucent emulgel was obtained under slight stirring, thereby determining the minimum amount of water necessary for gelation and emulgel formation.

[0213] Subsequently a similar sample was placed on a glass surface, this minimum amount of water needed was added and the time for complete rehydration of the film and the formation of a homogeneous emulgel was timed. Verification of the formation of a homogeneous emulgel was obtained with macroscopic visual observation of homogeneity and translucency. The tests were performed at a temperature of 20±l°C and in triplicate.

[0214] 6. Results

[0215] Multilayer films having a thickness of 0.45±2.75 mm were obtained by following the procedure described above. The amount of water required for rehydration is 2.0 ± 0.5 mL. The time necessary for rehydration is about 90 seconds under stirring at 20±l°C. This procedure leads to a milky, homogeneous, translucent and easily applicable, non-greasy and dry-touch emulgel.

[0216] REFERENCES

[0217] 1) Bom, S., Jorge, J., Ribeiro, H.M., Marto, J., 2019. A step forward on sustainability in the cosmetics industry: A review. Journal of Cleaner Production 225, 270-290. https: / / doi.org / 10.1016 / jjclepro.2019.03.255

[0218] 2) Martins, A.M., Marto, J.M., 2023. A sustainable life cycle for cosmetics: From design and development to post-use phase. Sustain. Chem. Pharm. 35, 101178. https: / / doi.Org / 10.1016 / j.scp.2023.101178

[0219] 3) Aguiar, J.B., Martins, A.M., Almeida, C., Ribeiro, H.M., Marto, J., 2022a. Water sustainability: A waterless life cycle for cosmetic products. Sustainable Production and Consumption 32, 35-514) Touitou, E., Dayan, N., Bergelson, L., Godin, B., Eliaz, M., 2000. Ethosomes — novel vesicular carriers for enhanced delivery: characterization and skin penetration properties. Journal of Controlled Release

[0220] 5) Sguizzato, M., Ferrara, F., Hallan, S.S., Baldisserotto, A., Drechsler, M., Malatesta, M., Costanzo, M., Cortesi, R., Puglia, C., Valacchi, G., Esposito, E., 2021b. Ethosomes and Transethosomes for Mangiferin Transdermal Delivery. Antioxidants 10, 768. https: / / doi.org / 10.3390 / antioxl005076 6) Paiva-Santos, A.C., Silva, A.L., Guerra, C., Peixoto, D., Pereira-Silva, M., Zeinali, M., Mascarenhas-Melo, F., Castro, R., Veiga, F., 2021a. Ethosomes as Nanocarriers for the Development of Skin Delivery

[0221] 7) Donthi, M.R., Munnangi, S.R., Krishna, K.V., Saha, R.N., Singhvi, G., Dubey, S.K., 2023. Nanoemulgel: A Novel Nano Carrier as a Tool for Topical Drug Delivery. Pharmaceutics 15, 164. Fathalla, D., Youssef, E.M.K., Soliman, G.M., 2020. Liposomal and Ethosomal Gels for the Topical Delivery of Anthralin: Preparation, Comparative Evaluation and Clinical Assessment in Psoriatic Patients. Pharmaceutics 12, 446. https: / / doi.org / 10.3390 / pharmaceuticsl2050446

[0222] 8) Raza, Z.A., Khalil, S., Ayub, A., Banat, I.M., 2020. Recent developments in chitosan encapsulation of various active ingredients for multifunctional applications. Carbohydrate Research 492, 108004.

[0223] 9) Rezvanian, M., Amin, M.C.I.M., Ng, S.-F., 2016. Development and physicochemical characterization of alginate composite film loaded with simvastatin as a potential wound dressing. Carbohydrate Polymers 137, 295-304. https: / / doi.Org / 10.1016 / j.carbpol.2015.10.091

[0224] 10) Amiri, S., Pashizeh, F., Moeinabadi-Bidgoli, K., Eyvazi, Y., Akbari, T., Salehi Moghaddam, Z., Eskandarisani, M., Farahmand, F., Hafezi, Y., Nouri Jevinani, H., Seif, M., Mousavi- Niri, N., Chiani, M., Tavakkoli Yaraki, M., 2023. Co-encapsulation of hydrophilic and hydrophobic drugs into niosomal nanocarrier for enhanced breast cancer therapy: In silico and in vitro studies. Environmental Research 239, 117292. https: / / doi.Org / 10.1016 / j.envres.2023.117292

[0225] 11) Carvalho, V.F., De Lemos, D.P., Vieira, C.S., Migotto, A., Lopes, L.B., 2017. Potential of Nonaqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin. AAPS PharmSciTech 18, 1739-1749. https: / / doi.org / 10.1208 / sl2249-016-0643-7

[0226] 12) Caddeo C, Sales OD, Valenti D, Saurf AR, Fadda AM, Manconi M. Inhibition of skin inflammation in mice by diclofenac in vesicular carriers: liposomes, ethosomes and PEVs. Int J Pharm. 2013 Feb 25;443(l-2):128-36. doi: 10.1016 / j.ijpharm.2012.12.041. Epub 2013 Jan 5. PMID: 2329908713) Mombeiny R, Tavakol S, Kazemi M, Mehdizadeh M, Hasanzadeh A, Karimi Babaahmadi M, Abedi A, Keyhanvar P. Anti-inflammatory ethosomal nanoformulation in combination with iontophoresis in chronic wound healing: An ex vivo study. IET NanobiotechnoL 2021 Dec;15(9):710-718. doi: 10.1049 / nbt2.12069. Epub 2021 Oct 18. PMID: 34694760; PMCID: PMC8806119

[0227] 14) Zhu, Xiaoliang PhD; Li, Fuli MM; Peng, Xuebiao MD; Zeng, Kang MM. Formulation and Evaluation of Lidocaine Base Ethosomes for Transdermal Delivery. Anesthesia & Analgesia 117(2):p 352-357, August 2013. | DOI: 10.1213 / ANE.0b013e3182937b74

Claims

1.CLAIMS1) Anhydrous and solid system in the form of a film for the delivery of active ingredients or drugs or mixtures thereof comprising:a. Phospholipid nanoparticles;b. a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionallyc. a plasticizing agent, preferably glycerin;wherein the phospholipid nanoparticles are loadable with at least one active ingredient or drug or mixtures thereof.2) Anhydrous and solid multilayer system in the form of a film of at least three layers for the delivery of active ingredients or drugs or mixtures thereof comprising:at least two systems according to claim 1 and at least one second solid and anhydrous film containing at least one oleolite of medicinal plants or a vegetable oil, at least one lipophilic vitamin and at least one wax of natural origin wherein the second film is arranged between two systems according to claim 1.3) Anhydrous and solid pharmaceutical composition in the form of a film and for topical use comprising the system according to claim 1 or the system according to claim 2 and pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives.characterised in that it is reconstitutable into semi-solid form by adding water at the time of topical application.4) Delivery system according to claim 1 or 2 and a pharmaceutical composition according to claim 3 wherein the phospholipid particles are selected from the group consisting of: ethosomes, phytosomes, liposomes.5) Delivery system according to claim 1 or 2 and pharmaceutical composition according to claim 3 wherein the film has a thickness comprised between 10 and 90 pm, preferably between 10 and 50 pm, more preferably between 10 and 20 pm.6) Delivery system according to claim 1 or 2 and pharmaceutical composition according to claim 3 wherein the phospholipids are one or more natural or synthetic phospholipids, pure25or in a mixture, preferably selected from the group consisting of: soy lecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine (DPPC), sphingomyelin.7) Delivery system according to claim 1 or 2 and pharmaceutical composition according to claim 3 further comprising a plasticizing agent, preferably glycerin.8) Delivery system according to claim 2 and pharmaceutical composition according to claim 3 wherein the oleolite from a medicinal plant is selected from the group consisting of calendula oleolite, chamomile oleolite, hypericum oleolite, arnica oleolite, lavender oleolite, helichrysum oleolite, rose oleolite, lime oleolite, yarrow oleolite.9) Delivery system according to claim 2 and a pharmaceutical composition according to claim 3 wherein the vegetable oil is selected from the group consisting of: sweet almond oil, jojoba oil, olive oil, sunflower oil, avocado oil, macadamia oil, grape seed oil, coconut oil.10) Delivery system according to claim 2 and pharmaceutical composition according to claim 3, wherein the lipophilic vitamin is vitamin A or vitamin E.11) Delivery system according to claim 2 and pharmaceutical composition according to claim 3 wherein the wax of natural origin is selected from the group consisting of beeswax, lanolin, carnauba wax, candelilla wax, jojoba wax, rice wax, sunflower wax.12) Pharmaceutical composition according to claim 3 reconstitutable into semi-solid form by adding water in a volume amount of less than or equal to 0.15 mL per cm2of film, preferably between 0.10 mL of H2O / cm2of film and 0.15 mL of H2O / cm2of film.13) Multilayer pharmaceutical composition according to claim 3 reconstitutable into semi-solid form by adding water in a volume amount comprised between 1.5 and 2.5 mL per cm2.14) Pharmaceutical composition according to claim 3 reconstitutable into semi-solid form by adding water in a time less than 30 seconds from the time of addition of water, preferably in a time comprised between 20 and 30 seconds, more preferably between 21 and 28 seconds.15) Multilayer pharmaceutical composition according to claim 3 reconstitutable into semi-solid form by adding water in a time of less than or equal to 90 seconds.16) Method for obtaining the pharmaceutical composition of claim 3 comprising the following steps:a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v;c) Optionally adding glycerin in a concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;e) Dehydrating the gel obtained from step d) to obtain a solid film.17) Method according to claim 9 wherein in step a) the solution of soy lecithin in ethanol is added to the aqueous phase solution at a rate comprised between 1 mL / min and 2 mL / min.18) Method according to claim 10 wherein the solution of soy lecithin in ethanol is added in a controlled manner to the aqueous phase, preferably at a rate comprised between 1 mL / min and 2 mL / min.19) Method according to claim 10 wherein in step e) the dehydration is carried out by drying, lyophilization.20) Method according to claim 12 wherein the dehydration is carried out by drying at a temperature comprised between 35 and 50°C, preferably at40°C.21) Method for obtaining the multilayer pharmaceutical composition of claim 3 wherein the first system is prepared according to the method of claim 16 and the second system is prepared by mixing the components and melting at a temperature not higher than 60°C and the multilayer is obtained by placing a small amount of the mixture on the first system and then placing a further first system and applying a pressure until assembly into the multilayer form.22) Anhydrous and solid pharmaceutical composition in the form of a film comprising phospholipid nanoparticles which contain at least one active ingredient or drug or mixtures thereof; a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC) and hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally a plasticizing agent, preferably glycerin; pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservatives characterized in that they are reconstitutable into semisolidform by adding water at the time of topical application obtained by means of a method comprising the steps of:a) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) or carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v; c) Optionally adding glycerin in concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;e) Dehydrating the gel obtained from step d) to obtain a solid film.23) Anhydrous and solid pharmaceutical composition in the form of a multilayer film comprising at least a first layer comprising phospholipid nanoparticles which contain at least one active ingredient or drug or mixtures thereof; a natural film-forming polymer preferably selected from hyaluronic acid, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and optionally a plasticizing agent, preferably glycerinand at least a second layer containing at least an oleolite of medicinal plants or a vegetable oil, at least a lipophilic vitamin and at least a wax of natural origin, pharmacologically acceptable excipients provided that said pharmacologically acceptable excipients are not preservativescharacterised in that it is reconstitutable into semi-solid form by adding water at the time of topical application obtained by means of a method comprising the steps of:in order to prepare the first layera) Solubilizing at least one active ingredient or drug or mixtures thereof in water or in an ethanol solution containing a phospholipid, and adding the ethanol solution to the aqueous phase to obtain a suspension of phytosomes or of ethosomes, preferably said phospholipid is soy lecithin;b) Adding to the suspension obtained from step a) a film-forming polymer preferably selected from hyaluronic acid and its salts, sodium alginate, carrageenan, gum arabic, xanthan gum, pectin, chitosan or mixtures thereof or semi-synthetic polymers such as hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC), carboxymethylcellulose (CMC) or synthetic polymers such as carbopol; and wherein said polymer is in a concentration comprised between 1% and 5% w / v, preferably 2% w / v; c) Optionally adding glycerin in concentration comprised between 1% and 3% w / v; d) Stirring and storing the mixture obtained from step c) for at least 12-24 hours to obtain the formation of a gel;e) Dehydrating the gel obtained from step d) to obtain a solid film;in order to prepare the second layer mixing at least one oleolite of medicinal plants or vegetable oil, at least one lipophilic vitamin and at least one wax of natural origin, preferably a mixture of calendula oleolite, soya lecithin, vitamin E and beeswax, and melting at a temperature not higher than 60°Cin order to prepare the multilayer placing on the first system a small amount of the mixture and then placing a further first system and applying a pressure until assembly of the multilayer form.24) Pharmaceutical composition of claims 2-8 and 14 for use as a medicament.25) Pharmaceutical composition of claims 2-8 and 14 for use for the treatment of dermatological disorders.26) Use according to claim 16, wherein the dermatological pathology is selected from the group consisting of: acne, rosacea, dermatitis, erythema, mycosis, skin infections, burns, insect bites.

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