Sublingual patch

Abstract

The invention relates to formulations for water-insoluble active pharmaceutical ingredients. More particularly, the invention relates to a mucoadhesive patch consisting of a first layer consisting of a mucoadhesive film and a second layer consisting of a self-emulsifying drug delivery system (SEDDS) lipid microstructure for delivery of a poor water-soluble active pharmaceutical ingredient or a water insoluble active pharmaceutical ingredient.

Description

[0001] SUBLINGUAL PATCH

[0002] FIELD OF THE INVENTION

[0003] The invention relates to formulations for water-insoluble active pharmaceutical ingredients. More particularly, the invention relates to a mucoadhesive patch consisting of a first layer consisting of a mucoadhesive film and a second layer consisting of a self-emulsifying drug delivery system (SEDDS) lipid microstructure for delivery of a poor water-soluble active pharmaceutical ingredient or a water insoluble active pharmaceutical ingredient.

[0004] BACKGROUND OF THE INVENTION

[0005] In the pharmaceutical industry, a critical aspect of preparing a desirable product is the ability to properly formulate a poorly water-soluble active pharmaceutical ingredient or a water insoluble active pharmaceutical ingredient. Many active pharmaceutical ingredients are extremely insoluble in water and, as a result, the oral bioavailability of these active pharmaceutical ingredients is low due to incomplete absorption. In addition, some formulations of extremely water-insoluble active pharmaceutical ingredients result in rapid precipitation of the active pharmaceutical ingredient upon aqueous dilution of the formulation under conditions simulating the gastrointestinal tract. Accordingly, it is actively searched to develop formulations for dissolving and solubilizing extremely water-insoluble active pharmaceutical ingredients.

[0006] One method for administering extremely insoluble active pharmaceutical ingredients is the self- emulsifying drug delivery system. A self-emulsifying drug delivery system is an uniphase liquid or semi-solid, typically comprising an oil and a surfactant, and having an oily nature, which forms an emulsion when contacted with an aqueous environment. Self-emulsifying drug delivery systems are easily administered and easy to manufacture. The self-emulsifying drug delivery systems offer the potential of improved oral absorption of active pharmaceutical ingredients that are difficult to dissolve in aqueous solution.

[0007] Sublingual administration of active pharmaceutical ingredients, which involves administering the active pharmaceutical ingredient under the tongue in the sublingual mucosa, has several advantages over oral administration, the most widely used route for administration of active pharmaceutical ingredients. It can minimize the degradation of active pharmaceutical ingredients during administration, as the enzymatic activity is limited in the sublingual region compared to the rest of the oral cavity and has physiological range of pH (6-7). Direct absorption into the underlying vascularized sublingual tissue allows fast access to blood capillaries for systemic delivery, bypassing hepatic first-pass metabolism and leading to a rapid onset of drug effects. Finally, it increases patient compliance among those who suffer from dysphagia. Dysphagia occurs among various population groups and is reported to affect around 3% of people globally. Removing the need for patient swallowing can be a major improvement in patient comfort and compliance. Formulations for sublingual drug delivery exist in various forms, including liquids, tablets, gels, sprays, or patches. Among these, the mucoadhesive patch is the most promising form because it increases the contact time between the formulation and the mucosa, reduces the dilution of the drug in saliva, and offers a more precise dosage compared to spray or liquid formulations.

[0008] For sublingually administered active pharmaceutical ingredients to reach the blood vessels in the sublingual mucosa, the active pharmaceutical ingredient should be dissolved into saliva and then permeate through the mucin layer and underlying epithelial membrane. Most sublingual drug delivery formulations focus on delivering Class 1 in the biopharmaceutical classification system (BCS) active pharmaceutical ingredients (API) which have high water solubility and high mucus permeability. Other formulations also deliver water-soluble complex primary proteins like vaccines or insulin. Although there is ongoing research to improve API permeation, the delivery of poorly water-soluble APIs classified as Class 2 and 4 in BCS which compose 75% of new drugs and 39% of the drugs on the market remains challenging.

[0009] In recent years, a new system has been developed to improve the oral absorption of poorly water-soluble active pharmaceutical ingredients: lipid self-emulsifying drug delivery system (SEDDS) is based on forming lipid micelles by dissolving in water in which the active pharmaceutical ingredients are dissolved, which allows their transport to the gastro-intestinal track. But also improves their mucus penetration thanks to their surfactant component.

[0010] An attempt to improve the oral absorption of poorly water-soluble active pharmaceutical ingredients is provided in US 2021 / 186860 Al, which discloses a buccal patch or SEDDS for enhancing the bioavailability of poorly water-soluble active pharmaceutical ingredients. Another attempt to improve the oral absorption of poorly water-soluble active pharmaceutical ingredients is provided by electrospun patches that comprise a randomly mixed combination of mucoadhesive fibers and SEDDS fibers (see Friedl et al., "SEDDS-loaded mucoadhesive fiber patches for advanced oromucosal delivery or poorly soluble drugs", Journal of Controlled release, vol. 348, 21 June 2022, pages 692-705). The fiber system of these electrospun patches comprises a randomly mixed combination of mucoadhesive thiolated polyacrylic acid fibers and SEDDS-loaded fibers fabricated by parallel electrospinning that provides a single layer which facilitates the dissolution and delivery of poorly water-soluble active pharmaceutical ingredients. Although these electrospun patches can increase the surface area by forming microstructures, their random deposition results in varying SA / V ratios, leading to inconsistent release profiles of active pharmaceutical ingredients between batches. Furthermore, the incorporation of SEDDS into the mucoadhesive polymers extends the release time of the active pharmaceutical ingredients to over 1 h, increasing the likelihood of saliva swallowing and patch loss during administration and reducing the total amount of encapsulated drugs (0.5% m / V). Lastly, in vivo administration of electrospun patches (electrospun fibers) showed that the drug distribution was mostly localized near the epithelial membrane but did not reach the basal lamina nor the blood vessels located below.

[0011] Using SEDDS as a lipophilic drug delivery system in the sublingual cavity could be an asset but requires developing a strategy for speeding up absorption of active pharmaceutical ingredients. Fast dissolution times of the drug formulation is an important factor for sublingual drug delivery in the context of absorption efficiency, patient compliance, and precision of dosage. A fast dissolution of sublingual drug formulations ensures quick release of the active pharmaceutical ingredient, allowing it to be absorbed for a longer period. Finally, fast dissolution can enhance dosing precision by minimizing the effects of external factors such as swallowing saliva or degradation of the delivery device over time. A dissolution time of less than 5 minutes is recommended for the sublingual drug delivery system. Therefore, fast delivery rate is necessary to apply lipid SEDDS in a sublingual drug delivery system.

[0012] To make lipid SEDDS in patch form, lipids need to be formed into a thin solid membrane. However, solid lipids have very poor mechanical properties. Fractured lipid parts can lead to imprecise dosing of active pharmaceutical ingredients, alterations in release kinetics of active pharmaceutical ingredients, and pose challenges in the administration and handling of such a patch. Furthermore, the patch needs to be bent according to the curvature of the sublingual mucosal region. Adding micro-patterned materials on a flexible membrane can reduce the risk of their mechanical failure. This has been widely used for flexible electronics. Although lipid structures with dimensions in the mm scale have been fabricated by inkjet printing, material extrusion methods, or conventional molding for drug implants and SEDDS tablets, structuring lipids at the micron size has not yet been done. The main hurdles for the microfabrication of lipids include their poor mechanical properties, low melting temperature, and the compatibility of lipids with organic solvents.

[0013] The sublingual administration of active pharmaceutical ingredients offers several advantages over traditional oral administration, particularly in minimizing degradation of active pharmaceutical ingredients, ensuring rapid systemic delivery, and increasing patient compliance with dysphagia. So far, only water-soluble active pharmaceutical ingredients can be administered sublingually because the formulation needs to dissolve rapidly in saliva. This limits the administration of poorly water-soluble active pharmaceutical ingredients which compose 75% of newly developed active pharmaceutical ingredients. Thus there is still a need for efficient sublingual administration system of poorly water-soluble active pharmaceutical ingredients, that provides fast release rate of the active pharmaceutical ingredient, allows high loading of the active pharmaceutical ingredient into the system, and provides enhanced penetration of the active pharmaceutical ingredient into the sub-mucosa.

[0014] SUMMARY OF THE INVENTION

[0015] An aspect of the present invention provides a mucoadhesive patch consisting of two layers, wherein a first layer consists of a mucoadhesive film, and a second layer consists of a selfemulsifying drug delivery system (SEDDS) lipid microstructure, wherein the mucoadhesive film consists of one or more mucoadhesive polymers, the SEDDS lipid microstructure consists of a self-emulsifying drug delivery system (SEDDS) and one or more active pharmaceutical ingredients, wherein the SEDDS comprises a lipid and a surfactant, the one or more active pharmaceutical ingredient is a lipophilic and a poorly water soluble active pharmaceutical ingredient, or a lipophilic and a water-insoluble active pharmaceutical ingredient. Another aspect of the present invention provides a use of the mucoadhesive patch of the present invention for delivering one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients.

[0016] A further aspect of the present invention provides a method for delivery of one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients to a subject, the method comprising application of the mucoadhesive patch of the present invention on mucosal surface of the subject.

[0017] BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1 shows (A) top view and (B) cross-sectioned view of the mucoadhesive patch.

[0019] Figure 2 shows (A) mucoadhesive patch for the sublingual administration of poorly water- soluble active pharmaceutical ingredients (API), composed of a SEDDS lipid microstructure that includes lipids, surfactants, and API, along with a gelatin-chitosan (GC) film and form lipid micelles by dissolving into saliva. (B) Advantages of mucoadhesive patch: mucoadhesion by GC layer, flexible, and rapid dissolution by honeycomb microstructure. (C) Active pharmaceutical ingredient absorption from the mucoadhesive patch by time: 1. Mucoadhesion 2. Dissolution of lipid into saliva, forming lipid micelles 3. Permeation into the mucosal layer 4. Dissolution of the GC film.

[0020] Figure 3 shows (A) Fabrication of mucoadhesive patch: A lipid composite layer placed on top of a gelatin-chitosan is nanoimprinted using a PVA mold. Nanoimprinting is done under O. IMPa at 45°C, followed by the dissolution of the PVA mold through immersion in a 50% ethanol / water solvent at 4°C. The final step involves drying at 24°C under vacuum. (B) Optical image of the 40 pm wall width mucoadhesive patch. (C) SEM images of mucoadhesive patch with wall width of 20 pm, 80 pm, and 160 pm.

[0021] Figure 4 shows (A) Dissolution of a lipid structure with wall thickness of 40 pm in artificial saliva at 37°C over time. (B) Dissolution rate of honeycomb lipid microstructures with different wall widths compared to an unstructured film of the same thickness. (C) Strain-Stress curve of a GC film and a lipid-coated GC film under elongation. (D) Critical strain of lipid film compared to honeycomb structure with wall width of 40 pm, and 20 pm on GC film. (E) Corresponding optical image of each structure under its critical strain. Figure 5 shows (a) Transepithelial and paracellular transport of Dil (red channel) released from SEDDS lipid microstructure. Cell nuclei were identified by DAPI (blue channel) (b) Released Dil (red channel) accumulation in the sublingual tissue. Cell nuclei were identified by DAPI (blue channel).

[0022] DETAILED DESCRIPTION OF THE INVENTION

[0023] All, documents, patents, patent applications, publications, product descriptions, and protocols which are cited throughout this application are incorporated herein by reference in their entireties for all purposes. The publications and applications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[0024] In the case of conflict, the present specification, including definitions, will control. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which the subject matter herein belongs. As used herein, the following definitions are supplied in order to facilitate the understanding of the present invention.

[0025] The term “comprise” is generally used in the sense of include, that is to say permitting the presence of one or more features or components. Also as used in the specification and claims, the language "comprising" can include analogous embodiments described in terms of "consisting of “ and / or "consisting essentially of’.

[0026] As used in the specification and claims, the singular form "a", "an" and "the" include plural references unless the context clearly dictates otherwise.

[0027] As used in the specification and claims, the term "and / or" used in a phrase such as "A and / or B" herein is intended to include "A and B", "A or B", "A", and "B".

[0028] To overcome the limitation of poorly water-soluble or water-insoluble active pharmaceutical ingredients delivery through sublingual administration, the mucoadhesive patch of the present invention has been developed. The mucoadhesive patch of the present invention is composed of a self-emulsifying drug delivery system (SEDDS) lipid microstructure fabricated (attached) on a mucoadhesive film, such as gelatin-chitosan (GC) film, which acts as a flexible mucoadhesive substrate as shown in Figure 1A. SEDDS lipid microstructures with feature dimensions of tens of micrometers were successfully fabricated.

[0029] An aspect of the present invention provides a mucoadhesive patch consisting of two layers, wherein a first layer consists of a mucoadhesive film, and a second layer consists of a selfemulsifying drug delivery system (SEDDS) lipid microstructure, wherein the mucoadhesive film consists of one or more mucoadhesive polymers, the SEDDS lipid microstructure consists of a self-emulsifying drug delivery system (SEDDS) and one or more active pharmaceutical ingredients, wherein the SEDDS comprises a lipid and a surfactant, the one or more active pharmaceutical ingredient is a lipophilic and a poor water soluble active pharmaceutical ingredient, or a lipophilic and a water-insoluble active pharmaceutical ingredient.

[0030] According to an embodiment, the present invention provides a mucoadhesive patch consisting of two layers, wherein a first layer consists of a mucoadhesive film, and a second layer consists of a self-emulsifying drug delivery system (SEDDS) lipid microstructure, wherein the mucoadhesive film consists of one or more mucoadhesive polymers, the SEDDS lipid microstructure consists of a self-emulsifying drug delivery system

[0031] (SEDDS) and one or more active pharmaceutical ingredients, wherein the SEDDS consists of a lipid and a surfactant, the one or more active pharmaceutical ingredient is a lipophilic and a poor water soluble active pharmaceutical ingredient, or a lipophilic and a water-insoluble active pharmaceutical ingredient.

[0032] In some embodiments of the mucoadhesive patch of the present invention, the SEDDS lipid microstructure consists of

[0033] • the SEDDS: 90 wt% to 99.9 wt%, and the one or more active pharmaceutical ingredients (APIs): 0.1 wt% to 10 wt%. The first layer consisting of the mucoadhesive film acts as a substrate (supporting layer, backing layer) for the second layer consisting of SEDDS lipid microstructure. The first layer and the second layer are directly adhered to each other. In some preferred embodiments, the first layer consisting of the mucoadhesive film is a backing layer and the second layer consisting of SEDDS lipid microstructure adheres to the first layer.

[0034] The term "mucoadhesive polymer" refers to compounds that adhere to the mucosa or mucosal surface. Mucoadhesive polymers include all classes of mucoadhesive polymers, including anionic polymers (e.g., alginate, xanthan gum, carageenan), cationic polymers (e.g., chitosan), non-ionic polymers (e.g., guar gum, galactomannan, gluconamman), amphoteric polymers, polymeric thiomers, polymers with acrylate end groups, dendrimers, boronic acid copolymers, synthetic glycopolymers, and polymeric blends and complexes. In some embodiments, the mucoadhesive polymers are selected from the group consisting of hydrophilic polymers, hydrogels, thiolated polymers, lectin-based polymers, and combinations thereof.

[0035] According to an embodiment of the mucoadhesive patch of the present invention, the one or more mucoadhesive polymers are selected from the group comprising gelatin, chitosan, polymethacrylates, N-carboxymethylchitosan, poly(acrylic acid)cysteine, polyethylene glycol) diacrylate, hydroxypropyl methylcellulose, cyanoacrylates, polyacrylic acid, carbopol, polycarbophil, sodium alginate, pectin, hyaluronic acid, polyvinyl alcohol, poly(butyl methacrylate-co-(2-dimethylamino) ethyl methacrylate-co-methyl methacrylate) (Eudragit), poly(methacrylic acid, methyl methacrylate), poly(methacrylic acid, ethyl acrylate), guar gum, and xanthan gum. In a preferred embodiment, the one or more mucoadhesive polymers are selected from the group comprising gelatin, chitosan, N-carboxymethylchitosan, hydroxypropyl methylcellulose, sodium alginate, pectin, hyaluronic acid, polyvinyl alcohol, poly(butyl methacrylate-co-(2-dimethylamino) ethyl methacrylate-co-methyl methacrylate) (Eudragit), poly(methacrylic acid, methyl methacrylate), poly(methacrylic acid, ethyl acrylate), guar gum, and xanthan gum.

[0036] More information about suitable mucoadhesive polymers can be found in the article Khutoryanskiy, Vitaliy V. "Advances in mucoadhesion and mucoadhesive polymers." Macromolecular bioscience 11.6 (2011): 748-764. According to an embodiment of the mucoadhesive patch of the present invention, the mucoadhesive film consists of 50 wt% gelatin and 50 wt% chitosan which are both biodegradable and edible polymers. Electrostatic interactions between the protonated chitosan and negatively charged mucin layers result in muco-adhesion. The interpenetration of the polymer chains into the mucin layer induced by the polymer hydration further enhances the muco-adhesion. The 1 : 1 ratio of gelatin to chitosan results in better mechanical properties and a lower water swelling ratio compared to other gelatin - chitosan ratios. According to some examples, the thickness of the mucoadhesive film layer, consisting of 50 wt% gelatin and 50 wt% chitosan, is 15 pm. In preferred embodiments of the mucoadhesive patch of the present invention, the thickness of the mucoadhesive film layer ranges from 5 pm to 30 pm, 5 pm to 20 pm, or 10 pm to 15 pm.

[0037] According to another embodiment of the mucoadhesive patch of the present invention, the lipid in the SEDDS is selected from the group comprising glyceryl esters of fatty acids, derivatives of mono, di, and tri glycerides, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl caprate, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, glyceryl monooleate, glycerol monolinoleate, glyceryl behenate, and hydrogenated soy phosphatidylcholine.

[0038] The composition of lipid SEDDS plays a key role in the dissolution time, size of micelles, and active pharmaceutical ingredient (drug) loading capacity of lipid SEDDS. In particular, the smaller the micelle size, the higher the efficiency of mucus layer penetration and cellular uptake (See Examples).

[0039] According to a further embodiment of the mucoadhesive patch of the present invention, the surfactant in the SEDDS is selected from the group comprising lauroyl polyoxyl-32 glycerides, polyoxyl-32 stearate, stearoyl polyoxyl-32 glycerides, PEG-32 stearate, polyethylene glycol 40 stearate, D-alpha-tocopheryl polyethylene glycol 1000 succinate, polyethylene glycol 660 hydroxy stearate, PEG-40 hydrogenated castor oil, polysorbate 80, polyoxyl 35 castor oil, caprylocaproyl macrogol-8 glycerides, macrogol 15 hydroxystearate, pol oxamer 407, and sorbitan monooleate.

[0040] According to some embodiments of the mucoadhesive patch of the present invention, the wall width of the SEDDS lipid microstructure ranges from 1 pm to 500 pm and the thickness of 1 pm to 250 pm. In preferred embodiments, the wall width ranges from 10 pm to 200 pm, 20 pm to 300 pm or 20 pm to 160 pm. In other preferred embodiments, the thickness ranges from 50 pm to 150 pm or 80 pm to 100 pm. In some other preferred embodiments, the wall width is 20 pm, 40 pm, 80 pm or 160 pm.

[0041] According to some embodiments, the SEDDS lipid microstructures of the present invention have a line width resolution of minimum 20 pm. This is the width of the line which composed 2D structure, which is wall width. It is affected by the ratio "wall width / thickness" of the SEDDS lipid microstructure. With the thickness of 90 pm, the minimum resolution is 20 pm. If the thickness to 5 pm, the resolution can be further decreases to 1 pm.

[0042] The thickness of the mucoadhesive film layer and the wall width and thickness of the SEDDS lipid microstructure are measured by an optical profiler, such as Bruker Contour X-200. A sample to be measured is simply loaded into the machine and scanned the desire location with VSI mode.

[0043] Optical profilometry is a non-destructive and non-contact imaging technique used for the topographical study of the materials surface which works on the principle of light instead of the physical probe in determining the data. The main feature of this technique is directing the light source to detect the three-dimensional data of the surface. Specifically, the optical profilometer is a type of microscope in which the light source is used to analyze the topography of the surface. The light from the profiler lamp splits into two paths by a beam splitter where one path is directed towards the surface and the other path is directed towards the reference mirror. The reflections from these two paths are recombined and are projected onto an array detector, the difference in the path of recombined beams is on the order of a few wavelengths which leads to less interference. The vertical resolution can be obtained in the order of several angstroms and the lateral resolution depends on the objective and ranges from 0.3-8 microns.

[0044] The Bruker Contour X-200 is an optical profiler providing three-dimensional surface profile measurements without contact. Two working modes are available: VSI (Vertical Shift Interference) and PSI (Phase Shift Interference). The VSI mode, based on white light vertical scanning interferometry, is dedicated to device measurement. The maximum measurable topography is 10mm and there are some limitations to measure slopes depending on the optics numerical aperture and surface roughness. The PSI mode, based on optical phase-shifting, is dedicated to roughness measurements with adjacent pixel -height differences smaller than 135nm. The system is able to run automatic stitching to grab larger fields.

[0045] According to some further embodiments, the shape of the SEDDS lipid microstructure can vary from a simple honeycomb structure to complicated structures, depending on the surface area to volume (SA / V) ratio requirements or the complexity of the structure. Typically, the shape of the SEDDS lipid microstructure is provided by a mold used during the preparation of the mucoadhesive patch of the present invention. The shape can be simply modified by changing the design of the mold.

[0046] According to some embodiments, the dissolution rate of the SEDDS lipid microstructure is faster with increasing SA / V ratio. In an embodiment, the SEDDS lipid microstructure has SA / V ratio of more than 40 in order to improved dissolution time of less than 5 minutes.

[0047] Providing a structure to the SEDDS lipid layer improves the mechanical stability of the SEDDS lipid layer, compared to an unstructured lipid layer. Indeed, using the SEDDS lipid microstructure accelerates the slow dissolution rate of SEDDS in a limited water-accessible environment by increasing the SA / V of the SEDDS structure. Microstructuring the SEDDS lipid layer also enhances the mechanical properties of brittle lipid by providing an inherently mechanically stable structure, like a honeycomb, allowing the mucoadhesive patch to deform according to the sublingual / buccal mucosa structure.

[0048] Thus according to some embodiments, the SEDDS lipid microstructure has a 3-dimensional microstructure. According to further embodiments, the microstructure is selected from honeycomb structure, serpentine structure and origami structure.

[0049] The 3 -dimensional structure can be passive or active with self-organized shape morphing. In addition, the 3-dimensional structure can be scaffold structure and / or porous structure.

[0050] In preferred embodiments, the SEDDS lipid microstructure is honeycomb SEDDS lipid microstructure. Such a structure has improved mechanical properties by internally distributing external stress into the honeycomb structure, allowing adaptation of the mucoadhesive patch of the present invention to the sublingual mucosal curvature (Figure IB). The honeycomb microstructure also increases the surface area of the SEDDS lipid microstructure, accelerating the dissolution of the lipid.

[0051] The size and the shape of the SEDDS lipid microstructure can be adjusted within the ranges provided herein, thus targeting a specific release volume and rate, depending on the active pharmaceutical ingredient and the application. The size and the shape of the SEDDS lipid microstructures are important factors for the efficacy of the mucoadhesive patches of the present invention. According to some embodiments, the total area of the SEDDS lipid microstructure layer (the second layer) should not cover more than 50% of the mucoadhesive film layer (first layer) in order to provide sufficient and optimal mucoadhesion with mucin layer during administration.

[0052] For sublingual administration (application), the dissolution time of the SEDDS lipid microstructure should ideally be fast, less than 5 minutes, for onset active pharmaceutical ingredient absorption and to minimize the effect of saliva and swallowing.

[0053] According to another embodiment of the mucoadhesive patch of the present invention, the active pharmaceutical ingredient (API) is Class 2 or Class 4 active pharmaceutical ingredient according to Biopharmaceutics Classification System (BCS). In a preferred embodiment, the active pharmaceutical ingredient (API) is selected from the group comprising Fenofibrate, Griseofulvin, Ketoconazole, Simvastatin, Carbamazepine, Danazol, Nifedipine, Sulfasalazine, Glibenclamide Cyclosporine, Furosemide, Sulfamethoxazole, Acyclovir, Indomethacin, and Prednisolone.

[0054] According to the FDA, an active pharmaceutical ingredient is considered highly soluble when the highest strength is soluble in 250 mL or less of aqueous media within the pH range of 1 - 6.8 at 37 ± 1 °C. Under this definition, if the active pharmaceutical ingredient is not highly soluble, then it is of low solubility. According to some embodiments, the poor water-soluble active pharmaceutical ingredients have a water solubility of < 1 mg / mL over the physiological pH range and the water-insoluble active pharmaceutical ingredients have a water solubility of <1 pg / ml over the physiological pH range. According to another embodiment of the mucoadhesive patch of the present invention, the SEDDS further comprises a hydro co-solvent. In preferred embodiments, the hydro co-solvent is selected from the group comprising polyethylene glycol, transcutol HP, and propylene glycol.

[0055] Hydro co-solvents can be optionally used to enhance solubility and improve active pharmaceutical ingredient release and dispersion of SEDDS.

[0056] According to an embodiment, the present invention provides a mucoadhesive patch consisting of two layers, wherein a first layer consists of a mucoadhesive film, and a second layer consists of a self-emulsifying drug delivery system (SEDDS) lipid microstructure, wherein the mucoadhesive film consists of one or more mucoadhesive polymers, the SEDDS lipid microstructure consists of a self-emulsifying drug delivery system (SEDDS) and one or more active pharmaceutical ingredients, wherein the SEDDS consists of a lipid, a surfactant and a hydro co-solvent, the one or more active pharmaceutical ingredient is a lipophilic and a poor water soluble active pharmaceutical ingredient, or a lipophilic and a water-insoluble active pharmaceutical ingredient.

[0057] According to some embodiments of the mucoadhesive patch of the present invention, the SEDDS comprises or consists of

[0058] • a lipid: 40 wt% to 80 wt%

[0059] • a surfactant: 20 wt% to 40 wt%, and

[0060] • a hydrophilic co-solvent: 0 wt% to 40 wt% or 0.001 wt% to 40 wt%.

[0061] According to other embodiments of the mucoadhesive patch of the present invention, the SEDDS consists of

[0062] • a lipid: 40 wt% to 80 wt%, and

[0063] • a surfactant: 20 wt% to 60 wt%.

[0064] According to some preferred embodiments, a surfactant has the HLB value greater than 11 or greater than 12. According to further preferred embodiments, the HLB value of a surfactant is from 11 to 20 or from 12 to 20. The SEDDS lipid microstructure consists of the SEDDS (comprising or consisting of lipids, surfactants, and optionally hydro co-solvents) and the one or more active pharmaceutical ingredients (APIs). The selection of lipids, surfactants and optionally hydro co-solvents for the SEDDS and the ratios of lipids, surfactants, optionally hydro co-solvents, and APIs can be adapted and adjusted to each API and dispersion requirements. The ratio between lipids, surfactants, optionally hydro co-solvents, and APIs can be varied according to the targeted type of SEDDS lipid microstructures. Typically, the higher is the ratio of surfactants and the more hydrophilic surfactants are used, the smaller micelle size after dispersion is obtained, but the API concentration will decrease, and dispersion time of the SEDDS lipid microstructure and digestion requirements will decrease but increase the possibility of precipitation of API after dispersion. The API concentration totally depends on the solubility of the API in the SEDDS composition.

[0065] Another aspect of the present invention provides a use of the mucoadhesive patch of the present invention for delivering one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients.

[0066] A further aspect of the present invention provides a method for delivery of one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients to a subject, the method comprising application of the mucoadhesive patch of the present invention on mucosal surface of the subject.

[0067] According to an embodiment, the mucosal surface of the subject is oral mucosal surface, preferably buccal or sublingual mucosal surface.

[0068] Once the mucoadhesive patch of the present invention is administered (applied) sublingually, it attaches to the mucin layer, and the SEDDS lipid microstructure dissolves into the saliva, trapped between the mucoadhesive film and the mucosa, forming micelles. These micelles permeate through the mucin layer and the epithelial membrane and access the underlying mucosal blood vessels (Figure 2C). The mucoadhesive film not only imparts flexible mucoadhesive properties to the mucoadhesive patch but also promotes the permeation of the released active pharmaceutical ingredient by acting as a backing layer. The combination of the SEDDS lipid microstructure with the mucoadhesive film successfully delivers poorly water- soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients through the sublingual mucosa, thereby expanding therapeutic options through sublingual administration.

[0069] The combination of the mucoadhesive film layer (first layer) with the SEDDS lipid microstructure layer (second layer) provides greatly improved delivery of poor water-soluble APIs or water-insoluble APIs as well as improved efficiency of the API absorption release from micelles. Indeed, when the SEDDS lipid microstructure is used alone, without a mucoadhesive film, dissolved micelles can be deviated to other locations in the oral cavity or simply be swallowed, hindering the sublingual / buccal absorption of the API. The mucoadhesive film confines the micelles between the sublingual / buccal mucosa and the mucoadhesive film, thus preventing deviation of micelles. Moreover, the mucoadhesive film can increase the permeation of the micelles into the underlying sublingual / buccal tissue by acting as a unidirectional release film, serving as a diffusion backing layer. Indeed, the mucoadhesive film layer enables prolonged contact with the mucin layer and enhances permeation of the released active pharmaceutical ingredient from the SEDDS lipid microstructure layer into the underlying tissue by acting as a diffusion backing layer. In addition, the mucoadhesive film serves also as a backing layer (support layer) for the SEDDS lipid microstructure. Indeed, the SEDDS lipid microstructure layer is built (fabricated) on the mucoadhesive film layer (see Figure 1 A).

[0070] Also, the SEDDS lipid microstructures used alone require an environment with excessive amounts of water and enzymes such as gastric intestinal environment to form micelles. The combination of the SEDDS lipid microstructure with the mucoadhesive film allows to eliminate this requirement and to use SEDDS lipid microstructure in sublingual and buccal administrations.

[0071] The combination of the mucoadhesive film with the SEDDS lipid microstructure formulation improves the stability of the mucoadhesive patch of the present invention, dose accuracy of one or more active pharmaceutical ingredients, and handling complexity compared to liquid oilbased sublingual / buccal administration.

[0072] Compared to the mucoadhesive patches consisting of only one layer of a mucoadhesive film, the mucoadhesive patch of the present invention allows better and increased loading of one or more active pharmaceutical ingredients. Further, compared to the mucoadhesive patches consisting of only one layer, such as electrospun patches comprising a combination of mucoadhesive thiolated polyacrylic acid fibers and SEDDS-loaded fibers, the mucoadhesive patch of the present invention uses pure SEDDS lipid microstructure, without mucoadhesive polymers, thereby enhancing release time of one or more active pharmaceutical ingredients within only 5 minutes (see Examples) by harnessing high surface area of SEDDS lipid microstructure which removes the saliva swallowing and patch loss during the oromucosal / buccal administration, and providing high loading capacity of active pharmaceutical ingredient (> 5% m / V) (see Examples). In addition, unlike the mucoadhesive patches consisting of only one layer, such as electrospun patches consisting of SEDDS parts and mucoadhesive parts in the same layer, the mucoadhesive patch of the present invention allows for deeper penetration of the drugs in the sub-mucosa (see Figure 5), due to the separated mucoadhesive film from the SEDDS lipid microstructure. The mucoadhesive film layer acts as a backing layer, reducing the diffusion of the released drug from the SEDDS lipid microstructure layer into the tissue and thereby improving the permeation of the released one or more active pharmaceutical ingredients into the underlying tissue. Moreover, using mucoadhesive polymers, such as chitosan, provides mucoadhesion and penetration enhancement due to the translocation of proteins forming tight junctions between epithelial cells.

[0073] Table 1 provides a summary of advantages of the mucoadhesive patch of the present invention comparing to the mucoadhesive patches of the prior art.

[0074] Table 1: Summary of advantages of the mucoadhesive patch of the present invention compared to the mucoadhesive patches of the prior art. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications without departing from the spirit or essential characteristics thereof. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is therefore to be considered as in all aspects illustrated and not restrictive, the scope of the invention being indicated by the appended claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

[0075] The foregoing description will be more fully understood with reference to the following Examples. Such Examples, are, however, exemplary of methods of practicing the present invention and are not intended to limit the application and the scope of the invention.

[0076] EXAMPLES

[0077] Preparation of Gelatin - Chitosan (GC) film

[0078] A Chitosan solution was prepared by dissolving 2 w / v% of chitosan (Low molecular weight, Sigma-Aldrich, St. Louis, MO, USA) into distilled water with 1 v / v% acetic acid (Sigma- Aldrich, St. Louis, MO, USA) under 1200 rpm stirring for 1 h. After glycerol was added to the chitosan solution with 10 wt% of dry chitosan, a Gelatin solution was prepared by dissolving gelatin (From porcine skin, Sigma-Aldrich, St. Louis, MO, USA) in distilled water with a 6 w / v% concentration under 1200 rpm stirring at 70°C. After glycerol was added to the gelatin solution with 10 wt% of dry gelatin. Then, the chitosan and gelatin solutions were mixed with a 1 : 1 polymer weight ratio, and its pH was adjusted between 5.2-6 using KOH solution to obtain a polyelectrolyte. The final solution was poured into a polystyrene petri dish and dried for 24h under vacuum at 24°C, and the Gelatin - Chitosan (GC) film was detached from the petri dish using tweezers.

[0079] Preparation of water dissolvable PVA mold

[0080] A positive Si mold was prepared by photolithography using AZ 1512 photoresist and deep reactive ion etching tool. First AY 1512 pattern patterned on Si substrate. After anisotropic Si etching was done with Si-Bosch process with holder temperature at 30°C with 75:1 photoresist mask selectivity and SF6 duration of 8s. The Si mold surface was treated with Trichloro(lH,lH,2H,2H-perfluorooctyl) silane (Sigma-Aldrich, St. Louis, MO, USA) to make its surface hydrophobic. The detailed process flow is described in the supporting information. A PVA solution was prepared by dissolving PVA (Mw 85000-12400, Sigma-Aldrich, St. Louis, MO, USA) in deionized water with a 7 w / v% concentration. The PVA solution was poured onto the Si mold. Vacuum was applied for 1 h, and then it was dried at 50°C for 24h. Preparation of the mucoadhesive patch

[0081] PEG-32 stearate (Gelucire 4816, surfactant) and Suppocire AP (glyceryl esters of fatty acids, lipid) granules were mixed in a 1 : 1 ratio using a vortex mixer. Afterward, they were melted at 50°C and mixed again using a vortex mixer. The active pharmaceutical ingredients (APIs) used in this study (Danazol, Fenofibrate, Tolfenamic acid, and DiL) were dissolved in molten lipids (the SEDDS) at 50°C with a concentration of 20 mg / ml. Subsequently, 10 pL of the SEDDS - API composition (SEDDS formulation) was drop-cast onto a Gelatin - Chitosan (GC) film, and a PVA mold was placed above it. Nanoimprinting was performed using NanoImprint EHN- 3250 under 0.1 MPa at 45°C for 15 minutes, with a cooling time of 20 minutes. After imprinting, the whole structure was released in 50% ethanol / water at 4°C for 2h to dissolve PVA. Then the device was dried under vacuum at 24°C for 24h.

[0082] If the API is high temperature-sensitive, the SEDDS formulation can be prepared simply by using a rotary granulator with moderate heat. All the components of the SEDDS formulation are placed in the device at the same time and rotated for homogeneous mixture.

[0083] DLS measurement

[0084] Different lipid formulations listed in Table 2 were dissolved in artificial saliva (Artificial Saliva for Pharmaceutical Research Amylase and Lysozyme customized, Biochemazone, Alberta, Canada) at 37°C, maintaining a volume ratio of 1 : 100. The resulting solutions underwent analysis using the Zetasizer Nano ZS (Malvern Panalytical GmbH, Herrenberg, Germany). Each sample underwent five independent 2mins runs. To minimize reflections and ensure accuracy, measurements were consistently taken at a scattering angle of 90°. The intensity autocorrelation function obtained from the measurements was fitted to derive the size distribution of particles in solution, considering their intensity-weighted profile. Deconvolution of the autocorrelation function employed the cumulants method, enabling the calculation of the intensity-weighted log-normal size distribution, including the average diameter and its polydispersity.

[0085] Evaluation of lipid microstructure dissolution rate

[0086] Honeycomb SEDDS lipid microstructures with different wall width and lipid film without microstructure was immersed in 50 pL artificial saliva (Artificial Saliva for Pharmaceutical Research Amylase and Lysozyme customized, Biochemazone, Alberta, Canada) at 37°C and the evolution of lipid microstructure was observed over time using micro camera. The final dissolution time was determined when there was no original form retained. The dissolution rate was calculated by dividing the total volume of lipid microstructures with the dissolution time.

[0087] Mechanical measurement

[0088] A Gelatin - Chitosan (GC) film, with a thickness of 15 pm, was prepared in a rectangular shape measuring 5 mm by 40 mm. The SEDDS formulation (lipid phase containing the API) was then coated on the GC film (layer), either with a thickness of 90 pm or in the form of honeycomb lipid microstructures with 2.5x2.5 mm dimension with 90 pm thickness, with varying wall widths (20 pm and 40 pm), prepared at the center of the GC film. Both ends of the sample were mounted on a Strain-Stress Measurement Machine (Linkam MFS, Linkam Scientific, Salfords, UK) at 37°C. Elongation strain was applied to the sample while measuring the stress exerted on the film. The film was observed over time using the mounted microscope to detect the strain at which the first crack appeared in the lipid, representing the critical strain of the lipid structure.

[0089] XRD measurement

[0090] XRD samples are prepared using the same methodology as for preparing the mucoadhesive patches with dimensions of 10x 10x0.1mm. The samples were stored at 24°C for 1 week, after which XRD measurements were conducted using Bruker D8 Discover (Bruker, MA, USA) in Bragg Brentano mode. The equipment was equipped with a Johansson Kalphal monochromator and a LynxEye ID detector. The total scan time was approximately 45 minutes. The samples were loaded into low-background silicon crystal sample holders, and a knife was placed above the sample to minimize background from air scattering.

[0091] FTIR measurement

[0092] FTIR samples are prepared using the same methodology employed for preparing the mucoadhesive parches with dimensions of 2.5x2.5x0.1mm. The samples were placed on the FTIR spectrometer (Spectrum 3, PerkinElmer, MA, USA) sample pellet, and spectrometry was measured five times for each sample.

[0093] In vitro active pharmaceutical ingredient (API) release measurement

[0094] For all in vitro drug release experiment, the mucoadhesive patch with 2.5x2.5 mm SEDDS lipid micostructure with 90 pm thickness which contains different APIs (Danazol, Fenofibrate, Tolfenamic acid, and DiL) with 20 mg / ml concentration was used. The mucoadhesive patch was immersed in 100 pL artificial saliva at 37°C, and the evolution of UV-Vis spectrometry of its supernatant (2pL) was measured every 20sec until the absorbance reached saturation and after 3h using a UV-vis spectrophotometer (NanoDrop™ 2000c Spectrophotometers, Thermo Fisher Scientific, Waltham, MA, USA). For solid APIs, APIs were dissolved in ethanol with 0.1 wt%, then it dispensed on glass substrate and dried for 24h. Glass substrate was immersed in 100 pL artificial saliva and the evolution of UV-Vis of its supernatant was measured after 3h.

[0095] In vitro active pharmaceutical ingredient penetration into Agarose gel

[0096] Agarose gel was prepared by dissolving 2 wt% agarose (Sigma-Aldrich, St. Louis, MO, USA) in water and heating it in the microwave at 700W for 10s, then cooling it down to 40°C. A volume of 750 pL of the tissue phantom solution was poured into a UV cuvette (Semi micro cuvette, BrandTech Scientific, Inc., Essex, UK) and allowed to solidify. Honeycomb SEDDS lipid microstructures with a wall width of 160 pm, both with and without the GC film containing DiL, were placed on the top surface of the agarose gel and immersed in 50 pL of artificial saliva at 37°C. UV-Vis spectroscopy of the agarose gel was conducted 1 mm below the top surface every 2 min until the absorbance saturated and after 3h.

[0097] Statistical Analysis

[0098] Data collected by at least three independent experiments were presented as the mean ± standard deviation. The significant difference between sample groups was determined by one-way ANOVA with Tukey's for post-hoc analysis. For all analyses, statistical significance was expressed as a p-value, p-value smaller than 0.05. (* p < 0.05) was considered statistically significant. All data were analyzed using Microsoft Excel (Microsoft, Redmond, WA, USA).

[0099] Results

[0100] The lipids play a key role in the dissolution time, size of micelles, and API loading capacity of SEDDS lipid microstructures. In particular, the smaller the micelle size, the higher the efficiency of mucus layer penetration and cellular uptake. Table 2 presents direct laser scattering (DLS) measurement of micelle size for different types of lipids with varying mixing ratios dissolved in artificial saliva at 37°C. Micelles of PEG-32 stearate and Lauroyl PEG-32 glycerides (both non-ionizable surfactants) in artificial saliva have typical dimensions of 12 and 15 nm respectively. When these two surfactants are combined in a 1 : 1 ratio with Suppocire AP and Suppocire CM (both lipids mixtures made from mono- di- and triglycerides with different hydroxyl value), the resulting micelles have dimensions ranging from 22 to 460nm, depending on the chosen combination. Small micelles of similar size to these obtained for the surfactant alone are obtained when combining Suppocire AP with PEG-32 stearate, whereas all other combinations result in micelles at least ten times larger. To further optimize the lipid and surfactant mixture, the ratio of PEG-32 stearate to Suppocire AP was varied between 1 :9 and 1 : 1, however, all tested ratios resulted in similar sizes of micelles. The dissolution rate of the lipid is proportional to the surfactant ratio, while API solubility is inversely proportional to the surfactant ratio. In a preferred embodiment, a SEDDS having a 1 : 1 ratio of PEG-32 stearate and Suppocire AP has been selected for the mucoadhesive patch formulation. This material has a dissolution time of 5 minutes and an adequate API loading capability while keeping the micelle size small. The zeta potential of the micelles from the selected SEDDS lipid microstructure is -2.43 mV allowing the micelles to diffuse freely through the mucus layer without ionic interaction. The micelles maintain their average size (13 nm) and zeta potential (-2.45 mV) without significant alteration after 24 hours at 37°C.

[0101] Table 2: DLS results of micelle size for different types of lipids with varying mixing ratios dissolved in artificial saliva at 37°C. (P-Stearate: PEG-32 stearate, L-P-Glycerides: Lauroyl PEG-32 Glyceride, S-AP: Suppocire AP, S-CM: Suppocire CM).

[0102] SEDDS lipid microstructures were prepared on mucoadhesive films, such as GC films, by nanoimprinting (Figure 3A). Molds made of standard materials such as silicon or PDMS damaged the fragile SEDDS lipid microstructure in the demolding process due to mechanical stress. Therefore, a dissolvable poly vinyl alcohol (PVA) mold was used to avoid applying mechanical stress to the SEDDS lipid structures during demolding. The PVA mold was prepared by molding PVA solution into a positive Si mold. Nanoimprinting has been performed with a pressure of 0.1 MPa at 45°C. For the dissolution of the PVA mold, the device was immersed in a 1 : 1 solution of ethanol in water at 4°C, which avoids the dissolution of the lipid microstructure and minimizes the swelling of the mucoadhesive film, such as GC film. Finally, mucoadhesive patches were dried at 24°C under vacuum.

[0103] The honeycomb SEDDS lipid microstructure was selected not only to increase the surface area to volume (SA / V) for fast dissolution time but also to enhance the mechanical strength of the fragile SEDDS lipid microstructure layer. Four different honeycomb structures with identical hexagon sides dimensions of 100 pm were prepared, each having wall thickness (20, 40, 80, and 160 pm) and a height of 90 pm. Figure 3B shows the optical image of honeycomb microstructure with 40 pm wall thickness on the mucoadhesive film (GC film). Figure 3C displays the SEM image of honeycomb with 20, 80, and 160 pm thick width. All structures were successfully fabricated without defects. Structures with wall thickness below 20 pm could not be fabricated because the PVA mold was damaged during its detachment from the Si mold due to its high aspect ratio.

[0104] The dimension of the SEDDS lipid microstructure in the mucoadhesive patch has been measured with an optical profiler and compared with the designed parameters to evaluate the fidelity of the fabrication process. The results (not shown) indicate that the SEDDS lipid microstructures are fabricated as designed with a sharp edge at their sidewalls, and lipid residues less than 1 pm in thickness exist inside the hexagon cavity. For all measures different line widths, the fabricated line width decreased by 3 pm from the designed dimension. This may be attributed to the shrinkage of the PVA mold during the drying process.

[0105] The calculated volume, surface area, and ratio of SA / V of honeycomb SEDDS lipid microstructures with different wall widths (20, 40, 80, 160 pm) and a SEDDS lipid layer without a honeycomb microstructure with a height of 90 pm in a 2.5 / 2.5mm rectangle are presented in Table 3. With the increase in wall thickness, the surface area and SA / V of the SEDDS lipid microstructure decreased, while its volume increased. There is more than 2 times SA / V difference between unstructured lipid layer and honeycomb microstructure with 160 pm thickness. According to Noyes-Whitney equation (Equation 1) where m is the mass and t is time, A is the surface area, D is the diffusion coefficient, h is diffusion layer thickness, Cs is solubility of the solute, and C is the concentration of the bulk solution, the dissolution rate of the structure is proportional to the surface area of the solute under diffusion-controlled condition.

[0106] (Equation 1)

[0107] The SEDDS lipid microstructure was immersed in 50 pL of artificial saliva at 37°C, and its dissolution has been observed over time, as shown in Figure 4A. The dissolution time of the lipid structure was determined visually and corresponds to the moment where the structure loses its original shape. The dissolution rate of the SEDDS lipid microstructure was faster with increasing SA / V ratio, reaching a maximum of 1.6 nL / sec for the structure with thinnest wall thickness (20 pm) and a minimum value of 0.15 nL / sec in the unstructured lipid layer (film) (Figure 4B). This demonstrates that the microstructure can significantly enhance the lipid dissolution rate.

[0108] Table 3: Volume, surface area, and ratio of surface area to volume (SA / V) of honeycomb SEDDS lipid structures of different wall thickness (20, 40, 80, 160 pm) and unstructured lipid layer (film). All structures have a height of 100 pm and a 2.5x2.5mm footprint.

[0109] Figure 4C is the stress-strain curve of the GC film (mucoadhesive film) and the GC film (layer) coated with a 90 pm lipid film (layer). The GC film has a yield strength of 0.53 MPa with an elastic modulus of 21.2 MPa, exhibiting plastic behavior until failure at a strain of 54%. The lipid-coated GC film has a yield strength of 0.5 MPa with an elastic modulus of 37.3 MPa. The lipid-coated GC film undergoes plastic behavior until a 19% strain, at which point delamination of the lipid film occurs, continuing until failure at a strain of 53%. The elastic modulus of the lipid film, calculated from equation 2, is 41.1 MPa:

[0110] E= (Eg*hg+El*hl) / (hg+hl) (2) where E is the elastic modulus of lipid coated GC film and Eg is the elastic modulus of GC film and hg is the thickness of GC film, El is the elastic modulus of lipid and hl is the thickness of the lipid film. The SEDDS lipid layer is more vulnerable to fracture under mechanical stress compared to the GC film (layer) since it has higher elastic modulus. The honeycomb microstructure enhances the mechanical stability of the structure against stress. The enhanced mechanical stability of the SEDDS lipid microstructure on the GC film was evaluated by its critical strain, which is determined as the strain at which the SEDDS lipid microstructure shows the first crack during elongation. Honeycomb SEDDS lipid microstructures with wall thickness of 40 and 20 pm on GC films have critical strains of 5.4% and 8.1%, respectively, while the lipid film has a critical strain of only 1.6% (Figure 4D). Figure 4E displays the corresponding optical image of the films at critical strain. The higher critical strain at 20 pm width microstructure is attributed to the increased hexagon unit density, distributing force more efficiently. These results indicate that the honeycomb micropattern does improve the mechanical properties of the fragile SEDDS lipid microstructure in the mucoadhesive patch.

[0111] Three different lipophilic drugs (Fenofibrate, Tolfenamic acid, Danazol) and lipophilic dye (DIL) with very poor water solubility (< 0.5pg / ml) have been selected as model active pharmaceutical ingredients (APIs) in this study. All three APIs were dissolved in the molten lipid at a concentration of 20 mg / ml to form lipid-drug composites (SEDDS lipid loaded with APIs). The FTIR spectra of lipid and lipid-drug composites after mucoadhesive patch fabrication show no alteration in the peaks from the lipid (C=O stretching of ester group at 1750 cm-1) in all 3 lipid-drug composites (data not shown). The peak of fenofibrate (C=O stretching of Ketone group at 1655 cm-1, and C-Cl stretch peak at 761 cm-1) and tolfenamic acid (C=O stretching of carboxyl group at 1683 cm-1 and N-H band at 1582 cm-1, and C-Cl stretch peak at 764 cm-1) are observed in each composite indicating that no chemical alteration occurred during the dissolution of the APIs into the lipid and during the fabrication process. There was no additional peak in the danazol-lipid composite compared to the lipid alone because the intrinsic peak of danazol overlaps with the peak of the lipid.

[0112] According to the X-ray diffraction (XRD) analysis of the lipid and lipid-drug composites after the mucoadhesive patch fabrication process, the lipid exhibits diffraction peaks at 29 = 18.9° and 23.2° indicating a semi-crystalline state. There were no additional diffraction peaks in any of the three lipid-drug composites, while solid API powder showed their own inherent intense peak referring their crystallinity (data not shown). This indicates that the lipophilic APIs are fully solubilized in the lipid in an amorphous state without crystallization. To study the in vitro drug release from the mucoadhesive patch, four mucoadhesive patches with same geometry (160 pm thick width) containing different lipophilic APIs (Fenofibrate, Tolfenamic acid, Danazol, DiL) were immersed in artificial saliva at 37°C, and the evolution of UV-Vis spectrum of the supernatant was measured every 20 seconds until the absorbance reached saturation, and 3 hours after immersion (data not shown). All mucoadhesive patches showed a gradual increase in their absorbance over time while maintaining their intrinsic UV- Vis peaks. All mucoadhesive patches with different APIs saturated above 90% of the absorbance after 3 hours, within 260 seconds while the same dose of APIs in solid powder form immersed in artificial saliva didn’t dissolve much after 3 hours. There was no significant difference in saturation time between different APIs: Fenofibrate (260 seconds), Tolfenamic acid, Danazol, and DiL (220 seconds) although their molecular weight is different (Tolfenamic acid: 261.7, Danazol: 337.5, DiL: 933.89, Fenofibrate: 360.8). These results suggest that the dissolution of SEDDS forming lipid micelles is the main mechanism of API release from the mucoadhesive patch and API release is independent of the type of API, as long as the API is dissolved in lipid composite (the SEDDS) in an amorphous state.

[0113] The API release kinetics from the mucoadhesive patch can be controlled by lipid structure design. The in vitro release profile of the mucoadhesive patch with 80 pm thick wall containing Fenofibrate saturated after 140 seconds (data not shown), which is 21% faster than the mucoadhesive patch with 160 pm thick wall. Its absorbance after 3 hours is also 20% lower because of its smaller volume. These results are consistent with the differences in volume and dissolution rates of the SEDDS lipid microstructure prepared in Table 3 and Figure 4B.

[0114] To investigate the effect of the mucoadhesive film, such as GC film, on the penetration of the released API into mucosal tissue, SEDDS lipid microstructures in combination with and without the mucoadhesive film, such as GC film, were placed on the top surface of an agarose gel and immersed in artificial saliva at 37°C (data not shown). The UV-Vis spectrum of the agarose phantom was measured every 1 minute overtime and after 3 hours. The DiL absorbance of the agarose gel increased over time in both conditions, indicating the penetration of released DiL from the SEDDS lipid into the agarose. The absorbance of the agarose gel with GC film saturated after 12 minutes, which is 95% of the absorbance after 3 hours, while the absorbance of the agarose gel without GC film continued to increase after 12 minutes and only reached 72% of the absorbance after 3 hours. After 3 hours, the absorbance of the agarose gel with GC film is 20% higher than the one without the agarose gel. The GC film not only enhanced the penetration of released DiL into the agarose but also increased the amount of DiL that penetrated into the agarose by reducing losses in the surrounding medium. The mucoadhesive film, such as GC film, acting as a diffusion barrier for dissolved APIs causing a uni-directional release of APIs into the underlying tissue.

Claims

28CLAIMS1. A mucoadhesive patch consisting of two layers, wherein a first layer consists of a mucoadhesive film, and a second layer consists of a self-emulsifying drug delivery system (SEDDS) lipid microstructure, wherein the mucoadhesive film consists of one or more mucoadhesive polymers, the SEDDS lipid microstructure consists of a self-emulsifying drug delivery system (SEDDS) and one or more active pharmaceutical ingredients, wherein the SEDDS comprises a lipid and a surfactant, the one or more active pharmaceutical ingredient is a lipophilic and a poorly water soluble active pharmaceutical ingredient, or a lipophilic and a water-insoluble active pharmaceutical ingredient.

2. The mucoadhesive patch of claim 1, wherein the one or more mucoadhesive polymers are selected from the group comprising gelatin, chitosan, polymethacrylates, N- carboxymethylchitosan, poly(acrylic acid)cysteine, polyethylene glycol) diacrylate, hydroxypropyl methylcellulose, cyanoacrylates, polyacrylic acid, carbopol, polycarbophil, sodium alginate, pectin, hyaluronic acid, polyvinyl alcohol, poly(butyl methacrylate-co-(2- dimethylamino) ethyl methacrylate-co-methyl methacrylate) (Eudragit), poly(methacrylic acid, methyl methacrylate), poly(methacrylic acid, ethyl acrylate), guar gum, and xanthan gum.

3. The mucoadhesive patch of any one of claims 1-2, wherein the lipid in the SEDDS is selected from the group comprising glyceryl esters of fatty acids, derivatives of mono, di, tri glycerides, glyceryl monocaprylate, glyceryl tricaprylate, glyceryl caprate, propylene glycol monocaprylate, caprylocaproyl macrogol-8 glycerides, glyceryl monooleate, glycerol monolinoleate, glyceryl behenate, and hydrogenated soy phosphatidylcholine.

4. The mucoadhesive patch of any one of claims 1-3, wherein the surfactant in the SEDDS is selected from the group comprising lauroyl polyoxyl-32 glycerides, polyoxyl-32 stearate, stearoyl polyoxyl-32 glycerides, PEG-32 stearate, polyethylene glycol 40 stearate, D-alpha- tocopheryl polyethylene glycol 1000 succinate, polyethylene glycol 660 hydroxy stearate, PEG- 40 hydrogenated castor oil, polysorbate 80, polyoxyl 35 castor oil, caprylocaproyl macrogol-8 glycerides, macrogol 15 hydroxystearate, pol oxamer 407, and sorbitan monooleate.

5. The mucoadhesive patch of any one of claims 1-4, wherein the active pharmaceutical ingredient (API) is Class 2 or Class 4 active pharmaceutical ingredient according to Biopharmaceutics Classification System (BCS).

6. The mucoadhesive patch of any one of claims 1-5, wherein the SEDDS further comprises a hydro co-solvent.

7. Use of the mucoadhesive patch of any one of claims 1-6 for delivering one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients.

8. A method for delivery of one or more poor water-soluble active pharmaceutical ingredients or water-insoluble active pharmaceutical ingredients to a subject, the method comprising application of the mucoadhesive patch of any one of claims 1-6 on mucosal surface of the subject.

9. The method of claim 8, wherein the mucosal surface of the subject is oral mucosal surface, preferably buccal or sublingual mucosal surface.