SI26054A - Super-saturable oil-free self-nanoemulsifying drug delivery system SNEDDS for poorly water-soluble pharmaceutical composition and procedure of preparation thereof - Google Patents

Abstract

The present invention relates to an oral super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS for pharmaceutical compositions of hydrophobic natural active pharmaceutical ingredients (APIs), emulsifiers / co-solvents and stabilized aqueous phases. The SNEDDS in the present invention shows increased drug loading capacity, self-emulsification, better stability, and improved bioavailability. Methods for preparing oral super-saturable nano-emulsifier pharmaceutical compositions in liquid and solid form are also described.

Description

Supersaturated oil-free self-nanoemulsifying drug delivery system - SNEDDS for poorly water-soluble pharmaceutical ingredients and its preparation process

Description

Technical field

The presented invention relates to a novel highly bioavailable, water-soluble, super-saturated, oil-free self-nanoemulsifying drug delivery system (SNEDDS) for pharmaceutical compositions of hydrophobic natural active pharmaceutical ingredients (APIs), emulsifiers/cosolvents/excipients, and stabilized aqueous phases.

The present invention relates to a self-nanoemulsifying drug delivery system (SNEDDS) containing all API components as a lipophilic micelle core and emulsifier/cosolvent and stabilizer excipients as a micelle shell in the aqueous phase, with a globular micelle size of less than 50 nm (Fig. 1).

This disclosure relates to methods for making a self-nanoemulsifying drug delivery system (SNEDDS) containing the above-mentioned components in the form of liquid SNEDDS (for spray, drops), semi-solid SNEDDS (gel, capsules), solid SNEDDS (powder, tablets, granules).

BACKGROUND OF THE INVENTION

The biodiversity observed on planet Earth offers many varieties of plants/trees that have been studied over the centuries to understand their use in everyday life as a source of food and medicine. The traditional medicinal system used these rich herbal resources alone or in combination with other necessary ingredients to treat various conditions. Despite this use of medicinal plants, there has been a backlog in the past years in obtaining a therapeutically effective drug / nutrient from a plant source.

Despite its long historical use, little has been achieved in the treatment of the disease. A major problem associated with hydrophobic plant compounds and extracts is their poor bioavailability, leading to poor or reduced efficacy. Most hydrophobic compounds such as curcuminoids, boswellic acids, resveratrol, hypericin, bacosides, black seeds, artemisinin, cannabinoids, ginseng extract and many others have been shown to have multiple therapeutic benefits such as anti-inflammatory, antioxidant, anti-obesity, memory-enhancing, anti-allergic , antimicrobial, antitumor and many other medicinal activities. But little has been achieved regarding these molecules for disease prevention and treatment precisely because of their poor bioavailability and lack of stability in the body. Table 1 shows examples of APIs and their therapeutic applications

Table 1

Antimicrobial agent Anti-inflammatory agent Neuroprotective properties Cardiovascular protection Antioxidants Medicines to treat cancer Artemis's Capsaicin Bacoside A Berberine Curcumin Curcumin Caffeinated Colchicine Bilobalide Curcumin Cyanidin Kaempferol acid Curcumin Curcumin Dihydrotanshinone Gingerol Paclitaxel Capsaicin Coumarin Eugenol Menthol Epigallocatechin3-Gallate Quercetin Quercetin Resveratrol Cannabinoids Galantamine Ginenosides Withaferin A Cannabinoids Quercetin Ginkgo biloba Glycyrrhizin Quercetin Resveratrol Silamarin Vankristin Cannabinoids

Many of the plant molecules discussed above are hydrophobic in nature and therefore not soluble in water. The poor bioavailability of these molecules reflects the lack of effective natural drugs on the market, despite their traditionally known benefits. On the other hand, biopharmaceuticals suffer from instability and biodegradation before reaching the target site.

Moreover, conventional methods and regular dissolution techniques are not efficient enough to dissolve high concentration of plant molecules/extracts and are also not successful in self-emulsification. Due to their lipophilic and hydrophobic nature, the selection of the right excipients, the correct combination of excipients and the formulation process of such a product is critical to achieving the desired product.

Solubility and dissolution is primarily a factor that limits the rate of oral bioavailability of many drugs. In the last two decades, various formulation strategies have been developed to improve drug solubility, to increase the rate and extent of drug absorption from the gastrointestinal tract - GIT (Shahba et al., 2012, 2016, 2017; Devraj et al., 2013; Mohsin et al., 2016). .

Self-emulsifying drug delivery systems belonging to lipid formulations (LBF) have been shown to improve slow and incomplete drug dissolution and facilitate the formation of a highly solubilized drug phase for enhanced drug absorption. Also, self-emulsifying preparations can be easily filled into soft and hard gelatin capsules due to their anhydrous nature (Pouton, 1985; Strickley, 2004) (Figure 2).

Self-emulsifying formulations are isotropic mixtures of an active medicinal compound in a combination of lipids, surfactants and water-soluble co-solvents that form ultrafine emulsions upon gentle mixing in the aqueous phase, such as the upper content of the Gl lumen (Fatouros et al., 2007; Kale and Patravale , 2008). Generally, self-emulsifying formulations are categorized as self-emulsifying (SEDDS), self-micro-emulsifying (SMEDDS), and self-nanoemulsifying drug delivery systems (SNEDDS). SEDDS, SMEDDS and SNEDDS can be fundamentally distinguished by their globule size upon aqueous dispersion (Pouton, 2000; Pouton and Porter, 2008) (Figure 2).

MECHANISM OF SELF-NANOEMULSIFICATION

According to Reiss, the energy required to increase the dispersion surface area for the self-emulsification process is less important compared to the entropy change that favors dispersion. The process of self-nanoemulsification is related to free energy. This means that the free energy of a conventional emulsion is a direct function of the energy essential for the creation of a new surface between the oil and water phases, and can be described by the equation:

DG = S N p r 2s where DG is the free energy associated with the process, N is the number of droplets of radius r, and s represents the interfacial energy. The emulsion is stabilized by emulsifiers only after the two phases of the emulsion have separated with respect to time to reduce the surface area. The emulsifier forms a monolayer particle of emulsion droplets, thus reducing the interfacial energy and providing a barrier to prevent coalescence. In the case of micron self-emulsifying systems, the free energy required to form an emulsion is either very small, positive or negative. Emulsification requires very little energy input, which involves destabilization by shrinking the local interfacial region.

Various processes take place during emulsification, including droplet spreading, adsorption of surfactant molecules, and droplet collision. These processes can occur simultaneously. Droplet scattering is feasible if the deforming force exceeds the Laplace pressure (PL), which is the interfacial force acting against droplet deformation:

Pl = (1/Λ1 + MR 2) · (1)

R1 and R2 are the smaller and larger radius of curvature of the deformed emulsion droplet, respectively, the interfacial force. Based on Laplace's equation, droplet size decreases with decreasing oil/surfactant ratio (increasing surfactant concentration). The formation of a spontaneous nanoemulsion requires not only a high concentration of surfactant, but also a surfactant with a high HLB (hydrophilic and lipophilic balance) above 12.

A development was the composition-based Lipid Formulation Classification System (LFCS), which categorized LBF (liquid-based formulations) into four different types (Pouton, 2000). LFCS explains in a very simple way the formation of different types of self-emulsifying formulations based on their types and composition. Briefly, Type I formulations feature 100% pure oil (surfactant-free) as a component. Type II and IIIA systems contain water-insoluble surfactants (HLB <10) with different % of oil in the formulation (type

II contains 60-80% oil and type IIIA 40-60% oil). Type IIIB formulations contain water-soluble surfactant and oil (20-50% oil), while Type IV formulations contain only water-soluble surfactant / co-solvent without oil. In general, Type II and/or Type IIIA formulations spontaneously form SEDDS (transparent) emulsions with droplet sizes from 250 nm to 1.0 pm. SNEDDS refers to formulations that form transparent microemulsions (oil in water / water in oil) with a particle diameter of 50 nm or less, belong to type IIIB and or type IV. SMEDDS, on the other hand, is a relatively newer term that represents droplet sizes between 20 and 200 nm and also provides a transparent appearance. Drug encapsulated in liquid dosage forms can be in a thermodynamically and kinetically stable form as SNEDDS (Kang et al., 2004; Elgart et al., 2013) (Figure 2 and Table 2).

Table 2. Types of oral LFCS lipid preparations, their advantages and limitations

composition / meaning type I type II type IIIA type IIIB type IV % triglycerides or mixed glycerides 100 40-80 20 <20 — Water-insoluble surfactants (HLB < 12) 20-60 0-20 Water-soluble surfactants (HLB > 12) 20-40 20-50 30-80 Hydrophilic co-solvents — — 0—40 20-50 0-50 Dispersion particle size (nm) rough 100-250 100-250 50-100 <50 The importance of diluting with water limited meaning Does not affect solvent capacity Some loss of solvent capacity Significant phase changes and potential loss Significant phase changes and potential loss

solvent capacities solvent capacities The meaning of digestibility A key requirement It's not critical, but it probably comes up It is not vital, but it can inhibit it Not required Not required

SUPER-SATISFACTORY APPROACH

The super-saturable approach is a promising approach for the use of drug compounds with poor water solubility. Super-saturating formulations are thermodynamically stable formulations capable of producing a supersaturated concentration in the aqueous environment of the gastrointestinal tract. These super-saturated formulations act on a spring-fall mechanism (Warren et al., 2010; Bevernage et al., 2013). The most common ways to achieve supersaturation are salts that rapidly dissolve amorphous solids, co-solvents and self-emulsifying formulations. All these formulations are called springs. The spring carries dissolved drug concentrations above the saturated (equilibrium) solubility. A disadvantage of such formulations is that supersaturated formulations cause precipitation when administered in vivo. Therefore, super-saturated formulations need to be optimized to reduce variability in use. A formulation component that inhibits nucleation or crystal growth acts as a parachute to stabilize metastable supersaturated formulations for a sufficient period of time for absorption to occur. The “parachute”, i.e. the polymeric inhibitor (Pl), slowly moderates the concentration to saturation (Figure 4). The formation of a supersaturated state and the subsequent inhibition of precipitation is called the "spring and parachute" approach. Excipients that can affect supermass include cellulose polymer (HPMC, HPC and MC) and other rheological polymers (PVP), surfactants (polysorbates, cremophor and TPGS) and cyclodextrins (Mathews & Sugano, 2010). Celluloses are the most commonly used precipitation inhibitors.

Super-satisfying SNEDDS

Super-saturable SNEDDS are designed to minimize drug precipitation from SNEDDS in the gastrointestinal tract. Super-saturable SNEDDS are thermodynamically stable formulations containing a reduced amount of surfactant and a polymeric precipitation inhibitor. SNEDDS prevent drug precipitation by creating and maintaining a supermassed state in vivo after dilution with water. Supersaturated formulations differ from supersaturated formulations because the latter are not thermodynamically stable, and drugs in supersaturated formulations can crystallize during storage. Therefore, the physical stability of supermassed formulations is fundamentally challenging and this limits their practical utility (Gao & Morozowich, 2006; Beverange et al., 2013).

Polymeric precipitation inhibitors used in super-saturated SNEDDS formulations are mainly water-soluble cellulosic polymers such as HPMC, PVP, methyl cellulose, HPMC phthalate, sodium CMC, which can maintain a supersaturated state by preventing drug precipitation (Xu & Dai, 2013). The three hydrophilic polymers were found to have precipitation inhibition ability in the order of PVP K17 > PEG 4000 > HPMC.

PVP KI7 (0.5%) was found to effectively inhibit precipitation. Another advantage of the super-saturated formulation approach is the reduced amount of surfactant in the formulation, thereby achieving an improved toxic hazard profile with supersaturated SNEDDS formulations.

REVIEW OF RELATED PATENTS

There are some attempts to use "type IV nanoemulsion" to emulsify poorly soluble drugs presented in the patent literature:

In US2010/0196456A1, US2010/0129453 Al Strasser (MiVital, SWISS) mentions gum arabic and/or rosin as natural emulsifiers for emulsifying poorly soluble drugs, including Q10. But the lack of stable quality of natural excipients is obvious. And these emulsions can only be used as a food supplement.

In US2015/0072012A1 Sripathy et al., in US2011/0229532A1 Nair et al. (Laila Pharmaceuticals Pvt, IN) disclosed nanoformulations of hydrophobic compounds that can be used as ayurvedic / dietetic ingredients of pharmaceutical drugs and nutritional supplements. But these emulsions refer to microemulsions of separate solubilized mean values of 200 nm and with a very high preference of 80% emulsifiers. Furthermore, releasing the API more than 24 hours after receipt does not refer to spontaneous "self-emulsification" within the meaning of the method of the present invention.

In patent series US2008/022.0102A1, US 2016/0128939 A9, US2004/0192768A1,

US 20200129452 by Behnam, Dariush of Aquanove AG (Darmstadt, DE) claims to be dissolved separate active chemicals based mostly on a rather large proportion of nonionic surfactants, especially polysorbate20 / polysorbate80 and often ethanolic solvents, and have nothing to do with SNEDDS.

In US2018/0071210A1, PCT/GB20 19/050009, authors Wilkhu and co-workers from GW Research Limited, Cambridge (GB) disclosed essential oil-free cannabinoid formulations in solid and gel form with excipients and with poloxamer as emulsifiers. The solvent can be selected from the group consisting of diacetin, propylene glycol, triacetin, monoacetin, propylene glycol diacetate, triethyl citrate and mixtures thereof. A type IV oral pharmaceutical formulation (OPF) containing at least one cannabinoid, at least one solvent, and at least one poloxamer can be rehydrated by adding 20 mL of water for injection at room temperature or by adding 20 mL of water for injection at 37°C. The formulation may be water-free, alcohol-free and/or oil-free, but this invention does not require any spontaneous self-nanoemulsification of the aforementioned formulations.

In US205/0232952A1, WO2003074027A2 Lambert et al of Novagali Pharma SA (FR) described a drug delivery system comprising: one or more poorly water soluble or water insoluble therapeutic agents, vitamin E, one cosolvent , derived from propylene glycol and ethanol, one or more bile salts, TPGS and another surfactant derived from tyloxapol and polyoxyl hydrogenated castor oil. Unfortunately, from the resulting microemulsions, when the drug concentration was higher than 1.5% w/w, it easily precipitated. The precipitation time was approximately 2 hours as the concentration was increased to 2.5% w/w.

In WO2012/033478, Murty et al of Murty Pharmaceuticals, Inc., 518 Codell Drive, Lexington, KY 40509 (US) used SEDDS cannabinoid formulations based on type I, type II and type III.

Currently, many poorly soluble products on the market claim to have high bioavailability, which is achieved by using phospholipids or vegetable oils, etc. However, none of the previously known methods reveal a supermassed self-nanoemulsifying formulation (SNEDDS) containing a unique proportion (mixture) of plant hydrophobic active compounds in an emulsifier/cosolvent phase and a stabilized aqueous phase to achieve spontaneous self-emulsification of the API in one micelle without oil phases.

OBJECTIVE OF THE INVENTION

Therefore, the presented discovery of type IV super-saturable SNEDDS provides a unique proportion of plant-based hydrophobic active compounds in the emulsifier/cosolvent phase and aqueous stabilized phase to ensure higher efficiency and spontaneous self-emulsification of APIs in a single micelle with sub-50 nm globular size, without oily phase, produced in different forms: liquid SNEDDS (for spray, drops), semi-solid SNEDDS (gel, capsules), solid SNEDDS (powder, tablets, granules).

This discovery is a potential successor in the field of drugs, biopharmaceuticals, nutritional supplements for human and/or animal use with a new super-saturated SNEDDS type IV nano-emulsifying composition with increased bioavailability and stability.

BRIEF DESCRIPTION OF IMAGES

Figure 1: Oil-free SNEDDS type IV nanomicelles

Figure 2: Types of oral lipid formulations according to the LFCS classification, their advantages and limitations

Figure 3: Conversion of liquid SNEDDS (L-SNEDDS) to solid SNEDDS (S-SNEDDS)

Figure 4: Super-saturating approach {"spring and parachute")

Figure 5: Visual evaluation method of CBD type I-IV LBF formulations

Figure 6: Effect of hydrophilic compositions on particle size and PDI of lipid-based formulations (LBF) for CBD

Figure 7 Cryo-transmission electron microscopy (cryo-TEM) observation of a blank nanoemulsion after a long period of storage (nine months) at room temperature (10,000x magnification)

Figure 8: The globule size distribution of the empty nanoemulsion after nine months of storage at room temperature

Figure 9: Globule size distribution of blank nanoemulsion (left), blank nanoemulsion after incubation with 0.1 N HC1 1:1 v/v (middle), and blank nanoemulsion after incubation with phosphate buffer (pH 6.8) 1:1 v/v in (right). Incubation was carried out at 37 °C Figure 10: Cytotoxic effect on different cell lines

Figure 11: Pseudo-ternami plot for SNEDDS CimetrA

Figure 12: Surface morphology of adsorbent Aerosil 200 and SNEDDS CimetrA in solid form (Ratio 50/50)

Figure 13: Synthesis flow diagram of CimetrA

SUMMARY OF THE INVENTION

The present invention discloses a novel, highly bioavailable, water-soluble, super-saturated, oil-free type IV self-nanoemulsifying drug delivery system (SNEDDS) for pharmaceutical formulations of hydrophobic natural active pharmaceutical ingredients (APIs), emulsifiers/cosolvents/excipients, and stabilized aqueous phase.

The present invention discloses a super-saturable self-nanoemulsifying drug delivery system (SNEDDS) containing all API components as a lipophilic (hydrophobic) micelle core and emulsifiers/cosolvent and stabilizer excipients as a shell (hydrated shell) of a micelle in an aqueous phase with globular size micelles less than 50 nm (Figure 1).

The present invention relates to methods of manufacturing a self-nanoemulsifying drug delivery system (SNEDDS) containing the above-mentioned components as liquid SNEDDS (for spray, drops), semi-solid SNEDDS (gel, capsules), solid SNEDDS (powder, tablets, granules). .

DETAILED DESCRIPTION OF THE INVENTION

This disclosure provides a novel oral super-saturable oil-free (LFCS type IV) self-nanoemulsifying system (SNEDDS) or drug delivery formulation with a unique proportion of plant hydrophobic active compounds/extracts in the emulsifier/cosolvent phase and stabilized aqueous phase with globule size micelles below 50 nm.

In yet another aspect, the disclosure provides super-saturating self-nanoemulsifying (SNEDDS) formulations containing single and/or combinations of plant hydrophobic active compounds/extracts in an emulsifier/cosolvent phase and a stabilized aqueous phase for good stability as protection against possible precipitation and biodegradation .

In yet another aspect, the disclosure provides super-saturable self-nanoemulsifying (SNEDDS) formulations containing single and/or combinations of plant hydrophobic active compounds/extracts in an emulsifier/cosolvent phase and a stabilized aqueous phase for various therapeutic, preventive and general health supplement applications for animals and people.

In yet another aspect, the disclosure provides super-saturable self-nanoemulsifying (SNEDDS) formulations containing single and/or combinations of plant hydrophobic active compounds/extracts in an emulsifier/cosolvent phase and a stabilized aqueous phase for use as dietary supplements or nutraceuticals/health supplements / general supplements / non-prescription drugs.

In yet another aspect, the disclosure provides super-saturable self-nanoemulsifying (SNEDDS) formulations containing single and/or combinations of plant hydrophobic active compounds/extracts in an emulsifier/cosolvent phase and a stabilized aqueous phase in a liquid, semi-solid or solid dosage form.

Various embodiments disclosed herein relate to super-saturable self-nanoemulsifying systems (SNEDDS) or formulations containing a dispersed phase in the amount of 10-95% by weight of the formulation, and an aqueous phase in the amount of 5-70%, by to the weight of the formulation. The dispersed phase comprises particles with an emulsifier containing a nonionic surfactant with an HLB value of 15 to 18, a cosolvent, and a hydrophobic pharmaceutical/biologically active material in an amount of 0.0001 to 10% based on the weight of the formulation. Optionally, auxiliary substances for stabilization can be included - stabilizers (pH regulator, antioxidants, precipitation inhibitors, etc.) in the amount of 0.001-10%.

In various embodiments, between 75% and 90% of the hydrophobic biologically active material is immediately self-emulsified when added to water, or spontaneously released from the nanoformulation when the nanoformulation is added to water.

Additionally, in various embodiments disclosed herein, a super-saturable self-nanoemulsifying drug delivery system (SNEDDS) comprises a hydrophobic biologically active material that is a natural product, a synthetically derived product, or a mixture thereof. The hydrophobic biologically active material can be an extract or phytochemical obtained from at least one plant selected from the group consisting of curcumin, ginseng, ginkgo biloba, garcinia mangostana, ocimum basilicum, zingiber officinale, tribulus terrestris, sphaeranthus index, annona squamosa, moringa oleifera , murraya koenigii and their mixtures. The hydrophobic biologically active material may be a compound selected from the group consisting of at least one curcuminoid selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin and bis-o-demethyl curcumin; at least one artemisinin compound, a Boswell acid compound; cannabinoids; black seed; resveratrol; hypericin; bacoside (i); xanthorhizol; pepperin, luteolin; pyrogallol; genistein; wogonin; morin; kaempferol; and their mixtures (Figure 6)

In various embodiments presented herein, the presented invention SNEDDS supersaturable self-nano formulation contains a dispersed phase comprising particles containing a nonionic surfactant (emulsifier) selected from the group consisting of polysorbates, polyethylene glycols, polyethylene glycol esters, glycerol esters and mixtures thereof.

In a preferred embodiment, the surfactants used in the present invention comprise nonionic surfactants. In another embodiment, the nonionic surfactants are selected from the group consisting of polyoxyethylene products of hydrogenated vegetable oils, polyethoxylated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, or a combination thereof. They are commercially available as CREMOPHOR® (from BASF) such as CREMOPHOR® EL (castor oil PEG-35), EMOPHOR®RH40 (hydrogenated castor oil PEG-40), CREMOPHOR®RH60 (hydrogenated castor oil PEG-60), LABRASOL® (PEG-8 caprylic / capric glycerides), GELUCIRE® (stearoyl polyoxyl glycerides), polysorbates, PLURONIC® L-64 and L-127 (block copolymers based on ethylene oxide and propylene oxide), TRITON™ X 100 (polyethylene glycol tert-octylphenyl ether), SIMULSOL™ (polyoxyethylated products containing polyoxyethylated lauric alcohol, polyoxyethylated stearyl alcohol, polyoxyethyl acids and the like) NIKKOL™ HCO-50 (polyoxyethylene (50) hydrogenated castor oil), NIKKOL™ HCO35 (polyoxyethylene (35 ) hydrogenated castor oil), NIKKOL™ HCO-40 (polyoxyethylene (40) hydrogenated castor oil), NIKKOL™ HCO-60 polyoxyethylene (60) hydrogenated castor oil) (from Nikko Chemicals Co. Ltd.) and TWEENS® (Polysorbates) (from ICI Chemicals). In a preferred embodiment, the surfactant is CREMOPHOR ® EL.

The preferred emulsifier is CREMOPHOR®RH40 (hydrogenated castor oil PEG-40). The surfactant can form a stable emulsion, preferably a fine SNEDDS emulsion, when in contact with an aqueous fluid, for example in the gastrointestinal tract (Figure 3). The surface-active substance in the sense of the present invention does not precipitate active pharmaceutical ingredients from the emulsion and therefore offers better stability of the formulation than the existing techniques. It also eliminates the use of polymeric molecular aggregation inhibitors and prevents API precipitation.

In one embodiment, the co-solvents in the present invention are selected from the group consisting of polyethylene glycol chain lengths (preferably with a molecular weight of 200 to 600), propylene glycol derivatives, and commercially available products such as TRANSCUTOL® (diethylene glycol monoethyl ether), CAPRYOL™ (propylene glycol monocaprylate type I), CAPRYOL™ 90 (propylene glycol monocaprylate type II), CAPMUL® (glyceryl caprylate), TETRAGLYCOL™ (tetrahydrofurfuryl diethylene glycol ether), LABRAFIL® (polyglycosyl glycerides), LUTROL® F68 (polaxomer 188) , CARBITOL™ (diethylene glycol monoethyl ether) and the like. In a preferred embodiment, the co-solvent is polyethylene glycol (PEG) with a molecular weight of 200^100, commonly known as PEG-200-400. In the embodiment of the presented invention, the co-solvents also act as solubilizers in the resulting composition.

A preferred cosolvent is PEG-400 (polyethylene glycol).

In one embodiment, the composition of the present invention may contain additives commonly used to prepare pharmaceutical formulations. These additives are stabilizers. Stabilizers may include antioxidants and pH regulators, desirable substances, precipitation inhibitors and stabilizing components.

In one embodiment, the antioxidant and pH regulator is selected from the group consisting of acetic acid, glacial acetic acid, lactic acid, citric acid, phosphoric acid, carbonic acid, histidine, glycine, barbital, phthalic acid, adipic acid, ascorbic acid (vitamin C ), maleic acid, succinic acid, tartaric acid, glutamic acid, benzoic acid, aspartic acid and salts (eg potassium, sodium, etc.) or combinations thereof. The antioxidant is incorporated in a suitable amount to oxidize excess ions in the formulation. In a preferred formulation, the antioxidant comprises less than about 10% by weight of the total formulation and, more preferably, from about 0.05% by weight to about 6% by weight of the total formulation.

In one embodiment, the gelling agent is selected from the group consisting of xanthan gum, carrageenan, locust bean gum, guar gum, modified celluloses, low esterified pectins, and colloidal silica. In a preferred embodiment, the desired agent is colloidal silica, which is available as AEROSIL 200.

In one embodiment, the stabilizing component of the formulation is selected from the group consisting of vitamin-E α-tocopherol, ascorbyl palmitate, BHT (butyl hydroxytoluene), BHA (butyl hydroxy anisole), propyl gallate, or malic acid.

If desired, the formulation may further include conventional pharmaceutical additives. Examples of pharmaceutical additives include, but are not limited to, surfactants (eg, sodium lauryl sulfate), colorants, flavors, preservatives, stabilizers, and/or thickeners. The formulation can have a liquid or semi-solid form and can be filled into a gelatin capsule if desired. After ingestion, the capsule bursts and releases the formulation. When the formulation comes into contact with an aqueous environment, for example in the gastrointestinal tract, the formulation spontaneously forms an emulsion. One advantage of the invention is that active agents with poor water solubility can be dissolved and formulated into a useful therapeutic formulation.

The preferred polymeric precipitation inhibitor for SNEDDS is PVP (polyvinylpyrrolidone), a synthetic polymer formed from linear 1-vinyl-2-pyrrolidinone groups. The use of polyvinylpyrrolidone as an excipient useful in self-emulsifying hydrophobic formulations has not yet been described. The degree of polymerisation of the polymer gives polymers of different weights with which polyvinylpyrrolidone can be characterized. The polyvinylpyrrolidone used in this invention can have a molecular weight of from about 2,500 to about 100,000. Increasing molecular weight of the polyvinylpyrrolidone polymer is associated with increasing viscosity, which is expressed as a K value. Polyvinylpyrrolidone polymers are commercially available from BASF Corporation (Parsippany, New Jersey, USA) under the trade name KOLLIDON™ and are generally available in K 12, 15, 17, 25, 30, 60 and 90. Preferred polymers have molecular weights from about 2,500 to about 20,000, corresponding to lower K values such as K12 and K25. A sufficient amount of polyvinylpyrrolidone is used to dissolve the desired amount of active substance. In order to take full advantage of the present invention, the active agent is dissolved in a carrier containing polyvinylpyrrolidone. The invention has the unique advantage that polyvinylpyrrolidone, which is commonly used to prepare solid formulations such as tablets or pellets, can dissolve an extremely water-insoluble lipophilic active agent. A preferred amount of polyvinylpyrrolidone in the formulation is about 0.1% by weight to about 10% by weight of the total formulation. A more preferred amount of polyvinylpyrrolidone in the formulation is about 0.1% by weight to about 3% by weight, and more preferably about 0.1% by weight to about 2% by weight.

Certain embodiments presented herein relate to free-flowing solid powders prepared from SNEDDS self-nano-formulations of the invention. Powders can be prepared by subjecting the nano-formulation (super-saturated oil-free self-nano-emulsifying drug delivery system - SNEDDS according to the invention) to encapsulation, nano-spray drying, thin-layer drying or lyophilization; or by combining the nano-formulation with a carrier selected from the group consisting of microcrystalline cellulose, precipitated silica, anhydrous dibasic calcium phosphate, mannitol, hydroxypropyl methylcellulose, cellulose, and mixtures thereof.

Other embodiments described herein relate to liquid nutraceutical compositions prepared by dispersing the nano-formulation in an aqueous medium. Further embodiments relate to gels or creams prepared by combining the nano-formulation with a wax or polymer. Suitable waxes or polymers include hydroxypropyl methylcellulose, isopropyl myristate, collagen, cetyl alcohol, metal salts of stearic acid and carbopol.

The various embodiments described herein relate to a process for preparing a supersaturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to the invention in liquid form comprising a hydrophobic biologically active material, the process comprising the following steps:

a) preheating the emulsifier, which comprises a nonionic surfactant with an HLB value of 15 to 18 and a co-solvent to a temperature above the melting point of the hydrophobic biologically active substance;

b) adding the hydrophobic biologically active material to the preheated emulsifier/cosolvent/stabilizer, and dissolving the hydrophobic biologically active material in the emulsifier/cosolvent/stabilizer to form a mixture;

c) cooling the mixture to 50 °C or to room temperature and

d) adding the desired amount of aqueous phase followed by mixing to obtain a nanoemulsified formulation of the hydrophobic active system containing particles with a particle size of less than 50 nm.

The mixture from step (b) is heated at a temperature in the range of 50-200 °C to obtain solubilization of the hydrophobic biologically active material in the emulsifier / co-solvent / stabilizer.

The mixture from step (b) is sonicated to obtain solubilization of the hydrophobic biologically active material in the emulsifier/cosolvent/stabilizer.

The mixture from step (b) is subjected to vortexing to obtain solubilization of the hydrophobic biologically active material in the emulsifier / cosolvent / stabilizer.

The mixture from step (b) is subjected to ultra-high pressure homogenization to obtain solubilization of the hydrophobic biologically active material in the emulsifier / co-solvent / stabilizer.

Detailed description of the process:

1) Prepare and sterilize the glassware for mixing the ingredients (2 containers) for the emulsified and aqueous phases

In container 1:

• Mix the emulsifiers / co-solvents / stabilizer at a room temperature of 22-25 °C. Mix for 15 minutes. The mixture is heated to 60-200 °C.

• Add each API component sequentially to the heated mixture, while mixing each component dissolves in 15-30 minutes. The mixture is always heated above the melting temperature of the individual API component.

• Turn off the heating. While stirring, let the mixture cool down to a temperature of 50 °C.

In container 2:

• We degas the distilled water (extraction with the help of a vacuum).

• Pour a certain % of degassed distilled water into container 2. Heat to 50 °C.

• Add a certain % of auxiliary substance for stabilization (pH regulator, antioxidants, precipitation inhibitors, etc.) to the heated distilled water while constantly stirring and maintaining the temperature at 50 °C.

2) Adding the desired amount of aqueous phase followed by mixing to obtain a nanoemulsified formulation of hydrophobic pharmaceutically active ingredients containing micelles with globule sizes between about 10 nm and about 50 nm. Slowly pour the contents of container 2 into container 1. Stir thoroughly for 30 minutes and maintain the temperature at 50 °C.

3) Finalization of the emulsification with a 10-minute ultrasonic treatment.

4) The resulting emulsion is vacuumed for 10 minutes, followed by filtration of the emulsion to remove foam.

5) Pour the obtained SNEDDS nanoemulsion into the prepared container for storage.

Various embodiments relate to the treatment of diseases selected from the group consisting of various viruses, inflammation, immune modulation, osteoarthritis, allergy, obesity, neurodegenerative disorders, diabetes, cancer, cardiovascular disorders and microbiological disorders by delivering the listed self-nanoemulsifiers (SNEDDS). formulations to the entity that needs it.

Various formulations have been developed using single or combination of hydrophobic compounds along with single or combinations of surfactants mentioned herein. After describing the disclosed subject matter by reference to certain embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification.

The invention is further described with reference to the following examples. Those skilled in the art will appreciate that many modifications to the materials and methods may be made without departing from the scope of the subject matter disclosed.

EXAMPLES

The present invention is further explained in the form of the following examples. However, it should be understood that the above examples are merely illustrative and should not be taken as limiting the scope of the invention. Various changes and modifications of the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications may be made without departing from the scope of the invention.

Example 1 (Comparative)

Design of self-nanoemulsifying formulations (SNEDDS) based on CBD (cannabidiol) model drug

Materials: CBD isolate (purity > 99.2%) from DB Labs (USA). MCT Neobee (medium-chain triglyceride, MCT), Stepan Company (USA). CH-40 (hydrogenated castor oil, HLB = 15) and ΡΕΕ-6-sorbitan monooleate (TO-106V, HLB = 10.5) from Nikko Chemicals (Tokyo, Japan). Coconut oil fatty acid (COFA) from Cremer oleo GmbH & Co. Hamburg, Germany. PEG-400 manufactured by Evonik (Germany).

The self-emulsifying nature of the various formulations after dispersion in water showed varying degrees of transparency, from clear to whitish milky suspension of the formulations. Formulations were optimized based on their self-emulsifying performance. Formulation compositions and appearance in aqueous dispersions are presented in Table 3. The most interesting formulation systems that were able to produce nano-emulsions (SNEDDS) belong to LFCS types IIIB and IV. These SNEDDS components (Table 3) were developed using polar glycerides and water-soluble surfactants and cosolvents.

Table 3. Visual evaluation of different formulations within the Lipid Formulation Classification Systems (LFCS) under certain self-emulsification conditions.

LFCS No. Composition Appearance Suitable as SNEDDS Guys F1 COFA or MCT Dull and undispersed Unsuccessful Type II F2 COFA:MCT(7:3)/TO106V(l/l) Milky / cloudy Unsuccessful Lilac type F3a CoFA:MCT(7:3)/CH-40(l/l) Blue Done Type Illb F3b MCT:PEG400(1:1)/CH-40(1/1) Translucent Done Type IV F4 CH-40:: PEG400 (3:1) Translucent Done

Example 2 (Comparative)

A method of visual evaluation of CBD formulations

A visual evaluation method was used to determine the self-emulsifying properties of the formulation (Craig et al., 1995; Kommuru et al., 2001). To prepare the sample, 100 μΐ of each formulation was diluted with 10 mL of water in a 20 mL glass vial (solution concentration 1:100) and mixed gently for 1 minute at room temperature. For the efficiency of self-emulsification, the method of visual assessment at the beginning can reduce the excessive use of chemicals. The visual assessment for each sample was observed/recorded immediately after preparation and then for several months.

A visual evaluation method was used as a guideline for evaluating the mixability, homogeneity and appearance of the formulations. Visual evaluation of type III-IV formulations (F3b-F4) confirmed that the emulsion formed when diluted with water was physically stable for several months. Both lipophilic and hydrophilic surfactants with HLB 10-15 were able to promote self-emulsification of pure oil. However, the resulting emulsions (F2, type II) appeared crude (visually cloudy/milky, larger droplet sizes, with lipophilic surfactant TO106V) (HLB number 10.5) (while the appearance with hydrophilic surfactant HC-40 ( HLB number 15) for types ΠΙΑ, IIIB and IV much better). They provided fine (bluish / transparent systems with no visible particles), uniform emulsion droplets, which, due to their fine particles, are more likely to empty from the stomach upon dispersion. Pure fatty acid and glyceride oils (eg COFA or MCT) showed very poor self-emulsifying properties and did not form SNEDDS. They formed oil globules that did not disperse in aqueous media, along with cloudy appearances. Formulations (type II) containing lipophilic ingredients (COFA:MCT7:3) /TO106V (1/1), i.e. F2 were milky and cloudy in appearance after aqueous dispersion and were also not suitable as a SNEDDS formulation (Fail as SNEDDS). However, when the glyceride oils were mixed with a water-soluble surfactant (hydrogenated castor oil surfactant) and a co-solvent, representative formulations were considered SNEDDS (done as SNEDDS, and their appearance was either clear or bluish with a homogeneous dispersion (e.g., F3a -F4).A comprehensive study on visual evaluation of formulations shows that the choice of excipients during a formulation development study affects the efficacy of the pharmaceutical drug such as stability, bioavailability and manufacturability (Craig et al., 1995) (Figure 5).

Example 3 (Comparative)

Determination of solubility, droplet size, polydispersity index (PDI) and zeta potential values

The droplet size, polydispersity index (PDI) and zeta potential (surface charge) of all representative diluted “F” systems were measured by laser light interference analysis technique using Zetasizer Nano (Model ZEN3600, Malvem, UK) particle sizing systems. Formulations were diluted 1:1000 v/v with water and mixed well for 1 minute. Diluted samples were transferred to cuvettes and 10 replicate readings were performed for each sample. Samples from each of three (3) separate batches of the formulation were used to determine droplet size and zeta potential values.

The effect of the water-soluble components in the different "F" formulations on the change in droplet size and PDI is clearly shown in Figure 6. In Figure 6, the Y-axis is represented in log 10, the results are represented as mean ± SD (n = 3). Formulation a type IV, which contained the highest concentration of water-soluble components, produced the smallest droplets after dilution with water (F5, 15.27 nm). The largest droplet sizes were produced with formulation type I (Fl, 1274 nm, PDI-0.88) as it contained 100% oil and the formulation was poorly dispersed in water. As the type II (F2) formulation contained 0-20% water soluble materials, the droplet sizes were significantly reduced to 235.27 nm (p < 0.005) with a lower PDI value of 0.22 (monodispersed). However, due to the increased number of water-soluble materials (40-80%) in the formulations of types IIIA and IIIB, the droplet sizes were significantly reduced in the 8535 nm region (p < 0.005). It was found that among all the formulation systems, comparatively F5 was the most stable system with small droplet size (15.27 nm) and lower PDI value (0.18) for CBD when diluted with water (Figure 6).

In addition, the zeta potential values of all CBD formulations were found to be between 1.0 and 44.0 mV. However, zeta potential (surface charge) values in formulations from 15.0 to 32.0 were reported to be very stable without droplet aggregation in the continuous phase (Table 3). This may be due to a higher concentration of nonionic surfactant, which may result in better self-emulsifying systems, causing a negatively charged interface around the oil droplets and thereby increasing the stability of the formulations. This result is consistent with previous reports (Mohsin et al., 2016). The reduction in droplet size may be due to more surfactants being available to stabilize the oil-water interface. In SNEDDS formulations, it is more likely that the larger the surface area, the faster and more complete the rate of drug absorption (Mohsin et al., 2016). In addition, the droplet size reduction represents the formation of a unique tightly closed surfactant film at the oil-water interface (Table 4), as it stabilizes the oil droplets (Gershanik and Benita, 2000; Pouton, 2000).

Table 4. Visual evaluation of different CBD formulations within lipid formulation sorting systems (LFCS) under specific self-emulsification conditions. (Figure 5, 6)

LFCS No. Composition Size nm Zeta Guys F1 COFA or MCT 1274.45 ± 350 17.73 ±5.86 Type II F2 COFA:MCT(7:3)/TO106V(l/l) 235.27 ±34.43 34.20 ± 1.6 Lilac type F3a COF A: MCT(7:3)/CH-40(1/1) 155.27 ±3.89 44.27 ±3.53 Type Hib F3b MCT:PEG400(1:1)/CH-40(1/1) 35.25 ±4.40 22.90 ± 0.44 Type IV F4 CH-40:PEG400(3:1) 15.27 ±4.43 19.55 ±6.42

The formulations were dispersed in water at a concentration of 1:1000 (% w/v). Data are presented as mean ± SD of n 3-6.

Example 4

In vitro - in vivo safety validation of hydrogenated castor oil PEG-40 as emulsifier and PEG-400 as co-solvent for oral nano-emulsion formulations

Example 4.1 Preparation of "empty nano-emulsion"

The blank nano-emulsion consisted of an oil phase of GMO, hydrogenated castor oil PEG-40 and PEG-400 (1:8:1) prepared using our established formula. The mixture of oil, surfactant and co-surfactant was stirred at 100 rpm for 2 hours. Further sonication for 10 min using a sonic bath apparatus (AMM Reactor Ultrasonic Cleaner, Shanghai, China) was used to complete the mixing process. To obtain a nano-emulsion, deionized water was added to the oil phase in a ratio of 5:1 and mixed gently. Following this protocol, an empty nano-emulsion was spontaneously formed.

Scientific research by Heni Rachmawati and co-workers (Nanoscience and Nanotechnology Research Center, Institut Teknologi Bandung, Jalan Ganesha 10, 40132 Bandung, Indonesia) conducted with a “blank nano-emulsion” with HC40 and PEG-400 emulsification system clearly confirmed our results , presented in Examples 1, 2, 3, i.e.: the nano-emulsion produced a transparent dispersion due to smaller oil droplets dispersed in the aqueous phase, which was confirmed by particle size measurement (Table 5) and microscopic observation.

Table 5. Physical parameters of blank nanoemulsion.

Parameters Value* Particle size (nm) 21.4 ±5.8 Polydispersity index 0.245 ±0.177 Zeta (ζ) potential (mV) -10.6 ± 1.12

* Each parameter was specified in triplicate.

Example 4.2 Stability study of empty nano-emulsion in gastrointestinal simulation fluids

The proposed delivery system of this nano-emulsion is for oral administration. In order to ensure the physical stability of the nano-emulsion, the effect on the state of the gastrointestinal tract (GIT) was evaluated using gastric simulating fluid (0.1 N HC1) and intestinal simulating fluid (phosphate buffer at pH 6.8) at 37 °C for 3 h. An equal volume ratio of nano-emulsion and GIT simulation fluid was mixed and observed visually and by particle size measurement as previously described.

Example 4.3 Stability study of empty nano-emulsion during storage

The physical stability of the empty nano-emulsion was performed by keeping the sample for nine months at room temperature. Observation was performed visually and by particle size measurement as previously described. A stable dispersion system formed by this established formula (Figure 14) was also demonstrated when the nano-emulsion was kept at room temperature for nine months. Also, extensive coalescence, which would be indicated by the transparency of the preparation, was not detected, which was also confirmed by the PSA data (globule diameter 25.1 nm, Pl 0.079) (Figure 7, 8).

Example 4.4 Cytotoxicity assay in vitro

The cytotoxic effect of blank nano-emulsion on several cell lines including NIH/3T3, 3T3SA, RSC-96, RAW 264.7, RBL-2H3, CHO-K1, Caco-2 and NCI-H292 was determined using the MTS assay in according to the manufacturer's protocol (Promega). Briefly, cells were trypsinized and plated in a 96-well plate at a density of 104 cells/well. Cells were grown overnight at 37 °C with 5% CO2. Cells were added with 20 mg/ml blank nano-emulsion. Next, cells were incubated overnight and immediately added with 20 µL of MTS to each well. Cells were re-incubated for 2 h at 37 °C with 5% CO2. Absorbance was measured at 490 nm using an enzyme-linked immunosorbent assay (ELISA) microplate reader (Biorad, Hercules, CA, USA). The result was presented as a percentage of cell survival compared to untreated controls (Figure 9, 10).

Example 4.5 Cytotoxicity assay and acute toxicity assay

Blank nano-emulsion did not show any cytotoxic effect (Figure 10).

No signs of straub, piloerection, ptosis, catalepsy, lacrimation, vocalization, salivation, tremors, convulsions or writhing were observed during the first 24 hours after administration of the test substance. This proves that the test substance did not cause a toxic effect on the central nervous system. Motor activity as well as body posture, breathing, urination and defecation were normal. In addition, all mice showed normal reflexes, indicating that the test substance did not affect the integrity of the spinal cord in the central nervous system.

Conclusions

A blank nano-emulsion consisting of the oil phase component GSO (glycerol monooleate), hydrogenated castor oil PEG-40 as a surfactant and PEG 400 as a co-surfactant (1:8:1) shows no negative response when incubated in different types of cell lines. These in vitro data are confirmed in vivo after 14 days of single-dose oral administration. The use of high concentration of hydrogenated castor oil PEG-40 to form clear spontaneous and stable oil droplets when challenged in simulating GIT fluids appears to be acceptable for oral delivery of such active compounds loaded into the developed nano-emulsion.

Example 5

Methods of formulation and preparation of the proprietary natural pharmaceutical product “CimetrA”, targeting the symptoms of COVID-19 based on oral SNEDDS in the form of spray and powder,

CimetrA is an oral self-nanoemulsifying drug system (SNEDDS) according to the present invention, which contains all API components (curcumin, boswellia, artemisinin) as a lipophilic micelle core and emulsifiers as a micelle shell, and vitamin C as a SNEDDS stabilizer and aqueous phase pH regulator .

Table 6. Formulation of CimetrA

CimetrA formulation w/w% content Artemisinin 0.6% API Boswellia 1.5% API Curcumin 95% 2.0% API Ascorbic acid 6.0% Excipient Cremaphor CH-40 20% Emulsifier PEG-400 5% Sotopil

Other optional Excipient

Distilled water 64.9%

Curcumin·. The curcumin product used was “Turmeric Oleoresin Curcumin Powder 95%” code EP-5001 from Green Leaf Extraction Pvt Limited, Kerala, India. Curcumin powder is CAS no. 458-37-7 and is a natural product obtained by solvent extraction of the rhizome of Curcuma Longa. According to the manufacturer, the curcumin content in the powder is at least 95%. This curcumin content is determined according to the ASTA 18.0 method.

Boswellia·. The term "Boswellia" refers specifically to the resin extract of the plant for incense. In particular: alpha-boswellic acid (CAS number 471-66-9), beta-boswellic acid (CAS number 631-69-6) and their derivatives, 3-O-acetyl-alpha-boswellic acid CAS number 89913-60- 0), 3-O-acetyl-beta-boswellic acid (CAS number 596870-7), 11-keto-beta-boswellic acid (KBA, CAS number 17019-92-0), and 3-O-acetyl-l 1keto -beta-boswellic acid (AKBA, CAS number 67416-61-9).

Artemisinin, Artemisinin, also called qinghaosu, is an antimalarial drug obtained from the sweet wormwood plant, Artemisia annua. Artemisinin is a sesquiterpene lactone (a compound consisting of three isoprene units attached to cyclic organic esters) and is distilled from the dried leaves or flower clusters of Artemisia annua.

Self-emulsification depends on the nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio, and the temperature at which self-emulsification occurs. Only very specific combinations of excipients lead to effective self-emulsifying systems (SNEDDS). The effectiveness of drug inclusion in SNEDDS depends on the specific physico-chemical compatibility of the drug / system. So, pre-formulation solubility and phase diagram studies are required to obtain an optimal formulation design.

Preparation of SNEDDS CimetrA (Figure 13)

1. Prepare and sterilize a glass container for mixing the ingredients (2 containers) and for storing the finished product.

2. Container no. 1

2.1. At a room temperature of 22-25 °C, mix 20% Cremaphor Tagat CH-40 and 5% PEG 400. Mix for 15 minutes. The mixture is heated to 60 °C.

Visual inspection of quality. Result: light yellow homogeneous transparent mixture.

2.2. Add 0.6% artemisinin to the heated mixture. During 15 minutes of mixing, artemisinin is completely dissolved. The mixture is heated to 80 °C.

Visual inspection of quality. Result: light yellow, homogeneous transparent mixture.

2.3 We inject 1.5% boswellia. Boswellia is completely dissolved during 15 minutes of mixing. The mixture is heated to 90 °C.

Visual inspection of quality. Result: dark yellow homogeneous transparent mixture.

2.4 Inject 2.0% curcumin. Curcumin is completely dissolved during 15 minutes of mixing. The mixture is heated to 95-98 °C.

Visual inspection of quality. Result: dark red (almost black) homogeneous transparent mixture.

2.5 Turn off the heating. While stirring, let the mixture cool down to a temperature of 50 °C.

3. Container no. 2

3.1 Degas the distilled water (vacuum extraction).

3.2 In container no. 2 pour 64.9% degassed distilled water. Heat to 50 °C.

3.3. Add 6% ascorbic acid to heated distilled water. Dissolve the ascorbic acid for 10 minutes with constant stirring and maintaining the temperature at 50 °C.

Visual inspection of quality. The result: a clear mixture

4. In container no. 1 slowly pour the contents of container no. 2. Stir thoroughly for 30 minutes and maintain the temperature at 50 °C.

Visual inspection of quality. Result: dark red homogeneous non-viscous transparent mixture.

5. Finalization of emulsification with a 10-minute ultrasonic treatment.

Visual inspection of quality. Result: dark red homogeneous non-viscous transparent mixture.

6. Vacuum the resulting emulsion for 10 minutes, then filter the emulsion to remove foam.

7. Pour the resulting nano-emulsion into a prepared container for storage.

The resulting emulsion contains the following APIs:

• Artemisinin - 0.6% • Boswellia - 1.5% • Curcumin - 2.0% • Ascorbic acid - 6.0% • Water - 64.9%

Characteristics of the emulsion:

• solubility in water (SNEDDS technology) • transparency (micelle size less than 50 nm) • low viscosity, high fluidity (very suitable for use in sprays) • stability during storage (maintenance of all properties, including no formation of sediment, turbidity or phase separation ingredients)

The flow chart for the production of CimetrA is shown in the schematic (Figure 13).

Example 6

Solid self-emulsifying / micro-emulsifying drug delivery systems

Self-emulsifying / micro-emulsifying drug systems require incorporation into capsules directly or conversion into granules, pellets and powders for dry-filled capsules as well as tablet preparations. The latter are possible through innovative adaptations of conventional equipment with relative ease and simplicity of procedures, using methods such as melt granulation, melt extrusion, solid support adsorption, spray cooling, spray drying, liquid-based supercritical methods, and high-pressure homogenization. Recently, pellets containing self-emulsifying mixtures were prepared using the technique of extrusion e-spheronization e.

For example, solid SNEDDS can be prepared from liquid SNEDDS by adding hardeners, namely by physical absorption with porous supports to obtain powders, by direct tablet compression, by extrusion spheronization of granules and by melt extrusion of pellets.

A high content of liquid formulation can be loaded (up to 70%) on the carrier, which not only maintains good flowability, but also enables the production of tablets with good cohesive properties and good content uniformity in both capsules and tablets. This obviously increases the options available to the formulator. In addition to providing the obvious benefits of the in vivo tablet dosage delivery system (improved drug absorption, etc.), the advantages of developing solid dosage forms are that a high content of liquid formulation can be loaded onto the carrier and the process gives good content uniformity. In terms of functionality and efficacy, the solubility properties of the final solid dosage form should not affect either the adsorption of the liquid formulation to the carrier, nor the state of the drug in the lipid formulation.

Self-emulsification depends on the nature of the oil/surfactant pair, the surfactant concentration and oil/surfactant ratio, and the temperature at which self-emulsification occurs. Only very specific combinations of excipients lead to effective self-emulsifying systems (SES). The effectiveness of the inclusion of drugs in SEDDS depends on the specific physicochemical compatibility of the drug / system. So, pre-formulation solubility and phase diagram studies are required to obtain an optimal formulation design.

Development and characterization of CimetrA solid SNEDDS

The ratio of adsorbent and SNEDDS

The proper ratio of Aerosil 200 adsorbent to CimetrA liquid SNEDDS can produce the free-flowing properties of solid SNEDDS. In this case, equal amounts of Aerosil 200 and CimetrA liquid SNEDDS (50/50% w/w) produced free-flowing powders suitable for immediate tablet compression. On the other hand, higher and lower amounts of Aerosil 200 with liquid SNEDDS CimetrA (33/67% w/w) produced significant dusting and greasy dust properties.

Free-flowing powders can be obtained in a simple way by adding an optimal amount of liquid lipid formulation to the selected carrier. In the example, the relationships between “liquid

SNEDDS" and "Aerosil 200" 50/50 (% w/w) produced a dry free-flowing powder. No significant changes were observed between these ratios due to the high adsorption capacity of the adsorbent (Aerosil 200) and the retention of liquid SNEDDS in their internal pores. Upon visual inspection, all SNEDDS powders were dry and free-flowing at this point, indicating an ideal choice of 50/50 (% w/w) ratio (Figure 12).

Literature

1. Bevemage J, Brouwers J, Brewster ME, Augustijns P. (2013). Evaluation of gastrointestinal drug supersaturation and precipitation: strategies and issues. Int J Pharm 453:25-35.

2. Colin W. Pouton, Self-emulsifying drug delivery systems: assessment of the efficiency of emulsification, International Journal of Pharmaceutics, Volume 27, Issues 2-3, 1985, Pages 335-348, ISSN 0378-5173, https:// doi.org/10.1016/03785173(85)90081-Χ.

3. Craig D.Q.M., Barker S.A., Banning D., Booth S.W. (1995). An investigation into the mechanisms of self-emulsification using particle size analysis and low frequency dielectric spectroscopy. Int. J. Pharm. 114 103-110. 10.1016/0378-5173(94)00222q

4. Elgart A., Chemiakov L, Aldouby Y., Domb A. J., Hoffman A. (2013). Improved oral bioavailability of BCS class 2 compounds by self-nano-emulsifying drug delivery systems. (SNEDDS): the underlying mechanisms for amiodarone and talinolol. Pharm. Really. 30 3029-3044. 10.1007/en 1095-013-1063-y

5. Fatouros, Dimitris & Karpf, Ditte & Nielsen, Flemming & Mullertz, Anette. (2007). Clinical studies with oral lipid-based formulations of poorly soluble compounds. Therapeutics and clinical risk management. 3. 591-604.

6. Gao P, Morozowich W. (2006). Development of supersaturable self-emulsifying drug delivery system formulations for improving the oral absorption of poorly soluble drugs. Expert Opin Drug Deliv 3:97-110.

7. Gershanik T., Benita S. (2000). Self-dispersing lipid formulations for improving oral absorption of lipophilic drugs. Eur. J. Pharm. Biopharm. 50 179-188. 10.1016/s0939-6411(00)00089-8

8. Heni Rachmawati et al. (Research Center for Nanosciences and Nanotechnology, Institut Teknologi Bandung, Jalan Ganesha 10, 40132 Bandung, Indonesia) The In Vitro-In Vivo Safety Confirmation of PEG-40 Hydrogenated Castor Oil as a Surfactant for Oral Nanoemulsion Formulation.

9. Kale A. A., Patravale V. B. (2008). Design and evaluation of self-emulsifying drug delivery systems. (SEDDS) of nimodipine. AAPS PharmSciTech 9 191-196. 10.1208/s 12249-008-9037-9.

10. Kang B.K., Lee J.S., Chon S.K., Jeong S.Y, Yuk S.H., Khang G., et al. (2004). Development of self-microemulsifying drug delivery systems. (SMEDDS) for oral bioavailability enhancement of simvastatin in beagle dogs. Int. J. Pharm. 274 65-73. 10.1016/j.ijpharm.2003.12.028

11. Kazi M, Al-Swairi M, Ahmad A, Raish M, Alanazi FK, Badran MM, Khan AA, Alanazi AM, Hussain MD. Evaluation of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) for Poorly Water-Soluble Talinolol: Preparation, in vitro and in vivo Assessment. Front Pharmacol. 2019 May 2; 10: 459. doi: 10.3389/fphar.2019.00459. PMID: 31118895; PMCID: PMC6507620.

12. Kommuru TR, Gurley B, Khan MA, Reddy IK (2001). Self-emulsifying drug delivery systems. (SEDDS) of coenzyme Q10: formulation development and bioavailability assessment. Int. J. Pharm. 212 233-246. 10.1016/s03785173(00)00614-1

13. Mathews C, Sugano K. (2010). Supersaturable formulations. Drug Deliv Sys 254:371-4.

14. Mohsin K., Alamri R., Ahmad A., Raish M., Alanazi F.K., Hussain M.D. (2016). Development of self-nanoemulsifying drug delivery systems for the enhancement of solubility and oral bioavailability of fenofibrate, a poorly water-soluble drug. Int. J. Nanomed. 11 2829-2838. 10.2147/IJN.S104187

15. Pouton CW. (2000). Lipid formulations for oral administration of drugs: nonemulsifying, self-emulsifying and 'self-microemulsifying' drug delivery systems. Eur J Pharm Sci, 11: S93-S98.

16. Pouton, C., and Porter, C. (2008). Formulation of lipid-based delivery systems for oral administration: materials, methods and strategies t. Adv. Another Deliv. Rev. 60, 625-637. doi: 10.1016/j.addr.2007.10.010

17. Ravi Devraj, Hywel D. Williams, Dallas B. Warren, Anette Mullertz, Christopher J.H. Porter, Colin W. Pouton. In vitro digestion testing of lipid-based delivery systems: Calcium ions combine with fatty acids liberated from triglyceride rich lipid solutions to form soaps and reduce the solubilization capacity of colloidal digestion products. International Journal of Pharmaceutics, Volume 441, Issues 1-2, 2013, Pages 323-333, ISSN 0378-5173, https://doi.Org/10.1016/j.ijpharm.2012.ll.024.

18. Shahba, Ahmad & Ahmed, A & Kazi, Mohsin & Abdel-Rahman, S & Alanazi, Fars. (2017). Solidification of cinnarizine self-nanoemulsifying drug delivery systems by fluid bed coating: Optimization of the process and formulation variables. Die Pharmazie. 72. 143-151. 10.1691/ph.2017.6089.

19. Strickley, R.G. Solubilizing Excipients in Oral and Injectable Formulations. Pharm Res 21, 201-230 (2004). https://doi.Org/10.1023/B:PHAM.0000016235.32639.23

20. Warren DB, Benameur H, Porter CJH, Pouton CV. (2010). Using polymeric precipitation inhibitors to improve the absorption of poorly water-soluble drugs: a mechanistic basis for utility. J Drug Target 18: 704-31.

21. Xu S, Dai, WG. (2013). Other precipitation inhibitors in supersaturable formulations. Int J Pharm 453:36^43.

Claims (20)

1. Super-saturated oil-free self-nano-emulsifying drug delivery system - SNEDDS for poorly water-soluble pharmaceutical ingredients, which includes: a) a dispersed phase in an amount of 10-95% by weight of the formulation, said dispersed phase including particles with a particle size of less than about 50 nm, said dispersed phase comprising: a. particles with an emulsifier containing a nonionic surfactant with an HLB value of 15 to 18, a cosolvent and b. hydrophobic biologically active material in the amount of 0.0001 to 10% based on the weight of the formulation and b) an aqueous phase in an amount of 5-70%, based on the weight of the formulation, whereby between 70 and 95% of the hydrophobic biologically active material is spontaneously released from the nanoformulation when the nanoformulation is added to water. 2. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1, where the hydrophobic biologically active material is a natural product, a synthetically obtained product or a mixture thereof. 3. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1, wherein the hydrophobic biologically active material is selected from the group consisting of: at least one curcuminoid selected from the group consisting of curcumin, demethoxycurcumin, bisdemethoxycurcumin and bis-o-demethyl curcumin; at least one boswellic acid compound; resveratrol; hypericin; bacoside(s); xanthorhizol; luteolin; pyrogallol; genistein; wogonin; morin; kaempferol; and mixtures thereof. 4. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS, according to claim 1, where the hydrophobic biologically active substance is an extract or phytochemical obtained from at least one plant selected from the group consisting of curcuma longa, black seed, artemisinin, boswellia, cannabinoids, ginseng, ginkgo biloba, garcinia mangostana, ocimum basilicum, zingiber officinale, tribulus terrestris, sphaeranthus indices, annona squamosa, moringa oleifera, murraya koenigii and their mixtures. 5. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1, where the emulsifier is selected from the group consisting of hydrogenated castor oil, polysorbates, polyethylene glycols, polyethylene glycol esters, glycerol esters, polyvinylpyrrolidone and mixtures thereof with HLB 15-18. 6. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 5, wherein the preferred emulsifier is selected from the group including hydrogenated castor oil, preferably Cremophor HC-40. 7. Super-saturable oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1, wherein the preferred co-solvent is selected from the group consisting of polyethylene glycol, preferably PEG-400. 8. A super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1, optionally including stabilizers including antioxidants, pH regulators, desired substances, precipitation inhibitors and stabilizing components. 9. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 8, wherein the preferred antioxidant and pH regulator is selected from the group consisting of ascorbic acid, preferably vitamin C. 10. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 8, wherein the preferred precipitation inhibitor is selected from the group consisting of polyvinylpyrrolidone, preferably Kollidon K 17. 11. A free-flowing solid powder prepared by subjecting the super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1 to encapsulation, nano-spray drying, thin-layer drying or lyophilization. 12. A free-flowing solid powder prepared by combining the super-saturated oil-free self-nano-emulsifying drug delivery system - SNEDDS according to claim 1 with a carrier selected from the group consisting of microcrystalline cellulose, precipitated silica, anhydrous dibasic calcium phosphate, mannitol, hydroxypropyl methylcellulose, cellulose and their mixtures. 13. A liquid nutraceutical composition prepared by dispersing a super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1 in an aqueous medium. 14. A composition in the form of a gel or cream containing a super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1 and a wax or polymer, wherein said wax or polymer is selected from the group consisting of hydroxypropyl methylcellulose, isopropyl myristate , collagen, cetyl alcohol, metal salts of stearic acid and carbopol. 15. A process for the preparation of a super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS in liquid form comprising a hydrophobic biologically active material, the process comprising the following steps: a) preheating the emulsifier, which comprises a nonionic surfactant with an HLB value of 15 to 18 and a co-solvent to a temperature above the melting point of the hydrophobic biologically active substance; b) adding the hydrophobic biologically active material to the preheated emulsifier/cosolvent/stabilizer and dissolving the hydrophobic biologically active material in the emulsifier/cosolvent/stabilizer to form a mixture; c) cooling the mixture to 50 °C or to room temperature and d) adding the desired amount of aqueous phase followed by mixing to obtain a nanoemulsified formulation of the hydrophobic active system containing particles with a particle size of less than 50 nm. 16. The process according to claim 15, in which the mixture from step (b) is heated at a temperature in the range of 50-200 °C to obtain the solubilization of the hydrophobic biologically active material in the emulsifier / co-solvent / stabilizer. 17. The method according to claim 15, in which the mixture from step (b) is subjected to ultrasonic treatment to obtain solubilization of the hydrophobic biologically active material in the emulsifier / co-solvent / stabilizer. 18. The process according to claim 15, in which the mixture from step (b) is subjected to vortexing to obtain solubilization of the hydrophobic biologically active material in the emulsifier / cosolvent / stabilizer. 19. The method according to claim 15, in which the mixture from step (b) is subjected to ultra-high pressure homogenization to obtain the solubilization of the hydrophobic biologically active material in the emulsifier/cosolvent/stabilizer. 20. Super-saturated oil-free self-nanoemulsifying drug delivery system - SNEDDS according to claim 1 for the treatment of inflammation, osteoarthritis, allergy, obesity, neurodegenerative disorders, diabetes, viral infections, cancer, cardiovascular disorders and microbial disorders.