Liposomal composition for topical administration

Abstract

The invention relates to a system consisting of coated liposomes which are loaded with an active substance that is enclosed in cyclodextrin. The invention further relates to the use of said liposomes for improving the penetration of poorly soluble active substances into the skin, and to a method for producing the coated liposomes.

Description

[0001] Liposomal composition for topical administration

[0002] The invention relates to a system of coated liposomes loaded with an active ingredient encapsulated in cyclodextrin. Furthermore, their use for improving the penetration of poorly soluble active ingredients into the skin and a method for producing the coated liposomes are described.

[0003] background

[0004] The topical application of active ingredients offers a variety of advantages. By applying them directly to the target site, it allows for targeted treatment without affecting the entire body. This significantly reduces the risk of systemic side effects compared to oral or parenteral administration. Furthermore, topically applied active ingredients are often better tolerated because they do not pass through the digestive tract and thus cannot cause gastrointestinal discomfort. Application is generally simple and does not require any special skills or equipment, making it convenient for patients. Furthermore, topical application minimizes the amount of the active ingredient that enters the bloodstream, reducing the risk of drug interactions. Dosage can often be easily adjusted by varying the amount or frequency of application to meet individual patient needs.Overall, the topical application of active ingredients offers an effective and gentle way to treat various diseases and complaints.

[0005] The skin fulfills an essential protective function for the human body. As the outermost barrier, the epidermis, the topmost layer of the skin, forms a physical barrier that prevents the penetration of microorganisms, chemicals, and other potentially harmful substances. Through its densely packed cells, lipids, and proteins, the epidermis provides effective protection against external influences.

[0006] In addition, the skin produces sebum, an oily substance that protects the skin from drying out and creates an acidic environment that inhibits the growth of harmful bacteria. This chemical barrier also contributes to the defense against pathogens. Additionally, the skin contains antimicrobial peptides that can fight infections.

[0007] The skin also serves as an immune barrier, as it houses a variety of immune cells that can recognize pathogens and activate the immune system to fight infections. These immune cells, such as Langerhans cells, play an important role in

[0008] Defense against infections and maintaining skin health.

[0009] Overall, the skin's protective function is crucial for protecting the body from external influences that could compromise health and well-being. Through its various barrier and defense mechanisms, the skin plays a key role in maintaining the body's integrity and minimizing the risk of infections and other harmful influences.

[0010] However, a disadvantage of these important protective functions is that they also keep cosmetic active ingredients on the skin surface, for which deeper penetration into the skin would be desirable.

[0011] Although the skin forms an effective barrier against the penetration of foreign substances, it is not impermeable. Some substances can diffuse through the skin and enter the body. Skin permeation is of particular importance in the pharmaceutical and cosmetic industries, as it influences the effectiveness of topically applied medications, creams, ointments, and cosmetics. A deeper understanding of skin permeation helps improve the efficacy and safety of topical products and optimize the targeted delivery of active ingredients.

[0012] The skin permeability of active ingredients depends on various factors, including molecular size, lipophilicity (fat solubility), charge, water solubility, and other physicochemical properties. In general, lipophilicity and a small molecular size can facilitate skin permeation, while hydrophilic and larger molecules often exhibit lower permeability. Furthermore, the properties of the specific active ingredient, such as concentration, solubility / dissolution rate, particle size, and crystallinity, play an important role. Other factors such as skin moisture, temperature, pH, and skin thickness can also influence skin permeation. Therefore, when developing topical products, it is important to consider the skin permeability of the active ingredients and implement appropriate strategies to improve penetration.

[0013] Shao Ping et al. (INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES, Vol. 119, 2018, pp. 53-59) disclose a composition containing liposomes loaded with resveratrol and coated with modified pectin. The effect of pH, ionic strength, and temperature on the stability of liposomes with different pectin concentrations

[0014] Coating is being examined.

[0015] Park Soo Nam et al. (JOURNAL OF INDUSTRIALAND ENGINEERING CHEMISTRY, Vol. 20, No. 4, 2014, pp. 1481-1485) disclose a composition containing liposomes loaded with resveratrol and coated with chitosan. According to the authors, the coated liposomes provide increased skin permeation efficiency. The coated liposomes containing resveratrol are said to effectively delay skin aging.

[0016] Sinsinwar Simran et al. (INTERNATIONAL JOURNAL OF PHARMACEUTICS, Vol. 609, 2021) describe liposomes for transdermal delivery containing a catechin / B-cyclodextrin complex. The liposomal composition is said to exhibit higher encapsulation efficiency and antibacterial activity compared to the catechin / cyclodextrin complex.

[0017] The object of the invention was therefore to develop a way to improve the skin permeation of cosmetic active ingredients.

[0018] Description

[0019] Surprisingly, it has been found that even poorly soluble active ingredients penetrate the skin very effectively when incorporated into a special system of coated liposomes. A first aspect of the invention therefore relates to an aqueous composition comprising liposomes loaded with at least one active ingredient and having a coating on their outer surface comprising modified starch, wherein the active ingredient is associated with an alkylated or hydroxyalkylated derivative of ß-cyclodextrin.

[0020] For the purposes of the invention, poorly soluble active ingredients are those with a solubility of up to 10 mg / ml in pure water at 20°C:

[0021] For corresponding active ingredients in the category “Practically Insoluble” and “Very Slightly Soluble” and, in a broader sense, also up to “Slightly Soluble”, the effective administration via topical dosage forms is problematic.

[0022] Both liposomal systems and cyclodextrins are frequently used to increase topical penetration. Liposomes have a lipid bilayer structure similar to the cell membrane, enclosing a cavity. They are frequently used as carriers for active ingredients, where they are able to transport hydrophobic molecules within their lipid bilayer and absorb hydrophilic active ingredients into their cavities. Cyclodextrins are cyclic oligosaccharides composed of α-1,4-glycosidically linked glucose molecules. This gives them a toroidal structure with a central cavity. This inner cavity is hydrophobic, while the outer surface is hydrophilic. The cavity provides space for the absorption of hydrophobic active ingredients, while the hydrophilic surface promotes solubility.

[0023] Particularly for poorly soluble active ingredients, the problem of the "solubility-permeability tradeoff" arises when formulating topical dosage forms, whereby the solubility of the active ingredient in the matrix of the dosage form and thus the effective active ingredient concentration is the driving force for penetration. At the same time, if the solubility is too high and the distribution coefficient between the dosage form and the skin is accordingly unfavorable, the permeability and ultimately also the penetration is reduced because the active ingredient is retained in the matrix. When poorly soluble active ingredients are to be formulated, there is often a trade-off as to whether the solubility should be increased while simultaneously reducing the permeability or vice versa. To overcome these problems, the effects of liposomes and cyclodextrins are combined by incorporating an active ingredient bound to cyclodextrin into liposomes.The incorporation of the active ingredient into cyclodextrin improves its solubility in the matrix, while the liposomes can significantly increase the desired transport through the skin.

[0024] According to the invention, alkylated and hydroxyalkylated derivatives of ß-cyclodextrin are used for this purpose. In these derivatives, the hydroxyl groups of the ß-cyclodextrin are etherified to form alkyl or hydroxyalkyl ether groups. Many hydrophobic active ingredients form inclusion complexes with these ß-cyclodextrin derivatives, which can significantly improve their solubility. Hydroxypropyl-ß-cyclodextrin has proven particularly suitable for this purpose. The weight fraction of the ß-cyclodextrin derivative in a composition according to the invention is 10-25% w / w, based on the total composition. Concentrations in the range of 12.5-22.5% w / w ß-cyclodextrin derivative, preferably 15-20% w / w ß-cyclodextrin derivative, are particularly advantageous.

[0025] According to the invention, liposomes serve to increase the permeability of the active ingredients, allowing them to cross the skin's barrier layer and be administered topically. The liposome bilayer comprises one or more phospholipids, whose proportion of the total composition amounts to 1-4% w / w. Concentrations in the range of 1.5-3% w / w, preferably 2-3% w / w phospholipids based on the total composition, are particularly advantageous.

[0026] In preferred embodiments of the invention, the liposomes further comprise one or more polyols. These are preferably selected from the group consisting of butylene glycol, pentylene glycol, propylene glycol, glycerin, and combinations thereof. The weight fraction of the polyols, based on the total composition, can be 2-20% w / w, preferably 5-15% w / w.

[0027] Surprisingly, it was found that permeability can be significantly improved even further if the liposomes are coated with an outer layer containing modified starch. The weight fraction of the modified starch, based on the total composition, is 0.5–1.5% w / w.

[0028] According to the invention, modified starch is understood to mean in particular starch ether derivatives such as hydroxypropyl starch and starch ester derivatives such as octenyl succinate starch, in which hydroxy groups of the glucose unit of the starch are etherified or esterified.

[0029] Key factors in selecting a suitable modified starch are, on the one hand, its degree of substitution and, on the other hand, its viscosity. The degree of substitution, expressed as a weight percent of the modified unit, refers to the dry mass and can be determined by titration. Starch used according to the invention preferably has a degree of substitution of 0.1-10% w / w, preferably 0.1-7%, more preferably 0.5-5% w / w or 0.5-3% w / w, based on the dry mass. The viscosity of the modified starch can be measured by rotational viscometry. The rotational viscometry method is explained in the standard ISO 1652:2011 Rubber latex - Determination of apparent viscosity by the Brookfield test method. For example, the measurement can be carried out using a Brookfield LV viscometer, spindle LV1, as a 10% w / w solution at 20°C.For the purposes of the invention, only starches with a low viscosity of <100 mPas are used, preferably <50 mPas, particularly preferably <25 mPas, and ideally <15 mPas in a 10% w / w solution at 20°C. Modified starches with a viscosity in this range are particularly well suited to achieving a uniform coating that also does not compromise the stability of the formulation. With higher-viscosity starches, however, the coating is so pronounced that it leads to formulation instability.

[0030] The polydispersibility index (PDI) of the modified starch-coated liposomes should advantageously be <0.3, as this indicates a narrow particle size distribution. A PDI value of <0.25 for the coated liposomes is preferred, and <0.2 is particularly preferred. If the starch is too long (too viscous) or the starch concentration is too high, irregular coating can occur, producing particles with an uneven coating, whereas low-viscosity starches lead to low PDI values. The particle size of the coated liposomes in a composition according to the invention is approximately 100-200 nm, preferably 125-175 nm.

[0031] Modified starch for coating the liposomes according to the invention can be obtained after gelatinization and shortening of the chain lengths by enzymatic treatment or dextrinization (fluidization) via a derivatization treatment. In preferred embodiments of the invention, the modified starch is derivatized with octenylsuccinate groups or hydroxypropyl groups. Octenylsuccinate groups can be introduced by treatment with octenylsuccinate anhydride, resulting in the structure shown in Figure 1 (sodium octenylsuccinate starch). The degree of substitution for octenylsuccinate starch is preferably about 0.1-10% w / w, in particular 0.5-7% w / w. Hydroxypropyl groups can be introduced analogously by treatment with propylene oxide, as illustrated in Figure 2. The degree of substitution for hydroxypropyl starch is preferably about 0.1-5% w / w, in particular 0.5-5% w / w. or 0.5-3% w / w.

[0032] Active ingredients that can be encapsulated with the coated liposomes according to the invention are, in particular, hydrophobic active ingredients with a low water solubility of 10 mg / ml or less (in pure water at 20°C). The encapsulation according to the invention is particularly advantageous for active ingredients with a water solubility of <1 mg / ml. The molecular weight of the active ingredients can be in the range of 200-1500 g / mol. The chemical structure of the active ingredients can, in principle, be freely selected, provided they are capable of a non-covalent interaction with cyclodextrin. They can be natural or synthetic substances with low water solubility.Preference is given to poorly soluble secondary plant substances and their glycosides such as stilbenoids (resveratrol, oxy resveratrol, pterostilbene, piceatannol, piceid, pinosylvin, rhaponticin, deoxyrhaponticin, gnetin, rhapontigenin, isorhapontigenin, isorhapontin, hopeaphenol), flavonoids (flavonols, flavanones, flavanols, isoflavones, flavonolignans), di-, sesqui- and triterpenes, chalcones (xanthohumol, phloretin, butein, flavokavain, hesperetin or naringenin chalcone), curcuminoids, lignans, hydroquinone derivatives (thymoquinone), cinnamic acid derivatives (ferulic acid, coumaric acid, chlorogenic acid), steroids, xanthones and anthraquinones, carotenoids.

[0033] Sehr gut geeignet ist das System darüber hinaus für schwerlösliche Peptide, insbesondere bis zu einem Molekulargewicht bis 1500g / mol wie Acetyl Hexa pepti de- 37, Tripeptide-29, Hexapeptide-2, Hexa pepti de- 33, Methyl Undecenoyl Dipeptide-16, Methyl Undecenoyl Leucinate, Oligopeptide-68, Decapeptide-12, Oligopeptide-34, Oligopeptide-50, Myristoyl Tetrapeptide-20, Acetyl Hexapeptide-8, Palmitoyl Tripeptide-1 / Palmitoyl Oligopeptide, Palmitoyl Tetrapeptide-7 / 3, Acetyl Octapeptide-3, Palmitoyl Pentapeptide-4, Palmitoyl Hexapeptide-12, Acetyl Pentapeptide- 1 , Palmitoyl Tripeptide-5, Pentapeptide- 18, Palmitoyl Tripeptide-38, Tripeptide-3, Acetyl Tetrapeptide-2, Hexapeptide-11 , Pentapeptide-3, Oligopeptide-24, Acetyl Decapeptide-3, Acetyl Tetrapeptide-11 , Palmitoyl Tripeptide-28, Decapeptide-4, Caprooyl Tetrapeptide-3, Myristoyl Octapeptide- 1 , Hexapeptide- 10, Hexapeptide-3, Hexapeptide-9, Tri peptide-1 , Acetyl Hexapeptide-49, Acetyl Dipeptide-1 cetyl ester, Acetyl Tetrapeptide-40,Decapeptide-23, Palmitoyl Tripeptide-8, Acetyl Tetrapeptide- 15, Acetyl Tetrapeptide-22, Hexapeptide-9, Myristoyl Hexapeptide-23, Palmitoyl Tripeptide-36, Myristoyl Tetrapeptide-4, Caffeoyl Tripeptide-1 , Acetyl Tetrapeptide-5, Dipeptide-2, Acetyl Hexapeptide- 1 , Palmitoyl Tetrapeptide-20 Amide, Acetyl Tetrapeptide-3, Octapeptide-2, Decapeptide- 18, Decapeptide-28, Oligopeptide-54, Oligopeptide-71 , Decapeptide-10, Biotinoyl Tripeptide-1 , Myristoyl Dipeptide-13, Myristoyl Pentapeptide- 17, Myristoyl Hexapeptide- 16, Palmitoyl Tripeptide-1 / Palmitoyl Oligopeptide, Hexapeptide-3, Pentapeptide- 25, Acetyl Hexapeptide-39, Tripeptide-41 , Tripeptide-3,

[0034] In addition, the system is suitable for poorly soluble active ingredients from the classes of analgesics and local anesthetics (lidocaine, benzocaine), antibiotics (neomycin, erythromycin, mupirocin), antifungals (clotrimazole, ketoconazole, terbinafine), corticosteroids, antipsoriatics (calcipotriol), antivirals (acyclovir), anti-inflammatories (diclofenac, ibuprofen), immunomodulators (tacrolimus, pimecrolimus), antioxidants (tocopherols), antihistamines (diphenhydramine, loratadine), antiacne agents and retinoids.

[0035] Pigment modulators (kojic acid).

[0036] The weight fraction of the active ingredient in a composition according to the invention is 0.1-3% w / w. Active ingredient loadings in the range of 0.25-2% w / w and, in particular, 0.5-1.5% w / w of active ingredient based on the total composition are particularly advantageous.

[0037] Due to its improved permeability, the composition according to the invention is particularly well suited for topical administration. It can be in the form of a cream, ointment, serum, or hydrogel, for example.

[0038] In addition to the coated liposomes, a composition according to the invention may comprise other conventional components of a formulation intended for topical administration.

[0039] The composition according to the invention can be formulated as a pharmaceutical or cosmetic composition. In a preferred embodiment, the composition according to the invention is intended for cosmetic use.

[0040] A further aspect of the invention relates to a process for producing an aqueous composition comprising coated liposomes loaded with alkylated or hydroxyalkylated ß-cyclodextrin and at least one active ingredient, comprising the steps of: a) preparing an aqueous solution of alkylated or hydroxyalkylated ß-cyclodextrin, in particular hydroxypropyl-ß-cyclodextrin and at least one active ingredient in order to associate the active ingredient with the cyclodextrin derivative, preferably in order to form an inclusion complex of the active ingredient in the cyclodextrin derivative, b) forming liposomes which enclose a cavity in which the active ingredient associated with the cyclodextrin derivative, in particular the inclusion complex of the active ingredient in hydroxypropyl-ß-cyclodextrin, is embedded, and c) coating the liposomes on their outer side with a coating which comprises modified starch.

[0041] During the preparation of an aqueous solution in step a), the active ingredient is combined with the cyclodextrin derivative, in particular hydroxypropyl-ß-cyclodextrin. For this purpose, an aqueous solution of the cyclodextrin derivative can be initially introduced, and the active ingredient can then be added. The combination with the cyclodextrin derivative significantly improves the solubility of hydrophobic active ingredients that are poorly soluble in water on their own. The process is particularly suitable for the active ingredients described above in connection with a composition according to the invention. Dissolution can also be further promoted by stirring and heating.

[0042] For the purposes of the invention, association is understood as a non-covalent interaction of the active ingredient with the cyclodextrin derivative, whereby the active ingredient is fully or partially absorbed into the cavity of the cyclodextrin derivative. Preferably, the active ingredient is incorporated into the cyclodextrin derivative to form an inclusion complex. 2-Hydroxypropyl-ß-cyclodextrin is particularly well suited for this purpose. The weight ratio of cyclodextrin to active ingredient is selected so that the active ingredient is absorbed into the cyclodextrin as completely as possible. Advantageously, the weight fraction of the active ingredient is approximately 0.1-3% w / w and the weight fraction of the ß-cyclodextrin derivative is approximately 10-25% w / w, in each case based on the

[0043] overall composition,

[0044] In the subsequent step b), liposome-forming molecules are added to the solution obtained in step a). These molecules assemble in the aqueous solution to form a bilayer membrane shell enclosing the active ingredient associated with cyclodextrin. For this purpose, conventional methods for producing liposomes, which are known in the art, can be used. Suitable liposome-forming molecules are amphiphilic lipids, such as, in particular, phospholipids. The amount of phospholipids is preferably selected such that their weight proportion of the total composition is approximately 1-4% w / w. Concentrations of 1-5% w / w or 2-3% w / w of phospholipids, based on the total composition, are particularly suitable. Furthermore, one or more polyols can be added, which are preferably selected from the group comprising butylene glycol, pentylene glycol, propylene glycol, glycerin, and combinations thereof.The weight fraction of the polyols can be selected so that, based on the total composition, it amounts to 2-20% w / w, preferably 5-15% w / w.

[0045] The resulting loaded liposomes are then coated on their exterior in step c) with a modified starch coating. For this purpose, the liposomes are brought into contact with a starch solution. Advantageously, the liposome solution obtained in step b) can be used directly, without the need for prior purification or isolation. The starch coating is formed using ultrasonic or high-pressure homogenization, with the pressure generally being lower than that used for the preceding liposome formation. This ensures that the previously formed liposomes are retained and no new liposome formation occurs. The pressure is preferably below 1000 bar, more preferably below 800 bar, and particularly preferably in the range of approximately 400-600 bar.

[0046] The starch quantity is selected in a range of 0.5–1.5% w / w based on the total mass of the preparation. These amounts are optimal for coating the liposomes, as a slight increase in particle diameter (Z-average) is observed, which, in combination with a slight jump in the zeta potential, indicates successful coating. At the same time, the polydispersity index (PDI) at these starch concentrations is still below 0.3, preferably below 0.25, or most preferably below 0.2, thus ensuring uniform coating.

[0047] Suitable starches for use in the method according to the invention are the modified starches described above in connection with a liposome composition.

[0048] Depending on the desired application, the coated liposomes can be further processed into a composition for topical administration. For this purpose, the composition can be formulated, for example, as a cream, ointment, serum, or hydrogel and, if necessary, combined with other components. The liposomal composition is particularly well suited for use in oil-in-water systems.

[0049] Typical other components in such systems, in addition to water as the main solvent, are oils and fats (such as mineral oil, silicone oils, vegetable oils such as jojoba oil or sunflower oil, jojoba oil, almond oil, argan oil, coconut oil, olive oil, sunflower oil, grape seed oil, avocado oil, shea butter, cocoa butter, macadamia nut oil, rosehip seed oil, evening primrose oil, tamanu oil, sesame oil and waxes such as beeswax, wool wax or paraffin), emulsifiers (such as lecithin, cetyl alcohol, stearyl alcohol, polysorbate 80, ceteareth, glyceryl stearate, sorbitan oleate, glycerol monostearate, polyglyceryl-3 methylglucose distearate, PEG-40 stearate, polyglyceryl-6 distearate, cetearyl glucoside, steareth-2, steareth-20, behenyl alcohol, alkyl glucosides) used, as well as preservatives (e.g.Phenoxyethanol, Benzoic acid, Ethylhexylglycerin, Parabens, Benzyl alcohol, Chlorphenesin, Diazolidinyl urea, DM DM Hydantoin, Imidazolidinyl urea, Methylchloroisothiazolinone, Methylisothiazolinone, Potassium sorbate, Sodium benzoate, Caprylyl glycol, Triclosan), Humectants (such as Glycerin, Hyaluronic acid, Propylene glycol, Sorbitol, Butylene glycol, Panthenol, Sodium PCA, Urea, Glycolic acid, Lactic acid) and Thickeners (such as Carbomers, Xanthan gum, Cellulose derivatives, Acrylates, Bentonite, Collagen, Guar gum, Alginic acid, Carrageenan, Silicones), Fragrances (such as Benzyl alcohol, Limonene, Linalool, Citronellol, Geraniol, Eugenol, Citral, Farnesol, Alpha-Isomethyl Ionone, Hydroxycitronellal, Coumarin, Hexyl Cinnamal, Benzyl Benzoate, Amyl Cinnamal, Benzyl Salicylate), Colors (such as Iron Oxides (e.g. CI 77491, CI 77492, CI 77499), Titanium Dioxide (CI 77891), Ultramarine Blue (CI 77007), Carmine (CI 75470), Chromium Oxides (CI 77288), FD&C Dyes (e.g. FD&C Yellow No.5 - CI 19140, FD&C Blue No. 1 - CI 42090), D&C dyes (e.g. D&C Red No. 27 - CI 45410, D&C Red No. 6 - CI 15850), Mica (CI 77019), Tin Oxide (CI 77861)), pH regulators (such as sodium hydroxide, potassium hydroxide, citric acid, sodium citrate, disodium phosphate, phosphoric acid, sodium bicarbonate), antioxidants (such as vitamin E (tocopherol), vitamin C (ascorbic acid), coenzyme Q10 (ubiquinone), resveratrol, green tea extract, grape seed extract (OPC), niacinamide (vitamin B3), ferulic acid, alpha lipoic acid, glutathione, astaxanthin), UV filters (such as avobenzone, octocrylene, octinoxate (octyl methoxycinnamate), Octisalat (Octyl Salicylate), Oxybenzone (Benzophenone-3), Homosalate, Mexoryl SX (Terephthalylidene Dicamphorsulfonic Acid), Mexoryl XL (Drometrizole Trisiloxane), Tinosorb S (Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine), Tinosorb M (Bis-Ethylhexyl Hydroxybenzoyl Hexyl Benzoate), Uvinul A PIus (Diethylamino Hydroxybenzoyl Hexyl Benzoate), Uvinul T 150 (Ethylhexyl Triazone)).

[0050] The following examples and figures are intended to further illustrate the invention. However, the invention is not limited to these specific examples, but extends to the entire scope of the claims.

[0051] Figures

[0052] Fig.1 Reaction scheme of the derivatization of starch with octenylsuccinate anhydride

[0053] Fig. 2 Reaction scheme of the derivatization of starch with propylene oxide

[0054] Examples

[0055] To determine an optimal formulation for skin penetration, the starches were first characterized, and formulations containing the poorly soluble active ingredients taxifolin, phloretin, naringin, and resveratrol were prepared. After final characterization, skin penetration was determined using a Franz diffusion cell in various dosage forms (cream, hydrogel). 1. Characterization of the starches (viscosity)

[0056] Various modified starches (sodium octenylsuccinate and hydroxypropyl starches) were tested for their viscosity. The dried starches were dissolved on a magnetic stirrer (20 g starch + 180 ml distilled water) to produce a 10% w / w solution. This solution was then measured using a Brookfield DVPIus viscometer (DVPLV) at 20°C.

[0057] 10% w / w sodium octenyl succinate starches:

[0058] 10% w / w hydroxypropyl starches:

[0059] 2. Drug formulations with taxifolin

[0060] Due to its low water solubility (<1mg / ml at 25°C) and poor skin penetration, taxifolin is very well suited as an active ingredient for increasing penetration by the invention.

[0061] 2.1 Material and sample preparation

[0062] Material: Taxifolin-rich skin extract (Lavitol 98% Taxifolin, Ametis JSC), Hydroxypropyl-ß-Cyclodextrin (Beaute CD 110, Roquette), Preformed liposomes (Natipide Eco, Lipoid), Sodium octenylsuccinate starch (Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230), Hydroxypropyl starches (Lycoat RS 780, Lycoat RS 720), Pentylene Glycol (Dermosoft Pentiol Eco, Evonik), HPLC Grade Water.

[0063] The overall composition according to the invention is as follows:

[0064] For the preparation (25g total), 5g of hydroxypropyl-ß-cyclodextrin was first completely dissolved in 14.75g of water with stirring (300rpm, 25°C). Then, 0.25g of taxifolin was added and stirred under identical conditions until the active ingredient was dissolved. 2.5g of Natipide Eco and 1.25g of Pentylene Glycol were added to this cyclodextrin / taxifolin solution and stirred for 30 minutes at 25°C and 300rpm until the product was homogeneous. A sample was then taken for particle size and zeta potential measurements.

[0065] Subsequently, 1.25 g of a 20% starch solution (6 different sodium octenylsuccinate starches [Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230] and 2 different hydroxypropyl starches [(Lycoat RS 780, Lycoat RS 720]) were added while stirring and the solution was homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in 3 cycles.

[0066] Samples were also taken from the finished product to measure particle size and zeta potential.

[0067] 2.2 Characterization of the samples (particle size and zeta potential)

[0068] The samples were analyzed for particle size (Z-average) and polydispersibility index (PDI) using photon correlation spectroscopy. The photon correlation spectroscopy method is described in ISO 22412:2017 - Particle size analysis - Dynamic light scattering (DLS). Zeta potential was also measured. The Malvern Zetasizer Lab Red Label (90°C light scattering angle) was used for the measurements. The samples were diluted 1:100 with filtered, HPLC-grade water before measurement.

[0069] Results before adding starch:

[0070] Results after starch addition and homogenization:

[0071] Formulations with at least + / -30 mV are considered stable, so low-viscosity starches are particularly suitable. A zeta potential shift into the neutral range is generally to be expected due to the starch coating and, like an increase in the Z-average, indicates the coating of the particles. Furthermore, complete coating is indicated by a unimodal distribution of the zeta potential, which is obtained after bringing the liposomes into contact with the starch solution and treating them with ultrasound / high-pressure homogenization. However, this is so pronounced in medium- to high-viscosity starches (Purity Gum Ultra, Lycoat RS 720, N-Creamer 2230) that it leads to formulation instability, whereas the low-viscosity, modified starches form a uniform coating and the formulation remains stable.

[0072] Likewise, a PDI (polydispersibility index) of <0.2 is desirable, as this indicates a narrow particle size distribution. If the starch is too viscous (too long) or the starch concentration is too high, irregular coating can occur, producing particles with an uneven coating, whereas low-viscosity starches lead to low PDI values. 2.3 Influence of starch concentration on particle size and zeta potential

[0073] In order to determine the effects of different concentrations of modified starch on the system and the coating behavior, active ingredient formulations were prepared according to 2.1., but instead of only 1% modified starch, the

[0074] Concentrations of 0.05%, 0.1%, 0.5%, 1.5%, and 3% were tested. The starches used were either Cleargum CO 03 or Lycoat RS 780. The particle sizes and zeta potential of the formulations were measured according to the method in section 2.2. Sodium starch octenylsuccinate (Cleargum CO 03):

[0075] Hydroxypropyl starch (Lycoat RS 780):

[0076] Starch concentrations in the range of 0.5–1.5% are particularly optimal, as they result in a slight increase in the Z-average particle diameter, which, in combination with a slight jump in the zeta potential, indicates successful coating. At the same time, the PDI of the coated liposomes is still below 0.2 at these starch concentrations, thus ensuring uniform coating. 2.4 Preparation of control samples (HP-ß-cyclodextrin or phospholipid)

[0077] To control penetration tests, drug formulations containing taxifolin and (i) only hydroxypropyl-ß-cyclodextrin or (ii) only Natipide Eco / phospholipids were also prepared. The overall composition is as follows:

[0078] HP-ß-Cyclodextrin / Taxifolin Phospholipid / Taxifolin

[0079] The preparation was carried out according to the previously described formulation. First, taxifolin, water, and the third component (either cyclodextrin or phospholipid) were stirred for 30 minutes at 25°C and 300 rpm. The solution was then homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in three cycles.

[0080] Samples were also analyzed for particle size and zeta potential:

[0081] 2.5 Preparation of cream formulation for penetration tests The active ingredient formulations after starch addition / homogenization and the control formulations were then incorporated into a cream formulation for the penetration tests. In addition, cream formulations with pure taxifolin were also prepared for comparison. The cream base used was anionic hydrophilic Creme SR, which had the following

[0082] Ingredients:

[0083] To prepare the final formulation, the water component and the native active ingredient or active ingredient-containing formulation were first mixed, and then homogenized with the cream base in a mortar. Creams containing 2% native taxifolin and containing 0.1% or 0.05% taxifolin were prepared in the form of the inventive active ingredient formulation prepared as described above with various strengths, or in the form of the control formulations containing either only HP-ß-cyclodextrin or only phospholipid.

[0084] The composition of the cream formulation containing native taxifolin was as follows:

[0085] The composition of the cream formulation containing 0.1% taxifolin as active ingredient formulation was as follows:

[0086] The composition of the cream formulation containing 0.05% taxifolin as active ingredient formulation was as follows:

[0087] A cream was prepared for an inventive formulation containing each of the strengths discussed above (HI-CAP 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230, Lycoat RS 780, Lycoat RS 720) with 0.1% or 0.05% taxifolin concentration, as well as the control creams.

[0088] 2.6 Penetration tests using a Franz diffusion cell

[0089] The cream formulations were then tested for skin penetration in a vertical amber glass Franz diffusion cell (PermeaGear 6 position Franz cell stirrer containing 6 jacketed Franz cells 11.28mm diameter, 8ml volume, 1.00 cm 2Membrane area). For this purpose, the water bath was heated to 32°C, the lower compartment consisted of 0.1% Tween 80 in HPLC-grade water, and the PermeaPad Skin membrane was used as the membrane. After applying the cream formulation to the upper compartment, the sampling arm and the upper compartment were sealed with Parafilm. Experiments were conducted in triplicate, and the average values ​​were calculated.

[0090] After 1 h, 2 h, 3 h, 4 h, and 24 h, 300 μl of each sample was removed from the lower compartment using a syringe and replaced with fresh, pre-tempered solution (0.1% Tween 80 in HPLC-grade water). The samples were analyzed undiluted by HPLC (Agilent 1260 Infinity II DAD). The concentration C in the lower compartment in pg / ml taxifolin (1 h, 2 h, 3 h, 4 h, and 24 h) was calculated cumulatively (taking into account the 300 μl removed in each case).

[0091] Of particular relevance here is the cumulative final concentration in the lower compartment after 24 hours, as this allows the calculation of the apparent permeability (Papp). This value is a concentration-independent measure of permeability, allowing the permeability of formulations to be compared even at different drug concentrations. The drug concentration in the lower acceptor compartment is measured after the end of the experiment (24 hours or 86,400 seconds), while the drug concentration in the upper donor compartment corresponds to the initial concentration at the start of the experiment. The membrane area of ​​the Franz cells used is 1 cm. 2 . Attached are the cumulative concentration in the lower compartment after 24 hours and the Papp

[0092] To find values ​​for the different formulations:

[0093] Control formulations:

[0094] Inventive taxifolin formulations 0.1%:

[0095] Inventive taxifolin formulations (0.05% cream):

[0096] 3. Drug formulations with naringin Due to its low water solubility (<1 mg / ml at 25°C) and poor skin penetration, naringin is also very suitable as an active ingredient for increasing penetration by the invention.

[0097] 3.1 Material & sample preparation

[0098] Material: Naringin (98%, S3 Chemicals), hydroxypropyl-ß-cyclodextrin (Beaute CD 110, Roquette), phospholipids (Lipoid P 75, 70% phosphatidylcholine / PC, Lipoid),

[0099] Sodium octenylsuccinate starch (Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230), hydroxypropyl starches (Lycoat RS 780, Lycoat RS 720), butylene glycol (Brontide, Genomatica), HPLC grade water.

[0100] The overall composition according to the invention is as follows:

[0101] For the preparation (25g total), 3.75g of hydroxypropyl-ß-cyclodextrin were first completely dissolved in 15.36g of water with stirring (300rpm, 25°C). Then, 0.125g of naringin was added and stirred under identical conditions until the active ingredient was dissolved. 1.075g of Lipoid P 75 and 3.75g of butylene glycol were added to this cyclodextrin / naringin solution and stirred for 30 minutes at 25°C and 300rpm until the product was homogeneous. To form the liposomes, the solution was then homogenized at 600 bar for 5 cycles using a high-pressure homogenizer (GEA, PandaPlus 1000).

[0102] Subsequently, 0.94 g of a 20% starch solution (6 different sodium octenylsuccinate starches [Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230] and 2 different hydroxypropyl starches [(Lycoat RS 780, Lycoat RS 720]) were added while stirring and the solution was homogenized using an ultrasonic homogenizer (Bandelin HD 4200 Sonotrode TS 106) at 150 W for 5 minutes (1 s pause, 30 s pulse).

[0103] 3.2 Preparation of control samples (HP-ß-cyclodextrin or phospholipid)

[0104] To control penetration tests, drug formulations containing naringin and (i) only hydroxypropyl-ß-cyclodextrin or (ii) only Lipoid P 75 / phospholipids were also prepared. The overall composition is as follows:

[0105] I) HP-ß-cyclodextrin / naringin

[0106] II) Phospholipid / Naringin

[0107] The preparation was carried out according to the previously described formulation. First, naringin, water, and the third component (either cyclodextrin or phospholipid) were stirred for 30 minutes at 25°C and 300 rpm. Subsequently, the solution (in the case of phospholipid addition) was homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 600 bar in 5 cycles to produce liposomes. As a final step, to ensure comparability to the inventive formulation, the cyclodextrin solution as well as the phospholipid solution were homogenized using an ultrasonic homogenizer (Bandelin HD 4200 Sonotrode TS 106) at 150 W for 5 minutes (1 second pause, 30 second pulse).

[0108] 3.3 Preparation of cream formulation for penetration tests

[0109] The active ingredient formulations after starch addition / homogenization and the control formulations were then incorporated into a cream formulation for penetration tests. In addition, cream formulations with pure naringin were also prepared for comparison. The cream was based on anionic hydrophilic cream SR, which had the following

[0110] Ingredients:

[0111] To prepare the final formulation, the water component and the native active ingredient or active ingredient-containing formulation were first mixed, and then homogenized with the cream base in a mortar. Creams containing 1% native naringin and 0.05% naringin were prepared in the form of the inventive active ingredient formulation prepared as described above with various strengths, or in the form of the control formulations containing either only HP-ß-cyclodextrin or only phospholipid.

[0112] The composition of the cream formulation containing native naringin was as follows:

[0113] The composition of the cream formulation containing 0.05% naringin as active ingredient was as follows:

[0114] One cream was prepared for each inventive formulation containing each of the strengths discussed above (HI-CAP 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230, Lycoat RS 780, Lycoat RS 720) with a 0.05% naringin concentration, as well as the control creams. 3.4 Penetration tests using a Franz diffusion cell

[0115] The cream formulations were then tested for skin penetration in a vertical amber glass Franz diffusion cell (PermeaGear 6 position Franz cell stirrer containing 6 jacketed Franz cells 11.28mm diameter, 8ml volume, 1.00 cm 2Membrane area). For this purpose, the water bath was heated to 32°C, the lower compartment consisted of 0.1% Tween 80 in HPLC-grade water, and the PermeaPad Skin membrane was used as the membrane. After applying the cream formulation to the upper compartment, the sampling arm and the upper compartment were sealed with Parafilm. Experiments were conducted in triplicate, and the average values ​​were calculated.

[0116] After 1 h, 2 h, 3 h, 4 h, and 24 h, 300 μl of the lower compartment were withdrawn using a syringe and replaced with fresh, pre-tempered solution (0.1% Tween 80 in HPLC-grade water). The samples were analyzed undiluted by HPLC (Agilent 1260 Infinity II DAD). The concentration C in the lower compartment in pg / ml naringin (1 h, 2 h, 3 h, 4 h, and 24 h) was calculated cumulatively (taking into account the 300 μl withdrawn in each case).

[0117] Of particular relevance here is the cumulative final concentration in the lower compartment after 24 hours, as this allows the calculation of the apparent permeability (Papp). This value is a concentration-independent measure of permeability, allowing the permeability of formulations to be compared even at different drug concentrations. The drug concentration in the lower acceptor compartment is measured after the end of the experiment (24 hours or 86,400 seconds), while the drug concentration in the upper donor compartment corresponds to the initial concentration at the start of the experiment. The membrane area of ​​the Franz cells used is 1 cm. 2 .

[0118] Below you can find the cumulative concentration in the lower compartment after 24 hours as well as the Papp values ​​for the different formulations:

[0119] Control formulations:

[0120] Inventive Naringin Formulations (0.05% Cream): 4. Active ingredient formulation with resveratrol

[0121] Due to its low water solubility (<0.1 mg / ml at 25°C) and poor skin penetration, resveratrol is also very suitable as an active ingredient for increasing penetration by the invention.

[0122] 4.1 Material & Sample Preparation

[0123] Material: Resveratrol (98%, Evolva), hydroxypropyl-ß-cyclodextrin (Beaute CD 110, Roquette), phospholipids (Natipide Eco, Lipoid), sodium octenyl succinate starch (Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230), Hydroxypropyl starches (Lycoat RS 780, Lycoat RS 720), Butylene Glycol (Brontide, Genomatica), HPLC grade water.

[0124] The overall composition according to the invention is as follows:

[0125] For the preparation (25g total), 3.75g of hydroxypropyl-ß-cyclodextrin was first completely dissolved in 12.375g of water while stirring (300rpm, 25°C). 0.125g of resveratrol was then added and stirred under identical conditions until the active ingredient was dissolved. 3.75g of Natipide Eco and 3.75g of butylene glycol were added to this cyclodextrin / resveratrol solution and stirred for 30 minutes at 25°C and 300rpm until the product was homogeneous.

[0126] Subsequently, 1.25 g of a 20% starch solution (6 different sodium octenylsuccinate starches [Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230] and 2 different hydroxypropyl starches [(Lycoat RS 780, Lycoat RS 720]) were added while stirring and the solution was homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in 3 cycles.

[0127] 4.2 Preparation of control samples (HP-ß-cyclodextrin or phospholipid)

[0128] To control penetration tests, drug formulations containing resveratrol and (i) only hydroxypropyl-ß-cyclodextrin or (ii) only Natipide Eco / phospholipids were also prepared. The overall composition is as follows:

[0129] I) HP-ß-cyclodextrin / resveratrol

[0130] II) Phospholipid / Resveratrol

[0131] The preparation was carried out according to the previously described formulation. First, resveratrol, water, and the third component (either cyclodextrin or phospholipid) were stirred for 30 minutes at 25°C and 300 rpm. The solution was then homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in three cycles.

[0132] 4.3 Preparation of gel formulation for penetration tests

[0133] The active ingredient formulations after starch addition / homogenization, as well as the control formulations, were then incorporated into a gel formulation for penetration tests. In addition, gel formulations with pure resveratrol were also prepared for comparison.

[0134] To prepare the final formulation, the pentylene glycol was first ground with the gelling agent hydroxypropylmethylcellulose (3800-5300 mPas, Carl Roth) in a mortar. The water portion and the native active ingredient or active ingredient-containing formulation were then mixed, and the mixture was homogenized with the ground pentylene glycol / HPMC while stirring in a mortar. The gel was ground until no lumps were visible and a uniform consistency was achieved. Gels containing 1% native resveratrol and 0.05% resveratrol were prepared in the form of the inventive active ingredient formulation prepared as described above with various strengths, or in the form of the control formulations containing either only HP-ß-cyclodextrin or only phospholipid.

[0135] The composition of the gel formulation containing native resveratrol was as follows:

[0136] The composition of the gel formulation containing 0.05% resveratrol as active ingredient formulation was as follows: One gel was prepared for each inventive formulation containing each of the strengths discussed above (HI-CAP 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230, Lycoat RS 780, Lycoat RS 720) with 0.05% resveratrol concentration, as well as the control gels.

[0137] 4.4 Penetration tests using a Franz diffusion cell

[0138] The gel formulations were then tested for skin penetration in a vertical amber glass Franz diffusion cell (PermeaGear 6 position Franz cell stirrer containing 6 jacketed Franz cells 11.28mm diameter, 8ml volume, 1.00 cm 2Membrane area). For this purpose, the water bath was heated to 32°C, the lower compartment consisted of 0.1% Tween 80 in HPLC-grade water, and the PermeaPad Skin membrane was used as the membrane. After applying the gel formulation to the upper compartment, the sampling arm and the upper compartment were sealed with Parafilm. Experiments were conducted in triplicate, and the average values ​​were calculated.

[0139] After 1 h, 2 h, 3 h, 4 h, and 24 h, 300 μl of each sample was removed from the lower compartment using a syringe and replaced with fresh, pre-tempered solution (0.1% Tween 80 in HPLC-grade water). The samples were analyzed undiluted by HPLC (Agilent 1260 Infinity II DAD). The concentration C in the lower compartment in pg / ml resveratrol (1 h, 2 h, 3 h, 4 h, and 24 h) was calculated cumulatively (taking into account the 300 μl removed in each case).

[0140] Of particular relevance here is the cumulative final concentration in the lower compartment after 24 hours, as this allows the calculation of the apparent permeability (Papp). This value is a concentration-independent measure of permeability, allowing the permeability of formulations to be compared even at different drug concentrations. The drug concentration in the lower acceptor compartment is measured after the end of the experiment (24 hours or 86,400 seconds), while the drug concentration in the upper donor compartment corresponds to the initial concentration at the start of the experiment. The membrane area of ​​the Franz cells used is 1 cm. 2 .

[0141] The cumulative concentration in the lower compartment after 24 hours as well as the Papp values ​​for the different formulations can be found below: Control formulations:

[0142] Inventive resveratrol formulations (0.05% gel):

[0143] 5. Drug formulations with phloretin

[0144] Due to its low water solubility (<0.1 mg / ml at 25°C) and poor skin penetration, phloretin is also very suitable as an active ingredient for increasing penetration by the invention.

[0145] 5.1 Material & sample preparation

[0146] Material: Phloretin (98%, Symrise), hydroxypropyl-ß-cyclodextrin (Beaute CD 110, Roquette), phospholipids (Lipoid P 75, 70% phosphatidylcholine / PC, Lipoid),

[0147] Sodium octenylsuccinate starch (Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230), hydroxypropyl starches (Lycoat RS 780, Lycoat RS 720), pentylene glycol (Dermosoft Pentiol Eco, Evonik), HPLC grade water.

[0148] The overall composition according to the invention is as follows:

[0149] For the preparation (25g total), 5g of hydroxypropyl-ß-cyclodextrin was first completely dissolved in 16.478g of water with stirring (300rpm, 25°C). Then, 0.25g of phloretin was added and stirred under identical conditions until the active ingredient was dissolved. 0.712g of Lipoid P 75 and 1.25g of pentylene glycol were added to this cyclodextrin / phloretin solution and stirred for 30 minutes at 25°C and 300rpm until the product was homogeneous. To form the liposomes, the solution was then homogenized at 600 bar for 5 cycles using a high-pressure homogenizer (GEA, PandaPlus 1000).

[0150] Subsequently, 1.56 g of a 20% starch solution (6 different sodium octenylsuccinate starches [Hi-CAPS 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230] and 2 different hydroxypropyl starches [(Lycoat RS 780, Lycoat RS 720]) were added while stirring and the solution was homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in 3 cycles.

[0151] 5.2 Preparation of control samples (HP-ß-cyclodextrin or phospholipid)

[0152] To control penetration tests, drug formulations containing phloretin and (i) only hydroxypropyl-ß-cyclodextrin or (ii) only Lipoid P 75 / phospholipids were also prepared. The overall composition is as follows:

[0153] I) HP-ß-cyclodextrin / phloretin

[0154] II) Phospholipid / Phloretin

[0155] The preparation was carried out according to the previously described formulation. First, phloretin, water, and the third component (either cyclodextrin or phospholipid) were stirred for 30 min at 25°C and 300 rpm. Subsequently, the solution (in the case of phospholipid addition) was homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 600 bar for 5 cycles to produce liposomes.

[0156] As a final step, the cyclodextrin solution as well as the phospholipid solution were homogenized using a high-pressure homogenizer (GEA, PandaPlus 1000) at 450 bar in 3 cycles to ensure comparability to the inventive formulation.

[0157] 5.3 Preparation of gel formulation for penetration tests

[0158] The active ingredient formulations after starch addition / homogenization, as well as the control formulations, were then incorporated into a gel formulation for the penetration tests. In addition, gel formulations with pure phloretin were also prepared for comparison.

[0159] To prepare the final formulation, the pentylene glycol was first ground with the gelling agent hydroxypropylmethylcellulose (3800-5300 mPas, Carl Roth) in a mortar. The water portion and the native active ingredient or active ingredient-containing formulation were then mixed, and the mixture was homogenized with the ground pentylene glycol / HPMC while stirring in a mortar. The gel was ground until no lumps were visible and a uniform consistency was achieved. Gels containing 2% native phloretin and 0.1% phloretin were prepared in the form of the inventive active ingredient formulation prepared as described above with various strengths, or in the form of the control formulations containing either only HP-ß-cyclodextrin or only phospholipid.

[0160] The composition of the gel formulation containing native phloretin was as follows: The composition of the gel formulation containing 0.1% phloretin as active ingredient formulation was as follows:

[0161] One gel was prepared for each inventive formulation containing each of the strengths discussed above (HI-CAP 100, Cleargum CO 03, Cleargum CO 01, Purity Gum 2000, Purity Gum Ultra, N-Creamer 2230, Lycoat RS 780, Lycoat RS 720) with 0.1% phloretin concentration as well as the control gels.

[0162] 5.4 Penetration tests using a Franz diffusion cell

[0163] The gel formulations were then tested for skin penetration in a vertical amber glass Franz diffusion cell (PermeaGear 6 position Franz cell stirrer containing 6 jacketed Franz cells 11.28mm diameter, 8ml volume, 1.00 cm 2Membrane area). For this purpose, the water bath was heated to 32°C, the lower compartment consisted of 0.1% Tween 80 in HPLC-grade water, and the PermeaPad Skin membrane was used as the membrane. After applying the gel formulation to the upper compartment, the sampling arm and the upper compartment were sealed with Parafilm. Experiments were conducted in triplicate, and the average values ​​were calculated.

[0164] After 1 h, 2 h, 3 h, 4 h, and 24 h, 300 μl of each sample was removed from the lower compartment using a syringe and replaced with fresh, pre-tempered solution (0.1% Tween 80 in HPLC-grade water). The samples were analyzed undiluted by HPLC (Agilent 1260 Infinity II DAD). The concentration C in the lower compartment in pg / ml resveratrol (1 h, 2 h, 3 h, 4 h, and 24 h) was calculated cumulatively (taking into account the 300 μl removed in each case).

[0165] Of particular relevance here is the cumulative final concentration in the lower compartment after 24 hours, as this allows the calculation of the apparent permeability (Papp). This value is a concentration-independent measure of permeability, allowing the permeability of formulations to be compared even at different drug concentrations. The drug concentration in the lower acceptor compartment is measured after the end of the experiment (24 hours or 86,400 seconds), while the drug concentration in the upper donor compartment corresponds to the initial concentration at the start of the experiment. The membrane area of ​​the Franz cells used is 1 cm. 2 .

[0166] Below you can find the cumulative concentration in the lower compartment after 24 hours as well as the Papp values ​​for the different formulations:

[0167] Control formulations:

[0168] Inventive phloretin formulations (0.1% gel):

Claims

Claims 1. Composition comprising water and liposomes loaded with at least one active ingredient and having on their outer side a coating comprising modified starch, wherein the modified starch is a starch in which hydroxy groups of the glucose unit of the starch are etherified or esterified, wherein the active ingredient is associated with an alkylated or hydroxyalkylated derivative of ß-cyclodextrin, in particular with hydroxypropyl-ß-cyclodextrin, and the weight fraction of the active ingredient is 0.1-3% w / w and the weight fraction of the ß-cyclodextrin derivative is 10-25% w / w, in each case based on the total composition, the liposomes comprise one or more phospholipids, and the weight fraction of the phospholipids is 1-4% w / w, based on the total composition, the weight fraction of the modified starch is 0.5-1.5% w / w, based on the total composition, and the coated Liposomes have a polydispersibility index (PDI) of < 0.3,preferably < 0.25 and particularly preferably < 0.2, and a particle size in the range of 100-200 nm, preferably 125-175 nm, as determined by photon correlation spectroscopy.

2. Composition according to claim 1, wherein the active ingredient forms an inclusion complex with hydroxypropyl-ß-cyclodextrin.

3. Composition according to claim 1 or 2, wherein the liposomes have a cavity in which the active ingredient associated with the ß-cyclodextrin derivative, in particular the inclusion complex of the active ingredient with hydroxypropyl-ß-cyclodextrin, is embedded.

4. Composition according to any one of the preceding claims, wherein the active ingredient has a water solubility of < 1 mg / ml.

5. Composition according to one of the preceding claims, wherein the liposomes further comprise one or more polyols, which are preferably selected from the group comprising butylene glycol, pentylene glycol, propylene glycol, glycerin and combinations thereof, wherein the weight fraction of the polyols based on the total composition can be 2-20% w / w, preferably 5-15% w / w.

6. Composition according to any one of the preceding claims, wherein the coating of the liposomes (i) modified starch with a degree of substitution of 0.1-10%, preferably 0.1-5%, more preferably 0.5-3% w / w, based on the dry matter, and / or (ii) obtained from a starch solution having a viscosity of < 100 mPas, in particular < 75 mPas, preferably < 50 mPas, particularly preferably < 25 mPas, most preferably < 15 mPas, as determined by rotational viscometry.

7. Composition according to one of the preceding claims, wherein the modified starch is modified with octenylsuccinate groups or hydroxypropyl groups, and the degree of substitution for hydroxypropyl starch is preferably 0.1-5% w / w, in particular 0.5-5% w / w or 0.5-3% w / w, and the degree of substitution for octenylsuccinate starch is preferably 0.1-10% w / w, in particular 0.5-7% w / w.

8. Composition according to one of the preceding claims, wherein the composition 0.25-2% w / w active ingredient, preferably 0.5-1.5% w / w active ingredient, 1.5-3% w / w phospholipids, preferably 2-3% w / w phospholipids, and / or 12.5-22.5% w / w ß-cyclodextrin derivative, preferably 15-20% w / w ß-cyclodextrin derivative.

9. A composition according to any one of the preceding claims, wherein the composition is a composition for topical administration, in particular a cream, an ointment, a serum or a hydrogel.

10. Composition according to any one of the preceding claims, wherein the composition is a cosmetic composition.

11. A process for the preparation of an aqueous composition of coated liposomes loaded with an active ingredient associated with an alkylated or hydroxyalkylated β-cyclodextrin derivative, comprising the steps of: a) preparing a solution of alkylated or hydroxyalkylated β-cyclodextrin derivative, in particular hydroxypropyl-β-cyclodextrin, and at least one active ingredient in order to associate the active ingredient with the β-cyclodextrin derivative, preferably to form an inclusion complex of the active ingredient in hydroxypropyl-β-cyclodextrin, b) forming liposomes enclosing a cavity in which the active ingredient associated with the ß-cyclodextrin derivative, in particular the inclusion complex of the active ingredient in hydroxypropyl-ß-cyclodextrin, is embedded, and c) coating the liposomes on their outer side with a coating comprising modified starch.

12. The method according to claim 11, wherein the modified starch is as defined in any one of claims 6 and 7.

13. The method according to claim 11 or 12, wherein in step b) liposome-forming molecules, in particular phospholipids, and optionally polyols such as butylene glycol, pentylene glycol, propylene glycol and / or glycerol, are added to the solution obtained in step a), preferably phospholipids in an amount in the range of 1-4% w / w, based on the total mass of the composition and optionally polyols in an amount in the range of 2-20% w / w, preferably 5-15% w, based on the total mass of the composition.

14. The method according to any one of claims 11-13, wherein coating the liposomes in step c) comprises contacting the liposomes obtained in step b) with a solution of the modified starch and ultrasonic or high pressure homogenization. 15 A process according to any one of claims 11-14, wherein the amount of starch based on the total mass of the composition is selected to be in the range of 0.5-1.5% w / w.

16. A process according to any one of claims 11-15 for preparing a composition according to any one of claims 1-10.

Images