Free-flowing topical formulation

Abstract

The present invention relates to a free-flowing topical powder formulation also termed as powder-to-cream formulation. The invention particularly relates to a formulation in the form of a powder but which, when applied, spreads on the skin just like a cream. The invention offers an ideal topical formulation having advantages of both a powder and a cream wherein ease of handling of powder is combined with the smoothness and spreadability of cream and presents a better choice for several active ingredients that are applied topically. The present invention provides a technology to deliver several actives from categories including but not limited to antiviral agents, Actives for Acne treatment, Alpha hydroxyacids, Anaesthetics (anesthestics), Antibacterials, Antifungals etc.

Description

[0001] Free-flowing Topical Formulation

[0002] Field Of the Invention

[0003] The present invention relates to a free-flowing topical powder formulation also termed as powder-to-cream formulation. The invention particularly relates to a formulation in the form of a powder but which, when applied, spreads on the skin just like a cream. The invention offers an ideal topical formulation having advantages of both a powder and a cream wherein ease of handling of powder is combined with the smoothness and spreadability of cream and presents a better choice for several active ingredients that are applied topically.

[0004] The present invention provides a technology to deliver several actives from categories including but not limited to antiviral agents, Actives for Acne treatment, Alpha hydroxyacids, Anaesthetics (anesthestics), Antibacterials, Antifungals, Azelaic acid, Anthralin, Antibiotics, Antihistamines, Antiperspirants, Antiseptics, Bleaching agents, Topical retinoids, Topical steroids, Topical silver therapy, sunscreening agents, Tanning agents, Cleansers, Insecticides, etc. antibacterials, antibiotics, and antifungals including their salts, hydrates, solvates, polymorphs etc. Since many of the actives belonging to the above categories are insoluble, they are incorporated in the form of their soluble forms including but not limited to salts, complexes, solvates, hydrates, amorphous forms, polymorphs, etc.

[0005] Some of the insoluble actives are incorporated 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 forming a co-amorphous system, also called an API- coformer co-amorphous system or a solid-state mixture.

[0006] Active ingredient or its soluble form such as salt or complex or co-amorphous system is dissolved or dispersed in a suitable water-miscible solvent and such solution or suspension is added to water and water miscible co-solvent, mixed well, and homogenized if needed to form a mixture. Further, the mixture is slowly added to an adsorbent or a composition of an adsorbent and blended well. The blend can be optionally subjected to drying to achieve the desired water content if needed.

[0007] Thus, the Powder-to-cream formulation of the present invention provides a cream formulation in the form of a powder. Powder particles contain small liquid droplets surrounded by a network of adsorbent particles. Powder turns into a cream upon rubbing on the skin. This technology provides several advantages of powder formulation such as ease of handling, unit dose packing, accurate dosing, no wastage etc. At the same time upon application, liquid material oozes out after applying slight pressure and a cream formulation with good spreadability and smooth texture results.

[0008] Preferably, the adsorbent is one or more silica or silicate or their combinations including but not limited to the ones listed under table 2.

[0009] Object Of The Invention

[0010] A first object of the invention is to provide a free-flowing topical formulation which has benefits of a powder formulation such as stability, flow, ease of handling, packing etc. and the feel of a cream such as smoothness, and spreadability when such formulation is rubbed on the skin. The powder-to-cream formulation of the present invention exhibits good flow properties before rubbing and excellent spreadability and smoothness upon rubbing it on the skin thus providing benefits of both powder and cream formulations.

[0011] Second object of the invention is to provide a topical formulation which can be unit dosed and accurately administered.

[0012] Third object of the invention is to provide a simple process for preparing a powder-to- cream formulation.

[0013] Yet another object of the invention is to incorporate insoluble active ingredients in powder-to-cream formulation by first converting them into a co-amorphous system using one or more co-formers. Background of the Invention

[0014] No prior art was found where powder is converted to cream.

[0015] Ultra Cream Powder is sold in market by KRYOLAN. The website mentions that “velvety, silky-soft finish foundation appears like a cream finish due to its Mica mineral content which creates a soft glow to the complexion.”

[0016] Mica minerals are silicates.

[0017] This technology does not cover a powder formulation in the first place since it is a foundation. Several anti-fungal dusting powders are in market but they do not form creams upon shear such as Candid dusting powder, tetmosol dusting powders etc.

[0018] Nystatin 100,000 Unit / Gram Topical Powder is available in market but it does not form cream and not meant for rubbing on the skin.

[0019] There is a need in the art to combine advantages of a powder and cream in a single formulation.

[0020] Summary of the Invention

[0021] Under the first aspect, the invention provides a free-flowing topical formulation which has the benefits of a powder formulation such as stability, flow, ease of handling, packing etc., and the feel of a cream such as smoothness, spreadability etc.

[0022] Under this aspect, the present invention provides a powder-to-cream formulation in the form of a powder having angle of repose below 30, preferably below 25 degrees, compressibility index not more than 15 (carr index) and Hausner’s ratio not more than 1.18. These values indicate good to excellent flow of material. Additionally, the said powder spreads easily on skin and exhibits a comparable spreadability. A marketed cream formulation having a 20 mm diameter spreads into a circle of from 90-100 mm diameter under the application of a standard weight wherein the powder of the present invention under the application of the same weight spreads from a circle of 20 mm diameter to nearly a circle having 70 - 100 mm diameter, preferably from 75 - 100 mm diameter.

[0023] Figures 10A2 and 10B2 provide images of a powder-to-cream formulation rubbed on the skin. The smoothness of the powder-to-cream formulation upon rubbing is comparable to a normal cream.

[0024] The powder-to-cream formulation of the present invention exhibits good flow properties before rubbing and excellent spreadability and smoothness upon rubbing it on the skin thus providing benefits of both powder and cream formulations.

[0025] Under the second aspect, the invention provides a free-flowing topical formulation that can be unit-dosed and accurately administered. While it is difficult to dispense cream formulation that can deliver an exact dose, it is easy to fill powder-to-cream formulations of the present invention in a unit dose pack such as a sachet; and enable users to apply a unit dose each time and spread the unit powder dose to a cream.

[0026] Under the third aspect, the invention provides a simple process for preparing Powder-to-cream formulations. Under this aspect, active or its more soluble form such as complex , salt, solvate , hydrate etc. is combined with a suitable solvent to form solution or suspension which is added to a water and a co -solvent miscible with water to form a mixture / solution which is added and blended with an adsorbent material or composition of an adsorbent material and subsequently dried to achieve desired water content.

[0027] .Under yet another aspect, the invention provides a free-flowing topical formulation incorporating a co-amorphous system containing an active ingredient which is insoluble.

[0028] Under this aspect, an insoluble active is first converted into its soluble form by forming a co-amorphous system having an active and a co-former. The co- amorphous system is then added to water and water miscible co-solvent to produce a solution or a mixture which is further added to adsorbent material or adsorbent composition in a controlled manner preferably while continuous mixing to produce a blend that can be subjected to drying to achieve desired water content in a certain range.

[0029] Brief Description of Drawing

[0030] Figure 1 provides a classification of fungal infections using causative fungus.

[0031] Figure 2 provides the Mechanism and various advantages of co-amorphous system.

[0032] Figure 3A provides DSC thermogram of bifonazole, citric acid, BF:CA (1: 1) and BF:CA (1:2).

[0033] Figure 3B provides XRD spectra for bifonazole, citric acid and co-amorphous systems of BF:CA (1: 1).

[0034] Figure 3C provides Infrared spectra for bifonazole and co-amorphous systems of BF:CA (1: 1).

[0035] Figure 4A provides an image of XRD spectra for Ketoconazole, malic acid, a physical mixture of Ketoconazole and malic acid, and a co-amorphous system of Ketoconazole and malic acid. Figure 4B provides an image of DSC spectra for Ketoconazole, malic acid, a physical mixture of Ketoconazole and malic acid, and a co-amorphous system of Ketoconazole and malic acid.

[0036] Figures 5A to 5C provide a pictorial depiction of a three steps process of preparing free-flowing topical powder formulations comprising preparing a liquid system (figure 5A), preparing an adsorbent or adsorbent composition (figure 5B) and adding the liquid system in the adsorbent or adsorbent composition (figure 5C).

[0037] Figure 5D provides an Image of a Rapid Mixer Granulator for industrial / large sale production of powder-to-cream formulations of the present invention.

[0038] Figures 6A and 6B respectively provide images of dry powder having low water content and wet powder with large particles.

[0039] Figures 7A - 7C provide images of powder-to-cream formulations of Bifonazole with different water contents from 10 - 12 %.

[0040] Figures 8A and 8B respectively provide images of powder-to-cream formulation prepared in accordance with the present invention and image of adsorbent powder. Figures 8C (Batch 3) and 8D (Batch 4) provide images of powder-to-cream formulations using citric acid co-former and with (Figure 8D) and without Neusilin® (Figure 8C).

[0041] Figs. 9A and 9B respectively provide Scanning Electron Microscopy (SEM) images of powder-to-cream formulation containing a Bifonazole co-amorphous system before and after rubbing. It is clearly seen that these images are completely different from each other and liquid oozing out upon rubbing of powder-to-cream formulation in Fig. 9B.

[0042] Figures 10A1 and 10A2 respectively provide powder-to-cream formulation containing a Bifonazole co-amorphous system before and after rubbing.

[0043] Figures 10B 1 and 10B2 respectively provide powder-to-cream formulation containing a Ketoconazole co-amorphous system before and after rubbing. Figure 11 provides a comparison of In Vitro Release profile of Powder-to-cream Formulation of the present invention containing Bifonazole co-amorphous system with release profile of a marketed formulation.

[0044] Figures 12A and 12B provide images of cream spread upon spreadability test for powder-to-cream formulations comprising Ketoconazole malic acid co-amorphous system and Bifonazole malic acid co-amorphous system respectively.

[0045] Figures 13A and 13B provide SEM images of powder to cream formulations before and after application of shear respectively comprising Bifonazole: Malic acid co- amorphous system.

[0046] Figures 13C and 13D provide SEM images of powder to cream formulations before and after application of shear respectively comprising Bifonazole: Citric acid co- amorphous system.

[0047] Figures 13E and 13F provide SEM images of powder to cream formulations before and after application of shear respectively comprising Ketoconazole: Malic acid co- amorphous system.

[0048] Figures 13G and 13H provide SEM images of powder to cream formulations before and after application of shear respectively comprising Ketoconazole: Citric acid co- amorphous system.

[0049] Figure 131 and 13 J provide Microscopic image of powder-to-cream formulation containing Clindamycin phosphate wherein the liquid complex of Clindamycin (black part) is coated by silica (white part) before rubbing and after rubbing respectively.

[0050] Figures 14A and 14B provide in vitro diffusion / release studies on powder-to-cream formulations incorporating co-amorphous systems employing bifonazole as active and co-formers malic acid (figure 14A) and citric acid (figure 14B) respectively.

[0051] Figure 14C provides in vitro diffusion / release studies on powder-to-cream formulations incorporating co-amorphous systems employing Ketoconazole as active and co-former malic acid. Figure 14D provides in vitro diffusion / release studies on powder-to-cream formulations incorporating Clindamycin phosphate.

[0052] Figures 15A, 15B and 15C provide Bifonazole and citric acid co-amorphous system release, Bifonazole and malic acid co-amorphous system release, Bifonazole and tartaric acid co-amorphous system release respectively.

[0053] Figures 16A, 16B and 16C provide Ketoconazole and citric acid co-amorphous system release, Ketoconazole and malic acid co-amorphous system release, Ketoconazole and tartaric acid co-amorphous system release respectively.

[0054] Figures 17 A and 17B provide In-vitro drug release study of i) powder to cream product (Bifonazole and ketoconazole in co-amorphous forms), ii) their marketed creams, iii) creams containing Bifonazole and ketoconazole in dispersed form without co-amorphous system, and iv) Bifonazole and co-former physical mixture dispersed cream.

[0055] Figure 17A shows 100% release of drug from Bifonazole powder to cream product while marketed cream shows around 85% drug release in 6 hours while the release of Bifonazole from BI dispersed powder to cream (without co-amorphous system) and BI: CA physical mixture (PM) dispersed cream shows negligible drug release around 20%.

[0056] Figure 17B shows 100% release of drug from Ketoconazole (co-amorphous) powder to cream product in about 2 to 5 hours while marketed cream shows around 100% drug release in 8 hours, Ketaconazole dispersed powder to cream (without co-amorphous system) and ketoconazole citric acid physical mixture dispersed cream shows comparatively less drug release 80% and 50 % respectively.

[0057] Detailed description of the invention.

[0058] The present invention relates to a free-flowing topical formulations also termed here as “powder-to-cream” formulations. A powder-to-cream formulation seamlessly transforms from a lightweight, user-friendly powder texture into a cream upon rubbing on the skin, providing a good and user-friendly application experience and enhanced benefits while ensuring stability, compatibility, and safety throughout its lifecycle.

[0059] In “Powder-to-cream Formulations”, powder particles contain small liquid droplets surrounded by a network of adsorbent particles. On applying shear, the adsorbent particles ooze out / exude / release such liquid droplets forming a smooth cream. Powder turns into a cream upon rubbing on the skin.

[0060] Careful selection of adsorbent is essential which can hold enough liquid and release it upon rubbing against skin without holding it further. Each adsorbent particle absorbs and / or holds small liquid droplets containing active.

[0061] This technology can deliver several actives whose compositions are topically applied from categories including but not limited to antiviral agents, Actives for Acne treatment, Alpha hydroxyacids, Anaesthetics (anesthestics), Antibacterials, Antifungals, Azelaic acid, Anthralin, Antibiotics, Antihistamines, Antiperspirants, Antiseptics, Bleaching agents, Topical retinoids, Topical steroids, Topical silver therapy, sunscreening agents, Tanning agents, Cleansers, Insecticides, and any other medicine that can be effectively delivered topically.

[0062] More preferably, this is an ideal technology for delivering topical anti-infectives such as antibacterials, antibiotics, and antifungals including their salts, hydrates, solvates, polymorphs etc.

[0063] 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 salt of any of methyl, phenyl, propyl undecanoate, Calcium salt of any of methyl, phenyl, propyl undecanoate.

[0064] Since many of the actives belonging to the above categories are insoluble, they are incorporated 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 actives are incorporated as a co-amorphous system.

[0065] 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 forming a co-amorphous system, also called an API-co-former co- amorphous system or a solid-state mixture.

[0066] Process of preparing a powder-to-cream formulation of the present invention comprises using an active ingredient in soluble form. An active ingredient or its soluble form is dissolved or dispersed in a suitable solvent and such solution or suspension is added to water and a co-solvent miscible with water, then it is mixed well, and homogenized if needed to form a mixture or solution. Further, the mixture or solution is slowly added to one or more adsorbent or a composition of one or more adsorbent and blended well. The blend is subjected to drying to achieve the desired water content if needed.

[0067] In an embodiment, water content of powder-to-cream formulation is 9 %. In another embodiment, water content is 13 %. In yet another embodiment, water content is 11%. In general, water content is from 7 - 15 %.

[0068] Further, for insoluble actives, the said “powder-to-cream” formulations preferably comprise a co-amorphous system that greatly impacts and enhances their solubility.

[0069] An active ingredient that is soluble; or if it can form a soluble salt can be directly employed without using a co-amorphous system.

[0070] A co-amorphous system refers to a solid-state mixture or combination of two or more components that exist in an amorphous (non-crystalline) state. In a co- amorphous system, the individual components form a disordered and homogeneous structure, lacking a defined long-range order characteristic of crystalline materials. Co-amorphous systems have gained significant attention in the field of pharmaceuticals and material science due to their unique properties and potential applications. In a traditional pharmaceutical formulation, the active pharmaceutical ingredient (API) is often mixed with various excipients to enhance its stability, solubility, and bioavailability. However, in co-amorphous systems, two or more APIs or API-excipient combinations are mixed in an amorphous state, forming a single-phase solid solution. This approach offers several advantages over traditional formulations, including improved dissolution rates, enhanced stability, and potential synergistic effects between the components.

[0071] Further, co-amorphous systems have the potential to incorporate two or more drugs with complementary mechanisms of action enabling them to exhibit synergistic effects resulting in enhanced therapeutic action.

[0072] There are different ways to form co-amorphous systems involving Active pharmaceutical ingredient. Preferably, API-Coformer co-amorphous system is employed. The co-former used is preferably an organic acid. Alternatively, suitable amino acid can also be employed. When two actives are used, they can also form an active l-active2 co-amorphous system.

[0073] The organic acid is one or more from Succinic acid, Tartaric acid, Citric acid, Oxalic acid, and Malic acid. Most preferably, malic acid and citric acid are used. The coformer is used in a certain amount. Drug-to-co-former ratios from 1:0.2 to 1:5, preferably from 1:0.5 to 1:5 are found suitable. The best co-amorphous systems were obtained by using a 1: 1, 1:2, and 1:3 ratio of drug and co-former.

[0074] One of the primary advantages of co-amorphous systems is the enhanced solubility of poorly soluble drugs. Amorphous drugs exhibit higher dissolution rates compared to their crystalline counterparts due to their disordered structure, which allows for easier interaction with the solvent. By forming a co-amorphous system with excipients or other APIs, the solubility of the drug can be further improved, leading to better bioavailability and faster onset of action. Moreover, co-amorphous systems can provide stability benefits. Many drugs are inherently unstable in their crystalline form, leading to issues such as poor longterm 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 in the co-amorphous matrix can provide protective effects, reducing the likelihood of drug degradation and extending the shelf life of the formulation.

[0075] The amorphous nature of the system allows for increased molecular mobility and closer interaction between components providing overall enhanced effects.

[0076] The development of co-amorphous systems requires careful selection of compatible components and optimization of the formulation parameters. Factors such as the ratio of the components, processing conditions, and stability considerations need to be taken into account. Techniques such as co-melting, co-solvent evaporation, spray drying, and ball milling are commonly employed to prepare co-amorphous systems. The co-amorphous nature of the formed complex can be confirmed by conducting X-ray diffraction studies of the complex and comparing the same with X-ray diffraction studies on crystalline active pharmaceutical ingredients in crystalline form. Other analytical tests such as DSC and IR studies can be conducted.

[0077] The co-amorphous systems were subjected to various studies.

[0078] Figures 3A, 3B, 3C provide DSC, XRD and IR data of co-amorphous systems of Bifonazole with co-former citric acid, and figures 4A and 4B provide XRD and DSC data of co-amorphous systems of Ketaconazole employing co-former malic acid.

[0079] In conclusion, 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 enhanced drug solubility, improved stability, and closer interactions between the components for enhanced effects.

[0080] Figure 2 provides the Mechanism and various advantages of co-amorphous system. Incorporating co-amorphous system in a formulation is challenging as it requires the addition of other ingredients that should not crystallize the amorphous active pharmaceutical ingredient of a co-amorphous system.

[0081] Alternatively, it is possible to include an active without a co-amorphous system in the free-flowing topical formulation of the present invention having powder form before application and cream form after application i.e. after rubbing into the skin. In such formulations, there is no need of a conformer and active can be directly added, dissolved or dispersed in a solvent.

[0082] For a powder-to-cream formulation, specific ingredients / non-actives are needed; and they are incorporated in a unique form.

[0083] These specific ingredients or non-actives should serve as a means of transforming powder into a smooth cream formulation upon subjecting to shear force such as rubbing on the skin.

[0084] Powder-to-cream Formulation offers several advantages. It remains dry over skin surface which promisingly help for treating infection. It is available in the form of Powder which is most stable type of formulation, easy to manufacture and transport, and there is no need of creating different packaging.

[0085] Powder-to-cream Formulation is a topical formulation which has benefits of a powder formulation such as flow, ease of handling, packing etc. and feel of a cream such as smoothness, spreadability etc.

[0086] The present invention provides a powder-to-cream topical formulation which before application / rubbing onto skin is in the form of a powder and after application turns into a cream.

[0087] Hereinafter the formulation is termed as “Powder-to-cream formulation”. This formulation incorporates benefits of a powder as well as of a cream. It is easy to handle, dispense and pack a powder formulation. It is desirable to apply cream as a topical formulation because of its smoothness and emollient action.

[0088] Powder-to-cream formulations of the present invention is found suitable for treating infections, more particularly, bacterial and fungal infections. They are also found useful for delivering anti-acne, anti-histamines and Anaesthetics.

[0089] Fungal infections, also known as mycoses, are caused by various types of fungi that can affect different parts of the body, Fungi are microscopic organisms present everywhere. 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, humid environments, and close contact with infected individuals or contaminated surfaces. Powder-to-cream formulations of the present invention are useful for targeting Topical fungal infection, providing relief from symptoms, treating infection, avoiding discomfort while and after application.

[0090] Fungal infections of skin are divided into i) superficial ii) cutaneous and iii) subcutaneous infections. Causative fungi for superficial infections include Trichophyton rubrum and Aspergillus fumigatus. Causative fungi for cutaneous infections include Trichophyton, Epidermophyton and Microsporum species. Causative fungi for subcutaneous infections include Sporothrix schenckii and Candida albicans.

[0091] Powder-to-cream compositions of the present invention can be employed in treating any of the above infection.

[0092] Active ingredients that can be employed include antiviral agents, Actives for Acne treatment, Alpha hydroxyacids, Anaesthetics (anesthestics), Antibacterials, Antifungals, Azelaic acid, Anthralin, Antibiotics, Antihistamines, Antiperspirants, Antiseptics, Bleaching agents, Topical retinoids, Topical steroids, Topical silver therapy, Sunscreening agents, Tanning agents, Cleansers, Insecticides, etc.

[0093] Preferred actives 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, Eflomithine, Erythromycin, Escharotic agents, 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, Salicyclic acid, Sinecatechins, Steroids, Tacrolimus, Tirbanibulin, Tretinoin, Urea, Vitamin A, Vitamin C, Vitamin D etc.

[0094] 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 salt of any of methyl, phenyl, propyl undecanoate, Calcium salt of any of methyl, phenyl, propyl undecanoate.

[0095] Active ingredient may have solubility in a system of solvent, co-solvent and water or it can be solubilized by adding suitable solubilizer. Alternatively, a small amount of oily component along with surfactant can be added to dissolve the active ingredient.

[0096] Yet preferably, co-amorphous system or complex of active ingredient can be employed. Suitable complexing agent can be used such as cyclodextrins. To prepare co-amorphous system, a suitable co-former can be selected.

[0097] In preparing Powder-to-cream formulations of an antifungal agent Bifonazole, citric acid and malic acid are selected as two co-formers. Various ratios of Bifonazole to co-formers are employed to achieve a co-amorphous system of Bifonazole. For example, table 1 provides various co-amorphous systems of Bifonazole employing different co-formers in different amounts.

[0098] A. Preparation of co-amorphous system of bifonazole

[0099] Bifonazole: Co-Former Ratio study data:

[0100] To prepare co-amorphous system of Bifonazole, co-formers citric acid and malic acid were employed. Process is similar to one described under example 1 for Ketoconazole. Active to Co-former ratio of 1:0.2 to 1:5 was tried. The results of Active to Co-former ratio of 1:0.5 to 1:3 are provided in table 1 below:

[0101] Synthesis of Co-amorphous system in different molar ratio

[0102] 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 complex in different solvents. The co-amorphous systems (CAM complex) synthesized in all three solvents showed similar characteristics shown in figures 15A, 15B, 15C and 16A, 16B and 16C.

[0103] Result: The CAM complex in different 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) synthesized in all three solvents were stable at RT. While BI: MA (1:1) and BI: TA (1: 1) showed some visual precipitation / crystal formation during stability (RT) (Refer tables 1 and 3).

[0104] Table 1: Preparation of Bifonazole and Co-former co-amorphous system employing different ratios of Bifonazole to co-formers

[0105] Process: Bifonazole along with the co-former in various ratios was dissolved in Acetone and kept in a hot air oven for 24 hrs. at 50°C to evaporate to obtain a co-amorphous system of Bifonazole and co-former.

[0106] B. Evaluation of co-amorphous system of bifonazole

[0107] Co-amorphous form of bifonazole was evaluated using DSC and XRD studies.

[0108] The results of these studies are provided in figures 3 A and 3B. Figure 3A provides DSC thermogram of bifonazole, citric acid, BF:CA (1: 1) and BF:CA (1:2). DSC thermograms of bifonazole and citric acid show sharp endothermic peak which determines their crystalline nature. Whereas, DSC thermograms of endothermic peaks of BF:CA (1: 1) and BF:CA (1:2) does not show any sharp peak that shows their amorphous nature. As shown in Figure 3B, XRD studies were done for bifonazole, citric acid and co- amorphous systems of BF:CA (1: 1). XRD studies of BF, CA show sharp peaks showing their crystalline nature, whereas c o - amo rp h o u s s y s te m BF: CA does not show any peak indicating amorphous nature. The powder-to-cream formulation of the present invention comprises an adsorbent material that can absorb large amount of liquid. Liquid is preferably made up of water and water miscible components. Additionally, liquid component comprises an active ingredient and one or more ingredients such as solvents, co-solvents, surfactants, co-formers, complexing agents, preservatives, buffers, emollients etc.

[0109] Additionally, small amount of an oily component can be present to solubilize active ingredient.

[0110] Preferably, adsorbent is silica. Various grades of Silica are available based on surface area, particle size and nature such as hydrophilic, hydrophobic, anhydrous, hydrated etc.. A suitable grade of Silica can be selected. Some brands of Silica which can be preferably employed include Aerosil 200, Aerosil R 972, Aerosil

[0111] R 812, SIPERNAT® 50 S and SIPERNAT ® 500 LS, Aeropearl®300 etc. Silica with surface area of from 100 - 600 m2 / g is found suitable. Silica with Particle size from 1 nm to 100 mm can be employed. Table 2 summarizes various grades and brands of silica and silicates used as adsorbent in the present invention.

[0112] Table 2: Grades of silica

[0113] The amount or content of adsorbent in a powder-to-cream formulation varies from 5 - 40 % w / w, preferably from 5 - 30 % w / w, more preferably, from 5 - 25 % w / w, and most preferably from 8 - 15 % w / w.

[0114] Liquid Component content is preferably at least 50 % w / w, preferably at least 60 % w / w and most preferably from 70 - 90 % w / w. Preferably, liquid component comprises active pharmaceutical ingredient in suspended state or in a dissolved state or in the form of a complex. More preferably, active ingredient is present in co-amorphous state along with a co-former. Most commonly employed co-formers include citric acid and malic acid.

[0115] In an embodiment, adsorbent content is 13 % and liquid component is 87 %. In another embodiment, adsorbent content is 20 % and liquid component is 80 %. In yet another embodiment adsorbent content is 25 % and liquid component is 75 %.

[0116] Two or more adsorbents can be combined as per need. Alternatively, two grades of same adsorbent also can be combined. For example, two grades of silica can together form an adsorbent. Different grades of silica selected include Mesoporous silica, Hydrophilic fumed silica, Hydrated silica, and Hydrophobic fumed silica. Additionally, few trials included magnesium aluminometasilicate (Neusilin® S2) in addition to silica.

[0117] In a few embodiments, Aeropearl 300 (Mesoporous silica) and Aerosil R 972 (Hydrophobic fumed silica) are employed in a ratio of from 1:20 to 20: 1. Most preferably, ratio of Aeropearl 300 (Mesoporous silica) and Aerosil R 972 (Hydrophobic fumed silica) is from 1:5 to 1: 15, most preferably from 1:7 to 1: 12.

[0118] Liquid component is prepared by incorporating active pharmaceutical ingredient. Liquid component comprises active ingredient and one or more ingredients selected from water, solvent, co-solvent, surfactant and solubilisers, emollient, buffer and preservatives. Preferably, glycerine is employed as a co-solvent. Additionally, small amount of an oily component can be present to solubilize active ingredient. Active ingredient can be suspended in fine form or dissolved or complexed by using a suitable complexing agent in a solvent and / or co -solvent. More preferably, active ingredient is present in co-amorphous state along with a co-former. Most commonly employed co-formers include citric acid and malic acid. Preferred solvents for dispersing active ingredient include polyethylene glycol, propylene glycol, glycerine, sorbitol, lactitol, iso-propyl alcohol, ethanol etc. Preferred complexing agents include different types of cyclodextrins such as alpha- cyclodextrin, betacyclodextrin, etc.

[0119] Hydroxy propyl 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, glycerine, sorbitol, lactitol, iso-propyl alcohol, ethanol etc. and further added to water and water miscible cosolvent such as glycerin to produce liquid system / liquid component.

[0120] Water insoluble actives can be fisrt dissolved in isopropyl alcohol or ethanol and then dispersed in suitable solvent mentioned above before adding to water and cosolvent. Small amounts of oils can be used to dissolve oil soluble actives and their emulsion / dispersion can be included in liquid component / system.

[0121] One or more solubilisers can be employed to solubilize an active ingredient. Preferred solubilizers include Poloxamer 407, Vitamin E TPGS etc.

[0122] Preferred ratio of an adsorbent to liquid component is from 1: 1.5 to 1: 10, more preferably from 1:3 to 1:9 and most preferably from 1:4 to 1:8.

[0123] A process for preparing Powder-to-cream formulations of the present invention comprises following steps:

[0124] 1) Weighing each ingredient separately;

[0125] 2) optionally, preparing a complex or co-amorphous form of an active ingredient using complexing agent or co-formers or preparing solubilized or fine suspended form of active ingredient;

[0126] 3) Suspending fine form of active ingredient or Dissolving complex or co- amorphous form of active in a suitable solvent;

[0127] 4) Mixing suspension or solution of step 3 thoroughly with water and co- solvent and homogenize if needed to prepare liquid component;

[0128] 5) Transferring the weighted amount of adsorbent to a mixer or granulator;

[0129] 6) Adding while mixing, liquid component containing active ingredient in suspended or solubilized form to the adsorbent in a mixer wherein addition can be controlled addition and mixing can be continued throughout the addition;

[0130] 7) Optionally drying the above mixture till its water content reaches between

[0131] 8 - 15 %, preferably, from 9 to 13 %.

[0132] Preferably, rapid mixer granulator is employed as a mixer as it provides several advantages such as efficient and homogenous mixing, rapid and continuous operation, flexibility of choosing variety of formulations and the product has improved flow properties, controlled granule size and controlled size distribution. Free flowing topical powder formulation according to the present invention preferably comprises i) From 65 - 95 % w / w of water, and a co-solvent; ii) From 5 - 25 % w / w of one or more adsorbent. iii) from 1 - 12 % w / w of a solution / suspension of an active ingredient.

[0133] The process for preparing a free-flowing topical powder formulation comprises following steps, i) Weighing each ingredient separately; ii) adding, dispersing, or dissolving 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 a co-former and then adding dispersing, or dissolving the same in a water-miscible solvent; iii ) Mixing suspension or solution of step ii thoroughly with water and water- miscible co-solvent and subjecting to homogenization if needed to prepare a liquid component; iv) Transferring the weighted amount of one or more adsorbents to a mixer or a granulator and mixing if needed; v) Adding while mixing, liquid component containing active ingredient to the adsorbent in a mixer wherein addition can be controlled addition and mixing can be continued throughout the addition; vi) Optionally drying the above mixture till its water content reaches between 7 - 15 %, preferably, from 9 to 13 %.

[0134] Water miscible solvent is selected from polyethylene glycol, propylene glycol, glycerine, sorbitol, lactitol, iso-propyl alcohol, ethanol. Water miscible co-solvent is glycerin. Adsorbent is selected from Different grades of silica and include Mesoporous silica, Hydrophilic fumed silica, Hydrated silica, and Hydrophobic fumed silica. Additionally, magnesium aluminometasilicate (Neusilin® S2) in addition to silica can be used. Soluble form of active is incorporated in water miscible solvent by forming salt or complex or by forming a co-amorphous system using various co-formers preferably selected from amino acids and organic acid.

[0135] Following examples illustrate the compositions of the present invention without limiting the scope in any way.

[0136] Example 1 - Preparation of co-amorphous system of Ketoconazole using various organic acids as co-formers

[0137] • Ketoconazole and low molecular weight organic acids(co-former) were taken according to molar ratios from 1:0.5 to 1:5.

[0138] • After weighing the solids, 20 ml of acetone / methanol was added to the beaker and stirred for about 5 minutes.

[0139] • After the complete dissolution of the solids, the beaker was kept in the oven for 48 hours for complete evaporation of the solvent. After the complete drying, a sticky semisolid mass was obtained. The semisolid mass was further dissolved in propylene glycol (carrier liquid).

[0140] • Samples were kept for visual stability assessment to check crystal growth if any at room temperature.

[0141] In the same way, Bifonazole co-amorphous systems were prepared.

[0142] Example 2: Co-amorphous trials of Ketoconazole and observations

[0143] Table 3: Co-amorphous trials of Ketoconazole and various co-formers

[0144] Example 3: Characterization of co-amorphous systems of Ketoconazole and

[0145] Bifonazole

[0146] XRD of ketoconazole

[0147] XRD of active ketoconazole, malic acid, KT:MA (1:2) ratio physical mixture, and complex was studied to determine pattern and crystallinity using Rigaku, SmartLab® SE X-ray Diffractometer, Cu Kp X-Ray source with 40 kV voltage fdter, current 45mA, the scanning rate of 20.00° / min and 20 range of 5-50°.

[0148] The XRD data is provided in Figure 4A. Individual peak of bifonazole, malic acid, and physical mixture of KT:MA (1:2) shows a sharp peak which indicates a crystalline nature and a broad peak indicates an amorphous nature.

[0149] DSC of ketoconazole

[0150] The thermal behavior and crystalline behavior of active ketoconazole, co-former malic acid, KT: MA (1:2) ratio physical mixture, and 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, and the heating was performed at 20°C / min till 600°C keeping an empty pan as a The DSC data is provided in Figure 4B. Individual peak of ketoconazole, malic acid, and physical mixture of KT: MA (1:2) shows a sharp peak which indicates a crystalline nature, and the broad peak of KT: MA (1:2) complex indicates an amorphous nature.

[0151] XRD of Bifonazole

[0152] XRD of active bifonazole, malic acid, BI: MA (1:2) ratio physical mixture, and complex was studied to determine pattern and crystallinity using Rigaku, SmartLab® SE X-ray Diffractometer, Cu Kp X-Ray source with 40 kV voltage filter, current 45mA, the scanning rate of 20.00° / min and 20 range of 5-50°.

[0153] Figure 3B provides XRD data. Individual peak of bifonazole, malic acid, and physical mixture of BI:Ma (1:2) show a sharp peak which indicates a crystalline nature and a broad peak indicates an amorphous nature.

[0154] DSC of bifonazole

[0155] The thermal behavior and crystalline 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). The samples were placed in an aluminum pan and sealed with an aluminum lid, and the heating was performed at 20°C / min till 600°C keeping an empty pan as a reference.

[0156] Figure 3A provides XRD data. Individual peak of bifonazole, malic acid, and physical mixture of BI: Ma (1:2) show a sharp peak which indicates a crystalline nature, and broad peaks of BI: Ma (1:2) complex indicate an amorphous nature.

[0157] Example 4: Characterization of co-amorphous systems of Bifonazole

[0158] XRD of Bifonazole

[0159] XRD of active bifonazole, malic acid, BI: MA (1:2) ratio physical mixture, and complex was studied to determine pattern and crystallinity using Rigaku, SmartEab® SE X-ray Diffractometer, Cu Kp X-Ray source with 40 kV voltage filter, current 45mA, the scanning rate of 20.00° / min and 20 range of 5-50°.

[0160] Figures 3B provides XRD data.

[0161] Individual peak of bifonazole, malic acid, and physical mixture of BI:Ma (1:2) show a sharp peak which indicates a crystalline nature and a broad peak indicates an amorphous nature.

[0162] DSC of bifonazole

[0163] The thermal behavior and crystalline 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). The samples were placed in an aluminum pan and sealed with an aluminum lid, and the heating was performed at 20°C / min till 600°C keeping an empty pan as a reference.

[0164] Figure 3A provides DSC data.

[0165] Individual peak of bifonazole, malic acid, and physical mixture of BI: Ma (1:2) show a sharp peak which indicates a crystalline nature, and broad peaks of BI: Ma (1:2) complex indicate an amorphous nature.

[0166] Example 5A Table 4A: Powder-to-cream formulations comprising Ketoconazole-co-former co-amorphous systems. Procedure:

[0167] 1. Ketoconazole conformer co-amorphous system was prepared as stated before.

[0168] 2. Ketoconazole conformer co-amorphous system was dispersed in Propylene Glycol with the help of a homogenizer. 3. Measured amounts of Glycerin and Water were taken in a container and stirred until homogenization.

[0169] 4. In the above mixture drug dispersion was weighed and stirred for 10 mins.

[0170] 5. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a blender for 3 mins. 6. The liquid system was injected dropwise in an aerosil bed on continuous high- shear mixing. Example 5B Table 4B: Powder-to-cream formulations comprising Bifonazole- co-former co-amorphous systems. Procedure:

[0171] 1. Bifonazole conformer co-amorphous system was prepared as stated before.

[0172] 2. Bifonazole conformer co-amorphous system was dispersed in Propylene Glycol with the help of a homogenizer.

[0173] 3. Measured amounts of Glycerin and Water were taken in a container and stirred until homogenization.

[0174] 4. In the above mixture drug dispersion was weighed and stirred for 10 mins.

[0175] 5. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a blender for 3 mins.

[0176] 6. The liquid system was injected dropwise in an aerosil bed on continuous high- shear mixing. Example 5C - Table 5 -Adsorbent - silica and silicate combination

[0177] Procedure for Batch 4

[0178] 1. Ketoconazole conformer co-amorphous system was prepared as stated before.

[0179] 2. Ketoconazole conformer co-amorphous system was dispersed in Propylene Glycol with the help of a homogenizer. 3. Measured amounts of Glycerin and Water were taken in a container and stirred until homogenization.

[0180] 4. In the above mixture drug dispersion was weighed and stirred for 10 mins.

[0181] 5. Aerosil R-972 and Aeropearl-300 Pharma and Neusilin were weighed separately and mixed in a blender for 3 mins. 6. The liquid system was injected dropwise in an aerosil bed on continuous high- shear mixing. Example 5D - Table 6 Powder to cream formulation without a co-amorphous system Procedure:

[0182] 1. Clindamycin Phosphate was dispersed in Propylene Glycol with the help of a homogenizer

[0183] 2. Measured amounts of Glycerin and Water were taken in a container and stirred until homogenization. 3. In the above mixture drug dispersion was weighed and stirred for 10 mins.

[0184] 4. Aerosil R-972 and Aeropearl-300 Pharma were weighed separately and mixed in a blender for 3 mins.

[0185] 5. The liquid system was injected dropwise in an aerosil bed on continuous high- shear mixing.

[0186] Example 6 - Evaluation of Powder- to-cream Formulations

[0187] Powder-to-cream formulations of Bifonazole are studied for following:

[0188] 1) SEM (Scanning Electron Microscopy) Studies

[0189] 2) Smoothness and feel studies

[0190] 3) Spreadability studies

[0191] 4) Microscopic studies

[0192] 5 ) pH, viscosity and surface tension studies

[0193] 6 ) Flow properties, Angle of Repose studies

[0194] 7) Anti-microbial studies

[0195] 8) Diffusion and In vitro release studies

[0196] SEM (Scanning Electron Microscopy) Studies

[0197] Figs. 7A, 7B and 7C provide images of Powder-to-cream formulations of the present invention having desired water content which is 10 %, 11 % and 12 % respectively. Figs. 6A and 6B respectively provide images of Powder-to-cream formulations where water content is low (Fig. 6A) or high leading to larger particles (Fig. 6B). The appearance of powders from images of Figs. 7A, 7B and 7C are significantly better and improved.

[0198] Figs. 8A and 8B respectively provide images of Powder-to-cream formulation of Bifonazole and silica indicating good flow properties of the formulation.

[0199] Figs. 8C provides an image of Powder-to-cream formulation of Batch 3 comprising co-amorphous system of ketoconazole and citric acid co-former where slight overwetting is observed due to hygroscopic citric acid co-former. This batch led to a good cream texture upon rubbing.

[0200] Fig. 8D is an image of Powder-to-cream formulation of Batch 4 where Neusiline, a synthetic magnesium alumino metasilicate, is added along with silica and the wetting effect has been abolished. Bifonazole and silica indicating good flow properties of the formulation. Figs. 9A and 9B respectively provide Scanning Electron Microscopy (SEM) images of powder-to-cream formulation before and after rubbing. It is clearly seen that these images are completely different from each other and liquid oozing out upon rubbing of powder-to-cream formulation in Fig. 9B.

[0201] Smoothness / Feel studies

[0202] To evaluate the smoothness, texture, and ease of application, the powder was applied on the volunteer’s skin area and rubbed to form cream.

[0203] Figures 10A1 and 10A2 provide the application of powder-to-cream formulation comprising Bifonazole co-amorphous system and the formation of cream upon rubbing powder on the volunteer’s hand.

[0204] Figures 10B 1 and 10B2 provide the application of powder-to-cream formulation comprising Ketoconazole co-amorphous system and the formation of cream upon rubbing powder on the volunteer’s hand.

[0205] The feel and texture of the creams formed upon rubbing is smooth and comparable to any other topical cream.

[0206] Spreadability studies on powder-to-cream formulations

[0207] Procedure: Double glass plate method: 2 grams of the cream was placed on a previously marked 20 mm diameter. After placing the cream 2ndglass plate was kept over the other and a constant weight was placed on the glass. After 5 min change in diameter was measured and further spreadability was calculated by the Knorst method:

[0208] Where, Ei is spreadability (mm2), d is diameter (mm).

[0209] Table 7: spreadability results

[0210] Figures 12A and 12B provide images of cream spread upon spreadability test for powder-to-cream formulations comprising Ketoconazole malic acid co-amorphous system and Bifonazole malic acid co-amorphous system respectively. pH of powder-to-cream formulations

[0211] A 10% cream solution was dispersed in distilled water and pH was recorded.

[0212] Table 8: pH readings

[0213] Viscosity Viscosity of the Liquid system was calculated by using Viscolead One by Fungilab.

[0214] Table 9: viscosity results

[0215] Surface tension of Liquid System. Du-Nouy Ring Method, also known as the Wilhelmy plate method, is used to measure the surface tension of liquids. It involves determining the force required to detach a thin ring or plate from the liquid surface. The surface tension of a liquid can provide insights into various aspects of its behavior and interactions.

[0216] High surface tension tends to result in poor wetting. Liquids with high surface tension may bead up or form droplets on surfaces, low surface tension promotes good wetting leading to the spreading of the liquid on a surface. High surface tension can make it more difficult for bubbles to form and stabilize. Lower surface tension supports the formation of stable bubbles.

[0217] Surface tension is related to viscosity. High surface tension can contribute to higher viscosity, affecting the flow behavior of liquid.

[0218] Table 10: surface tension results

[0219] Microscopy studies

[0220] Figures 13A and 13B provide SEM images of powder to cream formulations before and after application of shear respectively comprising Bifonazole: Malic acid co- amorphous system.

[0221] Figure 13A shows that the liquid system was entrapped inside aerosil.

[0222] Figure 13B shows that after applying shear and liquid oozed out.

[0223] Figures 13C and 13D provide SEM images of powder to cream formulations before and after application of shear respectively comprising Bifonazole: Citric acid co- amorphous system.

[0224] The liquid system was entrapped inside an aerosol. Due to the slight hygroscopic nature of citric acid, some amount of silica wetting was observed. After applying shear liquid comes out.

[0225] Figures 13E and 13F provide SEM images of powder to cream formulations before and after application of shear respectively comprising Ketoconazole: Malic acid co- amorphous system. In Figure 13E, the Liquid system was entrapped inside aerosil. On applying shear, thick cream is formed and also silica gets wet. Figures 13G and 13H provide SEM images of powder to cream formulations before and after application of shear respectively comprising Ketoconazole: Citric acid co- amorphous system.

[0226] Liquid globules entrapped were big so a thick consistency of cream was observed due to the wetting of Silica.

[0227] Figure 131 provides Microscopic image of powder-to-cream formulation containing Clindamycin phosphate wherein the liquid complex of Clindamycin (black part) is coated by silica (white part).

[0228] Anti-microbial studies

[0229] Finally, anti-microbial studies are conducted using Aspergillus niger on

[0230] 1. Bifonazole;

[0231] 2. Marketed cream composition of Bifonazole; and

[0232] 3. Powder-to-cream Formulation of Bifonazole prepared as per batch 3.

[0233] Table 11A provides zone of inhibition by Bifonazole, Marketed cream of Bifonazole and Powder-to-cream Formulation of Bifonazole prepared in accordance with the present invention. It is seen that Powder-to-cream composition has same and better zone of inhibition than the marketed cream formulation of Bifonazole.

[0234] Table 11A: Zone of inhibition for Powder-to-cream formulation of Bifonazole. Table 11B provides zone of inhibition by Ketoconazole , Marketed cream of Ketoconazole and Powder-to-cream Formulation of Ketoconazole prepared in accordance with the present invention. It is seen that Powder-to-cream composition has significantly higher zone of inhibition than the marketed cream formulation of Ketoconazole.

[0235] Table 11B - Zone of inhibition for Powder-to-cream formulation of Ketoconazole .

[0236] In-Vitro drug release

[0237] The effect of powder to cream formulation on permeation / drug release was studied using the Franz diffusion apparatus. Using Strat-M membranes (regenerated cellulose membrane) 8 hrs. or 4 hrs. release study was conducted. 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 active. The release media used was Methanol: Phosphate buffer pH 4.0 (7:3) having pH of 5.25-5.30. The permeation / release media for Clindamycin phosphate is a Phosphate buffer of pH 5.8. The skin conditions were mimicked by testing at 32 ± 0.5°C. Magnetic stirring was provided to properly mix the receptor media. The test parameters were the same as that of the IVRT test. The sampling amount was 1 mL which was analyzed UV spectrophotometric ally at 291 nm (wavelength) for ketoconazole powder to cream and 258 nm (wavelength) for bifonazole powder to cream using a 1 mL cuvette. For Clindamycin phosphate, samples are analyzed UV spectrophotometrically at a wavelength of 210 nm.

[0238] . To be removed can be updated with the data shared in updated figures fie

[0239] Powder-to-cream formulations incorporating 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.

[0240] Graphs are generated by plotting % Cumulative release of drug versus time as in 14A, 14B, 14C.

[0241] Figures 14A and 14B provide in vitro diffusion / release studies on powder-to-cream formulations incorporating co-amorphous systems employing bifonazole as active and co-formers malic acid (figure 14 A) and citric acid (figure 14B) respectively.

[0242] Figure 14C provides in vitro diffusion / release studies on powder-to-cream formulations incorporating co-amorphous systems employing Ketoconazole as active and co-former malic acid.

[0243] Figure 14D provides in vitro diffusion / release studies on powder-to-cream formulations incorporating Clindamycin phosphate.

[0244] The % Cumulative release is provided in table 12 below.

[0245] Table 12: Percentage of cumulative release of powder-to-cream formulation containing

[0246] Following table provides % cumulative release of Bifonazole from i) powder to cream product (Bifonazole in co-amorphous forms), ii) its marketed cream, iii) creams containing Bifonazole in dispersed form without co-amorphous system, and iv) Bifonazole and co-former physical mixture dispersed cream. Following table provides % cumulative release of Ketoconazole from i) powder to cream product (Ketoconazole in co-amorphous forms), ii) its marketed cream, iii) creams containing Ketoconazole in dispersed form without co-amorphous system, and iv) Ketoconazole and co-former physical mixture (PM) dispersed cream.

[0247] Figures 17 A and 17B provide In-vitro drug release study of i) powder to cream product (Bifonazole and ketoconazole in co-amorphous forms), ii) their marketed creams, iii) creams containing Bifonazole and ketoconazole in dispersed form without co-amorphous system, and iv) Bifonazole and co-former physical mixture dispersed cream.

[0248] Figure 17A shows 100% release of drug from Bifonazole powder to cream product while marketed cream shows around 85% drug release in 6 hours while the release of Bifonazole from BI dispersed powder to cream (without co-amorphous system) and BI: CA physical mixture (PM) dispersed cream shows negligible drug release around 20%.

[0249] Figure 17B shows 100% release of drug from Ketoconazole (co-amorphous) powder to cream product in about 2 to 5 hours while marketed cream shows around 100% drug release in 8 hours, Ketaconazole dispersed powder to cream (without co-amorphous system) and ketoconazole citric acid physical mixture dispersed cream shows comparatively less drug release 80% and 50 % respectively.

[0250] The above data shows that insoluble actives can be converted into their soluble forms using various techniques including forming co-amorphous system and this leads to significant enhancement in release of such actives in powder-to-cream formulations of the present invention.

Claims

ClaimsWe claim1. A free-flowing formulation for topical application in the form of a powder comprising a liquid component and a solid adsorbent.

2. The free-flowing topical powder formulation as claimed in claim 1 which converts into a cream upon application of shear.

3. The free-flowing topical powder formulation converting into cream on the application of shear as claimed in claim 2 devoid of any oil, or fatty substance, or waxy substance.

4. The free-flowing topical powder formulation as claimed in claim 2 wherein the liquid component comprises a mixture of dispersion of an active ingredient in a water-miscible solvent, water, and a water-miscible co-solvent.

5. The free-flowing topical powder formulation as claimed in claim 4 wherein the water-miscible solvent is selected from propylene glycol, polyethylene glycol, glycerin, sorbitol, lactitol, isopropyl alcohol, and ethanol.

6. The free-flowing topical powder formulation as claimed in claim 4 wherein the water-miscible co-solvent is glycerine.

7. The free-flowing topical powder formulation as claimed in claim 4 wherein water and water-miscible co-solvent together form at least 60 % of the composition, preferably at least 70 % of the composition.

8. The free-flowing topical powder formulation as claimed in claim 1 wherein the adsorbent is one or more silica.

9. The free-flowing topical powder formulation as claimed in claim 7 wherein silica is selected from one or more of Mesoporous silica, Hydrophilic fumed silica, Hydrated Silica, and Hydrophobic fumed silica.

10. The free-flowing topical powder formulation as claimed in claim 9 wherein the adsorbent additionally comprises a silicate.

11. The free-flowing topical powder formulation as claimed in claim 10 wherein the silicate is magnesium aluminometasilicate.

12. The free-flowing topical powder formulation as claimed in claim 4 wherein solution / suspension of the active ingredient comprises a co-amorphous system containing an active ingredient and a co-former.

13. The free-flowing topical powder formulation as claimed in claim 12 wherein co-former is selected from an organic acid or amino acid.

14. The free-flowing topical powder formulation as claimed in claim 13 wherein the co-former is an organic acid selected from malic acid, citric acid, tartaric acid, succinic acid, and oxalic acid.

15. The free-flowing topical powder formulation as claimed in claim 13 wherein the molar ratio of the active ingredient to the co-former is from 1 - 0.5 to 1 :5, preferably from 1 : 1 to 1 :3.

16. The free-flowing topical powder formulation as claimed in claim 4 comprising i) From 65 - 95 % w / w of water, and a co-solvent; ii) From 5 - 25 % w / w of one or more adsorbent; iii) from 1 - 12 % w / w of a solution / suspension of an active ingredient.

17. The free-flowing topical powder formulation as claimed in claim 16 comprising i) From 67 - 84 % w / w of water, and a co-solvent; ii) From 8 - 17 % w / w of one or more adsorbent; iii) from 4 - 12 % w / w of a solution / suspension of an active ingredient.

18. The free-flowing topical powder formulation as claimed in claim 16 wherein the adsorbent is a combination of Mesoporous silica and Hydrophobic fumed silica.

19. The free-flowing topical powder formulation as claimed in claim 16 wherein the adsorbent further comprises a silicate.

20. The free-flowing topical powder formulation as claimed in claim 16 wherein the adsorbent is a combination of Mesoporous silica, Hydrophobic fumed silica, and magnesium aluminometasilicate.

21. The free-flowing topical powder formulation as claimed in any of the preceding claims wherein an active is selected from antiviral agents, Actives for Acne treatment, Alpha hydroxy acids, Anaesthetics (anesthetics), Antibacterials, Antifungals, Azelaic acid, Anthralin, Antibiotics, Antihistamines, Antiperspirants, Antiseptics, Bleaching agents, Topical retinoids, Topical steroids, Topical silver therapy, sunscreening agents, Tanning agents, Cleansers, Insecticides, and any other medicine that can be effectively delivered topically.

22. The free-flowing topical powder formulation as claimed in any of the preceding claims wherein an active 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 any of methyl, phenyl, propyl undecanoate, Calcium salt of any of methyl, phenyl, propyl undecanoate.

23. A process for preparing a free-flowing topical powder formulation comprising iii) Weighing each ingredient separately; iv) adding, dispersing, or dissolving 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 a co-former and then adding dispersing, or dissolving the same in a water-miscible solvent; v) Mixing suspension or solution of step ii thoroughly with water and water- miscible co-solvent and subjecting to homogenization if needed to prepare a liquid component;vi) Transferring the weighted amount of one or more adsorbents to a mixer or a granulator and mixing if needed; vii) Adding while mixing, liquid component containing active ingredient to the adsorbent in a mixer wherein addition can be controlled addition and mixing can be continued throughout the addition; viii) Optionally drying the above mixture till its water content reaches between 8 - 15 %, preferably, from 9 to 13 %.

24. The process for preparing a free-flowing topical formulation as claimed in claim 23 wherein water-miscible solvent is propylene glycol and water-miscible cosolvent is glycerine.

25. The process for preparing a free-flowing topical formulation as claimed in claim 23 wherein adsorbent is selected from one or more of Mesoporous silica, Hydrophilic fumed silica, Hydrated Silica, and Hydrophobic fumed silica.

26. The process for preparing a free-flowing topical formulation as claimed in claim 19 wherein adsorbent additionally comprises magnesium aluminometasilicate.

27. The free-flowing topical powder formulation as claimed in any of the preceding claims providing at least 90 % Cumulative release of active over a period of 1 - 5 hrs.

Images