FIELD OF THE INVENTION
[0001] The present disclosure generally pertains to the technical field of self-nanoemulsifying drug delivery system (SNEDDS). In particular, the present disclosure pertains to an advantageous composition including an active ingredient having low aqueous solubility, an emulsifier and a co-solvent that exhibits superior bioefficacy of the active ingredient.

BACKGROUND OF THE INVENTION
[0002] Background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
[0003] Active ingredients such as oils generally possess multitude of advantageous biological properties and has been in use for several ages, for example, as nutraceuticals, diagnostics and for treatment and/or prevention of multitude of ailments. Particularly, oils such as peppermint oil and spearmint oil are known to possess various beneficial properties such as anti-inflammatory, analgesic, antispasmodic, astringent, carminative, decongestant, digestive, expectorant, stimulant, vasoconstrictor, antimicrobial and antifungal activities, besides being of nutritional value. Active oils are generally either totally water insoluble or have low water solubility. Formulating aqueous dosage forms including one or more active oils having low or poor aqueous solubility possess a great challenge. This problem is further accentuated by the fact that ready to serve or ready to ingest formulations may deteriorate and/or accelerate the deterioration of active ingredients. Dispersions of active oil in water results in biphasic systems with uneven distribution of active oil leading to variable amount of active oil in the stipulated dosage of multidose dosage forms.
[0004] Accordingly, the known strategies, such as preparation of dispersions and the likes used to prepare homogeneous solutions containing oil(s) dispersed within the water inherently suffers from several fold disadvantages. One of strategies includes preparation of water soluble granules or other solid delivery systems, and emulsification using various surfactant and co-surfactant systems. However, such systems are cost and energy intensive, require special equipments and/or devices or there are issues with the thermodynamic stability and shelf-life of the final products.
[0005] There is, thus, a need in the art for new and improved compositions including one or more active ingredients having low water solubility (e.g. oil) that are easy to prepare, less cost and energy intensive, thermodynamically stable, and having improved shelf-life while exhibiting superior bioefficacy and/or bioavailability of the active ingredient. The present invention satisfies the existing needs, as well as others, and generally overcomes the deficiencies found in the prior art.

OBJECTS OF THE INVENTION
[0006] An object of the present disclosure is to provide a composition with improved solubility of active ingredient having low aqueous solubility.
[0007] Another object of the present disclosure is to provide a self-nanoemulsifying drug delivery system (SNEDDS).
[0008] Another object of the present disclosure is to provide a self-nanoemulsifying drug delivery system (SNEDDS) that upon contact with the gastric fluid forms a stable emulsion.
[0009] Another object of the present disclosure is to provide a self-nanoemulsifying drug delivery system (SNEDDS) that upon contact with an aqueous media forms a stable emulsion.
[0010] Another object of the present disclosure is to provide a composition which is easy to prepare, does not require special equipments or devices,
[0011] Another object of the present disclosure is to provide a composition, which is economic and not energy intensive.
[0012] Still further object of the present disclosure is to provide a composition with improved thermodynamic stability and shelf-life.
[0013] Still further object of the present disclosure is to provide a self-nanoemulsifying drug delivery system (SNEDDS) composition that exhibits superior bioefficacy and/or bioavailability of the active ingredient.
[0014] Still further object of the present disclosure is to provide a method of preparation of a self-nanoemulsifying drug delivery system (SNEDDS).
[0015] Still further object of the present disclosure is to provide a method of preparation of a nano-emulsion.
SUMMARY OF THE INVENTION
[0016] The present disclosure generally pertains to the technical field of self-nanoemulsifying drug delivery system (SNEDDS). In particular, the present disclosure pertains to an advantageous composition including an active ingredient having low aqueous solubility, an emulsifier and a co-solvent.
[0017] An aspect of the present disclosure provides a composition including: an active ingredient with low aqueous solubility; an emulsifier; and a co-solvent, wherein the composition is a liquid composition that upon contact with an aqueous media forms an emulsion. In an embodiment, the composition is devoid of aqueous medium. In an embodiment, the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 200 nm. In an embodiment, the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 100 nm. In an embodiment, the active ingredient exhibits an octanol-water log P value ranging from about 1 to about 4. In an embodiment, the active ingredient comprises an oil selected from the group comprising peppermint oil, spearmint oil and combinations thereof, and wherein the active ingredient is present in an amount ranging from about 1% to about 30% by weight of the composition. In an embodiment, any or a combination of the emulsifier and the co-solvent exhibit a hydrophilic/lipophilic balance (HLB) value ranging from about 9 to about 14. In an embodiment, the emulsifier is selected from the group comprising polyethoxylated oils, polysorbates, castor oil ethoxylates, and combinations thereof, and wherein the emulsifier is present in an amount ranging from about 66% to about 90% by weight of the composition. In an embodiment, the co-solvent is selected from the group comprising propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and combinations thereof, and wherein the co-solvent is present in an amount ranging from about 0.5% to about 30% by weight of the composition. In an embodiment, the composition further comprises a solubilizer selected from the group comprising glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate/monocaprate, propylene glycol monolaurate, a medium chain fatty acid, and combinations thereof, and wherein the solubilizer is present in an amount ranging from about 0% to about 10% by weight of the composition. In an embodiment, the composition is formulated as any of an oral dosage form and a topical dosage form. In an embodiment, the composition is formulated as a self-nanoemulsifying drug delivery system (SNEDDS). In an embodiment, the composition is any of a pharmaceutical composition, a nutraceutical composition and a herbal composition. In an embodiment, the aqueous media comprises a gastric fluid.
[0018] In an embodiment, the composition includes: an oil that exhibits an octanol-water log P value ranging from about 1 to about 3 in an amount ranging from 1% to 30% by weight of the composition; an emulsifier selected from the group comprising polyethoxylated oils, polysorbates, castor oil ethoxylates and combination thereof in an amount ranging from 66% to 90% by weight of the composition; a co-solvent selected from the group comprising propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and combinations thereof in an amount ranging from 0.5% to 30% by weight of the composition; and a solubilizer selected from the group comprising glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate/monocaprate, propylene glycol monolaurate, a medium chain fatty acid and combination thereof in an amount ranging from 0% to 10% by weight of the composition, said composition being devoid of an aqueous medium, and said composition upon contact with a gastric fluid forms emulsion with droplets having a mean particle size (D50) ranging from 50 nm to 200 nm.
[0019] Another aspect of the present disclosure relates to a method of preparation of a nanoemulsion, the method comprising the steps of: effecting preparation of a self-nanoemulsifying drug delivery system (SNEDDS) comprising: an active ingredient with low aqueous solubility; an emulsifier; and a co-solvent, said SNEDDS being a liquid composition, devoid of aqueous medium; and contacting the self-nanoemulsifying drug delivery system (SNEDDS) with an aqueous media to effect preparation of the nanoemulsion.

DETAILED DESCRIPTION OF THE INVENTION
[0020] The following is a detailed description of embodiments of the disclosure. The embodiments are in such detail as to clearly communicate the disclosure. However, the amount of detail offered is not intended to limit the anticipated variations of embodiments; on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the present disclosure as defined by the appended claims.
[0021] Each of the appended claims defines a separate invention, which for infringement purposes is recognized as including equivalents to the various elements or limitations specified in the claims. Depending on the context, all references below to the "invention" may in some cases refer to certain specific embodiments only. In other cases it will be recognized that references to the "invention" will refer to subject matter recited in one or more, but not necessarily all, of the claims.
[0022] Unless the context requires otherwise, throughout the specification which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense that is as “including, but not limited to.” Additionally, the term "includes" means "comprises."
[0023] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
[0024] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and/or” unless the content clearly dictates otherwise.
[0025] In some embodiments, the numbers expressing quantities of ingredients, properties such as aqueous solubility, octanol-water partition coefficient, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The recitation of ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate value falling within the range.
[0026] Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. “such as”) provided with respect to certain embodiments herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.
[0027] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments.
[0028] The following discussion provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
[0029] Various terms as used herein are shown below. To the extent a term used in a claim is not defined below, it should be given the broadest definition permitted in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0030] The term “active ingredient having low aqueous solubility”, as used herein, refers to an active ingredient that is poorly water-soluble or essentially water-insoluble at a pH ranging from 5.0 to 9.0. Typically, the active ingredient having low aqueous solubility exhibits a water solubility of less than 1000 mg/L at a pH ranging from 5.0 to 7.0, preferably, less than 500 mg/L, more preferably less than 100 mg/L, and most preferably, less than 10 mg/L or even less than 0.01 mg/L.
[0031] The term “octanol-water log P value”, as used herein, is a measure of lipophilicity or hydrophobicity and refers to logarithm of the ratio of the concentrations of a solute between n-octanol and water, specifically for un-ionized solutes.
[0032] The term “hydrophilic/lipophilic balance (HLB) value”, as used herein, refers to an empirical value expressing the amphiphilic nature of emulsifiers. The least hydrophilic emulsifiers are assigned the lowest HLB values.
[0033] As used herein, the terms “composition” or “formulation,” are all intended to be used interchangeably.
[0034] As used herein, the terms “aqueous phase” or “aqueous fluid,” or “aqueous environment” or “aqueous media” are all intended to be used interchangeably and denotes the water or water based fluids.
[0035] As used herein, the term “devoid of aqueous medium” as used herein denotes that the composition includes aqueous medium in an amount less than about 5% by volume of the composition, preferably less than about 3% by volume of the composition and most preferably less than about 1% by volume of the composition.
[0036] The terms “% by w/w,” “weight percent,” “wt-%,” “percent by weight,” “% by weight,” and variations thereof, as used herein, refer to the concentration of a substance as the weight of that substance divided by the total weight of the composition and multiplied by 100. It is understood that, as used here, “percent,” “%,” and the like are intended to be synonymous with “weight percent,” “wt-%,” etc.
[0037] The present disclosure generally pertains to the technical field of self-nanoemulsifying drug delivery system (SNEDDS). In particular, the present disclosure pertains to an advantageous composition including an active ingredient having low aqueous solubility, an emulsifier and a co-solvent.
[0038] An aspect of the present disclosure provides a composition including: an active ingredient with low aqueous solubility; an emulsifier; and a co-solvent, wherein the composition is a liquid composition that upon contact with an aqueous media forms an emulsion. In an embodiment, the composition is devoid of aqueous medium.
[0039] In an embodiment, the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 200 nm. In an embodiment, the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 100 nm. However, a person skilled in the art would appreciate that the mean particle size (D50) of droplet may vary ranging from several micrometers to few nanometers, and accordingly, the compositions that may result in droplets with a mean particle size (D50) ranging from about 0.1 nm to about 10 µm is completely within the scope and spirit of the present disclosure. Preferably, composition of the present disclosure upon contact with an aqueous media results in a stable emulsion with droplet of mean particle size (D50) to the tune of few nanometers i.e. nano-emulsion.
[0040] In an embodiment, the active ingredient exhibits an octanol-water log P value ranging from about 1 to about 4. However, any other active ingredient that exhibit other octanol-water log P value (or different degrees of water solubility), as known to or appreciated by a person skilled in the art, can be utilized to serve its intended purpose as fully laid down in the present disclosure without departing from the scope and spirit of the present disclosure.
[0041] In an embodiment, the active ingredient comprises at least one oil selected from the group comprising peppermint oil, spearmint oil and combinations thereof. However, a person skilled in the pertinent art can readily appreciate that any other oil, such as essential oil having low aqueous solubility, for example, peppermint oil, spearmint oil, tea tree oil, mandarin oil, orange oil, lemon oil, cedarwood oil, eucalyptus oil and the likes, having one or more beneficial properties can be used in the present invention without departing from the scope and spirit of the present disclosure.
[0042] In an embodiment, the active ingredient is present in an amount ranging from about 1% to about 30% by weight of the composition. However, any other amount of the active ingredient can be formulated into the composition of the present disclosure without departing from the scope and spirit of the present invention. In an embodiment, the active ingredient is present in an amount ranging from about 3% to about 25% by weight of the composition. In an embodiment, the active ingredient is present in an amount ranging from about 5% to about 20% by weight of the composition.
[0043] In an embodiment, any or a combination of the emulsifier and the co-solvent exhibit a hydrophilic/lipophilic balance (HLB) value ranging from about 9 to about 14. However, a person skilled in the pertinent art should appreciate that emulsifier and/or co-solvent that exhibits other HLB value can be utilized in the present invention without departing from the scope and spirit of the present disclosure.
[0044] In an embodiment, the emulsifier is any emulsifier including, but not limited to, anionic, cationic, nonionic and amphoteric emulsifier. In an embodiment, the emulsifier is a nonionic emulsifier selected from the group consisting of polyethoxylated oils; polyethoxylated fatty acid diesters; polysorbates such as polysorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80; PEG-fatty acid mono and diesters such as PEG 35 castor oil; propylene glycol fatty acid esters such as caproyl 90; ethoxylated castor oil; polyethylene glycol alkyl ethers; polyglycerol esters; polyethoxylated fatty acid diesters; polyethylene glycol glycerol fatty acid esters; and/or combinations thereof. In an embodiment, the emulsifier is selected from the group consisting of polyethoxylated oils, polysorbates, castor oil ethoxylates, and/or combinations thereof. In an exemplary embodiment, the emulsifier is selected from the group consisting of polysorbate 20, polysorbate 80, PEG 35 castor oil, caproyl 90 and combinations thereof. In an embodiment, the emulsifier is selected from the group comprising polyethoxylated oils, polysorbates, castor oil ethoxylates, and combinations thereof. However, utilization of any other emulsifier, as known to or appreciated by a person skilled in the art, to serve its intended purpose is completely within the scope of the present disclosure. In an embodiment, the emulsifier is present in an amount ranging from about 66% to about 90% by weight of the composition. A person skilled in the art would appreciate that the amount of emulsifier may vary depending on the parameters such as droplet size, amount of oil and the likes and hence, utilization of emulsifier in any other amount is completely within the scope of the present disclosure, so far, the resulting formulation/composition exhibits the advantageous properties as disclosed as part of the present disclosure.
[0045] In an embodiment, the co-solvent is, for example, and without limitation, C1-C10 alcohols such as methanol, ethanol, propanol, isopropanol, butanol, pentanol, hexanol, heptanol, octanol, nonanol and decanol; polyols such as glycerol, propylene glycol and low molecular weight polyethylene glycols such as PEG 200, PEG 300 and PEG 400; diethylene glycol monoethyl ethers; triacetin; and glycofurol. In an embodiment, the co-solvent is selected from the group consisting of propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and/or combinations thereof. In an embodiment, the co-solvent is selected from the group comprising propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and combinations thereof. However, utilization of any other co-solvent, as known to or appreciated by a person skilled in the art, to serve its intended purpose as laid down in the present disclosure is completely within the scope of the present invention. In an embodiment, the co-solvent is present in an amount ranging from about 0.5% to about 30% by weight of the composition. A person skilled in the art would appreciate that the amount of co-solvent present in a composition may vary depending on the parameters such as amount of oil, water solubility of such oil and the likes and hence, utilization of co-solvent in any other amount is completely within the scope of the present disclosure, so far, the resulting formulation/composition exhibits the advantageous properties as disclosed as part of the present disclosure.
[0046] In an embodiment, the composition further includes a solubilizer. In an embodiment, solubilizer include monoesters of glycerin having fatty acid groups comprising about 8 to about 12 carbon atoms, monoesters of propylene glycol having fatty acid groups comprising about 8 to about 12 carbon atoms, medium chain fatty acids such as caprylic acid, capric acid and lauric acid, and/or combinations thereof. In an embodiment, the composition further comprises a solubilizer selected from the group comprising glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate/monocaprate, propylene glycol monolaurate, a medium chain fatty acid, and combinations thereof. However, utilization of any other solubilizer, as known to or appreciated by a person skilled in the art, to serve its intended purpose as laid down in the present disclosure is completely within the scope of the present invention. Preferably, the solubilizer is present in an amount ranging from about 0% to about 10% by weight of the composition. However, utilization of solubilizer in any other amount is completely within the scope of the present disclosure.
[0047] In an embodiment, the composition may further include additives such as preservatives, antioxidants, buffering agents, stabilizers, gelling agents and coloring agents. Preservatives can be, for example, benzoic acid, formaldehyde, sorbic acid, methyl parahydroybenzoate and propyl parahydroxybenzoate. Antioxidants can be, for example, ascorbyl palmitate, butylated hydroxytoluene, alpha-tocopherol, ß-carotene, ascorbic acid, lycopene, catechin, epicatechin, and epicatechin gallate. Buffering agents can be, for example, acetic acid, glacial acetic acid, lactic acid, citric acid, phosphoric acid, carbonic acid, histidine, glycine, barbital, phthalic acid, adipic acid, ascorbic acid, maleic acid, succinic acid, tartaric acid, glutamic acid, benzoic acid, aspartic acid, and salts (e.g., potassium, sodium, etc.) or combinations thereof. Gelling agent is selected from example, a group comprising of xanthan gum, carrageenan, locust bean gum, guar gum, modified celluloses, low-esterified pectines, and colloidal silicon dioxide. Stabilizers can be, for example, xylitol, sorbitol, sodium edentate, glycerine, ascorbic acid, and citric acid. Coloring agents can be any suitable coloring agent known in the art, used in the pharmaceutical, food or nutritional and herbal formulations.
[0048] In a preferred embodiment, the droplet size of the composition of the present invention is 50-200 nm. The composition of the present invention, by virtue of its choice of safe surfactants with lower IEG limits, does not lead to any precipitation of the active ingredient, and, thus provides a composition that is effective and stable over a wide period of time. Further, a stable self nano emulsifying composition with a mint loading ability of around more than 26%, hitherto unachieved, is a marked advancement over the existing art and paves way for further research and development on mint based products as a better, safer and with wide applications in herbal, nutritional and pharmaceuticals.
[0049] In an embodiment, the composition is formulated as an oral dosage form. In an embodiment, the composition is enclosed in a capsule. In an embodiment, the composition is formulated as a topical dosage form. In an embodiment, the composition is formulated as a self-nanoemulsifying drug delivery system (SNEDDS). In an embodiment, the composition is any of a pharmaceutical composition, a nutraceutical composition and a herbal composition. In an embodiment, the aqueous media comprises a gastric fluid. In an embodiment, the aqueous media includes water, buffer or any other hydrophilic fluid that upon contact with the composition of the present disclosure effects formation of an emulsion. In an embodiment, the aqueous media is in an amount sufficient to effect preparation of an emulsion with oil present as an internal phase and the aqueous media present as an external phase. In other words, the composition of the present disclosure upon contact with the aqueous media results in formation of a dispersion, wherein the active ingredient and/or the oil is present as droplets, dispersed, preferably, uniformly dispersed, within the aqueous media. The composition realized in accordance with embodiments of the present disclosure offers a unique advantage over the conventional formulation, wherein the composition of the present disclosure exhibits significant improvement of bioefficacy and/or bioavailability of the active ingredient(s). To explore its bioefficacy, the randomized, open-label study human trial in patients suffering with indigestion, flatulence and nausea was done to determine the increase in the bioeffcacy.
[0050] Another aspect of the present disclosure relates to a method of preparation of a nanoemulsion, the method comprising the steps of: effecting preparation of a self-nanoemulsifying drug delivery system (SNEDDS) including an active ingredient with low aqueous solubility; an emulsifier; and a co-solvent, said SNEDDS being a liquid composition, devoid of aqueous medium; and contacting the self-nanoemulsifying drug delivery system (SNEDDS) with an aqueous media to effect preparation of the nanoemulsion.
[0051] In an embodiment, the nanoemulsion of the invention can be formulated in to a suitable dosage form for administration to a human subject, including the nanoemulsion in a therapeutically/nutritionally effective amount and suitable excipients. Such excipients are well known in the art and hence, not provided in great detail herein for the sake of simplicity.
[0052] In an embodiment, the dosage form includes a dosage form for oral, topical, parenteral, ophthalmic, nasal and rectal administration. In an embodiment, the dosage form includes, but is not limited to, capsule, microcapsule, emulsion, liquid, lotion, ointment, cream, gel, aerosol, spray, paste and foam. In an embodiment, the dosage form includes an oral dosage form and/or a topical dosage form. In an embodiment, the dosage form is a dosage form including a soft and hard capsule of makes available. Accordingly, delivery methods of pharmaceutical formulations described herein include, but are not limited to, sublingual administration, buccal administration, parenteral administration, intraperitoneal (i.p.) administration, intravenous (i.v.) administration, intraarterial (i.a.) administration, topical administration, transdermal administration, intradermal (i.d.) administration, intramuscular (i.m.) administration, subcutaneous (sc) administration, and nasal administration.
[0053] The advantageous composition realized in accordance with embodiments of the present disclosure exhibits improved solubility of the active ingredient and/or oil in aqueous media. The composition(s) as realized in accordance with embodiments of the present disclosure exhibit self-nanoemulsifying property upon coming in contact with one or more aqueous media and are stable, thereby can be used to effectively deliver the active ingredient and/or oil having low aqueous solubility. In an embodiment, the composition can be formulated as a self-nanoemulsifying drug delivery system (SNEDDS). The system is able to spontaneously form nanoemulsions under gentle mixing provided by digestive motility of the stomach and intestine, following dilution by aqueous phases.
[0054] The present disclosure may be more fully understood by reference to the following examples. However, it is to be understood that the foregoing examples are merely illustrative and are not to be taken as limitations upon the scope of the invention. Various changes and modifications to 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.
[0055] Example 1
Components Amount (% w/w)
Peppermint Oil 30
Polysorbate 80 26
Polysorbate 20 39
PEG 200 4
Diethylene glycol monoethyl ether 2
[0056] Example 2
Components Amount (% w/w)
Peppermint Oil 21
PEG 35 Castor Oil 36
Polysorbate 20 36
PEG 200 7
[0057] Example 3
Components Amount (% w/w)
Peppermint Oil 15
Caproyl 90 9
PEG 35 Castor Oil 46
Polysorbate 80 27
Diethylene glycol monoethyl ether 3
[0058] Example 4
Components Amount (% w/w)
Spearmint Oil 26
Polysorbate 80 31
Polysorbate 20 36
PEG 200 7
[0059] Example 5
Components Amount (% w/w)
Spearmint Oil 26
PEG 35 Castor Oil 38
Polysorbate 20 30
PEG 200 6
[0060] Example 6
Components Amount (% w/w)
Spearmint Oil 14
Caproyl 90 6
PEG 35 Castor Oil 40
Polysorbate 80 32
Diethylene glycol monoethyl ether 8
[0061] Example 7
Components Amount (% w/w)
Peppermint Oil 24.6
Spearmint Oil 5.4
Polysorbate 80 25
Polysorbate 20 41
PEG200 4
[0062] Example 8
Components Amount (% w/w)
Peppermint Oil 10.5
Spearmint Oil 6.5
Caproyl 90 3.9
PEG 35 Castor Oil 42
Polysorbate 80 33
Diethylene glycol monoethyl ether 2.5
Ethanol 1.6
[0063] Example 9
Components Amount (% w/w)
Peppermint Oil 8.5
Spearmint Oil 18.5
PEG 35 Castor Oil 36
Polysorbate 20 31
Diethylene glycol monoethyl ether 6
[0064] Example 10
Components Amount (% w/w)
Peppermint Oil 15.6
Spearmint Oil 2.6
Polysorbate 80 31
Polysorbate 20 36
PEG 200 8.8
Diethylene glycol monoethyl ether 6
[0065] Method of Preparation (Examples 1 through 10)
[0066] The formulations with the formula as provided in each of the examples 1 through 10 hereinabove were prepared by firstly mixing solvent, surfactant and oil (if any); followed by adding active ingredient(s) to the blend and mixing it thoroughly to obtain stable liquid pharmaceutical composition.
[0067] Preparation of Nano-emulsion and Mean Droplet Size Analysis
[0068] The formulation as prepared in Example 1 was mixed with (i) 200 mL of purified water or 0.1 N HCl, and (ii) with a fluid simulating the properties of the gastric fluid. The nano-emulsions so formed were subjected to various analysis to assess properties thereof.
[0069] Immediate examination of the nano-emulsion, so formed, under the microscope revealed that the mean particle size (D50) of the droplets is 100 nm. Mean droplet size of the emulsion after lapse of 24 hr was found to be below 150 nm.
[0070] Stability Study
[0071] The formulation as prepared in Example 1 was filled in 30 ml PET bottle and filled in Hard Gelatin capsules of size 0 in 2 different packs - blister pack and glass bottle. Their stability data was generated. Stability studies were carried out for the Formulation at 40°C / 75% Relative Humidity for six months. The formulation was found to be stable for at least 6 months at accelerated stability conditions in both the packs. The results of the stability study are provided in Table 1 hereinbelow.
TABLE 1: Stability studies data of Mint SNEDDS of Example 1 in PET Bottle and capsules packed in blister pack/ glass bottle
Time PET Bottle
(Assay) Blister pack
(Assay) Glass bottle
(Assay)
0 Month 100.6% 100.1% 100.3%
1 Month 98.9% 98.6% 98.3%
2 Month 96.7% 96.4% 96.6%
3 Month 95.6% 96.1% 95.6%
6 Month 91.0% 92.0% 92.1%
[0072] Dispersibility Study
[0073] Dispersibility study was performed to evaluate efficiency of dispersibility of oral nanoemulsions. 2 mL of each formulations of Example 1 through Example 9 were added to 500 mL of distilled water and 0.1N HCl in a standard USP XXII dissolution apparatus 2. Speed of the paddle was adjusted to 50 rpm and the temperature was maintained at 37±0.5° C. (Pouton C W, 1997). The formulations were visually evaluated for clarity. The results are summarized in Table 2 hereinbelow.
[0074] Particle Size Distribution Study
[0075] One gram of each of the formulations of Example 1 through 10 was diluted in 200 mL-0.1N HCl/Water. The droplet size/distribution of the prepared emulsion was determined using MALVERN Particle Size Analyzer (Model Zetasizer Ver. 6.01, Malvern Instruments, UK) using He-Ne Red laser, 4.0 mW, 632.9 nm; temperature 25°C; refractive index, 1438; or with adjustment if needed. Each sample was analyzed in triplicate. It was found that Example 1 formulation had 90% of the particles having particle size less than 90 nm. The average Particle size was determined to be 90 nm with 91.6% particles having particle size of 85 nm. The results are summarized in Table 2 hereinbelow.
TABLE 2: Particle Size Distribution and Dispersibility Analysis
Formulation Particle Size (nm) Dispersibility
Water 0.1N HCl
Example 1 90 Clear Clear
Example 2 70 Clear Clear
Example 3 150 Hazy Hazy
Example 4 120 Clear Clear
Example 5 75 Clear Clear
Example 6 120 Hazy Hazy
Example 7 70 Clear Clear
Example 8 100 Hazy Hazy
Example 9 70 Clear Clear
Example 10 40 Clear Clear
[0076] In-Vitro Dissolution Study
[0077] The dissolution behaviours of Example 1 Mint loaded SNEDDS were compared using buffer solutions of pH 1.2, pH 4.5 and pH 6.8. Mint-SNEDDS was filled in hard gelatin capsules size 0 & 1 and introduced into 500 ml of a dissolution medium and maintained at 37°C in USP II dissolution apparatus using Japanese sinkers. The revolution speed of the paddle was kept constant at 50 rpm. The aliquot of 5 ml was withdrawn at 0, 30 and 60 min, and filtered through 0.45 µm membrane filters. The concentration of mint was determined on the basis of menthone determination. The removed volume was replaced each time with 5 ml of fresh medium. The dissolution of each capsule is calculated and the results are shown in Table 3 hereninbelow.
TABLE 3: Dissolution study
% Drug Released
Time
(min) Size 0 capsule Size 1 capsule
0.1N HCl 4.5 pH Acetate buffer 6.8 pH Phosphate buffer 0.1N HCl 4.5 pH Acetate buffer 6.8 pH Phosphate buffer
0 0 0 0 0 0 0
30 96.5 96.2 95.6 95.1 96.6 94.6
60 100 100 100 100 100 100

ADVANTAGES
[0078] The present disclosure provides a composition with improved solubility of active ingredient having low aqueous solubility.
[0079] The present disclosure provides a self-nanoemulsifying drug delivery system (SNEDDS).
[0080] The present disclosure provides a self-nanoemulsifying drug delivery system (SNEDDS) that upon contact with the gastric fluid forms a stable emulsion.
[0081] The present disclosure provides a self-nanoemulsifying drug delivery system (SNEDDS) that upon contact with an aqueous media forms a stable emulsion.
[0082] The present disclosure provides a composition which is easy to prepare, does not require special equipments or devices, economic and not energy intensive.
[0083] The present disclosure provides a composition with improved thermodynamic stability and shelf-life.
[0084] The present disclosure provides a method of preparation of a self-nanoemulsifying drug delivery system (SNEDDS).
[0085] The present disclosure provides a method of preparation of a nano-emulsion.

We Claim
1. A composition comprising:
an active ingredient with low aqueous solubility;
an emulsifier; and
a co-solvent,
wherein the composition is a liquid composition that upon contact with an aqueous media forms an emulsion.
2. The composition as claimed in claim 1, wherein said composition is devoid of aqueous medium.
3. The composition as claimed in claim 1, wherein the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 200 nm.
4. The composition as claimed in claim 1, wherein the emulsion comprises droplets with a mean particle size (D50) ranging from about 50 nm to about 100 nm.
5. The composition as claimed in claim 1, wherein the active ingredient exhibits an octanol-water log P value ranging from about 1 to about 3.
6. The composition as claimed in claim 1, wherein the active ingredient comprises an oil selected from the group comprising peppermint oil, spearmint oil and combinations thereof, and wherein the active ingredient is present in an amount ranging from about 1% to about 30% by weight of the composition.
7. The composition as claimed in claim 1, wherein any or a combination of the emulsifier and the co-solvent exhibit a hydrophilic/lipophilic balance (HLB) value ranging from about 9 to about 14.
8. The composition as claimed in claim 1, wherein the emulsifier is selected from the group comprising polyethoxylated oils, polysorbates, castor oil ethoxylates, and combinations thereof, and wherein the emulsifier is present in an amount ranging from about 66% to about 90% by weight of the composition.
9. The composition as claimed in claim 1, wherein the co-solvent is selected from the group comprising propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and combinations thereof, and wherein the co-solvent is present in an amount ranging from about 0.5% to about 30% by weight of the composition.
10. The composition as claimed in claim 1, wherein the composition comprises a solubilizer selected from the group comprising glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate/monocaprate, propylene glycol monolaurate, a medium chain fatty acid, and combinations thereof, and wherein the solubilizer is present in an amount ranging from about 0% to about 10% by weight of the composition.
11. The composition as claimed in claim 1, wherein the composition is formulated as any of an oral dosage form and a topical dosage form.
12. The composition as claimed in claim 1, wherein the composition is formulated as a self-nanoemulsifying drug delivery system (SNEDDS).
13. The composition as claimed in claim 1, wherein the composition is any of a pharmaceutical composition, a nutraceutical composition and a herbal composition.
14. The composition as claimed in claim 1, wherein the aqueous media comprises a gastric fluid.
15. The composition as claimed in claim 1, wherein the composition comprises:
an oil that exhibits an octanol-water log P value ranging from about 1 to about 3 in an amount ranging from 1% to 30% by weight of the composition;
an emulsifier selected from the group comprising polyethoxylated oils, polysorbates, castor oil ethoxylates and combination thereof in an amount ranging from 66% to 90% by weight of the composition;
a co-solvent selected from the group comprising propylene glycol, low molecular weight polyethylene glycols, triacetin, ethanol, glycofurol, diethylene glycol monoethyl ether and combinations thereof in an amount ranging from 0.5% to 30% by weight of the composition; and
a solubilizer selected from the group comprising glyceryl monocaprylate, glyceryl monocaprate, glyceryl monolaurate, propylene glycol monocaprylate, glyceryl monocaprylate/monocaprate, propylene glycol monolaurate, a medium chain fatty acid and combination thereof in an amount ranging from 0% to 10% by weight of the composition,
said composition being devoid of an aqueous medium, and said composition upon contact with a gastric fluid forms emulsion with droplets having a mean particle size (D50) ranging from 50 nm to 200 nm.
16. A method of preparation of a nanoemulsion, the method comprising the steps of:
effecting preparation of a self-nanoemulsifying drug delivery system (SNEDDS) comprising: an active ingredient with low aqueous solubility; an emulsifier; and a co-solvent, said SNEDDS being a liquid composition, devoid of an aqueous medium; and
contacting the self-nanoemulsifying drug delivery system (SNEDDS) with an aqueous media to effect preparation of the nanoemulsion.