Free-flowing topical formulation

Abstract

The present invention relates to a free-flowing topical powder formulation, also known as a powder-to-cream formulation. The invention particularly relates to a powder-formula that spreads on the skin like a cream upon application. The invention offers an ideal topical formulation with the advantages of both a powder and a cream, combining the ease of handling of the powder with the smoothness and spreadability of a cream, and is a better choice for multiple topically applied active ingredients. The present invention provides a technology for delivering various active ingredients from categories that include, among others, antiviral agents, acne treatment agents, alpha hydroxy acids, anesthetics, antibacterial agents, antifungals, etc.

Description

Field of invention The present invention relates to a free-flowing topical powder formulation, also known as a powder-to-cream formulation. The invention particularly relates to a formulation in powder form that, upon application, spreads on the skin like a cream. The invention offers an ideal topical formulation with the advantages of both a powder and a cream, combining the ease of handling of the powder with the smoothness and spreadability of the cream, and representing a better choice for multiple topically applied active ingredients. The present invention provides a technology for administering multiple active substances from categories including, but not limited to, antiviral agents, acne treatment agents, alpha-hydroxy acids, anesthetics (narcotics), antibiotics, antifungals, azelaic acid, anthralin, antibiotics, antihistamines, antiperspirants, antiseptics, bleaching agents, topical retinoids, topical steroids, topical silver therapy, sunscreens, tanning agents, cleansers, insecticides, etc., antibacterial agents, antibiotics, and antifungals, including their salts, hydrates, solvates, polymorphs, etc. Since many of the active ingredients belonging to the above-mentioned categories are insoluble, they are introduced in the form of their soluble forms, including but not limited to salts, complexes, solvates, hydrates, amorphous forms, polymorphs, etc. Some insoluble active ingredients are delivered as a complex or as a co-amorphous system. A co-amorphous system is a combination of two or more components that exist in an amorphous (non-crystalline) state. In such cases, the free-flowing topical powder formulation comprises a co-amorphous system containing an active ingredient and a coformer, also called an API-co-former co-amorphous system or solid mixture. The active ingredient or its soluble form, such as a salt, complex, or co-amorphous system, is dissolved or dispersed in a suitable water-miscible solvent. This solution or suspension is then added to water and a water-miscible co-solvent, mixed thoroughly, and homogenized if necessary to form a mixture. The mixture is then slowly added to an adsorbent or adsorbent composition and mixed well. The mixture may optionally be dried to achieve the desired water content. Thus, the powder-to-cream formulation of the present invention provides a cream formulation in powder form. The powder particles contain small liquid droplets surrounded by a network of adsorbent particles. When rubbed into the skin, the powder transforms into a cream. This technology offers several advantages of a powder formulation, such as ease of use, single-dose packaging, precise dosing, and zero waste. Simultaneously, upon application, liquid material is dispensed with slight pressure, resulting in a cream formulation with good spreadability and a smooth texture. Preferably, the adsorbent is one or more silicon dioxides or silicates or combinations thereof, including but not limited to those listed in Table 2. Objective of the invention A primary objective of the invention is to provide a free-flowing topical formulation that combines the advantages of a powder formulation, such as stability, flowability, ease of handling, and packaging, with the feel of a cream, such as smoothness and spreadability, when applied to the skin. The powder-to-cream formulation of the present invention exhibits good flow properties before application and excellent spreadability and smoothness when rubbed onto the skin, thus offering the advantages of both powder and cream formulations. The second objective of the invention is to provide a topical formulation that can be dispensed in single doses and administered precisely. The third objective of the invention is to provide a simple method for producing a powder-to-cream formulation. Another objective of the invention is to incorporate insoluble active ingredients into a powder-to-cream formulation by first converting them into a co-amorphous system using one or more co-formators. Background of the invention No preprint was found in which powder is converted into cream. Ultra Cream Powder is sold on the market by KRYOLAN. Their website states: "The velvety, silky-soft foundation works like a cream foundation due to its mica mineral content, which gives the skin a gentle glow." Mica minerals are silicates. This technology does not initially include a powder formulation, as it is a foundation. There are several antifungal powders on the market that do not form a cream under shear forces, such as Candid powder, Tetmosol powder, etc. Nystatin 100,000 units / gram topical powder is available on the market, but it does not form a cream and is not intended to be rubbed into the skin. There is a need in technology to combine the advantages of a powder and a cream in a single formulation. Summary of the invention From the first perspective, the invention offers a free-flowing topical formulation that has the advantages of a powder formulation such as stability, flowability, ease of handling, packaging, etc., and the feel of a cream such as smoothness, spreadability, etc. From this perspective, the present invention offers a powder-to-cream formulation in the form of a powder with an angle of repose of less than 30 degrees, preferably less than 25 degrees, a compressibility index of no more than 15 (Carr index), and a Hausner ratio of no more than 1.18. These values ​​indicate good to excellent flowability of the material. Furthermore, the powder spreads easily on the skin and exhibits comparable spreadability. A commercially available cream formulation with a diameter of 20 mm spreads into a circle with a diameter of 90 to 100 mm when a standard weight is applied, whereas the powder of the present invention spreads from a circle with a diameter of 20 mm to a circle with a diameter of 70 to 100 mm, preferably 75 to 100 mm, when the same weight is applied. Figures 10A2 and 10B2 show images of a powder-to-cream formulation rubbed onto the skin. The smoothness of the powder-to-cream formulation when rubbed in is comparable to that of a normal cream. The powder-to-cream formulation of the present invention exhibits good flow properties before application and excellent spreadability and smoothness when applied to the skin, thus offering the advantages of both powder and cream formulations. From a second perspective, the invention offers a free-flowing topical formulation that can be dispensed in single doses and administered precisely. While it is difficult to dispense a cream formulation that can deliver an exact dose, it is easy to fill powder-to-cream formulations of the present invention into a single-dose package such as a sachet, allowing users to apply a single dose each time and to dispense the single dose of powder into a cream. In the third aspect, the invention offers a simple method for producing powder-to-cream formulations. In this aspect, the active ingredient or its more soluble form, such as a complex, salt, solvate, hydrate, etc., is combined with a suitable solvent to form a solution or suspension. This solution is then added to water and a water-miscible co-solvent to form a mixture / solution. This mixture is then added to and mixed with an adsorbent or a composition of an adsorbent, and subsequently dried to achieve the desired water content. From another perspective, the invention offers a free-flowing topical formulation containing a co-amorphous system that includes an insoluble active ingredient. From this perspective, an insoluble active ingredient is first converted into its soluble form by forming a co-amorphous system with the active ingredient and a co-former. The co-amorphous system is then added to water and a water-miscible co-solvent to produce a solution or mixture, which is preferably added under continuous mixing to an adsorption material or adsorption composition to create a mixture that can be dried to achieve the desired water content within a specific range. Brief description of the drawing Fig. 1 shows a classification of fungal infections based on the causative fungi. Fig. 2 shows the mechanism and various advantages of the co-amorphous system. Fig. 3A shows the DSC thermogram of bifonazole, citric acid, BF:CA (1:1), and BF:CA (1:2). Fig. 3B shows the XRD spectra for bifonazole, citric acid, and co-amorphous systems of BF:CA (1:1). Fig. 3C shows the infrared spectra for bifonazole and co-amorphous systems of BF:CA (1:1). Fig. 4A shows an image of the XRD spectra for ketoconazole, malic acid, a physical mixture of ketoconazole and malic acid, and a co-amorphous system of ketoconazole and malic acid. Fig. 4B shows an image of the DSC spectra for ketoconazole, malic acid, a physical mixture of ketoconazole and malic acid, and a co-amorphous system of ketoconazole and malic acid.Figures 5A to 5C show a three-step process for producing free-flowing topical powder formulations, consisting of the preparation of a liquid system (Fig. 5A), the preparation of an adsorbent or adsorbent composition (Fig. 5B), and the addition of the liquid system to the adsorbent or adsorbent composition (Fig. 5C). Figure 5D shows a high-speed mixer-granulator for the industrial / large-scale production of powder-to-cream formulations of the present invention. Figures 6A and 6B show images of dry powder with low water content and wet powder with large particles, respectively. Figures 7A to 7C show images of powder-to-cream formulations of bifonazole with varying water contents of 10 to 12%. Figures 8A and 8B show images of a powder-to-cream formulation produced according to the present invention and an image of adsorbing powder.Figures 8C (Batch 3) and 8D (Batch 4) show images of powder-to-cream formulations using citric acid as a co-former and with (Fig. 8D) and without Neusilin® (Fig. 8C), respectively. Figures 9A and 9B show scanning electron microscope (SEM) images of a powder-to-cream formulation containing a bifonazole co-amorphous system, before and after rubbing. It is clearly visible that these images are completely different and that liquid is released when the powder-to-cream formulation in Figure 9B is rubbed. Figures 10A1 and 10A2 show a powder-to-cream formulation containing a bifonazole co-amorphous system, before and after rubbing, respectively. Figures 10B1 and 10B2 each show a powder-to-cream formulation containing a ketoconazole co-amorphous system, before and after rubbing.Figure 11 shows a comparison of the in vitro release profile of the powder-to-cream formulation of the present invention, which contains a bifonazole co-amorphous system, with the release profile of a commercially available formulation. Figures 12A and 12B show images of the cream applied after a spreadability test for powder-to-cream formulations, each containing a ketoconazole-malic acid co-amorphous system and a bifonazole-malic acid co-amorphous system, respectively. Figures 13A and 13B show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a bifonazole-malic acid co-amorphous system. Figures 13C and 13D show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a bifonazole-citric acid co-amorphous system. Figures 13E and 13D show SEM images of powder-to-cream formulations before and after the application of shear forces.Figures 13F show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a ketoconazole-malic acid co-amorphous system. Figures 13G and 13H show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a ketoconazole-citric acid co-amorphous system. Figures 13I and 13J show microscopic images of a powder-to-cream formulation containing clindamycin phosphate, where the liquid complex of clindamycin (black part) is coated with silicon dioxide (white part) before and after rubbing, respectively. Figures 14A and 14B show in vitro diffusion / release studies of powder-to-cream formulations with co-amorphous systems containing bifonazole as the active ingredient and malic acid (Figure 14A) or citric acid (Figure 14B) as co-formers.Figure 14C shows in vitro diffusion / release studies of powder-to-cream formulations with co-amorphous systems using ketoconazole as the active ingredient and malic acid as the co-former. Figure 14D shows in vitro diffusion / release studies of powder-to-cream formulations with clindamycin phosphate. Figures 15A, 15B, and 15C show the release of the bifonazole-citric acid co-amorphous system, the bifonazole-malic acid co-amorphous system, and the bifonazole-tartaric acid co-amorphous system, respectively. Figs. 16A, 16B and 16C show the release of the ketoconazole-citric acid co-amorphous system, the release of the ketoconazole-malic acid co-amorphous system, and the release of the ketoconazole-tartaric acid co-amorphous system, respectively. Figs. 17A and 17CFigure 17B shows the in vitro drug release study of i) the powder-to-cream product (bifonazole and ketoconazole in co-amorphous forms), ii) its marketed creams, iii) creams containing bifonazole and ketoconazole in dispersed form without a co-amorphous system, and iv) bifonazole and co-former physical mixture dispersed cream. Figure 17A shows 100% drug release from the bifonazole powder-to-cream product, whereas the commercially available cream exhibits a drug release of approximately 85% in 6 hours, while the release of bifonazole from the BI-dispersed powder-to-cream product (without a co-amorphous system) and the BI:CA physical mixture (PM) in dispersed cream exhibits a negligible drug release of approximately 20%.17B shows a 100% release of the active ingredient from ketoconazole (co-amorphous) powder into the cream product in approximately 2 to 5 hours, whereas the commercially available cream exhibits an active ingredient release of approximately 100% in 8 hours. Ketoconazole-dispersed powder-to-cream (without a co-amorphous system) and ketoconazole-citric acid physical mixture-dispersed cream show comparatively lower active ingredient releases of 80% and 50%, respectively. Detailed description of the invention. The present invention relates to free-flowing topical formulations, also referred to herein as "powder-to-cream" formulations. A powder-to-cream formulation seamlessly transforms from a light, user-friendly powder texture into a cream upon application to the skin, thus providing a pleasant and user-friendly application experience and enhanced benefits, while simultaneously ensuring stability, compatibility, and safety throughout its entire life cycle. In powder-to-cream formulations, the powder particles contain tiny liquid droplets surrounded by a network of adsorbing particles. Under shear stress, the adsorbing particles ooze out, releasing these liquid droplets and forming a smooth cream. When rubbed into the skin, the powder transforms into a cream. Careful selection of the adsorbent is crucial to ensure it can absorb sufficient liquid and release it into the skin when rubbed in, without retaining it. Each adsorbent particle absorbs and / or holds tiny droplets of liquid containing active ingredients. This technology can deliver multiple active ingredients whose compositions are applied topically, including, but not limited to, antiviral agents, acne treatment agents, alpha hydroxy acids, anesthetics (narcotics), antibiotics, antihistamines, antiperspirants, antiseptics, bleaching agents, topical retinoids, topical steroids, topical silver therapy, sunscreens, tanning agents, cleansers, insecticides, and any other medications that can be administered topically. Preferably, this is an ideal technology for the delivery of topical anti-infectives such as antibacterial agents, antibiotics, and antifungals, including their salts, hydrates, solvates, polymorphs, etc. Preferred antifungals include clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, fluconazole, itraconazole, posaconazole, miconazole, oxiconazole, sertaconazole, sulconazole, bifonazole, allylamines, naftifine, terbinafine, benzylamine, butenafine, polyene, nystatin, ciclopirox, tolnaftate, selenium sulfide, zinc salts of methyl, phenyl, or propyl undecanoate, and calcium salts of methyl, phenyl, or propyl undecanoate. Since many of the active ingredients belonging to the above-mentioned categories are insoluble, they are introduced in the form of their soluble forms, including but not limited to salts, complexes, soluble derivatives, solvates, hydrates, amorphous forms, polymorphs, etc. Some of the insoluble active ingredients are introduced as a co-amorphous system. A co-amorphous system is a combination of two or more components that exist in an amorphous (non-crystalline) state. In such cases, the free-flowing topical formulation comprises a co-amorphous system containing an active ingredient and a co-former, also called an API-co-former co-amorphous system or solid mixture. A method for producing a powder-to-cream formulation according to the present invention comprises the use of an active ingredient in soluble form. An active ingredient or its soluble form is dissolved or dispersed in a suitable solvent, and this solution or suspension is added to water and a water-miscible co-solvent, then mixed thoroughly and homogenized if necessary to form a mixture or solution. The mixture or solution is then slowly added to one or more adsorbents or a composition of one or more adsorbents and mixed thoroughly. The mixture is dried to achieve the desired water content if required. In one embodiment, the water content of the powder-to-cream formulation is 9%. In another embodiment, the water content is 13%. In yet another embodiment, the water content is 11%. Generally, the water content is between 7% and 15%. Furthermore, the aforementioned “powder-to-cream” formulations for insoluble active ingredients preferably include a co-amorphous system that strongly influences and improves their solubility. An active ingredient that is soluble or can form a soluble salt can be used directly without the use of a co-amorphous system. A co-amorphous system refers to a mixture or combination of two or more components in the solid state, existing in an amorphous (non-crystalline) state. In a co-amorphous system, the individual components form a disordered and homogeneous structure, lacking the defined long-range order characteristic of crystalline materials. Co-amorphous systems have garnered significant attention due to their unique properties and potential applications in pharmaceuticals and materials science. In a conventional pharmaceutical formulation, the active pharmaceutical ingredient (API) is often mixed with various excipients to enhance its stability, solubility, and bioavailability. In co-amorphous systems, however, two or more APIs or API-excipient combinations are mixed in an amorphous state, resulting in a single-phase solid solution.This approach offers several advantages over conventional formulations, including improved resolution rates, increased stability, and potential synergistic effects between the components. Furthermore, co-amorphous systems have the potential to integrate two or more active substances with complementary mechanisms of action, thereby enabling synergistic effects that lead to improved therapeutic efficacy. There are various ways to form co-amorphous systems with pharmaceutical active ingredients. Preferably, an API co-former co-amorphous system is used. The co-former used is preferably an organic acid. Alternatively, a suitable amino acid can also be used. If two active ingredients are used, they can also form an API1-API2 co-amorphous system. The organic acid is one or more of the following: succinic acid, tartaric acid, citric acid, oxalic acid, and malic acid. Malic acid and citric acid are most preferred. The co-former is used in a specific quantity. Ratios of active ingredient to co-former of 1:0.2 to 1:5, preferably 1:0.5 to 1:5, have proven suitable. The best co-amorphous systems were obtained using ratios of active ingredient to co-former of 1:1, 1:2, and 1:3. One of the main advantages of co-amorphous systems is the improved solubility of poorly soluble drugs. Amorphous drugs exhibit higher dissolution rates than their crystalline counterparts due to their disordered structure, which allows for easier interaction with the solvent. Forming a co-amorphous system with excipients or other APIs can further enhance drug solubility, resulting in better bioavailability and a faster onset of action. Furthermore, co-amorphous systems can offer stability advantages. Many drugs are inherently unstable in their crystalline form, leading to problems such as poor long-term storage stability and degradation. By converting the drug into an amorphous form and incorporating it into a co-amorphous system, stability can be significantly improved. The presence of excipients within the co-amorphous matrix can have a protective effect, reducing the likelihood of drug degradation and extending the shelf life of the formulation. The amorphous nature of the system allows for increased molecular mobility and closer interaction between the components, resulting in an overall improved effect. The development of co-amorphous systems requires a careful selection of compatible components and the optimization of formulation parameters. Factors such as the ratio of components, processing conditions, and stability aspects must be considered. Techniques such as co-melting, co-solvent evaporation, spray drying, and ball milling are frequently used to produce co-amorphous systems. The co-amorphous nature of the formed complex can be confirmed by X-ray diffraction studies of the complex and comparison with X-ray diffraction studies of crystalline pharmaceutical agents in crystalline form. Other analytical tests such as DSC and IR analyses can also be performed. The co-amorphous systems were subjected to various investigations. Figures 3A, 3B and 3C show DSC, XRD and IR data of co-amorphous systems of bifonazole with citric acid as a co-former, and Figures 4A and 4B show XRD and DSC data of co-amorphous systems of ketaconazole with malic acid as a co-former. In summary, co-amorphous systems represent an innovative approach to overcoming solubility and stability challenges in pharmaceutical formulations. By creating a homogeneous mixture of amorphous components, these systems offer improved drug solubility, enhanced stability, and closer interactions between the components for improved efficacy. Figure 2 illustrates the mechanism and various advantages of the co-amorphous system. Incorporating a co-amorphous system into a formulation is challenging because it requires the addition of other ingredients that must not crystallize the amorphous pharmaceutical agent of the co-amorphous system. Alternatively, it is possible to incorporate an active ingredient without a co-amorphous system into the free-flowing topical formulation of the present invention, which is in powder form before application and in cream form after application, i.e., after rubbing into the skin. In such formulations, no conformer is required, and the active ingredient can be added directly, dissolved, or dispersed in a solvent. A powder-to-cream formulation requires certain ingredients / non-active ingredients that are incorporated in a unique form. These specific ingredients or non-active ingredients should serve to transform the powder into a smooth cream formulation when it is subjected to a shear force such as rubbing it into the skin. The powder-to-cream formulation offers several advantages. It remains dry on the skin's surface, which is promising for treating infections. It is available in powder form, which is the most stable formulation, easy to manufacture and transport, and requires no separate packaging. The powder-to-cream formulation is a topical formulation that combines the advantages of a powder formulation, such as flowability, ease of use, packaging, etc., with the feel of a cream, such as smoothness, spreadability, etc. The present invention provides a topical powder-to-cream formulation which is in the form of a powder before application / rubbing onto the skin and transforms into a cream after application. The formulation will be referred to below as a "powder-to-cream formulation." This formulation combines the advantages of a powder and a cream. A powder formulation is easy to handle, dose, and package. Due to its smooth texture and emollient properties, it is desirable to apply it as a topical formulation. The powder-to-cream formulations of the present invention are suitable for the treatment of infections, in particular bacterial and fungal infections. They are also useful for the administration of anti-acne agents, antihistamines, and anesthetics. Fungal infections, also known as mycoses, are caused by various types of fungi that can infect different parts of the body. Fungi are microscopic organisms that are ubiquitous. Millions of people worldwide suffer from various fungal infections. Risk factors for such infections include a weakened immune system, prolonged use of antibiotics, poor hygiene, damp environments, and close contact with infected individuals or contaminated surfaces. The powder-to-cream formulations of the present invention are useful for the targeted treatment of topical fungal infections, the relief of symptoms, the treatment of infections, and the prevention of discomfort during and after application. Fungal infections of the skin are divided into i) superficial, ii) cutaneous, and iii) subcutaneous infections. Causative agents of superficial infections include Trichophyton rubrum and Aspergillus fumigatus. Causative agents of cutaneous infections include Trichophyton, Epidermophyton, and Microsporum species. Causative agents of subcutaneous infections include Sporothrix schenckii and Candida albicans. The powder-to-cream compositions of the present invention can be used to treat any of the above-mentioned infections. Active ingredients that can be used include antivirals, acne treatment agents, alpha hydroxy acids, anesthetics (narcotics), antibiotics, antifungals, azelaic acid, anthralin, antibiotics, antihistamines, antiperspirants, antiseptics, bleaching agents, topical retinoids, topical steroids, topical silver therapy, sunscreens, tanning agents, cleansers, insecticides, etc. Preferred active ingredients include ascorbic acid, benzoyl peroxide, bexarotene, bimatoprost, brimonidine, cantharidine, capsaicin, cidofovir, clascoterone, clindamycin, calcipotriol (calcipotriene), calcipotriol and betamethasone dipropionate, cannabinoids, diclofenac, dihydroxyacetone, coal tar, dithranol, eflornithine, erythromycin, escharotics, fluorouracil, fusidic acid, gentian violet, glycolic acid, growth factors, hydrogen peroxide, hydroquinone, imiquimod, ingenol mebutate, iodine, isotretinoin, metronidazole, minoxidil, mupirocin, nicotinamide, pimecrolimus, podophyllotoxin, potassium permanganate, roflumilast, salicylic acid, sinecatechins, steroids, tacrolimus, and tirbanibulin. Tretinoin, urea, vitamin A, vitamin C, vitamin D, etc. Preferred antimycotics are clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, fluconazole, itraconazole, posaconazole, miconazole, oxiconazole, sertaconazole, sulconazole, bifonazole, allylamine, naftifin, terbinafine, benzylamine, butenafine, polyene, nystatin, ciclopirox, tolnaftate, selenium sulfide, zinc salt of methyl, phenyl or propyl undecanoate, calcium salt of methyl, phenyl or propyl undecanoate. The active ingredient can be soluble in a system of solvent, co-solvent, and water, or it can be made soluble by adding a suitable solvent. Alternatively, a small amount of an oily component can be added along with a surfactant to dissolve the active ingredient. Preferably, however, a co-amorphous system or a complex of the active ingredient can be used. Cyclodextrin, for example, can be used as a suitable complexing agent. A suitable co-former can be selected to prepare a co-amorphous system. In the preparation of powder-to-cream formulations of an antifungal agent, bifonazole, citric acid, and malic acid are selected as two co-formers. Different ratios of bifonazole to co-formers are used to achieve a co-amorphous system of bifonazole. Table 1, for example, lists various co-amorphous systems of bifonazole, using different co-formers in varying amounts. A. Preparation of a co-amorphous system from bifonazole Bifonazole: Data for investigating the drug-to-co-former ratio: Citric acid and malic acid were used as co-formers to synthesize a co-amorphous system from bifonazole. The process is similar to that described for ketoconazole in Example 1. Drug-to-co-former ratios from 1:0.2 to 1:5 were tested. The results for drug-to-co-former ratios from 1:0.5 to 1:3 are shown in Table 1 below. Synthesis of a co-amorphous system in different molar ratios. Observations: The CAM complexes were synthesized in different molar ratios using three different solvents (acetone, ethanol, and methanol) to observe the formation of co-amorphous systems / CAM complexes in different solvents. The co-amorphous systems (CAM complex) synthesized in all three solvents showed similar properties, as shown in Fig. 15A, Fig. 15B, Fig. 15C and Fig. 16A.Figure 16B and Figure 16C show the results. Result: The CAM complex in various molar ratios BI:CA (1:1), BI:CA (1:2), BI:CA (1:3), BI:MA (1:2), BI:MA (1:3), BI:TA (1:2), BI:TA (1:3), KE:CA (1:1), KE:CA (1:2), KE:CA (1:3), KE:MA (1:1), KE:MA (1:2), KE:MA (1:3), KE:TA (1:1), KE:TA (1:2) and KE:TA (1:3), which were synthesized in all three solvents, were stable at room temperature. BI:MA (1:1) and BI:TA (1:1), however, showed some visual precipitation / crystal formation during the stability test (room temperature) (see Tables 1 and 3). Table 1: Preparation of a co-amorphous system of bifonazole and co-former using different ratios of bifonazole to co-formers. Bifonazole: Malic acid 1:1 Crystal formation Unstable 1:2 Semi-rigid product Stable 1:3 Semi-rigid product Stable Bifonazole: Tartaric acid 1:1 Semi-rigid product Stable 1:2 Semi-rigid product Stable 1:3 Semi-rigid product Stable Bifonazole: Citric acid 1:1 Semi-rigid product Stable 1:2 Semi-rigid product Stable 1:3 Semi-rigid product Stable Method: Bifonazole was dissolved in acetone together with the co-former in various ratios and stored in a hot air oven at 50 °C for 24 hours to evaporate it and obtain a co-amorphous system of bifonazole and co-former. B. Evaluation of the co-amorphous system of bifonazole The co-amorphous form of bifonazole was evaluated using DSC and XRD studies. The results of these investigations are shown in Fig. 3A and Fig. 3B. Fig. 3A shows the DSC thermogram of bifonazole, citric acid, BF:CA (1:1), and BF:CA (1:2). The DSC thermograms of bifonazole and citric acid show a sharp endothermic peak, confirming their crystalline nature. In contrast, the DSC thermograms of the endothermic peaks of BF:CA (1:1) and BF:CA (1:2) do not show a sharp peak, indicating their amorphous nature. As shown in Fig. 3B, XRD studies were performed on bifonazole, citric acid, and co-amorphous systems of BF:CA (1:1). XRD studies of BF and CA show sharp peaks, confirming their crystalline nature, while the co-amorphous system BF:CA shows no peaks, indicating an amorphous nature. The powder-to-cream formulation of the present invention comprises an adsorption material capable of absorbing large quantities of liquid. The liquid preferably consists of water and water-miscible components. Additionally, the liquid component comprises an active ingredient and one or more excipients such as solvents, co-solvents, surfactants, co-formers, complexing agents, preservatives, buffers, plasticizers, etc. Additionally, a small amount of an oily component may be present to make the active ingredient soluble. The adsorbent is preferably silicon dioxide. Various grades of silicon dioxide are available, based on surface area, particle size, and properties such as hydrophilic, hydrophobic, anhydrous, hydrated, etc. A suitable grade of silicon dioxide can be selected. Preferred silicon dioxide brands include Aerosil® 200, Aerosil® R 972, Aerosil® R 812, SIPERNAT® 50 S and SIPERNAT® 500 LS, Aeropearl® 300, etc. Silicon dioxide with a surface area of ​​100 to 600 m² / g is suitable. Silicon dioxide with a particle size of 1 nm to 100 mm can be used. Table 2 summarizes various grades and brands of silicon dioxide and silicates used as adsorbents in the present invention. Table 2: Grades of Silicon Dioxide AEROPEARL 300 Pharma Mesoporous Silica Evonik Industries Specific Surface Area (BET) - 260-360 m² / g Pore Volume 1.5-1.9 ml / g Average Particle Size 26-60 micrometers AEROSIL 200 Hydrophilic pyrogenic silicon dioxide Evonik Industries Surface area (BET) - 200 m² / g Average particle size - 12 nm SIPERNAT 50 S Hydrated silicon dioxide Evonik Industries Specific surface area (BET) - 500 m² / g Particle size - 18 micrometers AEROSIL® R 812 Hydrophobic pyrogenic silicon dioxide Evonik Industries Specific surface area (BET) - 230-290 m² / g AEROSIL R 972 Hydrophobic pyrogenic silicon dioxide Evonik Industries Specific surface area (BET) - 110-120 m² / g Neusilin® S2; alkaline, synthetic magnesium aluminometasilicate Fuji Chemicals Composition on dry basis: Al2O3: 29.1% - 35.5% MgO: 11.4% - 14.0% SiO2: 29.2% - 35.6% Specific surface area (m² / g): 110 Average particle size (µm): 115 The amount or content of adsorbent in a powder-to-cream formulation varies between 5 and 40 wt.%, preferably between 5 and 30 wt.%, more preferably between 5 and 25 wt.% and most preferably between 8 and 15 wt.%. The liquid component content is preferably at least 50% by weight, preferably at least 60% by weight, and most preferably 70 to 90% by weight. Preferably, the liquid component comprises a pharmaceutical active ingredient in suspended or dissolved form, or in the form of a complex. Even more preferably, the active ingredient is present together with a co-former in co-amorphous form. Citric acid and malic acid are among the most commonly used co-formers. In one embodiment, the adsorbent content is 13% and the liquid component content is 87%. In another embodiment, the adsorbent content is 20% and the liquid component content is 80%. In a further embodiment, the adsorbent content is 25% and the liquid component content is 75%. Depending on the requirements, two or more adsorbents can be combined. Alternatively, two grades of the same adsorbent can be combined. For example, two grades of silicon dioxide can together form one adsorbent. The selected silicon dioxide grades include mesoporous silicon dioxide, hydrophilic pyrogenic silicon dioxide, hydrated silicon dioxide, and hydrophobic pyrogenic silicon dioxide. In addition, magnesium aluminometasilicate (Neusilin®S2) was used alongside silicon dioxide in some experiments. In some embodiments, Aeropearl®300 (mesoporous silicon dioxide) and Aerosil®R 972 (hydrophobic pyrogenic silicon dioxide) are used in a ratio of 1:20 to 20:1. A ratio of Aeropearl®300 (mesoporous silicon dioxide) to Aerosil®R 972 (hydrophobic pyrogenic silicon dioxide) of 1:5 to 1:15 is preferred, and a ratio of 1:7 to 1:12 is preferred. The liquid component is prepared by incorporating the pharmaceutical active ingredient. The liquid component comprises the active ingredient and one or more components selected from water, solvent, co-solvent, surfactant and solubilizers, plasticizers, buffers, and preservatives. Preferably, glycerin is used as the co-solvent. Additionally, a small amount of an oily component may be present to soluble the active ingredient. The active ingredient may be suspended in fine form or dissolved or complexed in a solvent and / or co-solvent using a suitable complexing agent. Preferably, the active ingredient is present in a co-amorphous state together with a co-former. Citric acid and malic acid are among the most commonly used co-formers.Preferred solvents for dispersing the active ingredient are polyethylene glycol, propylene glycol, glycerin, sorbitol, lactitol, isopropyl alcohol, ethanol, etc. Preferred complexing agents are various types of cyclodextrins such as alpha-cyclodextrin, beta-cyclodextrin, etc. Hydroxypropyl-beta-cyclodextrin complexes are used for tofacitinib, tofacitinib citrate, policosanol, melatonin, and itraconazole to produce their soluble forms, which are dispersed in a solvent selected from polyethylene glycol, propylene glycol, glycerin, sorbitol, lactitol, isopropyl alcohol, ethanol, etc., and subsequently water and water-miscible co-solvents such as glycerin are added to produce a liquid system / component. Water-insoluble active ingredients can first be dissolved in isopropyl alcohol or ethanol and then dispersed in a suitable solvent of the above-mentioned solvents before being added to water and the co-solvent. Small amounts of oils can be used to dissolve oil-soluble active ingredients, and their emulsion / dispersion can be incorporated into the liquid component / liquid system. One or more solubilizers can be used to make an active ingredient soluble. Preferred solubilizers include poloxamer 407, vitamin E TPGS, etc. The preferred ratio of adsorbent to liquid component is between 1:1.5 and 1:10, preferably between 1:3 and 1:9 and most preferably between 1:4 and 1:8. A method for producing powder-to-cream formulations of the present invention comprises the following steps: 1) separately weighing each ingredient; 2) optionally producing a complex or co-amorphous form of an active ingredient using a complexing agent or co-former, or producing a soluble or finely suspended form of the active ingredient; 3) suspending the fine form of the active ingredient or dissolving the complex or co-amorphous form of the active ingredient in a suitable solvent; 4) thoroughly mixing the suspension or solution from step 3 with water and a co-solvent and optionally homogenizing to produce a liquid component; 5) transferring the weighed quantity of adsorbent to a mixer or granulator;6) While mixing, add the liquid component containing the active ingredient in suspended or dissolved form to the adsorbent in a mixer, whereby the addition can be controlled and the mixing can be continued throughout the entire addition; 7) Optionally, dry the above mixture until its water content is between 8 and 15%, preferably between 9 and 13%. Preferably, a high-speed mixer-granulator is used as the mixer, as it offers several advantages, such as efficient and homogeneous mixing, fast and continuous operation, flexibility in the selection of different formulations, and the product has improved flow properties, a controlled granule size, and a controlled size distribution. The free-flowing topical powder formulation according to the present invention preferably comprises i) 65 to 95 wt% water and a co-solvent; ii) 5 to 25 wt% of one or more adsorbents; iii) 1 to 12 wt% of a solution / suspension of an active ingredient. The process for preparing a free-flowing topical powder formulation comprises the following steps: i) Separately weighing each ingredient; ii) Adding, dispersing, or dissolving the active ingredient in a water-miscible solvent, or optionally preparing a complex or co-amorrheal form of an active ingredient using a complexing agent or co-former, and subsequently adding, dispersing, or dissolving the same in a water-miscible solvent; iii) Thoroughly mixing the suspension or solution from step ii with water and a water-miscible co-solvent, and optionally homogenizing to produce a liquid component; iv) Transferring the weighed quantity of one or more adsorbents to a mixer or granulator, and optionally mixing.v) During mixing, the liquid component containing the active ingredient is added to the adsorbent in a mixer, whereby the addition can be controlled and mixing can continue throughout the entire addition; vi) Optionally, the above mixture is dried until its water content is between 7 and 15%, preferably between 9 and 13%. The water-miscible solvent is selected from polyethylene glycol, propylene glycol, glycerin, sorbitol, lactitol, isopropyl alcohol, and ethanol. The water-miscible co-solvent is glycerin. The adsorbent is selected from various grades of silicon dioxide and includes mesoporous silicon dioxide, hydrophilic fumed silicon dioxide, hydrated silicon dioxide, and hydrophobic fumed silicon dioxide. In addition to silicon dioxide, magnesium aluminometasilicate (Neusilin® S2) may be used. The soluble form of the active ingredient is introduced into the water-miscible solvent by forming a salt or complex or by forming a co-amorphous system using various co-formers, preferably selected from amino acids and organic acids. The following examples illustrate the compositions of the present invention without limiting its scope in any way. Example 1 - Preparation of a co-amorphous system of ketoconazole using various organic acids as co-formers: • Ketoconazole and low molecular weight organic acids (co-formers) were taken in molar ratios of 1:0.5 to 1:5. • After weighing the solids, 20 ml of acetone / methanol were added to the beaker and stirred for about 5 minutes. • After complete dissolution of the solids, the beaker was stored in an oven for 48 hours to allow complete evaporation of the solvent. Upon complete drying, a sticky semi-solid mass was obtained. The semi-solid mass was further dissolved in propylene glycol (carrier liquid). • The samples were stored at room temperature for visual stability assessment to check for crystal growth (if present). Co-amorphous systems were prepared with bifonazole in the same manner. Example 2: Co-amorphous experiments with ketoconazole and observations. Table 3: Co-amorphous experiments with ketoconazole and various co-formers. 1Ketoconazole:1:2Semi-solid productStable Malic acid 1:3 Semi-solid product Stable 2Ketoconazole:1:1Semi-solid productStable Tartaric acid 1:2 Semi-solid product 1:3 Semi-solid product 3Ketoconazole:1:1Semi-solid productStable Citric acid 1:2 Semi-solid product 1:3 Semi-solid product 4Ketoconazole:1:1Crystal formationUnstable Oxalic acid 1:2 Crystal formation Unstable 1:3 Crystal formation Unstable 5Ketoconazole:1:1Crystal formationUnstable Succinic acid 1:2 Crystal formation Unstable 1:3 Crystal formation Unstable Example 3: Characterization of co-amorphous systems of ketoconazole and bifonazole XRD of ketoconazole The XRD of active ketoconazole, malic acid, KT:MA (1:2) ratio physical mixture and complex was investigated to determine pattern and crystallinity using Rigaku, SmartLab®SE X-ray diffractometer, Cu Kβ X-ray source with 40 kV voltage filter, current 45 mA, a scan rate of 20.00° / min and a 2θ range of 5-50°. The XRD data are shown in Fig. 4A. The individual peaks of bifonazole, malic acid, and the physical mixture of KT:MA (1:2) show a sharp peak, indicating a crystalline structure, while a broad peak indicates an amorphous structure. DSC of ketoconazole The thermal and crystallographic behavior of active ketoconazole, co-former malic acid, KT:MA (1:2), and the complex were observed using differential scanning calorimetry (DSC-60, Shimadzu, Japan). The samples were placed in an aluminum pan and sealed with an aluminum lid. Heating was carried out at 20 °C / min up to 600 °C, using an empty pan as a heat source. The DSC data are shown in Fig. 4B. The individual peaks of ketoconazole, malic acid, and the physical mixture of KT:MA (1:2) show a sharp peak, indicating a crystalline structure, while the broad peak of the KT:MA (1:2) complex suggests an amorphous structure. XRD of bifonazole The X-ray diffraction (XRD) of active bifonazole, malic acid, the physical mixture BI:MA (1:2), and the complex was investigated to determine the pattern and crystallinity. A Rigaku SmartLab®SE X-ray diffractometer, a Cu-Kβ X-ray source with a 40 kV voltage filter, a current of 45 mA, a scan rate of 20.00° / min, and a 2θ range of 5–50° were used. Fig. 3B shows the XRD data. The individual peaks of bifonazole, malic acid, and the physical mixture of BI:Ma (1:2) show a sharp peak, indicating a crystalline structure, while a broad peak indicates an amorphous structure. DSC of bifonazole The thermal and crystallographic behavior of active bifonazole, co-former malic acid, BI:MA (1:2) ratio, physical mixture, and complex were observed using differential scanning calorimetry (DSC-60, Shimadzu, Japan). Samples were placed in an aluminum pan and sealed with an aluminum lid. Heating was performed at 20 °C / min up to 600 °C, with an empty pan serving as a reference. Fig. 3A shows the XRD data. The individual peaks of bifonazole, malic acid, and the physical mixture of BI:Ma (1:2) show a sharp peak, indicating a crystalline structure, while the broad peaks of the BI:Ma (1:2) complex indicate an amorphous structure. Example 4: Characterization of co-amorphous systems of bifonazole XRD of bifonazole The XRD of active bifonazole, malic acid, the physical mixture BI:MA (1:2) and the complex was investigated to determine the pattern and crystallinity using a Rigaku, SmartLab®SE X-ray diffractometer, a Cu-Kβ X-ray source with a 40 kV voltage filter, a current of 45 mA, a scan rate of 20.00° / min and a 20° range of 5-50°. Fig. 3B shows the XRD data. The individual peaks of bifonazole, malic acid and the physical mixture of BI:Ma (1:2) show a sharp peak, which indicates a crystalline structure, while a broad peak indicates an amorphous structure. DSC of bifonazole The thermal and crystallographic behavior of active bifonazole, co-former malic acid, a physical mixture in a BI:MA ratio (1:2), and the complex were observed using differential scanning calorimetry (DSC-60, Shimadzu, Japan). Samples were placed in an aluminum pan and sealed with an aluminum lid. Heating was carried out at 20 °C / min up to 600 °C, with an empty pan serving as a reference. Fig. 3A shows the DSC data. The individual peaks of bifonazole, malic acid, and the physical mixture of BI:Ma (1:2) show a sharp peak, indicating a crystalline structure, while the broad peaks of the BI:Ma (1:2) complex indicate an amorphous structure. Example 5A Table 4A: Powder-to-cream formulations containing ketoconazole co-former-co-amorphous systems. Example 5A Table 4A: Powder-to-cream formulations containing ketoconazole co-former-co-amorphous systems. Glycerin solvent 686667 Water Solvent 101211 Silicon dioxide; Aerosil R-Adsorbent 113.3313.3313.33 silicon dioxide; AeropearlAdsorbent 21.681.671.67 PG-containing complex of active ketoconazole and co-former citric acid. Active solution / suspension 777 Observations - Good powder with the desired creamy texture when rubbed in Batch 1 - good flow properties and dry cream formed; Batch 2 - thick cream formed; Batch 3 - good powder formed, desired cream texture with a good skin feel and the desired distributability is achieved. Procedure: 1. The ketoconazole conformer co-amorphous system was prepared as previously described. 2. The ketoconazole conformer co-amorphous system was dispersed in propylene glycol using a homogenizer. 3. Measured amounts of glycerol and water were added to a container and stirred until homogenized. 4. The drug dispersion was weighed into the above mixture and stirred for 10 minutes. 5. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a mixer for 3 minutes. 6. The liquid system was injected dropwise into an Aerosil bed under continuous high-shear mixing. Example 5B Table 4B: Powder-to-cream formulations containing the bifonazole co-former co-amorphous system. Example 5B Table 4B: Powder-to-cream formulations containing bifonazole co-former co-amorphous system. Glycerin solvent 686667 Water Solvent 101211 Silicon dioxide; Aerosil R-Adsorbent 113.3313.3313.33 silicon dioxide; AeropearlAdsorbent 21.671.671.67 PG-containing complex of active ketoconazole and co-former citric acid. Active solution / suspension 777 Observations - Good powder with the desired creamy texture when rubbed in Batch 1 - good flow properties and dry cream formed; Batch 2 - thick cream formed; Batch 3 - good powder formed, desired cream texture with a good skin feel and the desired distributability is achieved. Procedure: 1. The bifonazole conformer co-amorphous system was prepared as previously described. 2. The bifonazole conformer co-amorphous system was dispersed in propylene glycol using a homogenizer. 3. Measured amounts of glycerin and water were added to a container and stirred until homogenized. 4. The drug dispersion was weighed into the above mixture and stirred for 10 minutes. 5. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a mixer for 3 minutes. 6. The liquid system was injected dropwise into an Aerosil bed under continuous high-shear mixing. Example 5C - Table 5 - Adsorbent - Combination of silicon dioxide and silicate. Example 5C - Table 5 - Adsorbent - Combination of silicon dioxide and silicate. Glycerin6767 Water1111 Silicon dioxide; Aerosil R-97213.3312.93 silicon dioxide; Aeropearl 3001.671.67 Neusiline (magnesium aluminometasilicate)-0.4 PG with a complex of the active ingredient ketoconazole and the co-former citric acid.77 8C8D Due to the hygroscopic properties of citric acid, a slight over-wetting of Aerosil was observed, which was reduced in batch 4 by the addition of Neusiline. Procedure for Batch 4 1. The ketoconazole conformer co-amorphous system was prepared as previously described. 2. The ketoconazole conformer co-amorphous system was dispersed in propylene glycol using a homogenizer. 3. Measured amounts of glycerin and water were added to a container and stirred until homogenized. 4. The drug dispersion was weighed into the above mixture and stirred for 10 minutes. 5. Aerosil R-972, Aeropearl-300 Pharma, and Neusilin were weighed separately and mixed in a mixer for 3 minutes. 6. The liquid system was injected dropwise into an Aerosil bed under continuous high-shear mixing. Example 5D - Table 6 Powder-to-Cream Formulation without Co-amorphous System Glycerin 50-80, preferably 60-70 Water 3-20, preferably 7-14 A-R9725 - 20, preferably 8-15 A-3000.25 - 2%, preferably 0.7-1.5 PG with clindamycin phosphate 2-12, preferably 4-9 Procedure: 1. Clindamycin phosphate was dispersed in propylene glycol using a homogenizer. 2. Measured amounts of glycerin and water were added to a container and stirred until homogenized. 3. The drug dispersion was weighed into the above mixture and stirred for 10 minutes. 4. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a mixer for 3 minutes. 5. The liquid system was injected dropwise into an Aerosil bed under continuous high-shear mixing. Example 6 - Evaluation of powder-to-cream formulations Powder-to-cream formulations of bifonazole are investigated with regard to the following aspects: 1) SEM investigations (scanning electron microscopy) 2) Investigations of smoothness and haptics 3) Investigations of spreadability 4) Microscopic investigations 5) Investigations of pH value, viscosity and surface tension 6) Investigations of flow properties and angle of repose 7) Antimicrobial investigations 8) Investigations of diffusion and in vitro release SEM examinations (scanning electron microscopy) Figures 7A, 7B, and 7C show images of powder-to-cream formulations of the present invention with desired water contents of 10%, 11%, and 12%, respectively. Figures 6A and 6B show images of powder-to-cream formulations with low water content (Figure 6A) and high water content (Figure 6B), respectively, which results in larger particles. The appearance of the powders in Figures 7A, 7B, and 7C is significantly better and improved. Figures 8A and 8B show images of a powder-to-cream formulation of bifonazole and silicon dioxide, which exhibit good flow properties. Fig. 8C shows an image of a powder-to-cream formulation from batch 3, comprising a co-amorphous system of ketoconazole and a citric acid co-former, exhibiting slight over-moistening due to the hygroscopic citric acid co-former. This batch resulted in a good cream texture upon application. Fig. 8D shows an image of the powder-to-cream formulation of batch 4, in which Neusilin, a synthetic magnesium aluminum metasilicate, was added along with silicon dioxide, thus eliminating the wetting effect. Bifonazole and silicon dioxide indicate good flow properties of the formulation. Figures 9A and 9B show scanning electron microscope (SEM) images of the powder-to-cream formulation before and after application. It is clearly visible that these images are completely different and that in Figure 9B, liquid is released when the powder-to-cream formulation is applied. Studies on suppleness / haptics To assess the smoothness, texture and ease of use, the powder was applied to the skin of a test subject and rubbed into a cream. Figures 10A1 and 10A2 show the application of the powder-to-cream formulation with a co-amorphous bifonazole system and the formation of a cream when the powder is rubbed on the subject's hand. Figures 10B1 and 10B2 show the application of the powder-to-cream formulation with a co-amorphous ketoconazole system and the formation of the cream when the powder is rubbed into the subject's hand. The skin feel and texture of the creams formed by rubbing are smooth and comparable to those of other topical creams. Investigations into the spreadability of powder-to-cream formulations: ➢ Double glass plate method: 2 grams of the cream were applied to a previously marked area with a diameter of 20 mm. ➢ After applying the cream, the second glass plate was placed on top of the first and a constant weight was placed on the glass. ➢ After 5 minutes, the change in diameter was measured and the further distributability was calculated using the Knorst method: Here, Ei is the distributability (mm²) and d is the diameter (mm). Table 7: Results on distributability Clindamycin phosphate powder-to-cream formulation 20954415.62 Bifonazole powder-to-cream formulation 20934183.27 Ketoconazole powder-to-cream formulation 20752375.63 MRKT BifonazolCREME20964534.16 MRKTKetoconazole CREAM20984775.94 Figures 12A and 12B show images of cream applied as part of a spreadability test for powder-to-cream formulations, each comprising a ketoconazole-malic acid co-amorphous system and a bifonazole-malic acid co-amorphous system. pH value of powder-to-cream formulations A 10% cream solution was dispersed in distilled water and the pH value was recorded. Table 8: pH measurements Powder-to-cream formulation comprising a co-amorphous system of Ke: MA54-5 Powder-to-cream formulation comprising a co-amorphous system of Bi:MA / Bi:CA4-54-5 Powder-to-cream formulation of clindamycin phosphate, batch 5C4-54-5 viscosity The viscosity of the liquid system was calculated using Viscolead One from Fungilab. Table 9: Viscosity results 1. Glycerin + Water + PG + Ke: MA Complex L110046.4 2. Glycerin+Water+PG+Bi:MA complex L110052 3. Powder-to-cream formulation with bifonazole and conformal co-amorphous system L43138389 4. Powder-to-cream formulation with ketoconazole and conformal co-amorphous system L43146145 5Glycerin+Water+PG+ClindamycinL110045 - 50 6 Clindamycin phosphate powder-to-cream formulation L43116900-117000 7Bifonazole cream available commercially L43121999 8 Ketoconazole cream available commercially L43132548 Surface tension of liquids. The Du Nouy ring method, also known as the Wilhelmy plate method, is used to measure the surface tension of liquids. It determines the force required to lift a thin ring or plate from the liquid surface. The surface tension of a liquid can provide information about various aspects of its behavior and interactions. High surface tension tends to lead to poor wetting. Liquids with high surface tension may bead up or form droplets on surfaces, while low surface tension promotes good wetting, causing the liquid to spread across a surface. High surface tension can make it difficult for bubbles to form and stabilize. Lower surface tension promotes the formation of stable bubbles. Surface tension is related to viscosity. High surface tension can contribute to higher viscosity and influence the flow behavior of the liquid. Table 10: Surface tension results 1. Glycerin + Water + PG57.19 2. Glycerol + Water + PG + Bi: MA Complex 53.83 3. Glycerin + Water + PG + Ke: MA Complex 56.96 4. Glycerin + Water + PG + Clindamycin 46-50 Microscopic examinations Figures 13A and 13B show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a co-amorphous system of bifonazole and malic acid. Figure 13A shows that the liquid system was enclosed in the Aerosil. Figure 13B shows that liquid was released after the application of shear. Figures 13C and 13D show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a co-amorphous system of bifonazole and citric acid. The liquid system was enclosed in the Aerosil. Due to the slightly hygroscopic properties of citric acid, some wetting by silicon dioxide was observed. After the application of shear forces, liquid escaped. Figures 13E and 13F show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a co-amorphous system of ketoconazole and malic acid. In Figure 13E, the liquid system was enclosed in Aerosil. Upon application of shear forces, a thick cream forms, and silicon dioxide is also wetted. Figures 13G and 13H show SEM images of powder-to-cream formulations before and after the application of shear forces, each containing a co-amorphous system of ketoconazole and citric acid. The enclosed liquid droplets were large, resulting in a thick consistency of the cream due to the wetting of the silicon dioxide. Fig. 13I shows a microscopic image of a powder-to-cream formulation containing clindamycin phosphate, in which the liquid complex of clindamycin (black part) is coated with silicon dioxide (white part). Antimicrobial studies Finally, antimicrobial studies with Aspergillus niger are carried out on 1. bifonazole; 2. a commercially available cream formulation of bifonazole; and 3. a powder-to-cream formulation of bifonazole, manufactured according to batch 3. Table 11A shows the inhibition range of bifonazole, a commercially available bifonazole cream, and a powder-to-cream formulation of bifonazole prepared according to the present invention. It is evident that the powder-to-cream formulation exhibits the same or a better inhibition range than the commercially available cream formulation of bifonazole. Table 11A: Inhibition range for the powder-to-cream formulation of bifonazole. 1Pure drugAAspergillus spp.11 mm 2 Commercially available cream B15mm 3 Powder-to-Cream Formulation C20mm 4 Control NC No inhibition zone observed Table 11B shows the inhibition zone of ketoconazole, the commercially available cream formulation of ketoconazole, and the powder-to-cream formulation of ketoconazole prepared according to the present invention. It is evident that the powder-to-cream formulation exhibits a significantly higher inhibition zone than the commercially available cream formulation of ketoconazole. Table 11B - Inhibition zone for powder-to-cream formulation of ketoconazole. 1Pure drugAAspergillus spp.14mm 2 Commercially available cream B12 mm 3 Powder-to-Cream Formulation C30 mm 4 Control NC No inhibition zone observed In vitro drug release The effect of the powder-to-cream formulation on permeation / drug release was investigated using the Franz diffusion apparatus. An 8-hour and a 4-hour release study were conducted using Strat-M membranes (regenerated cellulose membrane). These membranes were used to mimic skin permeation. The 20-ml loading cell (effective surface area 3.43 cm²) was loaded with a 200-mg formulation containing the active ingredient. The release medium used was methanol:phosphate buffer pH 4.0 (7:3) with a pH range of 5.25–5.30. The permeation / release medium for clindamycin phosphate is a phosphate buffer with a pH of 5.8. Skin conditions were simulated by tests at 32 ± 0.5 °C. The receptor medium was thoroughly mixed by magnetic stirring. The test parameters corresponded to those of the IVRT test.The sample volume was 1 ml, which was analyzed using a 1 ml cuvette by UV spectrophotometry at 291 nm (wavelength) for ketoconazole powder-to-cream and at 258 nm (wavelength) for bifonazole powder-to-cream. For clindamycin phosphate, the samples were analyzed spectrophotometrically at a wavelength of 210 nm. The removal can be updated with the data contained in the updated figures. Powder-to-cream formulations containing i) clindamycin phosphate, ii) bifonazole and malic acid co-amorphous system, iii) bifonazole and citric acid co-amorphous system, and iv) ketoconazole and malic acid co-amorphous system were subjected to in vitro release studies. The graphs were created by plotting the cumulative release of the active ingredient in percent over time as in 14A, 14B and 14C. Figures 14A and 14B show in vitro diffusion / release studies of powder-to-cream formulations with co-amorphous systems containing bifonazole as the active ingredient and malic acid (Fig. 14A) or citric acid (Fig. 14B) as the co-former. Fig. 14C shows in vitro diffusion / release studies of powder-to-cream formulations with co-amorphous systems using ketoconazole as the active ingredient and malic acid as the co-former. Fig. 14D shows in vitro diffusion / release studies of powder-to-cream formulations containing clindamycin phosphate. The percentage cumulative release is given in Table 12 below. Table 12: Percent cumulative release of the powder-to-cream formulation including Table 12: Percent cumulative release of the powder-to-cream formulation including 00000 0.25NA13.659.5121.91 0.554.4421.2321.2735.27 198.8836.7943.0836.12 2103.0555.358.4396.061 3-67.6566.45- 4-69.3573.57- 5-76.1883.35- 6-84.6990.55- 7-95.21101.05- 8---- The following table shows the cumulative release of bifonazole in percent from i) powder-to-cream product (bifonazole in co-amorphous forms), ii) its marketed cream, iii) creams containing bifonazole in dispersed form without a co-amorphous system, and iv) bifonazole and co-former physical mixture dispersed cream. 00000 0.542.7618.872.63.09 170.7444.135.626.74 2100.7467.3710.811.36 3111.2780.7214.3413.52 4107.0190.1316.1212.8 596.1683.8516.0314.62 693.8287.5516.3812.43 785.4679.8315.0112.86 887.5579.1214.759.5 The following table shows the cumulative release of ketoconazole in percent from i) powder-to-cream product (ketoconazole in co-amorphous forms), ii) its marketed cream, iii) creams containing ketoconazole in dispersed form without a co-amorphous system, and iv) ketoconazole and co-former physical mixture (PM) dispersed cream. 00000 0.530.0914.2811.0527.94 136.1156.9327.1835.57 292.1455.0136.0157.07 395.1969.7336.0174.17 499.9987.2247.6184.17 5104.719146.5475.46 6101.3896.849.7674.27 7103.0410146.5367.51 8101.899847.6163.21 Figures 17A and 17B show the in vitro drug release study of i) powder-to-cream product (bifonazole and ketoconazole in co-amorphous forms), ii) its marketed creams, iii) creams containing bifonazole and ketoconazole in dispersed form without a co-amorphous system, and iv) bifonazole and co-former physical mixture dispersed cream. Fig. 17A shows a 100% release of the active ingredient from the bifonazole powder-to-cream product, whereas the commercially available cream has an active ingredient release of about 85% in 6 hours, while the release of bifonazole from the BI-dispersed powder-to-cream product (without co-amorphous system) and the BI:CA mixture (PM) in dispersed cream has a negligible active ingredient release of about 20%. Figure 17B shows a 100% release of the active ingredient from ketoconazole (co-amorphous) powder into the cream product in approximately 2 to 5 hours, whereas the commercially available cream exhibits an active ingredient release of approximately 100% in 8 hours. Ketoconazole dispersed powder-to-cream (without a co-amorphous system) and ketoconazole-citric acid physical mixture dispersed cream show a comparatively lower active ingredient release of 80% and 50%, respectively. The data above show that insoluble active ingredients can be converted into their soluble forms using various techniques, including the formation of a co-amorphous system, leading to a significant improvement in the release of such active ingredients in powder-to-cream formulations of the present invention.

Claims

A free-flowing formulation for topical application in powder form, comprising a liquid component and a solid adsorbent. The free-flowing topical powder formulation according to claim 1, which transforms into a cream upon application of shear forces. The free-flowing topical powder formulation which transforms into a cream upon application of shear forces, according to claim 2, free from oil, fats or waxes. The free-flowing topical powder formulation according to claim 2, wherein the liquid component comprises a mixture of a dispersion of an active ingredient in a water-miscible solvent, water and a water-miscible co-solvent. The free-flowing topical powder formulation according to claim 4, wherein the water-miscible solvent is selected from propylene glycol, polyethylene glycol, glycerin, sorbitol, lactitol, isopropyl alcohol and ethanol. The free-flowing topical powder formulation according to claim 4, wherein the water-miscible co-solvent is glycerin. The free-flowing topical powder formulation according to claim 4, wherein water and water-miscible co-solvent together constitute at least 60% of the composition, preferably at least 70% of the composition. The free-flowing topical powder formulation according to claim 1, wherein the adsorbent is one or more silicon dioxides. The free-flowing topical powder formulation according to claim 7, wherein the silicon dioxide is selected from one or more of the following: mesoporous silicon dioxide, hydrophilic pyrogenic silicon dioxide, hydrated silicon dioxide and hydrophobic pyrogenic silicon dioxide. The free-flowing topical powder formulation according to claim 9, wherein the adsorbent additionally comprises a silicate. The free-flowing topical powder formulation according to claim 10, wherein the silicate is magnesium aluminometasilicate. The free-flowing topical powder formulation according to claim 4, wherein the solution / suspension of the active ingredient comprises a co-amorphous system containing an active ingredient and a co-former. The free-flowing topical powder formulation according to claim 12, wherein the co-former is selected from an organic acid or amino acid. The free-flowing topical powder formulation according to claim 13, wherein the co-former is an organic acid selected from malic acid, citric acid, tartaric acid, succinic acid and oxalic acid. The free-flowing topical powder formulation according to claim 13, wherein the molar ratio of the active ingredient to the co-former is 0.5 to 1:5, preferably 1:1 to 1:

3. The free-flowing topical powder formulation according to claim 4, comprising i) 65 to 95 wt% water and a co-solvent; ii) 5 to 25 wt% one or more adsorbents; iii) 1 to 12 wt% a solution / suspension of an active ingredient. The free-flowing topical powder formulation according to claim 16, comprising i) 67 to 84 wt% water and a co-solvent; ii) 8 to 17 wt% one or more adsorbents; iii) 4 to 12 wt% a solution / suspension of an active ingredient. The free-flowing topical powder formulation according to claim 16, wherein the adsorbent is a combination of mesoporous silicon dioxide and hydrophobic pyrogenic silicon dioxide. The free-flowing topical powder formulation according to claim 16, wherein the adsorbent further comprises a silicate. The free-flowing topical powder formulation according to claim 16, wherein the adsorbent is a combination of mesoporous silicon dioxide, hydrophobic pyrogenic silicon dioxide and magnesium aluminometasilicate. The free-flowing topical powder formulation according to any of the preceding claims, wherein an active ingredient is selected from antiviral agents, acne treatment agents, alpha hydroxy acids, anesthetics (narcotics), antibacterial agents, antifungals, azelaic acid, anthralin, antibiotics, antihistamines, antiperspirants, antiseptics, bleaching agents, topical retinoids, topical steroids, topical silver therapy, sunscreens, tanning agents, cleansers, insecticides and any other drugs that can be administered topically. The free-flowing topical powder formulation according to any of the preceding claims, wherein an active ingredient is selected from clotrimazole, econazole, efinaconazole, ketoconazole, luliconazole, fluconazole, itraconazole, posaconazole, miconazole, oxiconazole, sertaconazole, sulconazole, bifonazole, allylamines, naftifine, terbinafine, benzylamine, butenafine, polyene, nystatin, ciclopirox, tolnaftate, selenium sulfide, zinc salt of methyl, phenyl or propyl undecanoate, calcium salt of methyl, phenyl or propyl undecanoate. A method for preparing a free-flowing topical powder formulation, comprising: iii) separately weighing each ingredient; iv) adding, dispersing, or dissolving the active ingredient in a water-miscible solvent, or optionally preparing a complex or co-amorphous form of an active ingredient using a complexing agent or co-former, and subsequently adding, dispersing, or dissolving the same in a water-miscible solvent; v) thoroughly mixing the suspension or solution from step ii with water and a water-miscible co-solvent, and optionally homogenizing to produce a liquid component; vi) transferring the weighed quantity of one or more adsorbents into a mixer or granulator, and optionally mixing;vii) During mixing, the liquid component containing the active ingredient is added to the adsorbent in a mixer, whereby the addition can be controlled and the mixing can continue throughout the entire addition; viii) Optionally, the above mixture is dried until its water content is between 8 and 15%, preferably between 9 and 13%. Method for producing a free-flowing topical formulation according to claim 23, wherein the water-miscible solvent is propylene glycol and the water-miscible co-solvent is glycerin. Method for producing a free-flowing topical formulation according to claim 23, wherein the adsorbent is selected from one or more of the following: mesoporous silicon dioxide, hydrophilic pyrogenic silicon dioxide, hydrated silicon dioxide and hydrophobic pyrogenic silicon dioxide. Method for producing a free-flowing topical formulation according to claim 19, wherein the adsorbent further comprises magnesium aluminometasilicate. The free-flowing topical powder formulation according to any of the preceding claims, which provides a cumulative release of the active ingredient of at least 90% over a period of 1 to 5 hours.

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