Hydroalcoholic gel and method for producing the gel

Abstract

The present invention relates to a hydroalcoholic gel comprising at least 70% by weight of alcohol, between 5 and 10% by weight of an oil composition, between 0.15 and 6% by weight of a gelling agent, and between 0.01 and 0.1% by weight of a pH adjusting agent, wherein the gelling agent consists of between 0.05 and 2.0% by weight of a carbomer and between 0.1 and 4.5% by weight of a cellulose polymer composition. The hydroalcoholic gel is unique in that it destroys microorganisms and viruses, moisturizes the skin, does not leave an oily or sticky residue on the skin, and adheres firmly to the skin (even after washing), thereby providing long-lasting disinfectant efficacy.

Description

[Technical Field]

[0001] The present invention relates to a hydroalcoholic gel that provides both disinfecting and moisturizing benefits to the skin of a user. [Background technology]

[0002] It is well known that one of the best and easiest ways to protect against harmful bacteria and viruses is to thoroughly wash your hands with soap and water for at least 20 seconds. For example, hand hygiene is essential to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, especially in the absence of a vaccine or effective antiviral medications.

[0003] However, hand washing is not always practical, especially for healthcare workers, due to lack of access to running water and insufficient time to thoroughly wash hands. Alcohol-based hand sanitizers offer a quick and easy alternative.

[0004] In this regard, consumers are generally encouraged to use alcohol-based hand sanitizers containing at least 60% alcohol, but preferably higher concentrations of alcohol, which are effective in inactivating / killing most infectious agents, such as microorganisms and viruses. However, while alcohol-containing sanitizers are known to have good disinfecting activity and prevent infectious diseases, the use of high concentrations of alcohol on the skin often severely dries the skin because the alcohol dissolves sebum from the skin. As a result, continuous use of such sanitizers dries the user's skin, often causing redness, chapped skin, and cracked skin.

[0005] As a result, it is common to limit the alcohol content in hand sanitizers to about 60%. However, reducing the alcohol content in a composition has the undesirable effect of reducing the potency of the composition in killing infectious agents, i.e., bacteria, viruses, fungi, and protozoa.

[0006] The problem with known hand sanitizers is that even though the sanitizers can inactivate / kill most of the infectious agents that have accumulated on a user's hands, they do not have a long-lasting effect because the sanitizers are easily "washed off," for example, when the user goes out in the rain, sweats, or simply washes their hands. Thus, users must periodically reapply the hand sanitizer to achieve the desired antibacterial effect, which increases the problem of dry / red hands. Summary of the Invention

[0007] Therefore, there is a need for a hydroalcoholic gel with a high percentage of alcohol that effectively kills infectious agents, dries quickly, does not leave a sticky residue, does not overly dry the skin, and ensures that the composition has long-lasting disinfecting efficacy even after subsequent hand washing. [Brief explanation of the drawings]

[0008] [Figure 1] The visual appearance of the sample is shown. DETAILED DESCRIPTION OF THE INVENTION

[0009] These and further aspects are achieved in accordance with the present invention by providing a hydroalcoholic gel comprising at least 70% by weight of an alcohol, between 5 and 10% by weight of an oil composition, between 0.15 and 6% by weight of a gelling agent, and between 0.01 and 0.1% by weight of a pH adjusting agent, wherein the gelling agent consists of between 0.05 and 2.0% by weight of a carbomer and between 0.1 and 4.5% by weight of a cellulose polymer composition.

[0010] The hydroalcoholic gel is unique in that it contains a high concentration of alcohol, thereby effectively killing microorganisms, viruses, etc., on contact, but only low concentrations of other ingredients, such as gelling agents, without compromising moisturizing effects or product stability. Indeed, the hydroalcoholic gel according to the present invention is stable even after long-term storage. When used, the hydroalcoholic gel destroys microorganisms and viruses, moisturizes the skin, thereby avoiding redness, chapped skin, and cracking, does not leave an oily or sticky residue on the skin, and adheres firmly to the skin (even after washing), thereby providing long-term disinfecting effects. This long-term effect may be particularly important for healthcare workers and / or other groups who are exposed to infectious diseases from various sources throughout their daily lives.

[0011] It is generally recognized that alcohol concentrations of 70% by weight (or greater) kill / inactivate microorganisms on contact, for example, by denaturing proteins in bacterial cell membranes or proteins in viral capsids / envelopes. The alcohol used in the hydroalcoholic gels of the present invention can be any type of alcohol capable of killing / inactivating infectious agents. However, it is preferred that the alcohol be ethanol or isopropanol or a mixture thereof. For example, ethanol at a concentration of 70% by weight has been shown to be a powerful virucide, inactivating all lipophilic viruses (e.g., influenza virus) and many hydrophilic viruses (e.g., rotavirus).

[0012] It is preferred to have an alcohol concentration of at least 70% by weight in the hydroalcoholic gel according to the invention, although the alcohol content may be lower in some circumstances. The inventors have found that an alcohol concentration of about 65% by weight in the hydroalcoholic gel is sufficient to kill / inactivate relevant infectious agents, and in some circumstances the alcohol concentration may be as low as about 45% by weight in the hydroalcoholic gel.

[0013] Since proteins are denatured more rapidly by alcohol in the presence of water, preferred embodiments of hydroalcoholic gels according to the invention contain 5-20% by weight water, preferably between 12 and 18% by weight water.

[0014] To prevent the skin from drying out due to degreasing caused by the high alcohol concentration, the hydroalcoholic gel according to the present invention comprises an oil composition. Thus, the hydroalcoholic gel comprises both an aqueous phase and an oily phase, preferably the aqueous and oily phases combined into a bigel.

[0015] Although visually appearing as a single gel, a bigel is a homogeneous semi-solid dispersion in which an oleogel and an aqueous gel have been mixed together, for example, by applying high shear rates. A bigel is not an emulsion, and one of its main advantages is its improved stability compared to emulsions (water-in-oil and oil-in-water), emulgels, hydrogels, and oleogels, ensuring that the hydroalcoholic gels of the present invention remain stable. The improved physicochemical stability of bigels can be attributed to the formation of a very fine colloidal dispersion, which results from the immobilization of one gel (e.g., an oleogel) in a three-dimensional gel network of another gel (e.g., an aqueous gel). Upon storage at room temperature, the two components of the bigel do not separate, and therefore the hydroalcoholic gels of the present invention remain stable even after long storage periods, i.e., for more than one year.

[0016] Furthermore, no separation of the aqueous gel and oleogel is detected when the hydroalcoholic bigel is applied to the skin. Thus, converting the oleogel and hydrogel into a bigel provides good patient satisfaction without compromising the beneficial effects of the individual aqueous and oil phases.

[0017] The oil composition in the hydroalcoholic gel is preferably selected from mono-, di- and triglycerides of synthetic, semi-synthetic and natural origin, and mixtures thereof, such as a mixture of capric / caprylic triglycerides.

[0018] The synthetic mono-, di-, or triglyceride may be Miglyol 810 / 812 (Dynamit Nobel), and the semi-synthetic mono-, di-, or triglyceride may be propylene glycol isostearate, such as the product sold under the name "hydrophilol isostearique" (Gattefosse), and the polyglycolized glyceride "Labrafil® M 1944 CS" (Gattefosse). The naturally occurring mono-, di-, or triglyceride is preferably an oil of plant origin, such as sweet almond oil, argan oil, or palm oil. However, the oil composition of the present invention is preferably a mixture of capric / caprylic triglycerides, such as Labrafac® WL1349 (Gattefosse). Labrafac® WL1349 is a mixture of medium-chain triglycerides, primarily from caprylic acid (C8) and capric acid (C10).

[0019] When the oil composition is added to the hydroalcoholic gel at a concentration of between 5 and 10% by weight of the final product, the hydroalcoholic gel exhibits improved moisturizing effect on the skin and prevents the skin from drying out. Furthermore, because the concentration of the oil composition is relatively low, the composition does not provide a greasy feel by leaving an oily residue on the skin, thereby providing high user satisfaction.

[0020] The gelling agent used in the hydroalcoholic gel consists of a combination of carbomer and a cellulose polymer composition, the amount of which in the final composition is between 0.15 and 6% by weight.

[0021] Carbomer is a generic term for a family of polymers known as carbopols, which are homopolymers of acrylic acid crosslinked with allyl ethers of pentaerythritol, sucrose, and propylene. Collectively, they are dry powders with high bulk density and form acidic aqueous solutions (pH about 3.0) that thicken at higher pHs (about 5 or 6). They swell to up to 1000 times their original volume in aqueous solutions at that pH; therefore, the viscosity of the aqueous phase can be adjusted by adjusting the concentration of carbomer in the composition and the pH of the composition. Preferred examples of such carbomers are Carbopol 974 and Carbopol 980 NF.

[0022] Since the viscosity of carbomer is pH-dependent, carbomer acts as a gelling agent for at least the aqueous phase of the hydroalcoholic gel when the pH is adjusted to an optimum value. For Carbopol polymers, the optimum pH value is between 6.0 and 7.5, which corresponds well to the fact that the antimicrobial composition according to the invention is intended for topical and / or transdermal use in humans, for which it is preferable to provide a composition with a neutral pH value, i.e., about pH 7. Those skilled in the art will understand that it is not necessary to obtain a pH value of 7 in the composition, only that the pH value of the composition does not damage and / or irritate the epidermis / skin at the application site.

[0023] The pH adjuster may be any compound / composition capable of adjusting the pH of a composition to obtain an optimal pH, e.g., between 5.0 and 8.0, preferably between 6.0 and 7.5, such as sodium hydroxide (if a higher pH is desired) or sorbic acid (if a lower pH is desired). However, in a preferred embodiment, the pH adjuster is triethanolamine. Surprisingly, the inventors of the present invention have found that low concentrations of triethanolamine in the hydroalcoholic gel composition of the present invention provide both an optimal pH of between about 6.0 and about 7.5, a desired product viscosity, and a stable product without separation of the oil and aqueous phases, despite the commonly held belief that triethanolamine cannot be used to adjust the pH in compositions having an alcohol concentration greater than 60% by weight. In a preferred embodiment, the pH adjuster is added in an amount of between 0.01 and 0.1% by weight, preferably between 0.02 and 0.08% by weight, e.g., between 0.025 and 0.03% by weight, or between 0.05 and 0.06% by weight, based on the weight of the final hydroalcoholic gel of the present invention. Concentrations of triethanolamine greater than 0.1% by weight based on the final hydroalcoholic gel result in a gel composition that is not substantially homogeneous.

[0024] The term "cellulose polymer composition" as used herein refers to a composition comprising or consisting of at least one cellulose polymer. The cellulose polymer may be selected from ethyl cellulose, non-sodium carboxymethyl cellulose, and mixtures thereof. However, one preferred cellulose polymer composition is the gelling agent disclosed in applicant's PCT / EP2019 / 082893, or the Emulfree® CBG or Emulfree® P formulations available from Gattefosse. Emulfree® CBG contains isostearyl alcohol, butylene glycol cocoate, and ethyl cellulose, while Emulfree® P contains propylene glycol laurate, ethyl cellulose, and propylene glycol isostearate.

[0025] The cellulose polymer composition is particularly useful for gelling / thickening the oil phase, thus providing a stable and homogeneous final product. The cellulose polymer composition is added in an amount of 0.1 to 4.5% by weight of the final hydroalcoholic gel, preferably 1 to 4% by weight, for example about 2% by weight.

[0026] In a preferred embodiment, this amount of cellulose polymer composition in the hydroalcoholic gel provides a hydroalcoholic gel according to the invention comprising between 0.5 and 1.5 wt. % isostearyl alcohol, between 0.1 and 1 wt. % butylene glycol cocoate, and between 0.01 and 0.5 wt. % ethyl cellulose.

[0027] The present inventors have further found that to ensure that the hydroalcoholic gel according to the present invention can be used for topical use, i.e., that it can be easily applied to the skin, adheres firmly to the skin (even after washing), and does not leave the skin feeling oily or dirty, it is preferable that the hydroalcoholic gel have a viscosity of 1000 to 150,000 cP. By way of comparison, lotions typically have a viscosity in the range of 1000 to 30,000 cP (1 to 30 Pa·s), while creams and ointments have a higher viscosity of more than 30,000 cP (30 Pa·s), preferably more than 80,000 cP (80 Pa·s) and less than 150,000 cP (30 to 150 Pa·s). In a preferred embodiment, the hydroalcoholic gel has a viscosity in the range of 30,000 to 120,000 cP (20 to 120 Pa·s), preferably about 50,000 to 80,000 cP (50 to 80 Pa·s). All viscosities are measured at a temperature of 23°C and a viscosity of 0.8 s. -1 at a shear stress of 1000 MPa and measured using a Lamy VRM-08 viscometer equipped with an MS DIN module.

[0028] Those skilled in the art will understand that it is not always necessary to measure the viscosity of a hydroalcoholic gel to obtain a gel with a desired viscosity. Whether a gel has a viscosity suitable for use as a hand sanitizer can also be determined by feel. Also, once the ingredients and conditions for producing a gel with a desired viscosity are determined, it is possible to reproduce a gel with that particular viscosity by following the same procedure.

[0029] A person skilled in the art can easily obtain a hydroalcoholic gel having any desired viscosity, for example, by adjusting the concentration of the gelling agent, i.e., the concentration of the compound in the agent, oil composition and / or pH adjuster.

[0030] The present inventors have found that the hydroalcoholic gel of the present invention is long-lasting in that it significantly reduces the incidence of infectious agents on the skin surface for a period of approximately 3 to 4 hours, even after subsequent hand washing. Thus, when the gel is applied to the skin, it not only kills / inactivates microorganisms and viruses on contact, but also forms a thin film on the skin that remains effective for an extended period of time after application. This thin film prevents reinfection upon subsequent introduction of infectious agents and acts as a moisturizing layer by slowing water loss from the skin surface.

[0031] Without being bound by theory, it is believed that the oil composition spreads onto the skin and the gelling agent stabilizes the oil composition, adding support to the spreading and layering of the oil. The gelling agent may also interact with the user's skin surface, and it is likely that the combination of these interactions results in a very thin physical film layer of hydroalcoholic gel that remains on the skin surface and provides long-term disinfecting and moisturizing benefits.

[0032] To further enhance the disinfecting properties of the hydroalcoholic gel according to the present invention, in a preferred embodiment, the gel may further comprise a disinfectant component. The disinfectant component may be a quaternary ammonium salt or sodium hypochlorite, but in a preferred embodiment, the component is hydrogen peroxide. The disinfectant is preferably added to the hydroalcoholic gel in an amount between 0.1 and 6% by weight.

[0033] In combination, each compound of the unique hydroalcoholic gel provides a product with improved efficacy in inactivating bacteria and viruses on a user's skin. The unique relationship between the different compounds allows for the use of relatively low levels of both moisturizers and gelling agents while maintaining high concentrations of alcohol and, optionally, disinfectants, thereby providing a gel that maintains its disinfecting properties and exhibits both improved skin care and stability.

[0034] The hydroalcoholic gel is preferably for use as a hand sanitizer and the present inventors have found that preferred hydroalcoholic gels in this regard comprise the following ingredients: TIFF0007802370000001.tif55170

[0035] The hydroalcoholic gel according to the invention may, in an alternative embodiment, comprise at least one active ingredient which may be a pharmaceutical product.

[0036] Orally administered pharmaceuticals are subject to gastrointestinal degradation by acids or enzymes. Because hydroalcoholic gels are intended for topical administration, they may be particularly suitable for active pharmaceutical ingredients that are vulnerable to gastrointestinal degradation, such as protein or peptide therapeutics.

[0037] Due to the high alcohol concentration in the gel, it is preferable to use an active ingredient that is soluble in alcohol and can be transported across the dermis or epidermis. However, the active ingredient may be one that is primarily dissolved / distributed in the oil phase, or the gel may contain different active ingredients in each phase.

[0038] In certain intended uses, hydroalcoholic gels may contain the same active ingredient in both the oily and aqueous phases. This is advantageous because the inventors have found that the release profile of the active ingredient from such gels on the skin is significantly better than that obtained with compositions based on only one type of gel, either oily or aqueous. (Comparisons were made for a given volume of applied composition and a given concentration of active ingredient relative to the total weight of the composition.) This is particularly advantageous when using a gel as an active ingredient reservoir, for example, in a transdermal delivery system. On the skin, the active ingredient dissolved in the aqueous phase is rapidly taken up by the epidermal layer, thereby allowing transdermal passage to begin quickly. The active ingredient in the oily phase must first enter the aqueous phase to enter the epidermal layer as a function of its oil / water partition coefficient; therefore, this fraction in the oily phase is released with a greater delay after the active ingredient dissolved in the aqueous gel is released, thereby providing a sustained release profile.

[0039] The present invention also relates to a drug delivery system for an active ingredient. The drug delivery system is preferably a transdermal delivery system. However, since the inventors of the present invention have shown that hydroalcoholic gels, despite their high alcohol concentrations of more than 70% by weight, do not cause damage and / or irritation to the epidermis or mucosal tissues, mucosal delivery systems, for example, for buccal, nasal, vaginal, and rectal administration, are also contemplated within the scope of the present invention.

[0040] The transdermal and mucosal delivery systems of the present invention have several advantages, such as overcoming the drawbacks of conventional administration routes. For example, direct entry of drugs into the systemic circulation avoids the first-pass effect. Furthermore, administration of the delivery systems is generally non-invasive, thereby avoiding the unpleasant aspects of intravenous, intramuscular, or subcutaneous delivery methods. Furthermore, the active ingredient can be easily administered and removed from the application site as needed. Therefore, the drug delivery systems of the present invention are valuable for delivering an increasing number of active ingredients (drugs).

[0041] Suitable active ingredients may be any suitable compound / composition that can be delivered through the epidermis or mucosal tissue and may therefore be hormones; corticoids and corticoid derivatives; dermatological active ingredients; antibacterial agents; anti-inflammatory agents and wound repair agents.

[0042] In a preferred embodiment, the hydroalcoholic gel comprises a hormone selected from estradiol (or other estrogens), progesterone (or progestins) and testosterone, said hormone being present in the hydroalcoholic gel in an amount preferably between 0.5 and 2.5% by weight or more, more preferably between 0.5 and 1.5% by weight, relative to the total weight of the gel. In a preferred embodiment, the gel comprises 1% by weight of the hormone, preferably testosterone.

[0043] The present inventors have found that a preferred hydroalcoholic gel in this regard comprises the following ingredients: TIFF0007802370000002.tif57170

[0044] In a further preferred embodiment, the dermatological active ingredient comprises vitamin E and / or one or more essential oils and / or other skin hydrating compositions.

[0045] Vitamin E is known to have a "moisturizing and repairing" effect, which helps to strengthen the skin's barrier function. Vitamin E is lipid-soluble, allowing it to penetrate the dermis and preserve lipids. Vitamin E is preferably present in the hydroalcoholic gel at between 0.5 and 5.0 wt. %, more preferably between 1 and 4 wt. %, even more preferably between 3 and 3.5 wt. %, for example 3.3 wt. %, based on the total weight of the gel.

[0046] Essential oils are plant extracts made from flowers, leaves, and seeds. The essential oils used in the present invention have properties that are particularly useful for softening dry skin. For example, chamomile oil contains azulene, which is known to increase moisture and reduce inflammation; bergamot oil is known for its antibacterial and antifungal properties; hemp oil is known for its moisturizing effects; and sandalwood oil contains compounds known to increase moisture in the skin and reduce inflammation.

[0047] Other skin hydrating compositions, such as sodium hyaluronate, can also be added to the hydroalcoholic gel according to the present invention. Sodium hyaluronate is hydrophilic and attracts moisture to skin cells when applied topically. This increases skin hydration, thereby reducing dryness and flaking.

[0048] Examples of active ingredients that can be used in the hydroalcoholic gel are listed in Table A below. TIFF0007802370000003.tif173170

[0049] The hydroalcoholic gel according to the invention is preferably a bigel. Such bigels are usually obtained by preparing a hydrogel and an oleogel separately and then mixing the two gels together, for example by applying high shear rates. Examples of methods for formulating such bigels are disclosed, for example, in EP 1 083 880 and EP 2 120 865.

[0050] However, the inventors of the present invention have found that it is possible to provide a hydroalcoholic gel (bigel) in a single process line, i.e. without the need to first prepare an aqueous gel and an oleogel separately and then combine them.

[0051] The invention therefore also relates to a method for producing a hydroalcoholic gel according to the invention, comprising the following successive steps: a. combining alcohol and optionally water, thereby providing an aqueous solution; b. dispersing a carbomer in an aqueous solution, thereby providing a first intermediate composition; c. mixing a cellulose polymer composition with the first intermediate composition, thereby providing a second intermediate composition; d. mixing the oil composition with the second intermediate composition, thereby providing a third intermediate composition; and e. mixing a pH adjuster with the third intermediate composition, thereby providing a hydroalcoholic gel. The present invention relates to a method, comprising:

[0052] In an alternative embodiment, the method of manufacture may be modified so that step d occurs before step c, i.e., the oil composition is mixed with the first intermediate composition to provide a second intermediate composition, and then the cellulose polymer composition is mixed with the second intermediate composition to provide a third intermediate composition, with the remaining steps remaining unchanged.

[0053] The resulting gel will have the properties of a bigel, i.e., it is a homogeneous semi-solid system that visually appears as a single gel, has improved stability compared to emulsions, and does not leave a greasy or dirty feel on the skin. Even though the aqueous and oily phases are not prepared separately, one gel (e.g., an oleogel) is believed to be immobilized in the three-dimensional gel network of the other gel (e.g., an aqueous gel), just as if the two phases were first prepared separately and then mixed together. Thus, the present method provides a simpler and less expensive way to provide the desired hydroalcoholic gel with bigel properties than conventional methods for producing bigels.

[0054] In the method according to the present invention, the components are added to the composition stepwise, with each component being added before the next. Each component is mixed with the previously obtained intermediate composition, preferably with vigorous stirring, until the composition appears visually uniform. It is preferred to stir each intermediate composition for at least 10 minutes, as this has been shown to provide the desired stable gel. The inventors have found that, depending on the circumstances, it may be desirable to stir some of the steps for longer or shorter periods of time, for example, stirring the first intermediate composition provided in step b for 1 to 2 hours and the intermediate composition provided in step c for a shorter period of time, for example, about 5 minutes.

[0055] When the hydroalcoholic gel according to the invention comprises a hydrophilic disinfectant, said agent is preferably mixed with alcohol and water in step a.

[0056] Similarly, if the hydroalcoholic gel comprises an active ingredient that can be dissolved in alcohol and / or water, said active ingredient is preferably mixed with alcohol and water in step a, while the hydrophobic active ingredient is preferably mixed with the oil composition in step d or added to the oil composition before adding said composition to the composition obtained in step c.

[0057] The resulting hydroalcoholic gel disinfects, provides long-lasting disinfectant properties, prevents skin dryness, and does not cause skin irritation. In addition to the alcohol and oil composition, the hydroalcoholic gel contains a unique gelling agent and a pH adjuster at controlled concentrations, thereby providing a unique gel with bigel properties. These properties are believed to stabilize the formulation and contribute to eliminating the sticky feeling that follows the application of known disinfectants, such as those containing glycerol. Furthermore, the hydroalcoholic gel according to the present invention preferably does not contain any parabens and / or surfactants. [Example]

[0058] The general preparation procedure for each composition to obtain a hydroalcoholic gel was as follows: Each gel was prepared as follows.

[0059] An aqueous gel was first prepared by combining alcohol, water, and in some compositions, hydrogen peroxide (a disinfectant), and then carbomer Carbopol® 980 NF was dispersed into the mixture while stirring at 2000-6000 rpm using a SYLVERSON® type mixer, thereby providing an aqueous gel.

[0060] An oleogel was then prepared by mixing the oil composition of caprylic / capric triglyceride Labrafac® WL1349, optionally with a small amount of water (purified water (2) in the table below), with stirring using a magnetic stirrer for 5 minutes (or more). If Emulfree was part of the composition, Emulfree was then added with stirring using a magnetic stirrer for 10 minutes.

[0061] The oleogel was then added to the aqueous gel under high speed stirring at 13,500 rpm for 10 minutes using an ULTRA TURRAX® type mixer, and the resulting bigel was then transferred to a mortar. A pH adjuster (sodium hydroxide or triethanolamine) was then added under magnetic stirring to adjust the pH value of the bigel.

[0062] To test which compounds are suitable for providing gels with high alcohol concentrations, the following three compositions were prepared as described above: TIFF0007802370000004.tif63170

[0063] Compositions F1, F2 and F3 were slightly thick gels containing Carbopol clumps, and it was believed that the sodium hydroxide induced the formation of Carbopol clumps.

[0064] To evaluate whether the pH adjuster could be omitted, the following compositions were prepared: TIFF0007802370000005.tif57170

[0065] Formulation F4 was a liquid composition with two distinct phases: the oily and aqueous phases were immiscible, with Labrafac (the oil composition) below the aqueous phase.

[0066] To test whether the oil phase could be combined with the aqueous phase, composition F5 was formulated, which corresponds to F4 but with the addition of the cellulose polymer composition Emulfree® P. TIFF0007802370000006.tif57170

[0067] F5 provided a gel, and it could therefore be concluded that a cellulose polymer composition such as Emulfree® P was necessary to produce a gel with a high alcohol concentration. However, the resulting gel was not stable, and after 5 minutes the gel separated into two distinct phases.

[0068] To test whether higher concentrations of alcohol could be obtained, formulations F6 and F7 were prepared. TIFF0007802370000007.tif57170

[0069] These did not result in gel formation because the resulting compositions were liquid. F7 was more liquid than F6. After 10 minutes of preparation, F7 separated into two distinct phases, while F6 separated after 1 hour.

[0070] Therefore, to assess whether a pH adjuster could be used to obtain a more stable gel, the F6 composition was modified by adding a pH adjuster, thereby providing the F8 composition. TIFF0007802370000008.tif62170

[0071] Because sodium hydroxide was found to provide a gel with Carbopol mass, the pH adjuster triethanolamine was tested, even though it is generally recognized that only triethanolamine is suitable for compositions containing 60% alcohol by weight.

[0072] Triethanolamine strongly thickened the solution to provide a gel, but it was not uniform in appearance. To assess whether this was due to the concentration of triethanolamine, a modified version of F8, F9, was prepared.

[0073] F9 was prepared by adding 2 drops of triethanolamine to 100 g of gel having formulation F6 under propeller stirring. Surprisingly, the resulting gel was uniform, slightly thick, and stable for more than one day. The pH of the composition was 6.0. The resulting composition had the following formulation: TIFF0007802370000009.tif64170

[0074] It could therefore be concluded that not only can the hydroalcoholic gel composition contain very low concentrations of triethanolamine, preferably 0.1 wt. % or less, but said addition also provides a desired homogeneous hydroalcoholic gel with bigel properties.

[0075] To evaluate whether it is possible to avoid producing both an aqueous gel and an oleogel and instead produce a hydroalcoholic gel in a single continuous process, the following one-line (single step) manufacturing process was evaluated.

[0076] First, alcohol, water, and hydrogen peroxide (sterilant) were mixed, and then Carbopol® 980 (carbomer) was dispersed in the resulting solution with stirring and maintained for 10 minutes. Next, Emulfree® (cellulose polymer composition) was added to the resulting intermediate composition with stirring and maintained for 10 minutes. After that, Labrafac® WL1349 (oil composition) was added with stirring and maintained for 10 minutes. Finally, a pH adjuster (triethanolamine) was added with stirring and maintained for 10 minutes.

[0077] At the same time, we evaluated whether this new manufacturing process could be used to reduce the concentration of the cellulose polymer composition Emulfree without compromising the properties of the F9 gel, and the following two compositions were manufactured as described above: TIFF0007802370000010.tif62170

[0078] For the F10 formulation, stirring was carried out using a high-performance disperser that uses the rotor-stator principle.

[0079] F11 was stirred using a mixer that uses the propeller principle.

[0080] Both F10 and F11 were visually uniform and visually stable over time.

[0081] It could therefore be concluded that instead of having to first produce an aqueous gel and an oleogel and then combine both, a hydroalcoholic gel with bigel properties could be produced in a single process line, thereby greatly simplifying the manufacturing process.

[0082] The concentration of the cellulose polymer composition Emulfree can also be reduced without the appearance, stability and effectiveness of the hydroalcoholic gel according to the present invention.

[0083] To further evaluate the feasibility of hydroalcoholic gels according to the present invention and to test the stability of said gels, four hydroalcoholic gels were prepared based on the preferred hydroalcoholic gel compositions shown in Table I.

[0084] The four compositions had the following compositions: TIFF0007802370000011.tif83170

[0085] The hydroalcoholic gel was prepared using the following materials: TIFF0007802370000012.tif74170

[0086] Additionally, hydroalcoholic gels were prepared using either a two-step procedure where the aqueous gel and oleogel were prepared separately before mixing, or a one-step (one-line) manufacturing method according to the present invention.

[0087] The following equipment was used: -Scale METTLER (registered trademark) Toledo XS802S (APTYS 307) -Scale METTLER (registered trademark) Toledo XS6001 (APTYS 342) -Magnetic hotplate stirrer IKA RCT Basic (APTYS 318) -Mixer VMI® Turbotest + 35mm and 55mm Propellers (APTYS 317) -KITCHENAID Planetary Mixer (APTYS 487) F13L012: Hydroalcoholic gel containing 75% EtOH: Batch size: 700g Beaker: Stainless steel; 1200ml Propeller: 55mm

[0088] process TEA solution TEA needs to be diluted.

[0089] Prepare a solution containing purified water (2) and TEA with magnetic stirring.

[0090] One-step manufacturing using propellers -Weighing purified water into a beaker; - weighing and adding hydrogen peroxide; -Weighing and adding ethanol; - Weigh out and disperse Carbopol® 980 while stirring with a propeller (500-700 rpm for approximately 2 minutes), then stir at 700 rpm for 10 minutes; - Weigh and add Labrafac® into a beaker while stirring with a propeller; (800 rpm for approximately 2 minutes) then stirring at 800 rpm for 10 minutes, - Emulfree® is weighed into a beaker and stirred at 750 rpm for 10 minutes; - Slowly add the TEA solution to the beaker with propeller stirring (750 rpm for 1 minute), then stir at 1200 rpm for 5 minutes. F14L013: Hydroalcoholic gel containing 3.3% vitamin E: Batch size: 700g Beaker: Stainless steel; 1200ml Propeller: 55mm

[0091] process TEA solution TEA needs to be diluted.

[0092] Prepare a large solution containing purified water and TEA with magnetic stirring. Add the required amount of TEA solution to the preparation.

[0093] Vitamin E is solubilized in Labrafac® with magnetic stirring before adding the combined mixture to the beaker.

[0094] One-step manufacturing using propellers -Weighing purified water into a beaker; - weighing and adding hydrogen peroxide; -Weighing and adding ethanol; - Weigh out and disperse Carbopol® 980 while stirring with a propeller (500-700 rpm for approximately 2 minutes), then stir at 700 rpm for 10 minutes; - Labrafac® is weighed into a separate beaker, and Vitamin E is weighed and added. The beaker is placed under magnetic stirring until the Vitamin E is completely solubilized (approximately 2 minutes). With propeller stirring (750 rpm for approximately 2 minutes), the preparation is added to the gel, which is then stirred for 5 minutes at 750 rpm. - Emulfree® is weighed into a beaker and stirred at 750 rpm for 10 minutes; - With propeller stirring (750 rpm for 1 minute), slowly add the required amount of TEA solution to the beaker, then stir at 1300 rpm for 5 minutes. F15L014: Hydroalcoholic gel containing 45% EtOH: Batch size: 700g Beaker: Stainless steel; 1200ml Propeller: 55mm

[0095] process TEA solution TEA needs to be diluted.

[0096] Prepare a solution containing purified water (2) and TEA with magnetic stirring.

[0097] Note: In this formulation, the percentage of TEA was reduced due to the lower percentage of EtOH. At 0.056% TEA, the gel was too thick. The aim was to have visually the same viscosity for the 75% and 45% ethanol formulations.

[0098] One-step manufacturing using propellers -Weighing purified water into a beaker; - weighing and adding hydrogen peroxide; -Weighing and adding ethanol; - Weigh out and disperse the Carbopol® 980 while stirring with a propeller (700 rpm for approximately 2 minutes), then stir at 700 rpm for 10 minutes; - Labrafac® is weighed and added to a beaker with propeller stirring (750 rpm for approximately 1 minute), followed by stirring at 800 rpm for 5 minutes; - Emulfree® is weighed into a beaker and stirred at 800 rpm for 10 minutes; - With propeller stirring (800-1200 rpm for approximately 3 minutes), slowly add the TEA solution to the beaker, then stir at 1200 rpm for 5 minutes. F16L018: Hydroalcoholic gel containing 65% EtOH, 0.1% HLA and 3.3% Vitamin E: Batch size: 700g Beakers: Stainless steel; 250ml and 1200ml Propeller diameter: 35mm, 55mm Planetary Mixer: Blade K (Flat Beater)

[0099] process TEA solution TEA needs to be diluted.

[0100] Prepare a solution containing ethanol (3) and TEA with magnetic stirring.

[0101] Sodium hyaluronate Depending on the amount of ethanol, sodium hyaluronate will precipitate. It was not possible to make a gel containing 70% ethanol and 0.25% sodium hyaluronate. Ethanol is added in three portions to ensure that sodium hyaluronate does not precipitate.

[0102] Two-stage manufacturing using propeller and planetary mixers aqueous phase -Weigh 250 ml of purified water into a beaker; -Weigh out and disperse sodium hyaluronate while stirring with a propeller (750-1000 rpm for approximately 2 minutes; φ35 mm). - Weigh out and add hydrogen peroxide and stir at 1500 rpm for 3 minutes; - Transfer the sodium hyaluronate gel to a 1200 ml beaker, rinse with weighed ethanol (1), and stir at 650 rpm for 5 minutes (φ55 mm). -Weigh out and disperse Carbopol® 980 while stirring with a propeller (φ55 mm; 700-1200 rpm for approximately 3 minutes), then use a spatula to stir at 1200 rpm for 20 minutes, and again at 2500 rpm for 15 minutes.

[0103] Oil phase - Weigh and add Labrafac® into another beaker, then weigh and add Vitamin E. Place this beaker under magnetic stirring until a homogeneous mixture is obtained (approximately 2 minutes). - Emulfree® P is weighed and added, then stirred for 5 minutes with magnetic stirring. - Ethanol (2) is weighed and added to this preparation, then stirred for 5 minutes with magnetic stirring. The preparation is translucent and yellow. - With propeller stirring (φ55 mm; 2000 rpm for about 3 minutes), the oily phase obtained is added to the aqueous gel, and then stirred for 10 minutes. With propeller stirring at -2500 rpm, slowly add the TEA solution to the beaker, then stir with a planetary mixer at speed 2 for 5 minutes.

[0104] To test the stability of the four hydroalcoholic gels, a sample of each composition was placed at room temperature and a sample at 40° C. Each sample was evaluated for macroscopic appearance once a month at a time interval of three months.

[0105] The visual appearance of the samples is shown in the figure (Figure 1) and the results can be summarized as follows: F13L012: Hydroalcoholic gel containing 75% by weight EtOH: TIFF0007802370000013.tif95170F14L013: 70 wt% EtOH Hydroalcoholic gel with 3.3 wt% Vitamin E: TIFF0007802370000014.tif104170F15L014: Hydroalcoholic gel containing 45 wt% EtOH: TIFF0007802370000015.tif109170F16L018: Hydroalcoholic gel containing 65% by weight EtOH, 0.1% by weight HLA and 3.3% by weight Vitamin E: TIFF0007802370000016.tif118170

[0106] As is evident from the above results, all four hydroalcoholic gels remained substantially stable over the test period.

[0107] Alcohols used for industrial purposes may, in some circumstances, contain denaturants, i.e., agents that make the alcohol unsuitable for human consumption. To assess whether such denaturants affect the stability of the produced hydroalcoholic gels, several additional hydroalcoholic gels were produced using different alcohols, some of which contained denaturants.

[0108] The following alcohols were tested: TIFF0007802370000017.tif67170

[0109] All hydroalcoholic gels are made using the following process: - first mixing alcohol, water and hydrogen peroxide (a disinfectant); - then dispersing Carbopol® 980 (carbomer) in the solution obtained under stirring, maintaining stirring at 1000 rpm for 1 hour and 40 minutes; - then adding Emulfree® CBG (a cellulose polymer composition) to the intermediate composition obtained therefrom while stirring, and maintaining stirring at 1000 rpm for 5 minutes; - then, while stirring, adding Labrafac® WL1349 (oil composition) and maintaining stirring at 1000 rpm for 10 minutes, thereby obtaining a mixture; and - dissolving a pH adjuster (triethanolamine) in demineralized water and adding the solution obtained therefrom to the mixture obtained in the previous step while stirring, maintaining said stirring at 1500 rpm for 10 minutes; was produced using

[0110] The viscosity, pH and density of the resulting gel were measured.

[0111] Viscosity was measured using a Brookfield DV2T (R3V20) 1300-2300 cPs. TIFF0007802370000018.tif117170TIFF0007802370000019.tif122170TIFF0007802370000020.tif116170TIFF000 7802370000021.tif117170TIFF0007802370000022.tif121170TIFF0007802370000023.tif118170TIFF00078023700 00024.tif113170TIFF0007802370000025.tif108170TIFF0007802370000026.tif117170TIFF0007802370000027.t if112170TIFF0007802370000028.tif118170TIFF0007802370000029.tif118170TIFF0007802370000030.tif126170

[0112] As is evident from the above data, small variations in pH value, viscosity and density are observed depending on the choice of denaturant, and although these variations may seem insignificant, the choice of alcohol and denaturant can be important to obtain, for example, the desired pH value, viscosity or density.

[0113] During these experiments, it was further found that difficulties with stability can be observed if the components are not measured accurately. Therefore, it may be preferable to produce hydroalcoholic gels according to the present invention on a larger scale, i.e., not on a laboratory scale, since it is easier to accurately weigh out the compounds in the hydroalcoholic gel.

[0114] In conclusion, the resulting hydroalcoholic gel has a high alcohol content, ensuring that the gel effectively inactivates / kills pathogens, even after subsequent hand washing. The gel dries quickly and does not leave a sticky residue on the skin. At the same time, it exhibits a moisturizing effect, ensuring that frequent use of the gel does not overly dry the skin, and it remains stable even after long-term storage. Therefore, the hydroalcoholic gel is effective for use by both healthcare professionals, patients, and others concerned with preventing the spread of infectious diseases.

[0115] The foregoing description and examples have been set forth merely to illustrate the invention and are not intended to be limiting. Each of the disclosed aspects and embodiments of the invention may be considered individually or in combination with other aspects, embodiments, and variations of the invention.

[0116] Variations and combinations of the above principles and designs are anticipated within the scope of the present invention.

Claims

1. 1. A hydroalcoholic gel comprising at least 70% by weight of an alcohol, between 5 and 10% by weight of an oil composition, between 0.15 and 6% by weight of a gelling agent, and between 0.01 and 0.1% by weight of a pH adjuster, wherein the gelling agent consists of between 0.05 and 2.0% by weight of a carbomer and between 0.1 and 4.5% by weight of a cellulose polymer composition, based on the total weight of the hydroalcoholic gel, the alcohol being ethanol or isopropanol or a mixture thereof, the oil composition being selected from mono-, di-, and triglycerides of synthetic, semi-synthetic, and natural origin, and mixtures thereof, the cellulose polymer composition comprising (i) isostearyl alcohol, butylene glycol cocoate, and ethyl cellulose, or (ii) propylene glycol laurate, ethyl cellulose, and propylene glycol isostearate, the hydroalcoholic gel comprising both an aqueous phase and an oily phase, which are combined into a bigel, and the pH adjuster is triethanolamine.

2. 10. The hydroalcoholic gel of claim 1, wherein the hydroalcoholic gel further comprises between 5% and 20% water by weight.

3. 3. A hydroalcoholic gel according to claim 1 or 2, wherein the oil composition in the hydroalcoholic gel is a mixture of capric / caprylic triglycerides.

4. A hydroalcoholic gel according to any one of claims 1 to 3, having a pH value between 5 and 8.

5. 5. The hydroalcoholic gel of claim 4, wherein the amount of triethanolamine in the hydroalcoholic gel is between 0.02 and 0.08 wt. %, based on the total weight of the final hydroalcoholic gel.

6. Temperature 23°C and shear stress 0.8 s －１ 6. The hydroalcoholic gel of any one of claims 1 to 5, having a viscosity of between 1000 cp and 150,000 cp, measured using a Lamy VRM-08 viscometer equipped with an MS DIN module at 1000 rpm.

7. The hydroalcoholic gel according to any one of claims 1 to 6, further comprising a bactericidal component.

8. 8. The hydroalcoholic gel of claim 7, wherein the disinfecting component is a quaternary ammonium, sodium hypochlorite, hydrogen peroxide, or a mixture thereof.

9. 9. The hydroalcoholic gel of claim 7 or 8, wherein the antiseptic component is added to the hydroalcoholic gel in an amount between 0.1% and 6% by weight, based on the total weight of the final hydroalcoholic gel.

10. A hydroalcoholic gel according to any one of claims 1 to 9, comprising at least one active ingredient.

11. 11. The hydroalcoholic gel of claim 10, wherein the active ingredient is selected from hormones; corticoids and corticoid derivatives; dermatological active ingredients; antibacterial agents; anti-inflammatory agents and wound repair agents.

12. 12. A hydroalcoholic gel according to claim 10 or 11, wherein the active ingredient is a hormone in an amount between 0.5 and 2.5% by weight, based on the total weight of the final hydroalcoholic gel.

13. A method for producing a hydroalcoholic gel according to any one of claims 1 to 12, comprising the following successive steps: a. combining an alcohol and optionally water, thereby providing an aqueous solution; b. dispersing a carbomer in an aqueous solution, thereby providing a first intermediate composition; c. mixing a cellulose polymer composition with the first intermediate composition, thereby providing a second intermediate composition; d. mixing the oil composition with the second intermediate composition, thereby providing a third intermediate composition; and e. mixing a pH adjuster with the third intermediate composition, thereby providing a hydroalcoholic gel. A method comprising:

14. 14. The method of claim 13, wherein the order of steps c and d is changed to the reverse order, i.e., the oil composition is mixed with the first intermediate composition, thereby providing a second intermediate composition, and then the cellulose polymer composition is mixed with the second intermediate composition, thereby providing a third intermediate composition, and the remaining steps remain unchanged.

15. 15. The method according to claim 13 or 14, wherein each added compound is mixed with the already obtained solution or intermediate composition under vigorous stirring.

16. The method of any one of claims 13 to 15, wherein each intermediate composition is stirred for at least 10 minutes.

17. A hand disinfectant comprising the hydroalcoholic gel of any one of claims 1 to 10.

18. 18. The hand sanitizer of claim 17, wherein the hydroalcoholic gel comprises 70.0 wt.% alcohol, 7.0 wt.% oil composition, 2.5 wt.% gelling agent, and 0.056 wt.% triethanolamine, wherein the gelling agent consists of 0.5 wt.% carbomer and 2.0 wt.% cellulose polymer composition, all based on the total weight of the hydroalcoholic gel.

19. 18. The hand sanitizer of claim 17, wherein the hydroalcoholic gel comprises 70.0 wt.% alcohol, 7.0 wt.% oil composition, 2.5 wt.% gelling agent, and 0.028 wt.% triethanolamine, wherein the gelling agent consists of 0.5 wt.% carbomer and 2.0 wt.% cellulose polymer composition, all based on the total weight of the hydroalcoholic gel.

20. A transdermal or mucosal delivery system comprising the hydroalcoholic gel according to any one of claims 1 to 12.

21. 21. The transdermal or mucosal delivery system of claim 20, wherein the delivery system comprises at least 1% by weight of testosterone, based on the total weight of the hydroalcoholic gel.

22. 22. The delivery system of claim 21, wherein the hydroalcoholic gel comprises 1 wt. % testosterone, 70.0 wt. % alcohol, 7.0 wt. % oil composition, 4.5 wt. % gelling agent, and 0.028 or 0.056 wt. % triethanolamine, wherein the gelling agent consists of 0.5 wt. % carbomer and 4.0 wt. % cellulose polymer composition, all based on the total weight of the hydroalcoholic gel.

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