Fully-dilutable, self-microemulsifying delivery systems (smedds) for poorly water-soluble polar solutes

Abstract

A fully dilutable in aqueous phase self-microemulsifying system for the delivery of one or more polar oil active compounds having a positive characteristic curvature (Cc), comprising: a lecithin compound; a hydrophilic linker or a combination two or more hydrophilic linkers, the hydrophilic linker or the combination of two or more hydrophilic linkers having one hydrocarbon group with 6 to 10 carbon atoms, and the hydrophilic linker or the combination of two or more HLs having a Cc of about -5 or more negative than about -5; and a carrier oil.

Description

<DP=1>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²1²FULLY-DILUTABLE, SELF-MICROEMULSIFYING DELIVERY SYSTEMS ²(SMEDDS) FOR POORLY WATER-SOLUBLE POLAR SOLUTES ²FIELD OF THE INVENTION ²The present invention relates to surfactant and oil solutions containing a ²dissolved²pharmaceutical, food, cosmeceutical, biocide, or preservative compounds that ²are²sparingly water-soluble and having polar oil characteristics. The disclosed ²solutions are ²designed to form microemulsions upon addition of an aqueous phase to deliver ²polar ²components to organisms or tissues, resulting in delivery systems for topical, ²transdermal, ²oral, buccal, vaginal, nasal, and ophthalmic applications, as well as food and ²agricultural² applications.²BACKGROUND OF THE INVENTION ²Acosta and Nouraei [1] reviewed the state of the art on delivery systems, ²particularly for ²oral delivery applications in the food industry. The review points out that ²many delivery ²systems have not made it to the market because of their complexity in ²production, their²low loading capacity, the use of expensive ingredients, and the use of non ²food-grade²ingredients with unknown safety profile. Therefore, the need to use delivery ²systems that ²could be as concentrated as possible, using safe food-grade and preferably ²plant-derived ²ingredients, is advantageous towards finding a viable commercialization route. ²Among the ²possible delivery systems that could fit these advantageous characteristics, ²self-²emulsifying and self-microemulsifying systems are of interest because their ²nanoscale size²is often required to improve the uptake and bioavailability of the drug or ²active ingredient. ²Acosta and Nouraei defined microemulsions as Surfactant-Oil-Water (SOW) ²systems that ²exist in thermodynamic equilibrium with sizes often ranging between 1 and ²100nm. The ²authors further indicate that sizes lower than 500 nm are required for uptake ²by the²intestines. Furthermore, the authors indicated that small drop sizes in ²delivery systems are²always desired to improve the surface area / volume ratio of the delivery system ²(-²6 / diameter of the delivery system), particularly for systems that may ²experience slow mass ²transfer. The authors further point to two manufacturing advantages of ²microemulsions ²over conventional emulsions. The first advantage is that self-microemulsifying ²and self-²emulsifying systems do not need specialized high shear equipment (homogenizer, ²²colloidal mills, and others) to produce the delivery systems, and simple mild ²mixing is²<DP=2>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²2²enough to produce these delivery systems. The second advantage of self-²microemulsifying ²systems is that microemulsions, existing in thermodynamic equilibrium, do not ²need ²coating agents to stabilize the diluted product, which is important to ²economically produce ²delivery systems with 1-50 nm scales.²Self-microemulsifying drug delivery systems (SMEDDS) are mixtures of ²surfactants (or²surfactants +linkers) and oils that, upon dilution with an aqueous phase, form ²²microemulsions with sizes often ranging in the 1-200 nm range. The smaller ²drop size (1-²200 nm) of SMEDDS, compared to self-emulsifying drug delivery systems (SEDDS, ²200 ²nm-1000nm), gives a larger surface area to volume ratio for SMEDDS and enables ²the²transport of microemulsion environments through tight pores. For transdermal ²delivery,²most of the pore sizes available for drug delivery are smaller than 30 nm, and ²only soft ²delivery systems like soft vesicles or microemulsions can reach those pores, ²preferably ²compositions with sizes of 10 nm or smaller [2]. A similar pore size of 10 nm ²has been ²reported for intestinal tissue permeation [3]. The epithelial tissue of the ²bulbar conjunctiva² can have pore sizes as large as 7.5 nm [4].²Given the mesh-like structure of the mucous layer surrounding the intestinal ²epithelial ²tissue, particles with up to 200 nm are preferentially retained in that zone ²of the intestine, ²allowing for larger release time [5]. The same principle of particle transport ²and retention ²in mucous layers applies to other wet epithelial tissue such as those lining ²the buccal²cavity, the vaginal cavity, the lungs and airways, and the stomach [6]. SMEDDS ²are ideal²delivery systems in this regard as they can achieve particle sizes of 200 nm ²or smaller. The ²high concentration of oil and surfactants in water-free preconcentrates of ²SMEDDS ²enables ease of manufacture and high loading capacity of drugs with low water ²solubility. ²The water-free environment of SMEDDS is also beneficial in preventing ²microbial²growth, giving SMEDDS products greater biological stability.²The patent literature teaches of various examples of self-emulsifying systems ²of ²preconcentrates for drug delivery. The application WO / 2018 / 011808 describes ²the use of ²PEG-based surfactants such as Cremophor EL and Polysorbate 80 to design ²preconcentrates for the delivery of cannabinoids that form emulsions with 10 ²nm-100²in size. The USPTO application 20190015346A1 discloses the use of ²preconcentrates that²are also prepared with PEG-based surfactants such as Lauroyl ²polyoxylglycerides (PEG-²32 esters) as SEDDS for cannabinoids. The US patent 10,245,273 discloses the²<DP=3>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²3²formulation of SMEDDS and SEDDS for the delivery of testosterone esters using ²a ²mixture of hydrophilic and lipophilic surfactants, where the hydrophilic ²surfactant is PEG-²based, preferentially Cremophor RH 40 (PEG-40 Hydrogenated Castor Oil). US ²patent ²9,511,078 discloses the formulation of SEDDS with 50 nm to 800 nm in size for ²the²delivery of poorly soluble drugs using propylene glycol (PPG) monocaprylate ²solvent and²a PEG-based emulsifier. US patent 9,918,965 discloses the formulation of SEDDS ²and ²SMEDDS for diindolylmethane and associated components via the combination of ²two ²emulsifiers, one lipophilic emulsifier with HLB lower than 7, including ²lecithin ²components, and one hydrophilic emulsifier with HLB higher than 7, where the ²preferred²embodiments and examples make use of PEG-based hydrophilic emulsifiers. US ²patent²8,790,723 discloses a self-nano emulsified drug delivery system (SNEDDS) ²produced with ²a mixture of a low HLB surfactant and a high HLB surfactant, Cremophor EL (PEG ²35 ²ester of castor oil). US patent 8,728,518 discloses SEDDS compositions for ²butylphthalide ²containing an emulsifier agent that may include lecithin but is preferably a ²PEG ester of²castor oil or a PEG ester of glyceryl caprylate / caprate. US patent 7,022,337 ²discloses self-²emulsifying formulations for fenofibrate delivery and its derivatives using a ²combination ²of fenofibrate solubilizers (mainly PEG and polypropylene glycol or PPG ²compounds), ²stabilizers against crystallization (mainly alcohols and long-chain fatty ²acids), and ²surfactants, including lecithin among the possible candidates. US patent ²6,982,282²discloses self-emulsifying parenteral delivery systems for chemotherapeutics ²using,²preferably, PEGylated surfactants. US patent 7,419,996 discloses self-²emulsifying ²systems for the delivery of benzimidazole using aprotic solvents combined with ²mixtures ²of sorbitan monooleate and PEG20-sorbitan monooleate. US patent 6,960,563 ²discloses ²self-emulsifying cyclosporin delivery systems prepared with ethanol as a ²hydrophilic²solvent and PEG-glycerol trioleate as an emulsifier. US patent 8,962,696 ²discloses the²formulation of self-microemulsifying delivery systems for propofol using PEG-²containing ²surfactants. US patent application 20190216869A1 discloses the formulation of ²self-²emulsifying delivery systems for cannabinoids using a mixture of cosolvents ²(including ²ethylene glycol, polyethylene glycol, alcohols, and PEGs), surfactants (with ²HLB less than²8 and between 9 and 20), and water. US patent application 20190111021A1 ²discloses self-²emulsifying compositions to deliver tocotrienol using a carrier oil and a ²mixture of sorbitan ²monolaurate and PEG-20 sorbitan monooleate. US patent application 20190060300 ²discloses self-emulsifying compositions to deliver CB2 Receptor Modulators ²using a ²mixture of a surfactant with HLB<9 (including lecithin among the candidates) ²and a²<DP=4>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²4²surfactant with HLB>13, citing preferred compositions of PEG-based surfactants ²with 15 ²ethylene glycol groups or more. US patent application 20180250262A1 discloses ²self-²emulsifying compositions for the delivery of cannabinoids using a mixture of ²sesame oil, ²cyclodextrin, glyceryl behenate, lecithin, and PEG-6 caprylic / capric ²glycerides. US patent² application 20190183838A1 discloses SEDDS, SNEDDS, and SMEDDS compositions ²for the delivery of polyunsaturated fatty acids and its esters using at least ²one surfactant of ²ionic, nonionic, or zwitterionic nature, including examples containing ²lecithin as a ²surfactant, PEG-based surfactants (Tween 20, Tween 80) and short-chain ²alcohols, ²polyethylene glycol (PEG) and propylene glycol (PPG) as cosolvents. US patent²application 20180071210A1 discloses SEDDS compositions to deliver cannabinoids ²using ²PEG-PPG block copolymer surfactants and a polar solvent. US patent application ²²20140357708A1 discloses self-emulsifying compositions to deliver cannabinoids ²using ²triglycerides as a carrier oil to promote chylomicron / lipoprotein delivery ²(lymphatic ²transport) and reduce hepatic first-pass metabolism; and using lecithin, PEG-²based²surfactants, and C18+ polyglycerol surfactants to facilitate the self-²emulsification process.²The numerous examples drawn from the patent literature reveal various ²important trends. ²First, that self-emulsification or self-microemulsion is an active area of ²development given ²its success in improving the uptake of poorly water-soluble compounds. Second, ²that the ²formulations tend to be comprised of zwitterionic surfactants such as lecithin ²or nonionic²surfactants such as PEG-based surfactants and often rely on a combination of ²surfactants ²to achieve the desired performance. In several cases, these combinations are ²guided by the ²presence of a surfactant with HLB (hydrophilic-lipophilic balance) less than ²10 and one ²with HLB greater than 10. Finally, most examples use PEG-based surfactants, ²particularly ²surfactants with 15 or more ethylene glycol units. One aspect missing in the ²patent²literature cited above is any data or specifics about the dilutability of the ²disclosed ²compositions. The work of Chu et al. showed that the formation of self-²emulsifying ²systems depends on the composition of the aqueous phase and the dilution ratio ²[7]. After ²searching the patent literature, only US patent application 20190008770 and US ²patent ²7,182,950 addressed the dilution process, claiming full dilutability. US ²patent 7,182,950²uses ternary phase diagrams including a vertex of surfactant composition, oil ²composition, ²and aqueous phase composition to illustrate the complexity of producing fully ²dilutable ²delivery systems and that only certain compositions of surfactants and oil can ²be diluted ²with specific compositions of an aqueous phase and hydrophilic cosolvents that ²include²<DP=5>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²ethanol and glycerol. However, in physiological conditions, the aqueous phases ²diluting ²the composition do not contain these solvents, and instead, they are aqueous ²solutions ²containing salts, lipids, and proteins. US patent application 20190008770 does ²not ²introduce ternary phase diagrams to explain the dilution process but mentions ²dilution with²5 water and hydrophilic cosolvents ethanol, glycerol, propylene glycol, and ²PEG to achieve²full dilutability.²The use of PEG-based surfactants, especially those with more than 10 ethylene ²glycol ²groups, is often justified by the low toxicity of those surfactants and ²because they impart ²stealth characteristics to the delivery system [8]. This stealth ²characteristic means that²delivery systems with PEG-based surfactants tend to bypass metabolic pathways, ²leading²to extended circulation time in the blood. For oral delivery applications, ²however, being ²stealth is not desirable because it interferes with chylomicron assembly, ²which enables ²lymphatic transport. For example, Pluronic L-81, a PPG-PEG block copolymer, ²inhibits ²the uptake of beta-carotene when compared to surfactant-free delivery, while a ²simulated²bile salt delivery system enhances the bioavailability of beta-carotene [9]. ²The stealth²nature of PPG and PEG components is partially due to the lack of enzymes that ²can ²hydrolyze these components, considering that they are not found in nature. ²Nevertheless, ²due to the multiple and repeated exposure to PEG components, there is ²increasing evidence ²that humans are adapting to these components, and there are more frequent ²reports of PEG-²induced Accelerated Blood Clearance (ABC) and an autoimmune response called ²the ²complement (C) activation-related pseudoallergy (CARPA)

[10] . One the biggest ²drawback of the Pfizer-BioNTech COVID-19 vaccines is that they may cause ²allergic ²reactions due to presence of the PEG in its formulation. Because of these ²reasons, self-²emulsifying and self-microemulsifying compositions that are free of PEG and ²PPG² compounds are considered advantageous as delivery systems.²Acosta and Yuan (US Patent No. 9,918,934) disclosed microemulsion-based ²delivery ²compositions containing a lecithin compound as the main surfactant, a ²lipophilic linker ²having C12+ alkyl chain with HLB 5 or less; and C6-C9 surfactant-like ²hydrophilic linker. ²The disclosed formulations are PEG-free, PPG-free, and free of short-chain ²alcohol and²medium-chain alcohol. The disclosures in this patent, however, do not include ²SMEDDS²nor any description on how to produce water-free formulations that are fully ²dilutable.²<DP=6>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²6²For selected delivery applications, such as subcutaneous, buccal, topical, ²ophthalmic, and ²vaginal delivery is desirable for the delivery system to have solid-like (gel) ²and extended-²release properties. These desirable properties allow for a concentrated dose ²to be safely ²placed next to an epithelial tissue for extended-release of safe and effective ²doses of a wide²range of actives, including insulin and antimicrobials [11-14]. There are ²numerous gels²systems designed to deliver actives; however, lecithin-based gels offer the ²advantage of ²facilitating food-grade formulations and enabling lymphatic transport. Current ²lecithin-²based gels often use gelating agents to trap oils, emulsions, microemulsions, ²or even ²aqueous solutions, but not lecithin-based SMEDDS

[15] . The advantage of ²incorporating²SMEDDS into slow-release lecithin-based gel systems is that high ²concentrations of the²drug can be loaded into the gel, allowing slow and continuous release without ²reaching ²potentially toxic high "dump" doses. Gelled SMEDDS have been reported as a ²solid-like ²alternative to liquid SMEDDS, and they are produced by embedding gel-forming ²polymers ²with the SMEDDS composition

[16] . There are reports on the use of low ²molecular weight²gelators such as 12-hydroxystearic acid (12-HSA) and beta-sitosterol to ²produce²organogels of oil mixtures containing drugs to provide long release ²times[17,18]. ²However, the same references report that incorporating surfactants such as ²lecithin and ²polyglycerol esters reduce the mechanical strength of the gel and are, ²therefore, ²undesirable contaminants. These observations suggest that it is impossible to ²formulate a²gelled SMEDDS with a low molecular weight gelator such as 12-HSA or ²phytosterols with²extended-release properties. Perhaps due to this understanding in the field, ²no patents for ²gelled SMEDDS with low molecular weight gelators were found. The closest ²document is ²patent application W02008037697A1 on novel organogel particles that describes ²the use ²of 12-HSA hot-diluted in oils and then incorporated into an aqueous solution ²containing²surfactants under high intensity mixing to then produce gellosomes (dispersed ²gelled²phases). However, the reported invention required the use of water to induce ²the formation ²of gellosomes, which is contrary to the idea of producing water-free gelled ²SMEDDS.²For food and pharmaceutical applications, encapsulation of the delivery ²systems is often ²necessary to protect the stomach lining from the active ingredients and to ²protect active²ingredients from the acidic environment of the stomach. Therefore, ²encapsulated ²SMEDDS formulations are expected to produce useful formulas for various ²products, ²including nonsteroidal anti-inflammatory drugs (NSAIDs) that are known to ²affect the ²inner lining of the stomach. Initial attempts to encapsulate SMEDDS ²concentrated on²<DP=7>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²7²filling gelatin capsules with SMEDDS. However, more recent attempts include ²the ²embedding SMEDDS into polymer matrices that provide temporal protection ²against ²release in the stomach [16,19]. One report using spray-drying to encapsulate ²SMEDDS ²employed dextrose as a coating agent, but this agent does not produce ²protection against²acidic release (i.e., it is not an enteric coating)[201. One desirable feature ²of spray-dried²products is that it produces free-flowing powders that can be easily ²incorporated into food ²products, gel products, and pellets. Patent application US2018 / 0021349A1 ²discloses ²compositions of SMEDDS formulated with PEG-based surfactants mentioning ²potential ²encapsulation technologies, including spray-drying. However, the invention ²does not²disclose enteric encapsulation compositions. Enteric encapsulation of ²microemulsions has²been claimed in patent US6,280,770B1 accomplished by absorption of SMEDDS into ²a ²porous material with enteric protection properties. This brief review shows a ²clear gap in ²the technology for powder spray-dried SMEDDS formulations with enteric coating ²agents.²Hydrophilic-hpophilic difference (HLD) and Characteristic curvature (Cc)²Nouraei and Acosta

[21] produced the first example of lecithin + linkers fully ²dilutable²formulation, which was designed via the hydrophilic-lipophilic difference ²(HLD) ²framework, requiring the measurement of the characteristic curvature (Cc) of ²the linkers ²and lecithin, and the equivalent alkane carbon number (EACN) of the oil. The ²authors ²indicated that the minimum lipophilic linker to lecithin ratio necessary to ²prevent highly²viscous liquid crystals and gels was 1 part (by mass) of the lipophilic linker ²(sorbitan²monooleate or glycerol monooleate) for 1 part of lecithin. Furthermore, the ²authors used ²the net-average curvature (NAC) model, associated with the HLD, to predict the ²2-phase ²region of the ternary phase diagram. The authors used the HLD-NAC framework to ²²identify a region of the ternary phase diagram with a fully-dilutable region ²suitable for²SMEDDS formulations. The fully-dilutable composition disclosed by Nouraei and ²Acosta²was comprised of lecithin as the main surfactant, glycerol monooleate as a ²lipophilic linker ²and polyglycerol caprylate (Dermofeel0 G6CY) as a hydrophilic linker. The Cc ²of ²polyglycerol caprylate Dermofeel0 G6CY is around -3. The composition was PEG-²free, ²PPG-free, and free of medium and short-chain alcohols. Nouraei and Acosta ²highlighted²the complex nature of the formulation, indicating that a change in the ratios ²among the²linkers and lecithin was enough to eliminate the fully-dilutable path. The ²authors ²determined that the HLD value of the formulation can serve as a guideline to ²reach the ²conditions for full dilutability. The HLD is an empirical equation that ²relates the²<DP=8>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²8²formulation conditions to the proximity to the surfactant phase inversion ²point, where ²HLD=0

[21] . For systems containing nonionic surfactants such as those employed ²in the ²lecithin-linker compositions:²HLD = b=S -k=EACN + Cc + cr(T-25 C) (1)²where b, k and cT are constants that depend on the surfactant used and the ²electrolyte²dissolved in the aqueous phase. S is the salinity of the aqueous phase, ²normally expressed ²in g NaCl / 100 mL for saline solutions. T is the temperature of the systems in ²Celsius. The ²Cc is the characteristic curvature of the surfactant, with more hydrophilic ²surfactants ²having more negative Cc values. For linear alkanes, EACN is simply the number ²of²carbons in their chain, and for other oils, this value is determined ²experimentally using²methods reported in the literature

[22] .²An advantageous feature of SMEDDS is delivering concentrated doses of actives ²through ²living tissues (animals, plants, and microbial species). This feature makes ²SMEDDS a ²desirable technology to incorporate pharmaceutical active ingredients, ²nutraceuticals,²cosmeceuticals, and a wide range of biocides into pharmaceutical, food, ²cosmetic, cleaning²and disinfecting, and agrochemical compositions. Many components of interest ²in ²medical, cosmetic, food and agricultural applications are not simple ²hydrocarbons with a ²defined EACN. Instead, many of these components are polar oils.²Polar oils are a broad class of oils consisting of a heteroatom-linked polar ²group attached²to a nonpolar hydrocarbon, producing non-zero dipole moments and a non-zero ²polar²surface area. Polar groups include carboxylic acids, alcohols, amines, amides, ²ethers, ²esters, aldehydes, and haloalkanes. The polarity of these oils allows them to ²segregate ²towards the oil¨water interface, displaying a surfactant-like behavior and at ²the same time ²partition into the bulk oil phase, displaying an oil-like behavior. Polar oils ²have been found²to have a positive value of Cc or a value of apparent EACN that is negative ²

[23] .²Formulating microemulsion systems (including SMEDDS) with polar oils remains a ²²complex task, even for those skilled in the art

[24] .²Fig. 1 Illustrates the challenge of incorporating polar oils, in this case, ²ibuprofen ²(containing a carboxylic acid polar group), into the SMEDDS composition ²disclosed by²Nouraei and Acosta

[21] . The 10-10-80 (lecithin - glycerol monooleate - ²polyglycerol-6-²caprylate) system of Fig. 1, formulated with a 75 / 25 surfactant mixture / oil ²(ethyl caprate)²<DP=9>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²9²ratio (also known as a D75 SMEDDS), was fully dilutable in the absence of ²ibuprofen (top ²set of dilution vials). However, adding 5% ibuprofen to the SMEDDS disrupted ²the fully ²dilutable path (onset of phase separation) of the original SMEDDS. The ²introduction of a ²polar oil can induce a phase inversion of the surfactant into the oil. In HLD ²terms, this²would represent a positive HLD shift. The 10-10-80 system, with HLD= -1.85 ²

[21] , was²selected to mitigate this effect; however, not even this precaution prevented ²phase ²separation. Other attempts to restore the full dilutability included replacing ²ethyl caprate ²with mineral oil with high EACN (a negative HLD shift) and reducing the ²lecithin and ²lipophilic linker content to a minimum, all without success. The compositions ²disclosed²herein represent unexpected solutions to this formulation challenge. The ²compositions²disclosed herein overcome the challenge of formulating fully dilutable SMEDDS ²containing polar oil solutes.²SUMMARY OF THE INVENTION ²The present disclosure relates to lecithin-based, fully-dilutable self-²microemulsifying drug²delivery systems (SMEDDS) compositions used to solubilize and deliver poorly ²water-²soluble polar active ingredients. The delivery can be via topical, ²transdermal, oral, ²transnasal, buccal, vaginal, subcutaneous, parenteral, and ophthalmic routes ²in humans and ²animals for food, cosmetic and pharmaceutical applications. The compositions ²described ²in this disclosure are also useful in delivering actives to plants, insects ²and microorganisms²for agricultural, pest, and disease control. In embodiments, the lecithin-²based SMEDDS²compositions of the present disclosure are comprised of lecithin as the main ²surfactant, a ²hydrophilic linker (HL) comprising a C6-C10 surfactant with characteristic ²curvature (Cc) ²of about -5 or more negative than about -5 (also referred to as "extreme ²hydrophilic ²linker"), and a carrier oil phase. In aspects, the carrier oil phase has a ²positive equivalent²alkane carbon number (EACN) such as alkyl esters of fatty acids, terpenes, ²essential oils²and food-grade or pharma-grade hydrocarbons, or mixtures thereof that may be ²required ²to dissolve the polar oil solute in the SMEDDS. In aspects, the SMEDDS may ²also be ²comprised of a C10+ lipophilic linker having a characteristic curvature (Cc) ²more positive ²than +3. The disclosed fully-dilutable SMEDDS contains a poorly water-soluble ²polar oil²as an active ingredient having water solubility lower than 1 wt%, log P ²greater than 1.5,²and a positive characteristic curvature (Cc), or negative apparent EACN. The ²water-free ²SMEDDS are fully dilutable in isotonic solutions containing lipids and ²proteins typically ²found in biological fluids (i.e., intestinal fluids, CFS, tear fluid, saliva, ²sweat, plasma,²<DP=10>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²blood and so forth), producing drop sizes of 1 to 200 nm. The SMEDDS are free ²of short ²(Cl to C3) chain alcohol, medium (C4 to C8) chain alcohol, PEG, PPG, PEG-based ²²surfactants, and PPG-based surfactants.²The disclosed PEG-free and fully-dilutable lecithin-based SMEDDS increased the²5 transdermal permeation of solutes that are sparingly soluble in water and ²that have polar²oil characteristics. In another embodiment, the lecithin-based SMEDDS was ²shown to ²increase the absorption of the polar active ingredient via oral delivery, also ²producing a ²fast-acting transport of the polar active, whose plasma concentration remains ²relatively ²high for an extended period.²10 In another embodiment, the disclosed fully-dilutable lecithin-based ²SMEDDS further²comprises a low molecular weight organic gelator to produce gelled SMEDDS that ²offer ²an extended-release of the active for over one day of release. These gelled ²SMEDDS ²compositions are useful to avoid potentially undesirable burst release effects ²and reduce ²frequent dosing of active compounds.²In another embodiment, the disclosed fully-dilutable lecithin-based SMEDDS ²further²comprises a coating agent that imparts enteric protection during gastric ²passage. The ²composition is first diluted in an aqueous environment to generate a ²microemulsion ²containing a dispersion of the coating agent. The dispersion is then spray-²dried to generate ²free-flowing encapsulated SMEDDS particles. These encapsulated SMEDDS ²particles are²useful to incorporate SMEDDS into solid and semisolid products and tablets. ²The ²encapsulated SMEDDS protects the active from the gastric acid environment and ²protects ²the stomach lining from potential adverse effects induced by the delivered ²active.²Disclosed is a fully dilutable in aqueous phase self-microemulsifying system ²for the ²delivery of one or more polar oil active compounds having a positive ²characteristic²curvature (Cc), comprising: (a) a lecithin compound; (b) a hydrophilic linker ²(HL) or a²combination of two or more hydrophilic linkers (HLs), the HL or each of the ²HLs within ²the combination having one hydrocarbon group with at least 50% or more alkyl ²chain ²distribution between 6 to 10 carbon atoms (i.e., C6, C7, C8, C9 or C10), and ²the HL or the ²combination of two or more HLs having a Cc of about -5 or more negative than -²5; and (c)² a carrier oil.²<DP=11>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²11²In one aspect of the disclosed fully dilutable in aqueous phase self-²microemulsifying ²system, the delivery is topical, transdermal, oral, transnasal, buccal, ²vaginal, subcutaneous, ²parenteral, ophthalmic, transepidermal, transmembrane, and / or intravenous.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying² system, the lecithin compound concentration is about 1.5% to about 45% w / w.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the lecithin compound is vegetable lecithin, animal lecithin or ²synthetic lecithin ²containing at least 50% w / w of a mixture of phosphatidylcholine, ²phosphatidylinositol, ²phosphatidylethanolamine, phosphatidylserine, and phosphatidic acid, and ²lysotecithins.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the hydrophilic linker or the combination of two or more HLs is about ²10 wt% to ²about 86 wt% of the system.²In another aspect of the fully dilutable in aqueous phase self-²microemulsifying system, the ²combination of two or more HLs includes least one amphiphilic compound with a ²Cc less²negative than about -5 and the Cc of the combination is about -5 or more ²negative than²about -5.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the hydrophilic linker or the combination of two or more HLs comprises ²one or ²more of C6-C10 alkyl polyphosphates, polyphosphonates, polycarboxylates,²sulfosuccinates; , glutamates, C6-C10 esters of polyhydric alcohols, polyvinyl ²alcohol,²polyglycerols and their co-polymers with a degree of polymerization (n) higher ²than 2 ²(n>2), sucrose, maltose, oligosaccharides, polyglucosides (n>2), ²polyglucosamines, ²sorbitol, sorbitan, poly alpha hydroxy acids and their salts, C6-C10 amines, ²quaternary ²ammonium salts, amine oxides, C6-C10 alkyl aminopropionic acids, betaines,²sulfobetaines, phosphatidylcholines, phosphatidyl glycerols, or mixtures ²thereof²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the hydrophilic linker or at least one of the two or more HLs in the ²combination is ²a C6-C10 polyglycerol with a degree of polymerization n>2.²<DP=12>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²12²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the hydrophilic linker or at least one of the two or more HLs in the ²combination is²disodium C6-C10 glutamate, polyglycerol-6-caprylate or polyglycerol-10 ²caprylate.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the carrier oil has a positive equivalent alkane carbon number (EACN).²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the carrier oil concentration is about 10 wt% to about 70 wt%.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the carrier oil comprises of alkyl esters of fatty acids, ²monoglycerides,² diglycerides, triglycerides, alkanes, terpenes, or mixtures thereof²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the self-microemulsifying system further includes the one or more ²polar oil active ²compounds having a positive characteristic curvature (Cc).²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the concentration of the one or more polar oil active compounds is ²about 0.01 wt%²to about 80 wt%.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, each of the one or more polar oil active compounds having a positive ²characteristic ²curvature (Cc) has a log P greater than 1, molecular weight between 50 and ²100,000²Daltons, a polar area greater than 0.0 A2, an aqueous solubility less than ²about 1 wt%.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the one or more polar oil active compounds having a positive ²characteristic ²curvature (Cc) includes one or more hydrogen bonding donor compounds selected ²from a ²group consisting of C5+ alcohols, amines, peptides, organic acids, anthranilic ²acids, aryl²propionic acids, enolic acids, heteroaryl acetic acids, indole and indene ²acetic acids,²salicylic acid derivatives, nucleic acids, alkylphenols, para-aminophenol ²derivatives, ²terpene phenolics, cannabinoids, alkaloids, peptides, and halogenated ²compounds.²<DP=13>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²13²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the one or more polar active compounds include ibuprofen, nonylphenol, ²²cannabidiol, and eugenol.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the aqueous phase is water, biological fluids, aqueous electrolyte ²solutions,²carbonated drinks, fruit juices, or alcoholic beverages.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system further comprises a lipophilic linker.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying².. system, the lipophilic linker concentration is about 0.1 wt% to about 30.0 ²wt%.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the lipophilic linker includes one or more ingredients selected from a ²group ²consisting of C12+ alcohols, fatty acids, monoglyceride, sorbitan ester, ²sucrose ester, ²glucose ester.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the lipophilic linker includes one or more ingredients selected from a ²group ²consisting of dodecyl alcohol, oleyl alcohol, cholesterol, lauric acid, ²palmitic acid, oleic ²acid, omega 6-fatty acids, omega 3-fatty acids, esters of these fatty acids ²with sorbitol, ²maltitol, xylitol, isomalt, lactitol, erythritol, pentaerythritol, glycerol; ²for example, sorbitan² monooleate, and glycerol monooleate.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system further comprises of a low molecular weight organogelator ²that imparts ²semisolid properties and produces a slow releasing profile of the one or more ²polar oil ²active compounds.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the concentration of the organogelator is about 0.1 wt% to about 40.0 ²wt%.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the organogelator includes one or more ingredients selected from ²sterol-based²<DP=14>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²14²gelling agents, long-chain fatty acids, long-chain amines, and esters of long-²chain fatty²acids.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system further comprises an encapsulating agent that imparts solid-²like²properties and produce flowable powders that can form micellar solutions when ²diluted in²aqueous environments.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the concentration of the encapsulating agent is about 10% to about ²90.0% wt.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying²system, the encapsulating agent includes one or more ingredients selected from²amphiphilic polymers with a glass transition temperature ranging from about 45 ²C to about ²99 C.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system comprises between 30 parts of a mixture of the lecithin and ²hydrophilic²linker and 70 parts of the carrier oil (D30) and 90 parts of the mixture of ²lecithin and²hydrophilic linker and 10 parts of the carrier oil (D90).²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system comprises between 40 parts of a mixture of the lecithin and ²hydrophilic ²linker and 60 parts of the carrier oil (D40) and 80 parts of the mixture of ²lecithin and² hydrophilic linker and 20 parts of the carrier oil (D80).²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system is waterless.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemulsifying ²system, the system is free of polyethylene glycol, propylene glycol, and short ²and medium-²chain alcohols.²In another aspect of the disclosed fully-dilutable in aqueous phase self-²microemusifying ²system, the system has particle diameters smaller than 200 nm.²Disclosed is also a capsule comprising any one of the fully dilutable in ²aqueous phase self-²microemulsifying systems of the present disclosure.²<DP=15>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²Disclosed herein is also a method of delivering one or more polar oil active ²compounds ²having a positive characteristic curvature (Cc) across an epithelium, the ²method ²comprising contacting the epithelium with a composition comprising the fully ²dilutable in ²aqueous phase, self-microemulsifying system according to the present ²disclosure. In²5 aspects of ²the method, the composition is a cosmetic composition, a nutraceutical²composition, a food composition or a pharmaceutical composition.²Disclosed is also a method of delivering one or more polar oil active ²compounds having a ²positive characteristic curvature (Cc) to a subject comprising administering ²to a subject a ²fully dilutable in aqueous phase self-microemulsifying system comprising: (a) ²a lecithin²10 compound; ²(b) a hydrophilic linker (HL) or a combination of two or more hydrophilic²linkers (HLs), the HL or each of the HLs within the combination having one ²hydrocarbon ²group with at least 50% or more alkyl chain distribution between 6 to 10 ²carbon atoms and ²the HL or the combination of two or more HLs having a Cc of about -5 or more ²negative ²than -5; (c) a carrier oil; and (d) the one or more polar oil active compounds ²having the²15 positive ²Cc. In one aspect of this method the system is formulated for topical, ²transdermal,²oral, buccal, vaginal, nasal, subcutaneous, parenteral, transepidermal, ²transmembrane ²and / or ophthalmic delivery. In another aspect, the fully dilutable in aqueous ²phase, self-²microemulsifying system is any one of the systems of the present disclosure.² BRIEF DESCRIPTION OF THE DRAWINGS ²A detailed description of the preferred embodiments is provided herein below ²by way of ²example only and with reference to the following drawings, in which:²Fig. 1A shows the dilution of the 10-10-80 formulation at 75:25 Surfactant: ²Oil.²Fig. 1B shows the dilution of 10-10-80 formulation when loaded with 5% ²ibuprofen. SIF%²represents the mass percentage of fed-state simulated intestinal fluid (SIF) ²in the diluted²SMEDDS.²Fig. 2A shows the solubilization parameter for oil (heptane, diamonds) and ²water (squares) ²in middle phase microemulsions as a function of the salinity (g NaCl / 100 mL) ²in the ²aqueous phase. The point of equal solubilization for oil and water is ²indicated as S*, the²<DP=16>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²16²optimal salinity. The system corresponds to a 20 wt% Caprol0 6GC8 in mixture ²with the²reference surfactant C9E5.²Fig. 2B shows the optimal salinity (S*) for microemulsions produced with ²heptane as the ²oil phase and mixtures of Caprol0 6GC8 and C9E5, as a function of the molar ²fraction of² Caprol0 6GC8 in mixtures with C9E5.²Fig. 3A shows the optimal salinity (S*) for microemulsions produced with ²heptane as the ²oil phase and mixtures of ibuprofen and C9E5, as a function of the molar ²fraction of ²ibuprofen in mixtures with 5 wt% C9E5 in the aqueous phase.²Fig. 3B shows the optimal salinity (S*) for microemulsions produced with ²heptane as the²oil phase and mixtures of nonylphenol and C9E5, as a function of the molar ²fraction of²nonylphenol in mixtures with 5 wt% C9E5 in the aqueous phase.²Fig. 3C shows the optimal salinity (S*) for microemulsions produced with ²heptane as the ²oil phase and mixtures of eugenol and C9E5, as a function of the molar ²fraction of eugenol ²in mixtures with 5 wt% C9E5 in the aqueous phase.²Fig. 3D shows the optimal salinity (S*) for microemulsions produced with ²heptane as the²oil phase and mixtures of benzocaine and C9E5, as a function of the molar ²fraction of ²benzocaine in mixtures with 15 wt% C9E5 in the aqueous phase.²Fig. 3E shows the optimal salinity (S*) for microemulsions produced with ²cyclohexane as ²the oil phase and mixtures of cannabidiol (CBD) and C9E5, as a function of the ²molar²fraction of CBD in mixtures with 7 wt% C9E5 in the aqueous phase.²Fig. 4 shows the ternary phase diagram for a SMEDDS system formulated with ²soybean ²lecithin (10 parts), lipophilic linker (10 parts), and conventional ²hydrophilic linker ²Dermofeel0 G6CY (Cc=-3) (80 parts), and containing 5% ibuprofen, and ethyl ²caprate as ²carrier (solvent) oil.²Fig. 5 shows the ternary phase diagram for a fully dilutable SMEDDS system ²formulated²with soybean lecithin (10 parts), and extreme hydrophilic linker Polyaldo010-1-²CC (Cc=-²7.4) (90 parts) and containing 5% ibuprofen and ethyl caprate as carrier ²(solvent) oil.²Fig. 6 shows the ternary phase diagram for a fully dilutable SMEDDS system ²formulated ²with soybean lecithin (15 parts), lipophilic linker Peceol TM (15 parts), and ²extreme²<DP=17>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²17²hydrophilic linker Caprol0 6GC8 (Cc= - 6.4) (70 parts), and containing 5% ²ibuprofen,²and ethyl caprate as carrier (solvent) oil.²Fig. 7 shows the ternary phase diagram for a fully dilutable SMEDDS system ²formulated ²with soybean lecithin (10 parts), and extreme hydrophilic linker Polyaldo010-1-²CC (Cc=-²7.4) (90 parts), and containing 5% cannabidiol (CBD), and Limonene as carrier ²(solvent)²oil.²Fig. 8. Top picture: red channel image of the water dilution of D70 Lecithin- ²Polyaldo010-²1-CC-limonene formulation containing 5% CBD. Bottom picture: blue channel ²image of ²the water dilution of D70 Lecithin-Polyaldo 01 0- 1-CC-limonene formulation ²containing² 5% CBD.²Fig. 9 shows the cumulative transdermal permeation of nonylphenol (NP) through ²excised ²pig skin. Circles correspond to 10% NP formulated in a SMEDDS(i) produced 10 ²parts ²lecithin+90 parts Polyaldo010-1-CC, and ethyl caprate following a D50 dilution ²line and ²diluted with 70 parts FeSSIF and 30 parts of SMEDDS(i). Squares correspond to ²10% NP²formulated in a SMEDDS(ii) produced 15 parts lecithin+ 15 parts PeceolTM + 70 ²parts²Polyaldo010-1-CC, and ethyl caprate following a D50 dilution line and diluted ²with 70 ²parts FeS SIF and 30 parts of SMEDDS(ii). Triangles correspond to 10% NP ²diluted in a ²carrier oil (ethyl caprate) only.²Fig. 10 shows the plasma concentration of ibuprofen in male Sprague-Dawley ²rats after an²oral dose of 25 mg / kg ibuprofen. Circles correspond to the ibuprofen ²formulated in the²SMEDDS composition of Example 5. Triangles correspond to ibuprofen formulated ²as a ²suspension (control or reference case) in 0.1% (w / v) of sodium carboxymethyl ²cellulose ²solution. The dashed line corresponds to the first order and single ²compartment ²pharmacokinetic model fit of the SMEDDS plasma concentration data. The solid ²line²represents the first order and single compartment pharmacokinetic model fit of ²the plasma²concentration data obtained with the control case.²Fig. 11 shows the elastic (G') and shear (G") moduli obtained during the ²heating cycle ²experiments for a gelled SMEDDS prepared with equal parts of Lecithin-HL ²mixture and ²ethyl caprate and containing 5 wt% nonylphenol and 10 wt% HSA gelator. The ²Lecithin-²HL mixture contained (10 parts) lecithin and extreme hydrophilic linker ²Polyaldo010-1-²<DP=18>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²18²CC (90 parts). Rheological measurements were conducted using a heating rate of ²0.8² C / min, 10 rad / s, and 0.1% strain.²Fig. 12 shows the release of nonylphenol into FeSSIF as a function of the ²square root of ²release time from a gelled SMEDDS prepared with equal parts of Lecithin-HL ²mixture²and ethyl caprate and containing 5 wt% nonylphenol and 10 wt% HSA gelator. The ²²Lecithin-HL mixture contained (10 parts) lecithin and extreme hydrophilic ²linker ²Polyaldo010-1-CC (Cc=-7.4) (90 parts).²Fig. 13 shows the elastic (G') and shear (G") moduli obtained during the ²heating cycle ²experiments for a gelled SMEDDS prepared with equal parts of Lecithin-HL ²mixture and²ethyl caprate and containing 5 wt% nonylphenol and 18 wt% (squares) and 20 wt% ²²(circles) of a 1:1 weight ratio mixture of 13-sitosterol + y-oryzanol used as ²the gelator ²mixture. The Lecithin-HL mixture contained (10 parts) lecithin and extreme ²hydrophilic ²linker Polyaldo010-1-CC (90 parts). Rheological measurements were conducted ²using a ²heating rate of 0.8 C / min, 10 rad / s, and 0.1% strain.²Fig. 14 shows the release of nonylphenol into FeSSIF as a function of the ²square root of ²release time from a gelled SMEDDS prepared with equal parts of Lecithin-HL ²mixture ²and ethyl caprate, and containing 5 wt% nonylphenol and 18 wt% (squares) and ²20 wt% ²(circles) of a 1:1 weight ratio mixture of 13-sitosterol + y-oryzanol used as ²the gelator ²mixture. The Lecithin-HL mixture contained (10 parts) lecithin and extreme ²hydrophilic² linker Polyaldo010-1-CC (90 parts).²Fig. 15.A shows the particle size distribution and angle of repose for the ²encapsulated D60 ²SMEDDS prepared with 10 parts (by mass) of lecithin and 90 parts Polyaldo010-1-²CC ²(Cc=-7.4) using limonene as a carrier oil and containing 5% nonylphenol. ²Encapsulation ²was obtained via spray drying of 60 parts (by mass) of EUDRAGUARDO (natural ²non-²enteric coating agent) and 40 parts of the D60 SMEDDS.²Fig. 15.B shows the particle size distribution and angle of repose for the ²encapsulated D60 ²SMEDDS prepared with 10 parts (by mass) of lecithin and 90 parts Polyaldo010-1-²CC ²(Cc=-7.4) using limonene as a carrier oil and containing 5% nonylphenol. ²Encapsulation ²was obtained via spray drying of 60 parts (by mass) of EUDRAGITO FL 30 D-55 ²(enteric²coating agent) and 40 parts of the D60 SMEDDS.²<DP=19>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²19²Fig. 15C shows the particle size distribution and angle of repose for the ²encapsulated D60 ²SMEDDS prepared with 10 parts (by mass) of lecithin and 90 parts Polyaldo010-1-²CC ²(Cc=-7.4) using limonene as a carrier oil and containing 5% nonylphenol. ²Encapsulation ²was obtained via spray drying of 60 parts (by mass) of PROTECTTm ENTERIC ²(enteric² coating agent) and 40 parts of the D60 SMEDDS.²Fig. 16 shows the plasma concentration of CBD in male Sprague-Dawley rats ²after an oral ²dose of 10 mg / kg CBD. Circles correspond to the CBD formulated in the 20% CBD-²D70 ²SMEDDS composition of Example 16. Triangles correspond to the control case of ²CBD ²formulated as a 9.6 mg / ml solution in medium chain triglycerides (MCT). The ²squares²correspond to the CBD formulated in encapsulated (powder) 20%CBD-D70 SMEDDS²composition of Example 16.²In the drawings, one embodiment of the invention is illustrated by way of ²example. It is ²to be expressly understood that the description and drawings are only for the ²purpose of ²illustration and as an aid to understanding and are not intended as a ²definition of the limits²of the invention.²DETAILED DESCRIPTION OF THE INVENTION ²Unless defined otherwise, all technical and scientific terms used herein have ²the same ²meanings as commonly understood by one of ordinary skill in the art to which ²this ²disclosure belongs. Although any methods and materials similar or equivalent ²to those²described herein can be used in the practice or testing of the present ²disclosure, the²preferred methods, devices and materials are now described. All technical and ²patent ²publications cited herein are incorporated herein by reference in their ²entirety. Nothing ²herein is to be construed as an admission that the disclosure is not entitled ²to antedate such ²disclosure by virtue of prior disclosure.²All numerical designations, e.g., Characteristic curvature (Cc), pH, ²temperature, time,²concentration and molecular weight, including ranges, are approximations which ²are ²varied ( + ) or ( -) by increments of 1.0 or 0.1, as appropriate, or ²alternatively by a variation ²of + / - 20%, + / - 15 %, or alternatively + / - 10%, or alternatively + / - 5% or ²alternatively + / -²2%. It is to be understood, although not always explicitly stated, that all ²numerical²designations are preceded by the term "about". It also is to be understood, ²although not²<DP=20>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²always explicitly stated, that the reagents described herein are merely ²exemplary and that²equivalents of such are known in the art.²As used in the specification and claims, the singular form "a", "an" and "the" ²include ²plural references unless the context clearly dictates otherwise. For example, ²the term "a² 5 compound" includes a plurality of compounds, including mixtures thereof²As used herein, the term "comprising" is intended to mean that the ²compositions and ²methods include the recited elements, but do not exclude others. "Consisting ²essentially ²of' when used to define compositions and methods, shall mean excluding other ²elements ²of any essential significance to the combination for the intended use. Thus, a ²composition²10 consisting essentially of the elements as defined herein would not ²exclude trace²contaminants from the isolation and purification method and pharmaceutically ²acceptable ²carriers, such as phosphate buffered saline, preservatives and the like. ²"Consisting of' ²shall mean excluding more than trace elements of other ingredients and ²substantial method ²steps for administering the compositions of this disclosure. Embodiments ²defined by each²15 of these transition terms are within the scope of this disclosure.²In this document, the term self-microemulsifying drug delivery system (SMEDDS) ²is ²defined as a system that, upon dilution with an aqueous solution or phase, ²form ²microemulsions with sizes often ranging in the 1-200 nm range.²In this document, the term "fully dilutable SMEDDS" is defined as a system ²that, upon²20 dilution with an aqueous solution or phase, would produce a single-phase ²microemulsion²(pE), without excess phases (no liquid phase separation), no formation of ²precipitate and ²avoiding viscous (more than 1000 cP) liquid crystals, regardless of the ²aqueous solution ²content (from 0 / 100 of aqueous solution / SMEDDS to 99.99 / 0.001 of aqueous ²solution / SMEDDS).²The present disclosure relates to fully-dilutable SMEDDS compositions used to ²solubilize²and deliver poorly water-soluble polar active ingredients via topical, ²transdermal, oral, ²transnasal, buccal, vaginal, subcutaneous, parenteral and ophthalmic routes, ²transepidermal delivery in plants and soft-bodied insects, and transmembrane ²delivery in ²microorganisms. The fully-dilutable characteristic of the SMEDDS presented ²herein is not²disrupted by the addition of poorly water-soluble polar active compounds such ²as²<DP=21>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²21²ibuprofen, cannabidiol, nonylphenol, eugenol and so forth. That is, the ²introduction of a²polar oil does not induce a phase inversion of the surfactant into the oil.²In aspects, the fully-dilutable SMEDDS of the present disclosure comprises: ²(a) a lecithin ²compound; (b) a hydrophilic linker (HL) or a combination of two or more ²hydrophilic²linkers (HLs), the HL or each of the HLs in the combination having one ²hydrocarbon group²with at least 50% or more alkyl chain distribution between 6 to 10 carbon ²atoms and the ²HL or the combination of two or more HLs having a Cc of about -5 or more ²negative than ²about -5; and (c) a carrier oil. For clarity, in the case of a combination of ²two or more ²HLs, the combination has a Cc of about -5 or more negative of -5. In aspects, ²the fully-²dilutable SMEDDS further comprises the poorly water-soluble polar active ²ingredient (one²or more than one active ingredient may be included). In aspects, the fully ²dilutable ²SMEDDS comprises between 30 parts of a mixture of the lecithin and hydrophilic ²linker ²and 70 parts of the carrier oil (D30) and 90 parts of the mixture of lecithin ²and hydrophilic ²linker and 10 parts of the carrier oil (D90). In aspects, the fully dilutable ²in aqueous phase²SMEDDS comprises between 40 parts of a mixture of the lecithin and hydrophilic ²linker²and 60 parts of the carrier oil (D40) and 80 parts of the mixture of lecithin ²and hydrophilic ²linker and 20 parts of the carrier oil (D80). In aspects, the fully dilutable ²in aqueous phase ²SMEDDS is D30, D35, D40, D45, D50, D55, D60, D65, D70, D75, D80, D85, D90 or ²D95.²Defatted plant-based lecithin is combined with a special class of C6-C10 ²hydrophilic linker²having an extreme hydrophilic nature, quantified by a characteristic curvature ²(Cc) being ²more negative than about -5 to produce the desired SMEDDS. The Cc ²specification for the ²hydrophilic linker was found to be surprisingly necessary as two hydrophilic ²linker ²products with the same nominal structure can have highly different Cc values. ²Another²unexpected feature of the SMEDDS containing a polar oil active ingredient of ²the present²disclosure is that they do not require (i.e., optional) the addition of a C10+ ²lipophilic linker ²to prevent the formation of lecithin liquid crystals with viscosities greater ²than 1000 cP, ²surfactant precipitation or gel formation as previously reported by Nouraei ²and Acosta ²

[21] . Abdelkader et al. indicate the need to use glycerol monooleate (in the ²PECEOL²product), which has been used as lipophilic linker, at a ratio of at least 1 ²part of PECEOL / 1²part of lecithin to minimize the formation of insoluble phases

[25] . The ²SMEDDS ²compositions disclosed herein do not require the inclusion of PECEOL or any ²lipophilic ²linker to avoid the formation of insoluble phases or slowly dissolving SMEDDS. ²The²<DP=22>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²22²disclosed compositions comprise at least one part (by mass) of the extreme ²hydrophilic ²linker (Cc more negative than -5) for 1 part of lecithin. In aspects, the ²composition of the ²present disclosure comprises anywhere from one part (by mass) to 20 parts (by ²mass) of ²the extreme hydrophilic linker per one part (by mass) of lecithin. In aspects, ²the²composition of the present disclosure comprises one part (by mass) of lecithin ²to 1, 2, 3,²4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 parts (by mass) ²of the extreme ²hydrophilic linker. In aspects, the composition of the present disclosure ²comprises no ²more than 20 parts (by mass) of the extreme hydrophilic linker to one part (by ²mass) of ²lecithin. Compositions of more than 20 parts of the extreme hydrophilic linker ²to 1 part of² lecithin have insufficient capacity to solubilize the solvent oil.²The complexity of formulating fully dilutable SMEDDS, even for compositions ²comprising lecithin and extreme hydrophilic linkers, is evidenced in the work ²of Sundar et ²al.

[26] . In that work, mixtures of lecithin, lipophilic linker, and an ²extreme hydrophilic ²linker (Cc=-7.4) combined with hydrocarbons and diluted in water produced ²unstable²emulsions (not microemulsions) with drop sizes ranging from 1 to 100 microns ²(1,000 nm²to 100,000 nm). Sundar et al. used a weight fraction of lecithin + linkers in ²a mixture with ²the oil phase that was less than 10 wt%. As illustrated by the disclosed ²compositions shown ²in the ternary phase diagrams in Figs. 5, 6, and 7, the weight fraction of ²lecithin + linkers ²in a mixture with a solvent oil required to produce microemulsions upon ²dilutions with²aqueous solutions is very specific. This weight fraction is referred to as the ²dilution line²"D" and often ranging from 30 to 90 wt% (D30 to D90) or from 40 to 80 wt% (D40 ²to ²D80). This range in dilution lines is the dilutability window. Systems with ²too little lecithin ²+ linkers (under D30 or under D40) do not have enough surface-active material ²to ²solubilize all the solvent oil. Systems with too much lecithin + linkers (over ²D90 or over²D80) produce viscous liquid crystals, with viscosities greater than 1000 cP, ²that are not²dilutable within the typical dissolution test benchmark of 60 minutes applied ²to dilutable ²products

[27] . The fully dilutable SMEDDS compositions herein disclosed ²produce single ²phases upon dilution with aqueous solutions (free or optional of aqueous co-²solvents such ²as alcohols, glycerols or glycols) within 60 minutes of dilution and with ²minimal agitation² (manual test tube rotation at 60 rotations / minute, for 5 minutes).²The SMEDDS compositions of lecithin with extreme hydrophilic linkers (Cc more ²negative than -5) containing polar oils were found to be fully dilutable in ²aqueous fed-state ²simulated intestinal fluid (FeSSIF or SIF), used as an example of a biological ²fluid. For²<DP=23>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²23²dilutions containing between 20% and 80% of the aqueous phase (relevant to ²topical, ²transdermal, transnasal, buccal, vaginal and subcutaneous routes), the drop ²size of the ²system, measured via dynamic light scattering, was smaller than 10 nm. At ²dilutions ²between 80 to 99% aqueous phase, the size could grow up to 100 nm. Drop sizes ²of 10 nm²and smaller are desirable for penetration through epidermal tissue and ²membranes [2].²However, even drops of 200 nm are still desirable for improved epithelial ²tissue uptake in ²drug delivery applications, including oral delivery [5].²Lecithin²The formulation of lecithin linker microemulsions requires the use of a ²lecithin as a²surfactant in the SMEDDS. A desirable feature of lecithin-based SMEDDS is that ²lecithin²has generally recognized as safe (GRAS) status for food and pharmaceutical ²use. The term ²lecithin (including lysolecithin) refers to compounds or mixtures of ²phosphatidylcholines ²and other lipids and containing at least 50% w / w of a mixture of mono- and di- ²alkyl²phosphatidylcholines, phosphatidylethanolamines, ²phosphatidylinositols and²phosphatidylglycerols that can be obtained from animal (e.g., eggs), vegetable ²(e.g.,²soybean) sources or obtained through chemical synthesis. Preferred ²compositions are ²comprised of lecithin obtained from vegetable sources. Considering the minimum ²1 / 20 ²lecithin to extreme hydrophilic linker ratio and the minimum D30 line, then ²the minimum ²lecithin content in the disclosed SMEDDS compositions is 1.5 wt%. Considering ²the²maximum lecithin / extreme hydrophilic linker ratio of 1 / 1 and a maximum D90 ²line, then²the maximum lecithin content in the disclosed SMEDDS is 45 wt%. Similarly, the ²²minimum extreme hydrophilic linker content in lipophilic linker-free ²compositions is 10 ²wt%, and the maximum extreme hydrophilic linker content is 86 wt%. The term ²"lecithin" ²also includes synthetic-based phospholipid compounds. Non-limiting examples of²synthetic-based phospholipid compounds that can be used as the surfactant in ²the²SMEDDS includes stearamidopropyl PG-Dimonium Chloride Phosphate (and) Cetyl ²Alcohol. ArlasilkTM Phospholipid SV by Croda.²Extreme Hydrophilic Linkers²The hydrophilic linkers used in this disclosure are amphiphilic, surfactant-²like compounds²containing 6 to 10 carbon atoms in their alkyl group and a Cc of about (i.e., ²+ / - 20%) -5 or²more negative than about -5. Hydrophilic linkers used in the systems of the ²present²<DP=24>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²24²disclosure are also referred to as extreme hydrophilic linkers. Hydrophilic ²linkers also ²include a mixture of compounds with the main (50% or more) alkyl chain ²distribution in ²between C6-C10 and the Cc of the combined mixture being about -5 or more ²negative than ²about -5. That is, the extreme hydrophilic linker can be combined with other ²extreme HLs²or with a conventional hydrophilic linker (i.e., having a Cc less negative ²than -5 + / - 20%)²to form a mixture, provided that the Cc of the mixture is about -5 or more ²negative than - ²5. For example, a mixture of compounds with the main (50% or more) alkyl chain ²²distribution between C6-C10 having a combined Cc of -4.75 is an extreme ²hydrophilic ²linker. The hydrophilic group in these linkers can be anionic (sulfates, ²sulfonates,²phosphates, phosphonates, carboxylates, sulfosuccinates) such as octanoates, ²octyl²sulfonates, dibutyl sulfosuccinates; nonionic (carboxylic acids, alpha-hydroxy ²acids, esters ²of polyhydric alcohols, or glucosides, secondary ethoxylated alcohols, ²pyrrolidones) such ²as octanoic acid, 2-hydroxyoctanoic acid, hexyl and octyl polyglucosides, ²octyl ²pyrrolidone; cationic (amines, quaternary ammonium salts, amine oxides) such ²as²octylamine; or zwitterionic (alkyl aminopropionic acids, betaines, ²sulfobetaines,²phosphatidylcholines) such as octyl sulfobetaine, dibutyryl ²phosphatidylcholine, among ²others. Acosta et al. found that the short tail length of hydrophilic linkers, ²ranging between ²6 and 10 carbons, and preferably between 6 and 9 carbons, reduces the ²interfacial rigidity ²of surfactant-oil-water (SOW) systems, including microemulsions, facilitating ²a quick²solubilization process

[28] . While the 6-10 carbon range in hydrophilic ²linkers helps avoid²insoluble gel phases, the lecithin SMEDDS reported by Nouraei and Acosta

[21] ²produced ²with common hydrophilic linkers (Cc less negative than -5) still require the ²co-addition of ²a lipophilic linker to accomplish this feature. On the other hand, extreme ²hydrophilic ²linkers (Cc more negative than -5) can prevent the formation of insoluble ²lecithin phases²(lecithin gels) even without a lipophilic linker. The difference between a ²conventional²hydrophilic linker and an extreme hydrophilic linker is primarily observed via ²Cc values, ²obtained using the reference-test surfactant method of Zarate

[22] . The Cc ²value is linked ²to the structure of the surfactant or linker molecule. Acosta et al. indicate ²that the presence ²of highly hydrophilic groups like ionic sulfate or sulfonate groups or ²numerous hydrogen-²bonding groups produce negative shifts in the value of the Cc

[29] . Extreme ²hydrophilic²linkers contain multiple ionic groups or multiple hydrogen bonding groups in ²their ²headgroup. Sundar et al. reported a C8 extreme hydrophilic linker with a ²polyglycerol ²group containing- on average- 10 glycerol units; this polyglycery1-10-²caprylate has a Cc= ²-7.4 [26,30]. However, the number of charges or hydrogen bonding groups in the ²surfactant²<DP=25>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²headgroup is not a sufficient indicator for an extreme hydrophilic linker. For ²example, ²polyglycerol-6-caprylate produced by one surfactant manufacturer (Dermofeel0 ²G6CY) ²has been reported to have a Cc = -3.0

[30] . In example 1, the Cc determined for ²a ²polyglycerol-6-caprylate produced by a different surfactant manufacturer ²(Caprol0 6GC8)²5 is determined to be Cc= -6.4. Example 3 illustrates that a composition ²comprising²polyglycerol-6-caprylate by Dermofeel0 G6CY is not fully dilutable in the ²presence of ²ibuprofen, a polar oil. Unexpectedly, replacing the polyglycerol-6-caprylate ²Dermofeel0 ²G6CY with a polyglycerol-6-caprylate Caprol0 6GC8 results in a fully-dilutable ²²SMEDDS (see Example 5). Replacing polyglycerol-6-caprylate Dermofeel0 G6CY ²with²10 polyglycerol-10-caprylate, with an extreme negative curvature of -7.4 + / -² 1 (see table 15)²also results in a fully-dilutable SMEDDS (example 4). Disodium C6-C10 ²glutamate is ²another example of an extreme hydrophilic linker.²The definition of an extreme hydrophilic linker, therefore, includes any ²molecule ²containing C6-C10 hydrocarbon chains, with multiple ionic groups (sulfates, ²sulfonates,²15 benzene sulfonates, lignosulfonates, carboxylates, phosphates, ²phosphonates, ²polyphosphates, nitrates, quaternary ammonium groups, carbonates, ²sulfosuccinates, ²glutamates), multiple zwitterionic groups (betaines, phosphatidylcholines, ²peptides, ²polypeptides, hydrolyzed proteins, aminoxides), or multiple neutral hydrogen ²bonding ²groups (polyhydric alcohols, carbohydrate oligomers, polysaccharides, ²polyglycerols,²20 polyglucosides, polyvinyl alcohol) producing a molecule with Cc of about ²-5 or more²negative than about -5. The preferred hydrophilic linkers include polyglycerol ²esters of ²C6-C10 fatty acids, given their food additive status.²As previously described the term "about" as it relates to Cc includes a range ²of + / - 20%. ²Therefore, a Cc of about -5 would include a Cc of -4, -4.1, -4.2, -4.3, -4.4, -²4.5, -4.6, -4.7,² 25 -4.8, -4.9, -5 (i.e., -5 + 20% of -5).²Table 15 lists the Cc of selected biobased surfactants (adapted from [211). ²Lipophilic Linker²The compositions disclosed herein do not require the use of a lipophilic ²linker. Lipophilic ²linkers generally refer to amphiphilic molecules with 11 or more carbon in the ²alkyl chain.²Examples of lipophilic linkers include alcohols such as dodecyl alcohol, oleyl ²alcohol,²cholesterol; fatty acids such as lauric acid, palmitic acid, oleic acid, omega ²6-fatty acids,²<DP=26>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²26²omega 3-fatty acids; fatty acid esters of sorbitol, maltitol, xylitol, ²isomalt, lactitol, ²erythritol, pentaerythritol, glycerol. Lipophilic linkers are reported to ²increase the ²interaction and solubilization capacity of the solvent oil

[21] . In one of the ²embodiments, ²lipophilic linkers are included to improve the solvent oil solubilization ²capacity. The²lipophilic linker to lecithin ratio in the disclosed compositions is 1 / 1. ²Considering the²lipophilic linker / lecithin ratio of 1 / 1, the maximum lecithin / extreme ²hydrophilic linker ²ratio of 1 / 1, and a maximum D90 line, then the maximum lipophilic linker ²content in the ²disclosed SMEDDS is 30 wt%.²Carrier Oil²The solvent or carrier oil facilitates the dissolution of the polar oil solute ²(i.e., the active²ingredient) in the SMEDDS. The presence of solvent oil also hinders the ²formation of ²insoluble or slow-dissolving lecithin SMEDDS. On the other hand, too much ²solvent oil ²creates an emulsified excess oil phase upon the addition of water, which is ²incompatible ²with the idea of a fully dilutable SMEDDS. The ternary phase diagrams ²disclosed herein²show that the SMEDDS dilutability window ranges from D40 (+ / -10) to D80 (+ / -²10).²Therefore, the solvent oil content in the disclosed compositions ranges from ²10 wt% (at ²D90) to 70 wt% (at D30). The carrier oil can be a single solvent or a mixture ²of more than ²one solvent. Preferred solvent (carrier oil) includes alkyl esters of fatty ²acids such as ²isopropyl myristate, ethyl caprate, methyl oleate, ethyl oleate; terpenes such ²as limonene,²pinene; and mixtures of with mono- di ¨ and triglycerides used as cosolvents. ²In some²cases, the solvent oil could be completely or partially substituted by a polar ²oil active, for²example, vitamin E, ethyl esters or polyunsaturated fatty acids, or mixtures ²thereof²Polar Oil Active Compounds²The SMEDDS compositions disclosed herein are specifically designed to deliver ²poorly²soluble (in water) actives with a polar oil character. The limited aqueous ²solubility of these²drugs prevents them from being molecularly dissolved at concentrations ²required to impart ²the desired effect in the aqueous environments of bodily fluids in animals, ²plant and insect ²fluids, or in aqueous environments containing microorganisms. The SMEDDS ²provide ²these drugs with an amphiphilic media that is fully dilutable in aqueous ²environments,²producing microemulsion systems that contain the poorly soluble polar active ²ingredient²in thermodynamic equilibrium. Lecithin-linker microemulsions formulated with²<DP=27>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²27²conventional hydrophilic linkers (Cc less negative than -5) and containing ²poorly soluble ²polar actives, such as beta-sitosterol, have been disclosed [7]. However, ²ternary phase ²diagrams of those compositions reveal that they are not fully dilutable with ²aqueous ²solutions. Instead, the dilution of compositions comprising conventional ²hydrophilic²linkers with intestinal fluid leads to the formation of unstable emulsions (as ²opposed to²thermodynamically stable microemulsions) with drop sizes often ranging from ²200 to 1000 ²nm. The lack of a fully dilutable path for lecithin and conventional ²hydrophilic linkers in ²systems containing a poorly soluble polar oil is also illustrated in Example 3 ²and Fig. 4 for ²a system containing ibuprofen as polar oil. The use of the disclosed ²compositions to²achieve a fully dilutable path with ibuprofen and an extreme hydrophilic ²linker is shown²in Example 4 and Fig. 5.²The special nature of polar oils has only been recently fully quantified using ²the ²hydrophilic-lipophilic-difference (HLD) framework [23,31]. According to that ²quantification, a polar oil can be partly considered to behave as a surfactant ²with positive²characteristic curvature (Cc) and partly as an oil with a negative equivalent ²alkane carbon²number (EACN). A positive Cc or a negative EACN leads to a positive shift in ²HLD, ²which is effectively compensated by the highly negative Cc value of the ²extreme ²hydrophilic linker.²"Poorly soluble oils" are defined as having an aqueous solubility of less than ²1% w / w in²isotonic solutions at room temperature and being soluble in the organic ²(carrier) solvents,²according to US Patent No. 9,918,934. Ghayour and Acosta noted that polar oils ²are a ²broad class of oils consisting of heteroatom-linked polar groups attached to a ²nonpolar ²hydrocarbon group

[23] . The disclosed compositions are comprised of polar oils ²²containing a polar group, having an aqueous solubility lower than 1 wt%, logP ²of 1 or²greater, having hydrogen bonding donors or hydrogen bonding acceptor groups, a ²non-²zero dipole moment or a non-zero polar surface area, and a positive Cc or ²negative EACN, ²determined as per the method of Ghayour and Acosta, using a nonionic ²surfactant as a ²reference surfactant [23,31].²Example 2 illustrates the use of the method of Ghayour and Acosta to determine ²the Cc of²ibuprofen, nonylphenol, eugenol, benzocaine, and cannabidiol (CBD) as example ²polar²oils. Table 1 in Example 2 shows evidence that candidate polar oils with ²logP>l, having ²aqueous solubilities of less than 1 wt%, having non-zero polar areas or dipole ²moments,²<DP=28>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²28²and hydrogen bonding donors or acceptors have a positive Cc value. Example 4 ²and Fig. ²show disclosed compositions for SMEDDS containing ibuprofen. Example 5 and ²Fig. 6 ²show disclosed compositions for SMEDDS containing ibuprofen, extreme ²hydrophilic ²linker and glycerol monooleate (GMO) as a lipophilic linker. Examples 6 and 7 ²show²5 disclosed ²compositions containing nonylphenol as an example of polar oil combined with²an extreme hydrophilic linker. Examples 8 and 9 and Fig. 7 show disclosed ²compositions ²containing cannabidiol (CBD), as example polar oil. Example 12 presents a ²disclosed ²composition containing eugenol as polar oil and an extreme hydrophilic linker.²The polar oil actives can be used in a variety of applications, including but ²not limited to,²nutritional or nutraceutical applications in humans and animals; the delivery ²of²pharmaceutically active ingredients (API), including cannabinoids; as biocides ²or biostatic ²(preservatives) compounds in food, pharmaceutical, cosmetic, antiseptic, ²disinfectant, and ²agrochemical applications. Examples 10, 11 and 16, and Figs. 9, 10 and 16 show ²the ²improved flux and delivery performance in transmembrane and oral delivery ²applications²achieved with the disclosed SMEDDS compositions comprising an extreme ²hydrophilic²linker and a polar oil (nonylphenol shown in Fig. 9, ibuprofen shown in Fig. ²10, and CBD ²in Fig. 16). Example 16 also includes an encapsulated or powder version of the ²SMEDDS ²that provides a fast delivery of CBD, used as an example polar oil²Some polar oils, such as vitamin E and ethyl esters of polyunsaturated fatty ²acids, can also²play the role of lipophilic linkers and oil solvents. The maximum polar oil ²content in a²given composition can be estimated considering a D30 dilution line and a 1:1:1 ²ratio of ²lecithin: extreme hydrophilic linker: lipophilic linker. Under those ²conditions, the ²maximum polar oil content is 80 wt%.²The list of polar oils actives include, but is not limited to halogenated ²compounds such as²fenbuconazole, Prochlorperazine, Triazolam, Fenchlorphos, Diazepam, Lorazepam,²Griseofulvin, Chlorzoxazone, Metazachlor, Metolachlor, Dimethenamid, ²Lufenuron, ²Chlortoluron, Linuron, Metoxuron, Diuron, Diflubenzuron, Fluometuron, ²Chlorbromuron, Cyproconazole, Triticonazole, Triadimefon, Triadimenol, ²Tebuconazole, ²Propiconazole, Epoxiconazole, Prochloraz; long chain alcohols such as ²Lovastatin,²Danazo , Equilin, Equilenin, Danthron, Estriol, alpha-tocopherol, Estradiol, ²Stan lone,²Terfenadine, Dihydroequilenin, Norethisterone, Quinestrol, Quinidine, ²Haloperidol, ²Benperidol, Perphenazine, Simvastatin, Testosterone, Prasterone, ²Methyltestosterone,²<DP=29>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²29²Estrone, Oxazepam, Pentazocin, Betamethasone, Triamcinolone, Dexamethasone, ²Abiraterone, Cortisone, Corticosterone, Prednisolone, Butylparaben, ²Hydrocortisone, ²Phenolphthalein, Quinidine, Quinine, Diosmetin, Propylparaben, prostaglandins, ²²Ethylparaben, Atropine, Hyoscyamine, methylparaben, Butylated hydroxytoluene,²Retinol, eugenol, linalool, Citronellol, terpenols, alkylphenols, para-²aminophenol ²derivatives, terpenephenolics, Cannabidiol, Tetrahydrocannabinol, Cannabinol, ²Cannabigerols, Cannabichromenes; amines such as Clofazimine, Amitriptyline, ²Promethazine, Phenytoin, Tenoxicam, Indapamide, Bumetanide, Carbamazepine, ²Metoclopramide, Butamben, Heptabarbital, Oxamniquine, Reposal, Pentobarbital,²Benzocaine, barbiturates, Phenacetin, Glutethimide, Chlordiazepoxide, ²Disopyramide, ²Simazine (6-chloro-N2,N4-diethyl-1,3,5-triazine-2,4-diamine), Atrazine (6-²chloro-N2-²ethyl-N4-i s opropyl-1,3,5 -tri azine-2,4-di amine), ²Propazine (6-chloro-N,N'-bis(1-²methylethyl)-1,3,5-triazine-2,4-diamine), Prometrine, Desmetrine, Terbutrine; ²acids such ²as Fenbufen, Diclofenac, Sulindac, Indoprofen, Indomethacin, Flufenamic acid, ²Iopanoic²acid, Diflunisal, Naproxen, Ibuprofen, Mefenamic acid, Flurbiprofen, Nalidixic ²acid, ²Ketoprofen, Alclofenac, Diatrizoic acid, Salicylic acid, Aspirin, Benzoic ²acid, anthranilic ²acids, arylpropionic acids, enolic acids, heretoaryl acetic acids, indole and ²indene acetic ²acids, salicylic acid derivatives, nucleic acids, Phenoxyacetic acid, 2,4-²dichlorophenoxyacetic acid, MCPA (2-(2,4-dichlorophenoxy)propanoic acid, 4-²(2,4-²dichlorophenoxy)butanoic acid). The disclosed compositions can be further ²comprised of ²mixtures of two or more polar oils.²The use of biological solutions and water as diluting media is a useful and ²distinctive ²feature of the disclosed formulation. Biologically relevant aqueous solutions ²such as ²FeSSIF, used in all disclosed examples except for Examples 9 and 12, make the ²disclosed²compositions useful in pharmaceutical, cosmetic, food and agrochemical ²products. ²Examples 9 and 10 show that deionized water alone is also a suitable solvent ²for the ²dilution of the disclosed SMEDDS compositions. This is also a desirable ²feature for the ²disclosed SMEDDS, as these SMEDDS could be incorporated into clear liquids ²such as ²bottled or tap water, soft drinks, juices, energy drinks, and alcoholic ²beverages with less²than 20% alcohol. Example 9 shows that intermediate dilutions can produce ²turbidity ²values close to 100 NTU, compatible with the turbidity of many fruit juices ²and milk-²containing products and that at high dilutions (more than 95% aqueous phase), ²this ²turbidity can approach 0 NTU, close to that of clear drinks.²<DP=30>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²The disclosed SMEDDS compositions are water-dilutable, but they do not require ²the ²addition of water. Traces of water in the SMEDDS composition could be present ²due to ²the moisture in lecithin and in extreme hydrophilic linkers resulting from the ²manufacture, ²transport or storage of these ingredients.²5 An unexpected feature of the disclosed compositions is that introducing a ²relatively high²concentration of polar oils, of 5wt % or more in the SMEDDS, that serve as low ²molecular ²weight organogelators, can induce the formation of self-dispersing gels whose ²rate of ²dispersion can be controlled by the type and concentration of the ²organogelator. Polar oils ²that serve as low molecular weight organogelators include C12+ long-chain ²fatty acids²10 such as 12-hydroxystearic acid (12-HSA) and stearic acid; long-chain ²fatty acid esters of²polyhydric alcohols such as sorbitol monostearate (Span 60); long-chain amines ²such as ²Octadecanamide and (R)-12-hydroxyoctadecanamide; and sterol-based ²organogelators ²such as cholesterol, beta-sitosterol, gamma-oryzanol, and mixtures thereof²Example 13 discloses a D60 SMEDDS composition containing nonylphenol as model ²oil²15 and 10% 12-HAS as organogelator. The rheological data for this gelled ²SMEDDS, shown²in Fig. 11, indicates that this composition retains a gel-like structure until ²30 C. When ²this gel was immersed in FeSSIF, the SMEDDS was fully diluted in the FeSSIF ²media. ²However, this release was not immediate (within 15 minutes) as it would ²normally happen ²in a SMEDDS dilution test. Instead, as evidenced in Fig. 12, a complete ²release took nearly²20 one day. A slow-release is a desirable feature for SMEDDS compositions ²when the active²ingredient is present in SMEDDS at high concentrations and whose immediate ²release ²could create undesirable side effects or unnecessary high concentrations of ²the active ²ingredient. A slow-release is also desirable to avoid frequent dosing, ²particularly when the ²dosing protocol requires complicated procedures such as subcutaneous ²injections or the² 25 surgical implantation of delivery devices.²Example 14 presents another composition of gelled-SMEDDS, using a mixture of ²beta-²sitosterol and gamma-oryzanol as organogelators and nonylphenol as model polar ²oil. Two ²concentrations of the mixture of organogelators were tested, 18 wt% and 20 ²wt%. The ²rheological properties for these systems are shown in Fig. 13, where the ²melting point for²30 the 18 wt% organogelator system was found to be 28 C, and the melting ²point for the 20²wt% system was approximately 43 C. The release of the SMEDDS in these two ²organogel²<DP=31>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²31²systems is presented in Fig. 14, where complete release from the 18 wt% system ²is²expected after 12 days, and for the 20 wt % system is expected after 27 days.²The compositions disclosed in Examples 13 and 14 evidenced the tunable nature ²of the ²release profile, from hours to nearly a month, by adjusting the selection of ²the² organogelator and its concentration in the SMEDDS composition.²The SMEDDS containing the polar oils of the present disclosure may be ²administered in ²the form of a tablet, granules, pellets or other multiparticulates, capsules, ²minitablets, ²beads, and as a powder, or any other suitable dosage form.²In another embodiment, solid encapsulated lecithin-linker SMEDDS containing ²polar oils²are produced by combining the disclosed lecithin-linker SMEDDS containing ²polar oils²with amphiphilic polymeric encapsulants having a glass transition temperature ²of less than ²100 C. Having polymers with a low glass transition temperature, less than 100 ²C, allows ²for the spray drying encapsulation process at temperatures below 100 C. These ²low ²temperatures prevent the flash evaporation of the aqueous spray media, leading ²to more²homogenous coating and the prevention of hot spots that could impact the ²quality of heat-²sensitive polar oil solutes. The disclosed compositions could include ²polyacrylates or ²acrylate copolymers containing C2+ pendant hydrophobic groups that lend an ²amphiphilic ²nature to the polymer. The encapsulating polymer can also be obtained from ²natural ²sources such as shellac, a polyester resin of polyhydroxy carboxylic acids, ²and²hydrophobically modified starches such as acetylated starches.²Example 15 discloses three encapsulated SMEDDS compositions, the first ²composition ²comprising a non-enteric polymer, EUDRAGUARDO (acetylated starch E1420), the ²second composition comprising an enteric EUDRAGIT L30 D-55 (methacrylic acid ²and ²ethyl acrylate copolymer), and the third composition comprising a PROTECTTm²ENTERIC (shellac + sodium alginate) coating. The SMEDDS formulations contained ²²nonylphenol as model polar oil. All the compositions were produced using a 40% ²²SMEDDS loading, and feed spray drier temperatures of 70 C. All three ²encapsulated ²SMEDDS released more than half of the polar oil within one hour of exposure to ²FeS SIF. ²In acidic media, typical of gastric conditions, the encapsulating media ²hindered or²preventing the release of the encapsulated SMEDDS. This pH-controlled release ²is useful²to prevent the release of the polar oil solute in the stomach, which is a ²desirable feature in²<DP=32>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²32²delivering active ingredients that can affect the lining of the stomach. The ²solids produced ²by the encapsulation process yielded flowable powders with resting angles near ²30 , and ²particles ranging from 2 to 10 microns that make the powders amenable to ²integration into ²solid products, including flour, baked products, spices, and products ²compressed into² pellets or tablet pills.²The following examples are intended to illustrate, but not limit the ²disclosure.²EXAMPLES ²Example 1. Determination of the characteristic curvature (Cc) for extreme ²hydrophilic ²linker Caprol0 6GC8 (polyglycerol-6-caprylate) ²The characteristic curvature (Cc) of the candidate hydrophilic linker with ²extremely²negative Cc (Cc< -5) was determined following the mixed reference and test ²surfactant ²method used by Zarate et al.

[22] . In short, the test surfactant Caprol0 6GC8 ²(polyglycerol-6-caprylate, molecular weight = 593 g / mol) was mixed with a ²reference ²surfactant, Dehydol OD50 (C9E5, molecular weight = 346 g / mol) with a ²calibrated Cc of²- 1.6 for a 10 wt% total surfactant concentration in the aqueous phase. For ²each mixture of²Caprol0 6GC8 and the reference C9E5, the total surfactant concentration in the ²aqueous ²phase was maintained at 10 wt%. The salinity phase scans were conducted by ²vortex-²mixing 2 mL of the aqueous surfactant solution, containing a set value of ²sodium chloride ²(g NaCl / 100 mL of aqueous surfactant solution or %w / v NaCl) with 2 mL of n-²heptane at²room temperature in 2-dram vials sealed with a silicone-lined cap. The vials ²were mixed²for 30 seconds twice a day for three days and then left to separate ²(equilibrate) for two ²weeks before reading the phase volumes of excess oil and water for systems ²that formed ²middle phase microemulsions. The difference between the initial volume added ²to the vial ²(2 mL), and the excess phase volume was considered the volume solubilized. The ²ratio²between the volume solubilized (in mL) and the total mass of surfactant ²mixture (0.2 g)²was reported as the solubilization parameter (SP) for the given phase at the ²set salinity. ²The graph of solubilization parameter for excess oil and water as a function ²of salinity was ²used to determine the optimal salinity (S*) of the system, where the SP for ²oil and water ²is the same

[22] . Fig. 2A presents an example of the salinity phase scan SP ²curve for a²system containing 20 parts (by mass) of the test surfactant Caprol0 6GC8 and ²80 parts (by²mass) of the reference surfactant C9E5.²<DP=33>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²33²Salinity scans for mixtures of Caprol0 6GC8: C9E5 were conducted for mass ²ratios 10:90, ²20:80, 30:70, 40:60 and 50:50. The optimal salinity (S*) for every ratio was ²determined ²versus the molar fraction of test surfactant Caprol0 6GC8, and graphed as ²shown in Fig. ²2B to determine the slope of the linear regression (dS* / dx = 40.4 %NaC1), and ²determine² the Cc of the test surfactant, according to Zarate

[22] :²Cc test surfactant = Cc reference surfactant -1).(dS* / dx) (2)²Using the value of b= 0.12 (%NaC1A-1) for C9E5, according to Zarate et al. ²

[22] , then Cc ²Capro106GC8 = -1.6 -0.12(%NaC1A-1).(40.4% NaCl) = -6.4. This result highlights ²that, ²surprisingly, the nominal structure of a surfactant is not enough to indicate ²its characteristic²curvature, considering that Dermofeel0 G6CY, another polyglycerol-6-caprylate, ²has²been found to have a Cc = -3 by Nouraei and Acosta

[21] who used the same ²methodology ²for Cc measurement. The reason for the large difference in Cc between Caprol0 ²6GC8 ²and Dermofeel0 G6CY is unclear, but it is likely linked to the geometrical ²configuration ²of the headgroup, a factor not considered when citing a given surfactant or ²hydrophilic²linker structure

[32] . Another outstanding feature of Capro106GC8 having a Cc ²value of²-6.4 is that there is only one additional hydrophilic linker reported in the ²literature with ²extreme negative curvature (Cc<-5), the polyglycerol-10-caprylate Polyaldo010-²1-CC, ²with Cc =-7.4

[30] .²Example 2. Determination of the characteristic curvature (Cc) for poorly water-²soluble ² polar active ingredients. ²The definition of a poorly water-soluble active compounds having an aqueous ²solubility ²lower than 1 wt% in deionized water at room temperature follows that of US ²Patent No. ²9,918,934. The definition of the polar nature of the active ingredient follows ²that of ²Ghayour and Acosta

[23] , where the polar oil at low concentrations, typically ²less than²30% in the system, behaves as a surfactant with a characteristic curvature ²determined via²Equation 2, using the same salinity phase scan methodology described in ²Example 1. The ²Cc value reported for these polar oils is expected to be positive when using ²the procedure ²described in Example 1. Table 1 presents the dS* / dx values from Fig. 3 for the ²example ²polar oil active ingredients, ibuprofen (molecular weight 206 g / mol, Sigma-²Aldrich²ReagentPlus0, 99%), nonylphenol (molecular weight 220 g / mol, Sigma-Aldrich ²technical²grade), cannabidiol (CBD, molecular weight 314 g / mol, The Valens Company, ²96.3%),²<DP=34>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²34²eugenol in clove oil (molecular weight 164 g / mol, NOW essentials, technical ²grade), and ²benzocaine (molecular weight 165 g / mol, Sigma-Aldrich 99%). As indicated by ²the values ²in Table 1, key factors required for the active are low water solubility ²(lower than 1 wt%), ²a relatively high logP (higher than 1), a non-zero dipole moment, and the ²presence of²hydrogen bonding groups. These characteristics are likely to result in ²positive²characteristic curvatures (Cc) typical of polar oils, as confirmed by the ²values in Table 1.²Table 1. Properties and calculated characteristic curvature of example poorly ²water-²soluble active ingredients for fully-dilutable lecithin-based SMEDDS. The ²aqueous ²solubility, the negative logarithm of the dissociation constant (pKa), the ²logarithm of the²octanol-water partition constant (logP) and the number of hydrogen (H) bonding ²donor²and acceptor groups were obtained from the Drugbank database for ibuprofen, ²eugenol, ²benzocaine and cannabidiol. For nonylphenol, the information was obtained from ²the ²ChemSpider database, which was also used to obtain all polar areas. Dipole ²moments ²obtained from Tantishaiyakul et al.

[33] . The values of dS* / dx from Fig. 3 and ²Cc were²obtained using the methodology of Example 1, with C9E5 as reference ²surfactant.²Property Ibuprofen Nonylphenol Eugenol Benz o caine C ²annabidiol²(C BD)²Molecular weight 206 220 164 165 314²(g / mol)²Aqueous solubility 0.0021 0.0007 0.14 0.13 0.0013²( wt%)²pKa 5.3 Neutral Neutral 2.51 Neutral²logP 3.8 5.8 2.7 1.9 6.1²Dipole moment (Debye) 1.9 1.6 2.8 3.9 1.9²Polar area (A2) 37 20 29 52 40²Number of H-donors 1 1 1 2 2²Number of H-acceptors 2 2 2 3 2²dS* / dx (%w / v NaCl) -54 -73 -37 -27 -38²Cc +4.9 +7.2 +2.8 +1.6 +2.6²Example 3. Ibuprofen in SMEDDS with conventional hydrophilic linker (Cc=-3) ²In these formulations, soybean-extracted lecithin with Cc= 5.5 was used as the ²principal ²surfactant to produce the SMEDDS formulation. The hydrophilic linker used was ²a²conventional hydrophilic linker, polyglycerol-6-caprylate, product name ²Dermofeel0²G6CY, with Cc =-3.0. The lipophilic linker used was glycerol monooleate, ²product name ²PeceolTM with Cc= 6.6. The carrier (solvent) oil phase was ethyl caprate with²<DP=35>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²EACN= 5.1. The SMEDDS was produced by first mixing 10 parts (by mass) of ²Lecithin ²with 10 parts of the lipophilic linker PeceolTM and 80 parts of the ²hydrophilic linker ²Dermofeel0 G6CY using a vortex-mixer. A prescribed ratio of 25 parts (by mass) ²of ethyl ²caprate (carrier oil) and 75 parts of the Lecithin + linkers mixture was then ²mixed using a²5 vortex-²mixer. 95 parts (by mass) of the resulting mixture were then mixed with 5 ²parts of²ibuprofen powder. The mixture was then vortex-mixed until no residual solids ²were ²observed in the liquid solution. The resulting solution was then diluted with ²fed-state ²simulated intestinal fluid (FeSSIF) at wt% ranging from 10 to 90. The diluted ²systems ²were vortex-mixed and then left to equilibrate for two weeks at room ²temperature before²10 recording ²any phase separation. Phase separation was recorded based on visual ²observation²of a separate layer of excess oil or water or the presence of drops visible to ²the naked eye ²(- 1 micron or larger).²Table 2. Composition, and number of phases obtained upon FeSSIF dilution of ²the ²lecithin-based SMEDDS disclosed by Nouraei and Acosta

[21] containing 5% ²ibuprofen²15 as example ²of polar active. Columns (a) through (f) represent the weight percentage of ²(a)²lecithin; (b) lipophilic linker, glycerol monooleate (PeceolTm); (c) ²hydrophilic linker ²polyglycerol-6-caprylate Dermofeel0 G6CY (Cc = -3.0); (d) Fed-state simulated ²intestinal ²fluid (FeSSIF) containing 0.57% w / v NaOH, 1.18% w / v NaCl, 0.86% w / v acetic ²acid, ²0.83% w / v sodium taurocholate, and 0.28% w / v lecithin; (e) ibuprofen; (f) is ²the carrier²20 (solvent) ²oil, ethyl caprate. The system corresponds to a dilution line D75, containing ²75²parts of surfactant + linkers mixture for every 25 parts of carrier oil (ethyl ²caprate).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases²SMEDDS 7.13 7.13 57 0 5 23.74 1²10 / 90 6.41 6.41 51.3 10 4.5 21.38 1²20 / 80 5.7 5.7 45.6 20 4 19 1²30 / 70 4.99 4.99 39.9 30 3.5 16.62 1²40 / 60 4.28 4.28 34.2 40 3 14.24 2²50 / 50 3.56 3.56 28.5 50 2.5 11.88 2²60 / 40 2.85 2.85 22.8 60 2 9.5 2²70 / 30 2.14 2.14 17.1 70 1.5 7.12 2²80 / 20 1.43 1.43 11.4 80 1 4.74 2²90 / 10 0.71 0.71 5.7 90 0.5 2.38 2²Additional dilution tests were conducted using dilution lines D10, D20, D30, ²D40, D50, ²D60, D70, D80, and D90. The resulting phases after FeSSIF dilution were then ²recorded²<DP=36>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²36²in the ternary phase of Fig. 4. As indicated by the data in Table 2 and Fig. ²4, the formulation ²with conventional hydrophilic linker Dermofeel0 G6CY (Cc = -3.0) is a SMEDDS ²formulation because it can form microemulsions with the addition of up to 30% ²of the ²aqueous phase (dilution 30 / 70), but it is not a fully-dilutable SMEDDS because ²higher² FeSSIF content produced phase separation.²Example 4. Ibuprofen in fully-dilutable SMEDDS with an extreme hydrophilic ²linker. ²SMEDDS were formulated with soybean-extracted lecithin (Cc=+5.5) as the ²principal ²surfactant, combined with an extreme hydrophilic linker, polyglycerol-10-²caprylate, ²Polyaldo010-1-CC (Cc =-7.4). The formulation was free of a lipophilic linker. ²The solvent²oil phase was ethyl caprate with EACN= 5.1

[21] . The SMEDDS was produced by ²first²mixing 10 parts (by mass) of Lecithin with 90 parts of the hydrophilic linker ²Polyaldo010-²1-CC using a vortex-mixer. A prescribed ratio of 40 parts (by mass) of ethyl ²caprate ²(carrier oil) and 60 parts of the Lecithin + hydrophilic linker mixture was ²then mixed using ²a vortex-mixer. 95 parts (by mass) of the resulting mixture were then mixed ²with 5 parts²of ibuprofen powder. The mixture was then vortex-mixed until no residual ²solids were²observed in the liquid solution. The resulting solution was then diluted with ²fed-state ²simulated intestinal fluid (FeSSIF) at wt% ranging from 10 to 99. The diluted ²systems ²were vortex-mixed and then left to equilibrate for two weeks at room ²temperature before ²recording any phase separation. Phase separation was recorded based on visual ²observation²of a separate layer of excess oil or water or the presence of drops visible to ²the naked eye²(¨ 1 micron or larger). The viscosity of the formulation was determined via A ²Carri-Med ²CSL2 Rheometer (TA Instruments, New Castle, DE, USA) at 25 C, averaging the ²values ²obtained at shear rates ranging from 10 to 100 1 / s. A Brookhaven (Holtsville, ²NY, USA) ²BI90 PLUS Particle Size Analyser was used to measure the drop size of the ²diluted²microemulsions via photocorrelation spectroscopy of a 90 -scattered 635 nm ²laser beam.²The data in Table 3 summarize the observations with the D60 dilution line (60 ²parts ²surfactant mixture, 40 parts carrier oil), indicating that a single-phase ²(full dilutability) was ²obtained with 10% to 99% FeSSIF as the diluting aqueous phase. These results ²illustrate ²the fully-dilutable nature of the SMEDDS produced with the extreme hydrophilic ²linker²Polyaldo010-1-CC (Cc=-7.4). After repeating the dilution experiment for ²dilution lines²D10, D30, D50, D70, and D90, the ternary phase diagram of Fig. 5 was produced. ²As per²the diagram, for dilution lines between D40 to D70, there is a path of full ²dilutability.²<DP=37>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²37²Table 3. Composition, number of phases obtained upon FeSSIF dilution, ²viscosity and ²drop size of lipophilic linker-free, lecithin-based SMEDDS prepared with the ²extreme ²hydrophilic linker Polyaldo010-1-CC and 5% ibuprofen. Columns (a) through (f) ²represent the weight percentage of (a) lecithin; (b) PeceolTM; (c) extreme ²hydrophilic linker²Polyaldo010-1-CC (Cc = -7.4); (d) FeSSIF; (e) ibuprofen; (f) ethyl caprate. ²The system²corresponds to a dilution line D60, containing 60 parts of surfactant + ²hydrophilic linker ²mixture for every 40 parts of carrier oil (ethyl caprate).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Viscosity Size²cP nm²SMEDDS 5.7 0 51.3 0 5 38 1²10 / 90 5.13 0 46.17 10 4.5 34.2 1 100 20 19 2²20 / 80 4.56 0 41.04 20 4 30.4 1 80 20 38 4²30 / 70 3.99 0 35.91 30 3.5 26.6 1 70 10 8 2²40 / 60 3.42 0 30.78 40 3 22.8 1 40 10 2 1²50 / 50 2.85 0 25.65 50 2.5 19 1 30 10 2 1²60 / 40 2.28 0 20.52 60 2 15.2 1 25 5 3 1²70 / 30 1.71 0 15.39 70 1.5 11.4 1 20 5 2 1²80 / 20 1.14 0 10.26 80 1 7.6 1 15 2 14 2²90 / 10 0.57 0 5.13 90 0.5 3.8 1 4 2 21 2²99 / 1 0.057 0 0.513 99 0.05 0.38 1 1 1 110 10²99.9 / 0.1 0.006 0.051 99.9 0.005 0.038 1 1 1 ²50 10²Example 5. Ibuprofen in SMEDDS with lipophilic and extreme hydrophilic linkers ²²Fully-dilutable SMEDDS were formulated with soybean-extracted lecithin ²(Cc=+5.5) as²the principal surfactant, extreme hydrophilic linker, polyglycerol-6-²caprylate, ²Caprol0 6GC8 (Cc =-6.4), and lipophilic linker glycerol monooleate (PeceolTM, ²Cc=+6.6). The carrier (solvent) oil phase was ethyl caprate. The SMEDDS was ²produced ²by first mixing 15 parts (by mass) of Lecithin with 15 parts of the lipophilic ²linker²(PeceolTm) and 70 parts of Caprol0 6GC8 using a vortex-mixer. A prescribed ²ratio of 40²parts (by mass) of ethyl caprate (carrier oil) and 60 parts of the Lecithin + ²linkers mixture ²was then mixed using a vortex-mixer (D60 composition). 95 parts (by mass) of ²the ²resulting mixture were then mixed with 5 parts of ibuprofen powder. The ²mixture was then ²vortex-mixed until no residual solids were observed in the liquid solution. ²The resulting² solution was then diluted with fed-state simulated intestinal fluid (FeSSIF).²<DP=38>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²38²Table 4. Composition, number of phases upon FeSSIF dilution, viscosity, and ²drop size of ²lipophilic linker-free, lecithin-based SMEDDS prepared with the extreme ²hydrophilic ²linker Capro106GC8, lipophilic linker PeceolTM and 5% ibuprofen. Columns (a) ²through ²(f) represent the weight percentage of (a) lecithin; (b) lipophilic linker; ²(c) extreme²hydrophilic linker polyglycerol-6-caprylate Capro106GC8 with Cc = -6.4; (d) ²FeSSIF; (e)²ibuprofen; (f) ethyl caprate. The system corresponds to a dilution line D60, ²containing 60 ²parts of surfactant + hydrophilic linker mixture and 40 parts of carrier oil ²(ethyl caprate).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Viscosity Size²cP nm²SMEDDS 8.6 8.6 39.9 0 5 38 1 N.D. N.D.²10 / 90 7.7 7.7 35.9 10 4.5 34.2 1 170 20 47 10²20 / 80 6.8 6.8 31.9 20 4 30.4 1 85 10 7 1²30 / 70 6.0 6.0 27.9 30 3.5 26.6 1 80 10 7 1²40 / 60 5.1 5.1 23.9 40 3 22.8 1 70 10 4 1²50 / 50 4.3 4.3 20.0 50 2.5 19 1 60 10 3 1²60 / 40 3.4 3.4 16.0 60 2 15.2 1 40 5 6 1²70 / 30 2.6 2.6 12.0 70 1.5 11.4 1 20 5 6 1²80 / 20 1.7 1.7 8.0 80 1 7.6 1 15 2 8 1²90 / 10 0.9 0.9 4.0 90 0.5 3.8 1 4 1 30 3²N. D.: not determined²Additional dilution lines D10, D20, D30, D40, D50, D70, D80 and D90 were also²evaluated using the same procedure used to produce the dilution line D60 ²presented in²Table 4. The results from these studies are summarized in the ternary phase ²diagram of ²Fig. 6. According to the phases outlined in Fig. 6, a full dilutable path was ²obtained ²between D50 and D70.²The composition of Example 3 is similar to that of Example 5, with two ²differences, first²that Example 3 had more hydrophilic linker (80 parts) as compared to Example 5 ²(70²parts). The second difference is that although both examples used a ²hydrophilic linker with ²the nominal structure of polyglycerol-6-caprylate, the Dermofeel0 G6CY product ²used in ²Example 3 had a Cc= -3 and the Capro106GC8 product used in Example 5 was an ²extreme ²hydrophilic linker with Cc=-6.4. While having more hydrophilic linker should ²have helped²Example 3 compensate for the presence of polar active (ibuprofen), it was the ²use of an²extreme hydrophilic linker (Cc more negative than -5) what allowed the ²compositions of ²Example 5 obtain a fully-dilutable path.²<DP=39>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²39²Example 6. Nonylphenol in SMEDDS with extreme hydrophilic linker (Cc=-7.4) ²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of the hydrophilic linker Polyaldo010-1-CC using a vortex-mixer. A prescribed ²ratio of ²40 parts (by mass) of ethyl caprate and 60 parts of the Lecithin + hydrophilic ²linker mixture²was then mixed using a vortex-mixer. 90 parts (by mass) of the resulting ²mixture were²then mixed with 10 parts of nonylphenol used as model polar oil. The resulting ²solution ²was diluted with FeSSIF. The diluted systems were vortex-mixed and then left ²to ²equilibrate for two weeks at room temperature.²Table 5. Composition, number of phases upon FeSSIF dilution, viscosity, and ²drop size of²lipophilic linker-free, lecithin-based SMEDDS prepared with the extreme ²hydrophilic²linker Polyaldo010-1-CC and containing 10% Nonylphenol. Columns (a) through ²(f) are ²weight percentage of (a) lecithin; (b) lipophilic linker; (c) extreme ²hydrophilic linker ²Polyaldo010-1-CC (Cc = -7.4); (d) FeSSIF; (e) nonylphenol; (f) ethyl caprate. ²The system ²corresponds to a dilution line D60, containing 60 parts of surfactant + ²hydrophilic linker² mixture for every 40 parts of carrier oil (ethyl caprate).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ²Viscosity Size²cP nm²SMEDDS 5.4 0.0 48.6 0 10 36 1 N.D. N.D²10 / 90 4.9 0.0 43.7 10 9 32.4 1 90 10 2 1²20 / 80 4.3 0.0 38.9 20 8 28.8 1 60 20 2 1²30 / 70 3.8 0.0 34.0 30 7 25.2 1 70 10 4 1²40 / 60 3.2 0.0 29.2 40 6 21.6 1 30 5 4 1²50 / 50 2.7 0.0 24.3 50 5 18 1 25 5 3 1²60 / 40 2.2 0.0 19.4 60 4 14.4 1 20 2 5 1²70 / 30 1.6 0.0 14.6 70 3 10.8 1 16 2 4 1²80 / 20 1.1 0.0 9.7 80 2 7.2 1 14 2 3 1²90 / 10 0.5 0.0 4.9 90 1 3.6 1 5 2 40 10²99 / 1 0.05 0.00 0.49 99.00 0.10 0.36 1 1 1 ²100 10²The existence of a single-phase throughout the entire dilution of the D60 ²composition in ²Table 5 confirms the fully-dilutable nature of the D60 composition containing ²10% ²nonylphenol. This D60 composition is the same as that used for 5% ibuprofen in ²Example²4, further confirming the suitability of the lipophilic linker-free ²formulations to produce²fully-dilutable formulations with a range of polar actives.²<DP=40>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²Example 7. Nonylphenol in SMEDDS with extreme hydrophilic linker and limonene. ²²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of the hydrophilic linker Polyaldo010-1-CC using a vortex-mixer. A prescribed ²ratio of ²40 parts (by mass) of limonene (racemic mixture, technical grade) and 60 parts ²of the²5 Lecithin + hydrophilic linker mixture was then mixed using a vortex-²mixer. 95 parts (by²mass) of the resulting mixture were then mixed with 5 parts of nonylphenol ²used as model ²polar oil. The resulting solution was diluted with FeSSIF. The diluted systems ²were vortex-²mixed and then left to equilibrate for two weeks at room temperature.²Table 6. Composition, number of phases obtained upon FeSSIF dilution, ²viscosity and²10 drop size of lipophilic linker-free, lecithin-based SMEDDS prepared with ²the extreme²hydrophilic linker Polyaldo010-1-CC and 5% Nonylphenol. Columns (a) through ²(f) are ²weight percentage of (a) lecithin; (b) lipophilic linker; (c) extreme ²hydrophilic linker ²Polyaldo010-1-CC with Cc = -7.4; (d) FeSSIF; (e) nonylphenol; (f) limonene. ²The system ²corresponds to a dilution line D60, containing 60 parts of surfactant + ²hydrophilic linker² 15 .. mixture for every 40 parts of carrier oil (limonene).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Viscosity Size²cP nm²SMEDDS 5.7 0.0 51.3 0 5 38 1 N.D. N.D²10 / 90 5.1 0.0 46.2 10 4.5 34.2 1 240 20 2 1²20 / 80 4.6 0.0 41.0 20 4 30.4 1 170 20 2 1²30 / 70 4.0 0.0 35.9 30 3.5 26.6 1 110 10 3 1²40 / 60 3.4 0.0 30.8 40 3 22.8 1 80 10 5 1²50 / 50 2.9 0.0 25.7 50 2.5 19 1 60 5 8 2²60 / 40 2.3 0.0 20.5 60 2 15.2 1 50 5 6 2²70 / 30 1.7 0.0 15.4 70 1.5 11.4 1 25 2 5 2²80 / 20 1.1 0.0 10.3 80 1 7.6 1 7 2 23 3²90 / 10 0.6 0.0 5.1 90 0.5 3.8 1 2 2 110 20²99 / 1 0.06 0.00 0.51 99.0 0.05 0.38 1 1 1 ²130 20²99.9 / 0.1 0.006 0.000 0.051 99.90 0.005 0.038 1 1 ²1 36 4²The data in Table 6 confirm the fully-dilutable nature of the D60 composition ²containing ²5% nonylphenol and limonene as the carrier or solvent oil. This D60 ²composition is the ²same as that of Example 6 except that ethyl caprate was substituted for a ²terpene, limonene,² 20 exemplifying the variety of carrier (solvent) oils that can be used.²<DP=41>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²41²Example 8. Cannabidiol (CBD) in SMEDDS with an extreme hydrophilic linker. ²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of the hydrophilic linker Polyaldo010-1-CC using a vortex-mixer. A prescribed ²ratio of ²40 parts (by mass) of limonene (racemic mixture, technical grade) and 60 parts ²of the²Lecithin + hydrophilic linker mixture was then mixed using a vortex-mixer. 95 ²parts (by²mass) of the resulting mixture were then mixed with 5 parts of CBD used as ²model polar ²oil. The resulting solution was diluted with FeSSIF. The diluted systems were ²vortex-²mixed and then left to equilibrate for two weeks at room temperature.²Table 7. Composition, number of phases obtained upon FeSSIF dilution, ²viscosity (from²Example 7-same SMEDDS, different drug), and drop size of lipophilic linker-²free, ²lecithin-based SMEDDS prepared with the extreme hydrophilic linker Polyaldo 0 ²1 0-1 -C C ²and 5% CBD. Columns (a) through (f) are weight percentage of (a) lecithin; (b) ²lipophilic ²linker; (c) extreme hydrophilic linker Polyaldo010-1-CC with Cc = -7.4; (d) ²FeSSIF; (e) ²CBD; (f) limonene. The system corresponds to a dilution line D60, containing ²60 parts of²surfactant + hydrophilic linker mixture for every 40 parts of carrier oil ²(limonene).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Viscosity Size²cP nm²SMEDDS 5.7 0.0 51.3 0 5 38 1 N.D. N.D²10 / 90 5.1 0.0 46.2 10 4.5 34.2 1 240 20 3.5 2²20 / 80 4.6 0.0 41.0 20 4 30.4 1 170 20 4.0 2²30 / 70 4.0 0.0 35.9 30 3.5 26.6 1 110 10 1.5 2²40 / 60 3.4 0.0 30.8 40 3 22.8 1 80 10 6.0 2²50 / 50 2.9 0.0 25.7 50 2.5 19 1 60 5 7.5 3²60 / 40 2.3 0.0 20.5 60 2 15.2 1 50 5 3.0 2²70 / 30 1.7 0.0 15.4 70 1.5 11.4 1 25 2 2.5 2²80 / 20 1.1 0.0 10.3 80 1 7.6 1 7 2 35 9²90 / 10 0.6 0.0 5.1 90 0.5 3.8 1 2 2 35 10²95 / 5 0.06 0.00 0.51 99.0 0.05 0.38 1 1 1 ²40 13²99 / 1 0.006 0.000 0.051 99.90 0.005 0.038 1 1 ²1 90 10²Additional dilution lines DO, D10, D20, D30, D40, D50, D70, D80, D90 and D100 ²were ²evaluated; the results from these studies are summarized in the ternary phase ²diagram of ²Fig. 7. According to the phases outlined in Fig. 7, a fully dilutable path was ²obtained² between D45 and D60.²<DP=42>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²42²Example 9. Cannabidiol (CBD) in SMEDDS diluted in distilled water. ²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of hydrophilic linker Polyaldo010-1-CC using a vortex-mixer. A prescribed ²ratio of 30 ²parts of limonene and 70 parts of Lecithin + hydrophilic linker mixture was ²then mixed²using a vortex-mixer. 95 parts (by mass) of the resulting mixture were then ²mixed with 5²parts of CBD used as model polar oil. The resulting solution was diluted with ²distilled ²water. The diluted systems were vortex-mixed and then left to equilibrate for ²two hours at ²room temperature before taking a picture of the system for image analysis.²Table 8. Composition, number of phases obtained upon distilled water dilution, ²light²attenuation coefficient (Kd, In-1) and estimated turbidity (NTU) of lecithin-²based²SMEDDS prepared with the extreme hydrophilic linker Polyaldo010-1-CC and 5% ²CBD. ²Columns (a) through (f) are weight percentage of (a) lecithin; (b) lipophilic ²linker; (c) ²extreme hydrophilic linker Polyaldo010-1-CC with Cc = -7.4; (d) distilled ²water; (e) ²CBD; (f) limonene. The system corresponds to a dilution line D70, containing ²70 parts of²surfactant + hydrophilic linker mixture for every 30 parts of carrier oil ²(limonene).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Kd, m-1 NTU² SMEDDS 6.65 0 59.85 0 5 28.5 1 0 1 0 4²10 / 90 5.99 0 53.87 10 4.5 25.65 1 0 1 0 4²20 / 80 5.32 0 47.88 20 4 22.8 1 3 1 12 4²30 / 70 4.66 0 41.90 30 3.5 19.95 1 0 1 0 4²40 / 60 3.99 0 35.91 40 3 17.1 1 0 1 0 4²50 / 50 3.33 0 29.93 50 2.5 14.25 1 5 1 20 4²60 / 40 2.66 0 23.94 60 2 11.4 1 7 1 28 4²70 / 30 2.00 0 17.96 70 1.5 8.55 1 21 1 84 4²80 / 20 1.33 0 11.97 80 1 5.7 1 27 1 108 4²90 / 10 0.67 0 5.99 90 0.5 2.85 1 12 1 48 4²95 / 5 0.33 0 2.99 95 0.25 1.43 1 16 1 64 4²99.3 / 0.7 0.047 0 0.42 99.3 0.035 0.20 1 1 1 ²4 4²The attenuation, Kd = 1 / light path length*ln(transmittance through ²water / transmittance ²through the sample), was based on transmittance estimated using image-J ²analysis of grey ²levels in the red channel of the test tubes in Fig. 8. The NTU turbidity of ²the samples was²estimated as 4*Kd, based on approximate literature correlations

[34] .²<DP=43>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²43²Example 10. Transdermal permeation of nonylphenol formulated in SMEDDS with ²extreme hydrophilic linker (Cc=-7.4) ²SMEDDS compositions produced without and with a lipophilic linker, containing ²10% ²nonylphenol (NP), used as polar oil homolog for alkyl phenols with logP >5, ²were diluted²with FeSSIF at a dilution ratio of 30 parts of SMEDDS / 70 parts of FeSSIF. An ²aliquot of²400 IA of the diluted SMEDDS was then placed on the donor compartment of a ²MatTek ²Permeation Fixture (EPI-100-FIX). This permeation fixture was used to fasten 8 ²1 mm ²diameter, 800 100 um thickness disks of dermatomed pig ear skin (backside) ²procured ²from a local market. The ears were washed and thawed with running water at ²room²temperature before use. The disks were carefully inspected to discard disks ²with follicular²pores or skin defects. The selected disks were placed with the epidermis ²facing the donor ²compartment of the permeation fixture. Once the diluted SMEDDS was placed in ²the ²donor compartment, the receiver side of the fixture was placed in one of the ²wells of a 6-²well plate and filled with 5 mL of the receiver solution. Care was taken so ²that no bubbles²were trapped between the receiver solution and the disk. The receiver ²consisted of a²phosphate buffer solution with 1.5% of Tween080 used to simulated lipoproteins ²in ²plasma.²The 6-well plate was placed in an incubator shaker with mild agitation at 37 ²C. The ²receiver solution was sampled after 10, 20, 30, 45, 60 minutes, 2, 3, and 4 ²hours. At each²sampling time, the entire volume of the receiver solution was collected and ²replaced with²a fresh receiver solution. For the analysis of the nonylphenol that permeated ²into the ²receiver solution, a 200 uL aliquot of the receiver solution was placed in a ²98 well plate ²for fluorescence intensity measurement (Excitation at 230 nm and emission at ²304 nm). ²The emission signal was compared to a calibration curve (R2=0.9998) produced ²with²standard nonylphenol concentrations in the receiver solution. The ²nonylphenol²concentration in the receiver solution was then used to construct the ²cumulative ²permeation curve presented in Fig. 9. The slopes of the linear trend lines in ²the cumulative ²permeation curves represent the average flux (F) of drug permeated. The ²permeability (k) ²was then calculated as k=F / Ca (neglecting the drug concentration in the ²receiver), where²Ca is the concentration of the drug in the donor solution. Table 9 presents ²the composition²and permeability of the SMEDDS formulation without and with a lipophilic ²linker and a ²nonylphenol solution in ethyl caprate.²<DP=44>²CA 03204168 2023-05-24² WO 2022 / 140843 PCT / CA2021 / 051794²44²As shown by the data in Table 9, the use of SMEDDS(i) produced the largest ²permeability, ²being 6.7 times that obtained with nonylphenol in oil. SMEDDS(ii) produced a ²permeability that was 4.4 times that obtained with nonylphenol in oil. This ²observation ²exemplifies the usefulness of the disclosed SMEDDS formulations in improving ²the²transport of polar actives through epithelial tissue.²Table 9. Composition, number of phases obtained upon FeSSIF dilution, and ²nonylphenol ²transdermal permeability formulated in (i) lipophilic linker-free, lecithin-²based SMEDDS ²prepared with the extreme hydrophilic linker Polyaldo010-1-CC; in (ii) ²lecithin-based ²SMEDDS prepared with the extreme hydrophilic linker Polyaldo010-1-CC and ²lipophilic²linker PeceolTM; and in (iii) ethyl caprate (oil) only. Columns (a) through ²(f) are weight²percentage of (a) lecithin; (b) Peceol0; (c) Polyaldo010-1-CC; (d) FeSSIF; (e) ²²nonylphenol; (f) ethyl caprate. SMEDDS (i) and (ii) systems correspond to a ²dilution line ²D50, containing 50 parts of surfactant + linkers mixture for every 50 parts of ²carrier oil ²(ethyl caprate), and diluted at 70 / 30 ratio with FeSSIF²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ²Permeability²cm / hr²70 / 30 diluted 1.35 0 12.15 70 3 13.5 1 (8 1).10-4²SMEDDS(i)²70 / 30 diluted 2.025 2.025 9.45 70 3 13.5 1 (5.3 ²0.6).10-4²SMEDDS(ii)² Oil(iii) 0 0 0 0 10 90 1 (1.2 0.1).10-4²Example 11. Oral delivery of ibuprofen formulated in SMEDDS with extreme ²hydrophilic ²linker (Cc=-6.4) ²The SMEDDS composition of Example 5, produced with lipophilic linker PeceolO, ²extreme hydrophilic linker Caprol0 6GC8, and containing 5% ibuprofen, was used ²as an²oral delivery system with male Sprague-Dawley rats (350 20 g, supplied by ²Charles²River Laboratories Canada). The rats were acclimatized for a week in a ²temperature-²controlled environment with free access to water and food. Rats were randomly ²assigned ²to two groups (5 animals in each) depending on whether they received ibuprofen ²in ²suspension (control) or in SMEDDS (the composition of Example 5, top row of ²Table 4).²These preparations were administered to animals by oral gavage at a dose of 25 ²mg / kg.²Blood samples (100 pL) were withdrawn through the saphenous vein at 5, 10, 20, ²30, 45, ²60, 90, 120, 240 and 480 minutes after administration and collected in Heparin-²coated ²tubes. The plasma was separated by centrifugation and stored at ¨20 C for ²analysis. For²<DP=45>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²the control group, ibuprofen was suspended in 0.1% (w / v) of sodium ²carboxymethyl²cellulose (Na-CMC) solution using a high shear homogenizer and hand-shaken ²once more ²immediately before use. All the in vivo experiments were conducted according ²to the ²guiding principles in the use of animals, as adopted by the University Animal ²Care² 5 Committee (UACC) of the University of Toronto.²To measure the ibuprofen concentration in plasma, 50 [tI, of plasma samples ²were diluted²with 150 [tI, acetonitrile, then spiked with 50 ²flufenamic acid solution in acetonitrile²as an internal standard. The samples were vortexed, centrifuged, and the ²supernatant was ²filtered using a 0.2 p.m syringe microfilter. Twenty [tI, of the filtrate was ²injected into²10 HPLC. The ratio of ibuprofen AUC to the flufenamic acid AUC was compared ²against a²calibration curve (R2= 0.986) to determine the concentration of ibuprofen.²The plasma concentration curves for the SMEDDS formulation and the control are ²²presented in Fig. 10. Table 10 presents the pharmacokinetic parameters after ²fitting the ²plasma concentration data to a single compartment, first-order model. The ²value of tmax is²15 the time when the plasma concentration reaches its peak (C..). AUC o_sh ²is the area under²the plasma concentration curve, from the time of dosing until 8 hours after ²dosing. The ²value of ka is the first order adsorption constant, and kl0 is the first-order ²elimination ²constant. The data in Table 10 show that, compared to the control, the SMEDDS ²formulation produced a significant increase in C., AUC0-8h, and ka was ²obtained²20 (p<0.05). The SMEDDS produced an increase in AUC (proportional to drug ²uptake) of²3.9 times compared to the control and an increase of 3.5 times in Cm..²Table 10: Pharmacokinetic parameters for orally administered ibuprofen using ²the ²SMEDDS formulation of Example 5 containing 5% ibuprofen and an aqueous ²suspension ²of 5% ibuprofen in 0.1% (w / v) of sodium carboxymethylcellulose solution.²Parameter Unit SMEDDS Control²tmax min 22.1 8.0 42 22²Cmax pg / m1 28.9 3.4 8.2 1.0²AUC 0-8 h p.g / ml*min (7.3 2.2)*103 (1.85 0.79)*103²ka* 1 / min 0.23 0.11 0.08 0.04²km 1 / min 0.004 0.002 0.012 0.012 ²<DP=46>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²46²Example 12. Clove oil (eugenol) in SMEDDS with extreme hydrophilic linker (Cc=-²7.4) ²and diluted with deionized (DI) water ²A fully-dilutable SMEDDS was produced by mixing 10 parts (by mass) of lecithin ²with ²90 parts of the hydrophilic linker Polyaldo010-1-CC using a vortex-mixer. A ²prescribed²ratio of 35 parts (by mass) of ethyl caprate and 65 parts of the lecithin + ²hydrophilic linker²mixture was then mixed using a vortex-mixer. 95 parts (by mass) of the ²resulting mixture ²were then mixed with 5 parts of clove oil (70% eugenol, Cc =+2.8) used as ²model polar ²oil. The resulting solution was diluted with deionized water. The diluted ²systems were ²vortex-mixed and then left to equilibrate for two weeks at room temperature. ²Table 11² summarizes the phase behavior obtained upon dilution with DI water.²Table 11. Composition, number of phases obtained upon water dilution, ²viscosity and drop ²size of lipophilic linker-free, lecithin-based SMEDDS prepared with the ²extreme ²hydrophilic linker Polyaldo010-1-CC, 5% clove oil (eugenol) and diluted with ²deionized ²(DI) water. Columns (a) through (f) are weight percentage of (a) lecithin; (b) ²lipophilic²linker; (c) Polyaldo010-1-CC (d) DI water; (e) clove oil (eugenol); (f) ethyl ²caprate. The²system corresponds to a dilution line D65, containing 65 parts of surfactant + ²hydrophilic ²linker mixture for every 35 parts of carrier oil (ethyl caprate).²Dilution %(a) %(b) %(c) % (d) %(e) %(f) Phases ² Viscosity Size²cP nm² SMEDDS 6.2 0.0 55.6 0 5 33.2 1 N.D²10 / 90 5.6 0.0 50.0 10 4.5 29.9 1 650 50 53 5²20 / 80 4.9 0.0 44.5 20 4 26.6 1 170 20 48 5²30 / 70 4.3 0.0 38.9 30 3.5 23.3 1 130 20 30 4²40 / 60 3.7 0.0 33.3 40 3 20.0 1 120 15 2 1²50 / 50 3.1 0.0 27.8 50 2.5 16.6 1 90 10 2 1²60 / 40 2.5 0.0 22.2 60 2 13.3 1 21 5 2 1²70 / 30 1.9 0.0 16.7 70 1.5 10.0 1 7 2 3 1²80 / 20 1.2 0.0 11.1 80 1 6.7 1 2 2 25 3²90 / 10 0.6 0.0 5.6 90 0.5 3.3 1 1 1 42 3²99 / 1 0.1 0.0 0.6 99 0.05 0.3 1 1 1 28 3²The data in Table 11 confirms the fully-dilutable nature of the D65 ²composition. The table²further confirms that the polar active, eugenol, in clove oil can also have ²solubilities close²to 1 wt% and log P values closer to 1. The example also demonstrates the ²ability to dilute ²the disclosed SMEDDS with pure water.²<DP=47>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²47²Example 13. Nonylphenol in HSA-gelled SMEDDS with an extreme hydrophilic ²linker²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of the hydrophilic linker Polyaldo010-1-CC (Cc=-7.4) using a vortex-mixer. A ²prescribed ²ratio of 40 parts (by mass) of limonene (racemic mixture, technical grade) and ²60 parts of²the Lecithin + hydrophilic linker mixture was then mixed using a vortex-mixer. ²95 parts²(by mass) of the resulting mixture were then mixed with 5 parts of nonylphenol ²used as ²model polar oil. The resulting solution was used as the organic solvent for ²the low ²molecular weight organogelator 12-hydroxystearic acid (12-HSA). The ²organogelator was ²added at 10 wt. % in mixture with the SMEDDS. The mixture was heated in a ²temperature-²controlled water bath to 80 C and then maintained at that temperature until ²the gelator was²fully dissolved in the oil phase, producing a transparent / translucent ²solution. After vortex ²mixing, the samples were cooled down to room temperature, where the system ²solidified ²for 48 hours.²The rheological behavior of the resulting gel was evaluated using a Carri-Med ²CSL2²Rheometer (TA Instruments, USA). A 4-cm stainless steel parallel-plate ²geometry was²attached, and a newly prepared hot melted gel was poured onto the lower ²rheometer plate. ²The lower plate temperature was controlled via Peltier Plate, initially set at ²80 C, then ²cooled down to 20 C in 90 minutes, and then left to rest at 20 C for 90 ²minutes. At that ²point, the oscillatory experiment was commenced, and the sample was heated ²from 20 C²to 80 C at the rate of 0.8 C / min. The oscillatory test was conducted using a ²gap size of²200[tm, maintaining the shear stress (t), shear strain (y) and frequency ²constant at 75Pa, ²0.001 (0.1%) and lOrad / s, respectively. The dynamic moduli G' and G" (Pa) were ²²recorded during the heating cycle as a function of temperature. Fig. 11 ²presents these ²values of elastic (G') and shear (G") moduli for the gelled D60 SMEDDS as a ²function of²temperature. Pure gel behavior (G'>G") was observed when the temperature was ²lower²than 30 C. This example illustrates that, contrary to previous observations in ²the literature, ²it is possible to produce gels with low molecular weight gelators and oils in ²the presence ²of a high concentration of surfactants.²The SMEDDS formulation (Lec: HL 10:90, D60, 5% nonylphenol, 10% 12-HSA) was²used to prepare the drug-loaded gelled SMEDDS. 32 5 mg of melted gel SMEDDS ²was²poured into aluminum pans (6 mm diameter, 2mm height) and let to cool down and ²solidify ²at room temperature for 24 hrs. The disk-shaped gels were then placed in 1-²dram glass²<DP=48>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²48²vials, and 3 mL of FeS SIF was added. The vials were placed into an isothermal ²shaker set ²at 100 rpm and 25 C. At specific time intervals, the aqueous phase of the ²vials was ²removed for analysis and the vials were re-filled with fresh FESSIF. At each ²sampling ²time, the entire volume of the receiver solution was collected and replaced ²with a fresh²receiver solution. For the analysis of the nonylphenol that permeated into the ²receiver²solution, a 200 !IL aliquot of the receiver solution was placed in a 98 well ²plate for ²fluorescence intensity measurement (Excitation at 230 nm and emission at 304 ²nm). The ²emission signal was compared to a calibration curve (R2=0.9998) produced with ²standard ²nonylphenol concentrations in the receiver solution. The concentration of ²nonylphenol in²the receiver solution was then used to construct the cumulative release versus ²the square²root of time, as shown in Fig. 12. The linear trendline in Fig. 12 is typical ²of controlled ²release systems that regulate the release of the active via diffusion. The ²release time can ²be estimated as (1 / slope of trendline)^2, which is 27 hours for the system in ²Fig. 12. In the ²absence of the gelling agent, the release is nearly instantaneous, on the ²scale of seconds to² .. minutes.²Example 14. Nonylphenol in phytosterol-gelled SMEDDS with extreme hydrophilic ²linker²The SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with 90 ²parts ²of the hydrophilic linker Polyaldo010-1-CC (Cc=-7.4) using a vortex-mixer. A ²prescribed ²ratio of 40 parts (by mass) of limonene (racemic mixture, technical grade) and ²60 parts of²the Lecithin + hydrophilic linker mixture was then mixed using a vortex-mixer. ²95 parts²(by mass) of the resulting mixture were then mixed with 5 parts of nonylphenol ²used as ²model polar oil. The resulting solution was used as the organic solvent for ²the low ²molecular weight with a mixture of 18 and 20 wt% of organogelators 13-²sitosterol and y-²oryzanol mixed at a weight ratio of 1:1. The mixture was heated in a ²temperature-²controlled water bath to 90 C and then maintained at that temperature until ²the gelator was²fully dissolved in the oil phase, producing a transparent / translucent ²solution. After vortex ²mixing, the samples were cooled down to room temperature, where the system ²solidified ²for 48 hours.²The rheological behavior of the resulting gel was evaluated using a Carri-Med ²CSL2²Rheometer (TA Instruments, USA) following the methodology indicated in Example ²13.²Fig. 13 presents these values of elastic (G') and shear (G") moduli for the ²gelled D60 ²SMEDDS as a function of temperature. Pure gel behavior (G'>G") was observed ²when the²<DP=49>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²49²temperature was lower than 42 C for the system with 20 wt% gelators and lower ²than 28 C ²for the system with 18 wt% gelators. This example further illustrates the ²production of ²gelled SMEDDS and that the mechanical properties of the gel such as G', G", ²the melting ²temperature can be adjusted using different gelators and their concentration.²32 5 mg of melted gelled SMEDDS formulation (Lec: HL 10:90, D60, 5% ²nonylphenol,²and 18 and 20 wt% organogelator mixture) was poured into aluminum pans and let ²to cool ²down and solidify at room temperature for 24 hrs. The disk-shaped gels were ²then placed ²in 1-dram glass vials, and 3 mL of FeSSIF was added. The vials were placed ²into an ²isothermal shaker set at 100 rpm and 25 C. At specific time intervals, the ²aqueous phase²of the vials was removed for analysis and the vials were re-filled with fresh ²FESSIF. At²each sampling time, the entire volume of the receiver solution was collected ²and replaced ²with a fresh receiver solution. For the analysis of the nonylphenol that ²permeated into the²receiver solution, a 200 ²aliquot of the receiver solution was placed in a 98 well plate²for fluorescence intensity measurement. The nonylphenol concentration in the ²receiver²solution was then used to construct the cumulative release versus the square ²root of time²for the 18 wt% and 20 wt% gelator systems, as shown in Fig. 14. The ²experimental data ²for both systems were fitted with linear trendlines typical of diffusion-²controlled release. ²The release time, estimated as (1 / slope)^2, is 285 hours (12 days) for 18 wt% ²gelators and ²641 hours (27 days) for 20 wt% gelators.² Example 15. Encapsulated SMEDDS with extreme hydrophilic linker²A D55 SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with ²90 parts ²of the hydrophilic linker Polyaldo010-1-CC (Cc=-7.4) using a vortex-mixer. A ²prescribed ²ratio of 45 parts (by mass) of limonene (racemic mixture, technical grade) and ²55 parts of ²the Lecithin + hydrophilic linker mixture was then mixed using a vortex-mixer. ²This D55²SMEDDS was then loaded with 5 wt% nonylphenol used as model polar oil. This ²loaded²SMEDDS composition was then encapsulated with three coating agents, ²EUDRAGUARDO natural non-enteric coating agent; EUDRAGITO FL 30 D-55; and ²PROTECTTm ENTERIC.²To encapsulate the D55 SMEDDS with EUDRAGUARDO (acetylated Starch E1420,²Evonik), 7.5 g of this polymer dissolved in 100 ml of distilled water + 5g of ²D60²SMEDDS, for a final loading of 40% loading in the final solid. 12.5 % total ²core + coat²<DP=50>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²concentration. The mixture was stirred for 1 hr before use. Stirring continued ²during spray²drying.²To encapsulate the D55 SMEDDS with EUDRAGIT L30 D-55 (30% dispersion of ²methacrylic acid and ethyl acrylate copolymer NF, Evonik), 25 mL of the ²polymer²5 suspension (equal to 7.5 g solid materials) were dissolved in 33 ml of ²distilled water + 5g²of SMEDDS, for a final loading of 40% SMEDDS in the final solid. The mixture ²was ²stirred for 1 hr before use. Stirring continued during spray drying.²To encapsulate the D55 SMEDDS with PROTECTTm ENTERIC (shellac + sodium ²alginate, Sensient0 Pharmaceuticals), 2.5 g of Protect Clear SA powder (Na-²alginate),²10 dissolved in 100 ml of distilled water, stir 30 min and then add 18.25 ²mL of polymer²suspension, Protect ENLA (equal to 5.25 g solid materials) + 5g of SMEDDS, for ²a final ²loading of 40% (6:4, polymer: oil). The mixture stirred for 1 hr before use; ²stirring the feed ²continues during spray drying²The suspensions of the D55 SMEDDS and each coating agent were then spray-dried ²using²15 a Model HT-RY 1500 spray dryer (Zhengxhou Hento Michinery Co. Ltd) ²equipped with²a lmm nozzle, operating with an air pressure of 25 psi, an inlet temperature ²of 70 C, and ²a flow rate of 6 mL / min. The resulting powders were then subjected to release ²tests in ²acidic conditions to simulate gastric conditions and near-neutral pH to ²simulate intestinal ²conditions.²20 For the release test, 50 mg of the finished product powders (containing 20 ²mg of ²SMEDDS) were placed in four 15-mL falcon centrifuge tubes. 5 mL of an aqueous ²HC1 ²solution at pH 1.3 was added to the samples. The tubes were shaken for 1 hr in ²a ²temperature-controlled shaker (37 C, 100 rpm). After one hour, the samples ²were ²centrifuged at 2000 rpm for 5 min. The supernatants were removed for analysis. ²The solids²25 left at the bottom of the test tube were then mixed with 5 ml of FeSSIF, ²and the tubes were²shaken for 1 hr at 37 C and 100 rpm. The aqueous HC1 solution at pH 1.3 and ²FeSSIF ²were used as references for the release in gastric and intestinal conditions. ²The ²supernatants were removed for analysis. The concentration of the released ²nonylphenol in ²the supernatant was determined via fluorescence spectroscopy, using the same ²method² 30 employed in Example 10.²<DP=51>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²51²The particle size distribution obtained with each of the encapsulated SMEDDS ²was ²determined via optical microscopy, observing samples of the particles placed ²on a glass ²slide with an Olympus BX-51 microscope used in transmitted light mode. The ²micrographs obtained using a 50X objective were then analyzed using the ImageJ²software's particle analysis tool. Volume-based cumulative size distribution ²for²EUDRAGUARDO, EUDRAGITO FL 30 D-55, and PROTECTTm ENTERIC are shown ²in Figs. 15.A, 15.B, and 15.C, respectively. The inset in each Figure shows ²the angle of ²repose images obtained using the hollow cylinder test method[351.²Table 12. Composition, % release in HC1, % release in FeSSIF, average particle ²size and² angle of repose of encapsulated D55 SMEDDS formulated with lecithin, extreme ²hydrophilic linker Polyaldo010-1-CC and limonene with nonylphenol as model ²polar oil. ²Columns (a) through (e) are weight percentage of (a) lecithin; (b) Polyaldo010-²1-CC; (c) ²nonylphenol; (d) limonene, (e) encapsulating polymer. Column (f) presents the ²% release ²of the SMEDDS in HC1 solution, column (g) presents the % release of the SMEDDS ²in²FeSSIF, column (h) presents the average particle size of the encapsulated ²SMEDDS; and²(i) is the angle of repose of the encapsulated SMEDDS.²Encapsulating %(a) %(b) %(c) %(d) %(e) (f)% (g)% (h)pm (i)deg.²polymer²EUDRAGUARDO 2.66 23.94 2.00 11.40 60.00 13 1% 100 1% 4.2 1.5 36 1²EUDRAGITO 2.66 23.94 2.00 11.40 60.00 17 1% 91 1% 5.1 1.5 37 3²PROTECTTM 2.66 23.94 2.00 11.40 60.00 0 1% 53 1% 6.4 1.5 30 1²Example 16. Oral delivery of CBD formulated in SMEDDS and encapsulated SMEDDS ²²with extreme hydrophilic linker (Cc=-7.4) ²The control CBD composition was prepared by adding lg of CBD in 99g of medium ²chain²triglyceride (MCT) oil (Organic Pure C8 MCT Oil, 99.2% C8 triglycerides), for ²a final ²CBD concentration of 9.6 mg / mL.²A D70 SMEDDS was produced by first mixing 10 parts (by mass) of lecithin with ²45 parts ²of the hydrophilic linker Polyaldo010-1-CC (Cc=-7.4) and 45 parts of the ²hydrophilic²linker Dermofeel0 G6CY (Cc=-3) using a vortex-mixer. Considering the molecular ²²weights for these hydrophilic linkers, shown in Table 15, this 1:1 mass ratio ²represents a ²molar ratio of 1.13 moles of Polyaldo010-1-CC (Cc=-7.4) to 1.695 mol parts of ²Dermofeel0 G6CY (Cc=-3). Using the molar fraction linear mixing rule for Cc ²used by²<DP=52>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²52²Zarate et al.

[22] , then the Cc for the mixture is (-7.4)*1.13 / (1.13+1.695) + ²(-²3)*1.695 / (1.13+1.695) = -4.76, which is within the -5 + 20% boundary set for ²the least ²negative value of the Cc of the combined extreme hydrophilic linker. A ²prescribed ratio of ²15 parts (by mass) of limonene (racemic mixture, technical grade), 15 parts of ²ethyl oleate²(for a total of 30 parts of oil) were added to 70 parts of the Lecithin + ²hydrophilic linker²mixture (i.e., the mixture of 45 parts Polyaldo010-1-CC and 45 parts of ²Dermofeel0G6CY) and then mixed using a vortex-mixer. 80 parts of this D70 ²SMEDDS ²where then vortex-mixed with 20 parts of CBD to produce a 20 wt% loaded D70 ²SMEDDS. This will be referred to as the 20%CBD-D70 SMEDDS composition.² To encapsulate the 20%CBD-D70 SMEDDS with EUDRAGIT L30 D-55 (30% dispersion²of methacrylic acid and ethyl acrylate copolymer NF, Evonik), 164.4 mL of the ²polymer ²suspension (equal to 49.3 g solid materials) were dissolved in a mixture of 33 ²mL of ²FeSSIF and 134 g of distilled water. Once this suspension was homogenized, 33 ²g of ²20%CBD-D70 SMEDDS were added, for a final loading of 40 wt% of 20%CBD-D70²SMEDDS in the final solid. The mixture was stirred for 1 hr before drying. ²Stirring²continued during spray drying, a process that was undertaken using a Model HT-²RY 1500 ²spray dryer (Zhengxhou Hento Michinery Co. Ltd) equipped with a lmm nozzle, ²operating ²with an air pressure of 25 psi, an inlet temperature of 60 C, and a flow rate ²of 6 mL / min. ²To confirm the CBD loading in the dry powder, a solvent extraction procedure ²was²undertaken, followed by HPLC determination of the CBD concentration. The ²resulting²concentration was determined to be 7.1% CBD in the encapsulated 20%CBD-D70 ²SMEDDS, indicating that the encapsulation efficiency was 89%.²To conduct the pharmacokinetic studies with these three compositions (control ²CBD, ²20%CBD-D70 SMEDDS, and encapsulated 20%CBD-D70 SMEDDS), male Sprague-²Dawley rats (250 20 g, supplied by Envigo, Indianapolis, In, USA) were used ²as animal²models. The pharmacokinetic study was carried out by Nucro-Technics ²(Scarborough, ²ON, Canada), a contracted facility authorized to conduct studies with ²cannabinoids and ²approved to conduct animal studies using animal care protocols that meet ²ethical practices ²for animal studies in Canada. The rats were acclimatized for a week in a ²temperature-²controlled environment with free access to water and food. Rats were randomly ²assigned²to three groups, (a) 10 rats in a control group with CBD dissolved in medium ²chain ²triglyceride (MCT), (b) 12 rats in a SMEDDS group with CBD dissolved in a ²liquid ²SMEDDS formulation, and finally (c) 8 rats in a group does with CBD formulated ²in²<DP=53>²CA 03204168 2023-05-24²WO 2022 / 140843 PCT / CA2021 / 051794²53²powder encapsulated SMEDDS. Table 13 presents the summary of the dosing ²conditions ²for these three test groups. Each test group was subdivided into two (for CBD ²control and ²CBD Powder) or three (for CBD SMEDDS) sub-groups to ensure that the number of ²blood ²sampling events was 6 or less for each rat. A total of 11 sampling events ²considered at 10²min, 20 min, 30min, 45min, lh, 1.5h, 2h, 4h, 6h, 8h and 10h. At each sampling ²event,²blood samples (450 50 pL) were withdrawn from the jugular vein (or the orbital ²sinus) ²into tubes containing anticoagulant K2EDTA. Following the collection of blood ²samples, ²the blood was placed in a refrigerated centrifuge for 15 minutes to separate ²the plasma, ²and the recovered plasma was stored in cryovials frozen at -60 C. The plasma ²samples²were analyzed using a LC-MS / MS method for plasma quantitation of CBD and 7-²COOH-²CBD, having a limit of quantification of 5.0 ng / mL. The LC-MS / MS method ²involved the ²use of a mobile phase A: 70% Methanol, 5 mM Ammonium Acetate, 0.1% Formic ²Acid; ²and mobile phase B: 90% Methanol, 5 mM Ammonium Acetate, 0.1% Formic Acid. The ²²flow rate was 0.5 mL / min and the gradient conditions were as follows 0-3 min, ²80% A²and 20% B; 3.01-6 min, 100 %B; 6.01-8 min, 80% A. An ACE Excel 5 Super C18 (75 ²x²3.0 mm, 5 pm) chromatography column was used. Temperature of column: 25 C. ²Spectrometer mass conditions: Gas Temperature: 350 C. Capillary: 4KV. Gas ²Flow: 13 ²L / min²Table 13: Summary of test groups used in the pharmacokinetic study of CBD, ²including² dose, dose concentration, dose volume and dosing instructions.²Research group CBD control CBD SMEDDS CBD Powder²Dose 10 10 10²(mg / Kg)²CBD Dosing conc. 9.6 1.28 1.061²(mg / mL)²Dosing volume 1.04 7.81 10.37²(ml / Kg)²Formulation²Dosing method The required dosing 0.268 g ²of SMEDDS 40 mL phosphoric acid²volume was (20% CBD) diluted solution ²(pH3) + 0.6 g²administered by oral with 38.95 mL powder ²SMEDDS to²gavage FeS SIF, administered Produce ²a suspension²by oral gavage. dosed by oral gavage²The plasma concentration curves for the CBD control, the 20%CBD-D70 SMEDDS ²(referred to as SMEDDS in Fig. 16), and the encapsulated 20%CBD-D70 SMEDDS ²(referred to as powder in Fig. 16) are presented in Fig. 16. Table 14 presents ²the²<DP=54>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²54²pharmacokinetic parameters after fitting the plasma concentration data to a ²noncompartmental analysis for extravascular systems programmed in PKSolver ²

[36] . The ²reason that a non-compartmental model had to be used is because of the double-²peak ²feature of the SMEDDS and the powder curves in Fig. 16, which cannot be ²reproduced by²a typical single compartment model. The value of tm is the time when the ²plasma²concentration reaches its peak (C..). AUC 0-10h is the area under the plasma ²concentration ²curve, from the time of dosing until 10 hours after dosing. The value of AUCo-²inf represents ²an estimation of the area under the curve extrapolated to an infinite release ²time, estimated ²based the decay trend obtained with the last 4 points of the curve.²Table 14: Pharmacokinetic parameters for orally administered CBD in the ²control, in the²liquid (SMEDDS) 20%CBD-D70 SMEDDS, and in the encapsulated (powder) 20%CBD-²D70 SMEDDS.²Parameter Unit Control SMEDDS Powder²tmax hours 1.5 0.5 0.33²Cmax ng / ml 78 121 162²AUC 0-10 h ng / ml*hr 404 454 520²AUC 0-inf ng / ml*hr 423 840 578²As illustrated by the tmax values in Table 14, the SMEDDS (20%CBD-D70 SMEDDS) ²and² powder (encapsulated 20%CBD-D70 SMEDDS) compositions reduce the time to reach²C. by at least 65% of the time required by the control. This is definitely an ²advantageous ²feature of these formulas as it facilitates the potential for fast-acting ²effects of the ²cannabinoid. The C. obtained with the SMEDDS is more than 50% greater than the ²C. ²of the control, and the C. obtained with the powder more than doubled the C. ²of the²control. The 10-hour area under the curves (AUC 0_10h) were about 10% and 30% ²larger²for SMEDDS and the powder, respectively, as compared to the control. The ²assessed ²infinite absorption (AUC 0-inf) was substantially larger for the SMEDDS ²(nearly twice that ²of the control) because the plasma concentration of CBD was nearly constant in ²the last ²four measurements for the SMEDDS curve.²While Example 3 shows that the use of conventional hydrophilic linker ²Dermofeel0 could²not produce a fully dilutable formulation, Example 16 shows that a ²conventional ²hydrophilic linker when used in combination with an extreme hydrophilic linker ²like²<DP=55>²CA 03204168 2023-05-24²WO 2022 / 140843 ²PCT / CA2021 / 051794²Polyaldo010-1-CC, can result in a fully dilutable system when the ²combination / mixture²has a Cc of about -5 or more negative than about -5.²Table 15. Characteristic curvatures of selected biobased surfactants.²Surfactant Cc MW vs / as L²(g / mol) (A) (A)²Oleic acid 0 0.1 282²Sodium oleate -1.7 0.1 304 8.4 30²Sodium octanoate -2.1 0.1 166 4.6 12²Soybean lecithin +5.5 1.3 750 11.7 34²Glycerol monooleate +6.6 1.5 450 ²Polyglycerol-6-caprylate -3.0 0.7 590 9.9 19²(Dermofeel0 G6CY)²Polyglycerol-6-caprylate (Caprol0 6GC8) -6.4 1.28 593²Sorbitan monolaurate, Span 20 +3.5 0.8 346²Tween 20 -4.4 1.0 1228 24.3 23²Tween 80 -3.0 0.7 1310 25.8 34²Sodium lauroyl sarcosinate -4.2 0.2 293 5.8 20²Sucrose palmitate -0.8 0.2 581 17.8 23²Sucrose distearate +4 0.2 875 12.0 34²Disodium stearoyl capryl glutamate -5 0.2 457 7.9 34²C18 sophorolipid +7 1.5 688 13.0 34²Monorhamnolipid -1.4 0.3 577 14.5 16²Dirharrmolipid -1.3 0.3 650 14.2 16²GY19 lipopeptides +4.9 1 1050 NA NA²Polyglycery1-10-caprylate (Polyaldo0 10- -7.4 1 885 NA NA²1-CC)²C12-C14 polyglycoside +0.5 0.2 480 16.1 25²Sorbitan monooleate (Span 80) +5.0 1 430²C6 polyglucoside -2.2 0.5 380 8.8 12²Note: lipophilic linkers are noted with the symbol " ."²5 REFERENCES CITED ²[1] E.J. ²Acosta, M. 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Claims

CLAIMS 1. A fully dilutable in aqueous phase self-microemulsifying system for the delivery of one or more polar oil active compounds having a positive characteristic curvature (Cc), comprising: a lecithin compound; a hydrophilic linker (HL) or a combination of two or more HLs, the HL or each of the HLs within the combination having one hydrocarbon group with at least 50% or more alkyl chain distribution between 6 to 10 carbon atoms, and the HL or the combination of two or more HLs having a Cc of about -5 or more negative than -5; and a carrier oil, wherein the system is free of polyethylene glycol, propylene glycol, and short and medium-chain alcohols.

2. The fully dilutable in aqueous phase self-microemulsifying system of claim 1, wherein the delivery is topical, transdermal, oral, transnasal, buccal, vaginal, subcutaneous, parenteral, ophthalmic, transepidermal, transmembrane, or intravenous.

3. The fully dilutable in aqueous phase self-microemulsifying system of claim 1, wherein the lecithin compound concentration is about 1.5% to about 45% w / w.

4. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 3, wherein the hydrophilic linker is about 10 wt% to about 86 wt° / o.

5. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 4, wherein the combination of two or more HLs includes at least one amphiphilic compound with a Cc less negative than -5 and the Cc of the combination is about -5 or more negative than -5.

6. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 5, wherein the hydrophilic linker or the combination of two or more HLs comprises one or more of C6-C10 alkyl polyphosphates, polyphosphonates, polycarboxylates, sulfosuccinates, glutamates; C6-C10 esters of polyhydric alcohols, polyvinyl alcohol, Date Re1rue / Date Received 2024-02-15 60 polyglycerols and their co-polymers with a degree of polymerization (n) higher than 2 (n>2), sucrose, maltose, oligosaccharides, polyglucosides (n>2), polyglucosamines, sorbitol, sorbitan, poly alpha hydroxy acids and their salts, C6-C 10 amines, quaternary ammonium salts, amine oxides, C6-C 10 alkyl aminopropionic acids, betaines, sulfobetaines, phosphatidylcholines, phosphatidyl glycerols, or mixtures thereof.

7. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 5, wherein the hydrophilic linker or at least one of the two or more HLs in the combination comprises a C6-C10 polyglycerol with a degree of polymerization n>2, or wherein the hydrophilic linker or at least one of the two or more HLs in the combination is disodium C6- C10 glutamate, polyglycerol-6-caprylate or polyglycerol-10 caprylate.

8. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 7, wherein the carrier oil has a positive equivalent alkane carbon number (EACN).

9. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 8, wherein the carrier oil concentration is about 10 wt% to about 70 wt° / 4.

10. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 9, wherein the carrier oil comprises of alkyl esters of fatty acids, monoglycerides, diglycerides, triglycerides, alkanes, terpenes, or mixtures thereof.

11. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1-10, wherein the self-microemulsifying system further comprises the one or more polar oil active compounds having a positive characteristic curvature (Cc).

12. The fully dilutable in aqueous phase self-micoremulsifying system of claim 11, wherein the concentration of the one or more polar oil active compounds is about 0.01 wt° / 4 to about 78.3 wt%.

13. The fully dilutable in aqueous phase self-microemulsifying system of claim 11 or claim 12, wherein each of the one or more polar oil active compounds having a positive characteristic curvature (Cc) has a log P greater than 1, molecular weight between 50 and 100,000 Daltons, a polar area greater than 0.0 A2 , an aqueous solubility less than 1 wt%. Date Re1rue / Date Received 2024-02-15 61 14. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 11 to 13, wherein the one or more polar oil active compounds having a positive characteristic curvature (Cc) includes one or more hydrogen bonding donor compounds selected from the group consisting of C5+ alcohols, amines, peptides, organic acids, anthranilic acids, aryl propionic acids, enolic acids, heteroaryl acetic acids, indole and indene acetic acids, salicylic acid derivatives, nucleic acids, alkylphenols, para-aminophenol derivatives, terpene phenolics, cannabinoids, alkaloids, and halogenated compounds.

15. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 11 to 14, wherein the one or more polar active compounds include ibuprofen, nonylphenol, cannabidiol, and eugenol.

16. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 15, wherein the aqueous phase is water, biological fluids, aqueous electrolyte solutions, carbonated drinks, fruit juices, or alcoholic beverages.

17. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 16, wherein the system further comprises a lipophilic linker.

18. The fully dilutable in aqueous phase self-microemulsifying system of claim 17, wherein the lipophilic linker concentration is about 0.1 wt° / 4 to about 30.0 wt%.

19. The fully dilutable in aqueous phase self-microemulsifying system of claim 17 or 18, wherein the lipophilic linker includes one or more ingredients selected from the group consisting of C12+ alcohols, fatty acids, monoglyceride, sorbitan ester, sucrose ester, glucose ester, cholesterol, and esters of lauric acid, palmitic acid, oleic acid, omega 6-fatty acids, omega 3-fatty acids with sorbitol, maltitol, xylitol, isomalt, lactitol, erythritol, pentaerythritol, or glycerol.

20. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 19, wherein the system further comprises a low molecular weight organogelator that imparts semisolid properties and produces a slow releasing profile of the one or more polar oil active compounds, wherein the concentration of the organogelator is about 0.1 wt% to about 40.0 wt%, and wherein the organogelator includes one or more ingredients selected from sterol-based gelling agents, long-chain fatty acids, long-chain amines, and esters of long-chain fatty acids. Date Re1rue / Date Received 2024-02-15 62 21. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 20, wherein the system further comprises an encapsulating agent to form a solid encapsulated system, wherein the encapsulating agent imparts solid-like properties and produce flowable powders that can form micellar solutions when diluted in aqueous environments.

22. The fully dilutable in aqueous phase self-microemulsifying system of claim 21, wherein the concentration of the encapsulating agent is about 10 wt% to about 90.0 wt% of the solid encapsulated system.

23. The fully dilutable in aqueous phase self-microemulsifying system of claim 21 or 22, wherein the encapsulating agent includes one or more ingredients selected from amphiphilic polymers with a glass transition temperature ranging from about 45°C to about 99°C.

24. The fully dilutable in aqueous phase self-microemulsifying system according to any one of claims 1 to 23, wherein the system is waterless, and wherein the system has particle diameters smaller than 200 nm.

25. A use of the system according to any one of claims 1 to 24 for delivering one or more polar oil active compounds having a positive characteristic curvature (Cc) to a subject. Date Re1rue / Date Received 2024-02-15