The present disclosure relates generally to pharmaceutical formulations. Specifically, the present disclosure provides a pharmaceutical formulation comprising of solid lipid nanoparticles of Nateglinide. More specifically, the disclosure provides a pharmaceutical formulation comprising of solid lipid nanoparticles of Nateglinide and curcumin, wherein curcumin is a bio-enhancer.
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] Solubility and dissolution rate still remain a challenge for pharmaceutical scientists. These difficulties are more apparent with hydrophobic drugs, and with high number of hydrophobic drugs entering the drug discovery and product development pipeline, these issues have become even more important to settle. Pharmaceutical actives belonging to Biopharmaceutics Classification System (BCS) class II and IV present solubility-related challenges during formulation development. Strategies for improving solubility and dissolution rate include forming soluble salts for ionizable drugs, reducing crystal size, forming soluble pro-drugs, using amorphous forms, co-solvents and super disintegrants, or using surface active self-emulsifying systems.
[0004] With sophisticated size reduction technologies being developed in recent years, size reduction to nanoparticles has attracted lot of attention in the formulation development of hydrophobic drugs. Nanoparticles can be generated by many means, like top-down approaches such as size reduction by advanced milling techniques or by bottom-up approaches like precipitation. According to Noyes-Whitney's equation, size reduction to the nanometre range can significantly increase the interfacial surface area, thereby increasing the rate of dissolution and aqueous solubility, which in turn leads to enhancement of drug bioavailability. Increase in interfacial surface area also increases the reactivity of a

drug to specific molecular targets and enhances its pharmacological action. Thus,
use of a nanoparticulate drug delivery system improves the bioavailability and
reactivity of the drug. However, there is still scope for improvement in
bioavailability of drugs in these nanoparticulate drug delivery systems.
[0005] Nateglinide is a hydrophobic drug for diabetes mellitus belonging to BCS
class II. It is a highly permeably but poorly water soluble drug and due to its poor
solubility, the bioavailability of the drug is limited.
[0006] There is a need in the art to develop new formulations of the anti-diabetic
drug, Nateglinide, that improve its solubility and bioavailability in the
physiological environment.
OBJECTS OF THE INVENTION
[0007] An object of the present disclosure is to provide a pharmaceutical formulation of Nateglinide that enhances its solubility and dissolution rate. [0008] An object of the present disclosure is to provide a pharmaceutical formulation comprising of solid lipid nanoparticles of Nateglinide and curcumin. [0009] An object of the present disclosure is to provide a pharmaceutical formulation that improves the bioavailability of Nateglinide.
SUMMARY OF THE INVENTION
[0010] This summary is provided to introduce a selection of concepts in a
simplified form that are further described below in Detailed Description section.
This summary is not intended to identify key features or essential features of the
claimed subject matter, nor is it intended to be used as an aid in determining the
scope of the claimed subject matter.
[0011] Aspects of the present disclosure relate to a pharmaceutical formulation
comprising of solid lipid nanoparticles consisting of active components - drug
Nateglinide and its bio-enhancer curcumin.
[0012] In an aspect, the present disclosure provides a pharmaceutical formulation
comprising of solid lipid nanoparticles comprising of:

a core consisting of Nateglinide, pharmaceutical^ active salts or hydrates
thereof; bio-enhancer curcumin; and a lipid matrix; and
a coating consisting of a surfactant;
wherein the coating covers the core of the nanoparticles. [0013] In an embodiment, the lipid matrix may comprise of glyceryl behenate, glyceryl monostearate, stearic acid, beeswax, cholesterol or combinations thereof. [0014] In an embodiment, the surfactant may be selected from polysorbate, poloxamer, or combinations thereof.
[0015] In an embodiment, the formulation consists of Nateglinide in a weight percentage range of about 40% to about 45% of the formulation. [0016] In an embodiment, the formulation consists of curcumin in a weight percentage range of about 0.1% to about 5% of the formulation. [0017] In an embodiment, the formulation consists of the lipid matrix in a weight percentage range of about 40% to about 45% of the formulation. [0018] In an embodiment, the formulation consists of the surfactant in a weight percentage range of about 2% to about 5% of the formulation. [0019] In an aspect, the present disclosure provides a process of preparing a pharmaceutical formulation comprising the steps of:
(a) weighing Nateglinide, pharmaceutically active salts or hydrates thereof, bio-enhancer curcumin, a lipid matrix, and a surfactant;
(b) heating the lipid matrix above its melting temperature and mixing with the Nateglinide and curcumin by magnetic stirring to give a pre-emulsion;
(c) preparing an aqueous solution of the surfactant in water;

(d) homogenizing the pre-emulsion with the aqueous solution of the surfactant by a high speed homogenizer at about 2500 rpm for about 60 minutes to give a coarse oil-in-water mixture;
(e) ultrasonicating the mixture using probe sonicator followed by centrifuging in a high speed centrifugator at about 10000 rpm to give the solid lipid nanoparticles; and
(f) separating and lyophilizing the solid lipid nanoparticles to give the formulation.

[0020] In an aspect, the present disclosure provides a method of treatment, amelioration or prevention of diabetes mellitus in a subject by administering to the subject a therapeutically effective amount of the pharmaceutical formulation. [0021] In still another aspect, the present disclosure relates to use of the pharmaceutical formulation as a medicament for diabetes mellitus. [0022] Other aspects of the invention will be set forth in the description which follows, and in part will be apparent from the description, or may be learnt by the practice of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0023] 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.
[0024] All publications herein are incorporated by reference to the same extent as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply. [0025] 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.

[0026] In some embodiments, numbers have been used for quantifying weights, percentages, ratios, and so forth, to describe and claim certain embodiments of the invention and 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 and attached claims 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 numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements. [0027] 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 persons in the pertinent art have given that term as reflected in printed publications and issued patents at the time of filing.
[0028] As used in the description herein and throughout the claims that follow, the meaning of "a," "an," and "the" includes plural reference unless the context clearly dictates otherwise. Also, as used in the description herein, the meaning of "in" includes "in" and "on" unless the context clearly dictates otherwise. [0029] 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."
[0030] 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. Unless otherwise indicated herein, each individual value is incorporated into the specification as if it were individually recited herein.

[0031] 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. [0032] Groupings of alternative elements or embodiments of the invention disclosed herein are not to be construed as limitations. Each group member can be referred to and claimed individually or in any combination with other members of the group or other elements found herein. One or more members of a group can be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified.
[0033] The description that follows, and the embodiments described therein, is provided by way of illustration of an example, or examples, of particular embodiments of the principles and aspects of the present disclosure. These examples are provided for the purposes of explanation, and not of limitation, of those principles and of the disclosure.
[0034] It should also be appreciated that the present disclosure can be implemented in numerous ways, including as a system, a method or a device. In this specification, these implementations, or any other form that the invention may take, may be referred to as processes. In general, the order of the steps of the disclosed processes may be altered within the scope of the invention. [0035] The headings and abstract of the invention provided herein are for convenience only and do not interpret the scope or meaning of the embodiments. [0036] 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.
[0037] As used herein, the term 'solid lipid nanoparticle' refers to nanoparticles
comprising a lipid core which is in solid phase and is made of a lipid matrix which
solubilizes the active components and wherein the lipid core is stabilized by
surfactants surrounding the core.
[0038] The term 'therapeutically effective amount' refers to an amount that is
sufficient to produce the desired effects without causing side-effects.
[0039] The term, "subject" as used herein refers to an animal, preferably a
mammal, and most preferably a human. The term "mammal" used herein refers to
warm-blooded vertebrate animals of the class 'mammalia' , including humans,
characterized by a covering of hair on the skin and, in the female, milk-producing
mammary glands for nourishing the young, the term mammal includes animals
such as cat, dog, rabbit, bear, fox, wolf, monkey, deer, mouse, pig and human.
[0040] In an embodiment, the present disclosure provides a pharmaceutical
formulation comprising of solid lipid nanoparticles comprising of:
a core consisting of Nateglinide, pharmaceutically active salts or hydrates
thereof; bio-enhancer curcumin; and a lipid matrix; and
a coating consisting of a surfactant;
wherein the coating covers the core of the nanoparticles. [0041] In an embodiment, the pharmaceutically active salts or hydrates of Nateglinide may be selected from calcium salt, magnesium salt, potassium salt, sodium salt, ammonium salt, monohydrate, sesquihydrate, dihydrate, trihydrate, hemihydrate, or combinations thereof.
[0042] Nateglinide and curcumin form the active components that possess anti-diabetic effect. Curcumin (diferuloylmethane) is the major curcuminoid contained in the rhizome of Curcuma longa L. (turmeric) that has been shown to have several biological and pharmacological activities. It is an herbaceous plant of the family Zingiberaceae that has been considered an important therapeutic agent in Indian and Chinese traditional medicine; it is mainly cultivated in tropical and

subtropical region. Turmeric or Curcuma longa is a natural product, whose medicinal properties have been extensively studied and a wide variety of therapeutic effects on several diseases have been mainly attributed to its curcuminoid content. Turmeric contains 69.4% carbohydrates, 6.3% protein, 5.1%> fat, 5.8%o essential oils, and 3.6%> of curcuminoids; the main curcuminoids in commercial curcumin are 77% curcumin (curcumin I), 17% demethoxycurcumin (curcumin II), 3% bis-demethoxycurcumin (curcumin III), and cyclocurcumin (curcumin IV). Curcumin has multiple biological and pleiotropic activities as an anti-oxidant, anti-bacterial, anti-neoplastic, anti-proliferative, and anti¬inflammatory agent. Curcumin is safe, as it is well tolerated even at a dose of 12 g day"1 in phase-I clinical trials and has also been declared as GRAS (generally regarded as safe) by United States Food and Drug Administration. [0043] In an embodiment, the lipid matrix may comprise of glyceryl behenate, glyceryl monostearate, stearic acid, beeswax, cholesterol or combinations thereof. [0044] In an embodiment, the surfactant may be selected from polysorbate, poloxamer, or combinations thereof.
[0045] In an embodiment, the formulation consists of Nateglinide in a weight percentage range of about 40% to about 45% of the formulation. [0046] In an embodiment, the formulation consists of curcumin in a weight percentage range of about 0.1% to about 5% of the formulation. [0047] In an embodiment, the formulation consists of the lipid matrix in a weight percentage range of about 40% to about 45% of the formulation. [0048] In an embodiment, the formulation consists of the surfactant in a weight percentage range of about 2% to about 5% of the formulation. [0049] In the formulation, the active components- Nateglinide and curcumin have high loading. In an embodiment, the entrapment efficiency for Nateglinide in the formulation may range from 50% to about 100%).
[0050] The formulation provides a uniform size distribution in the nanoparticles. In an embodiment, the formulation has nanoparticles in a particle size range of about 20nm to about 800nm. In an embodiment, the nanoparticles are spherical, elliptical, or rod shaped, preferably the nanoparticles are spherical.

[0051] In an embodiment, the formulation may be administered in a solid dosage form including powder, tablet, capsule, sachet, granules, lozenges, beads, patch, or suppositories. In an embodiment, the formulation may also be administered in a semi-solid or liquid dosage form, including aerosols, gels, hydrogel, solutions, syrups, suspensions or emulsions. In an embodiment, the formulation may preferably be administered orally, intravenously, transdermally, rectally, subcutaneously, or parenterally.
[0052] In an embodiment, the formulation may further comprise a pharmaceutically acceptable excipient. Said pharmaceutically acceptable excipient includes, but is not limited to, stabilizers, filler, preservatives, solvents, binder, buffers, flavoring agents, or coloring agents.
[0053] In an embodiment, the pharmaceutically acceptable excipient may be selected from lemon flavor, strawberry flavor, mint flavor, sucrose, maltose, lactose, saccharin, carbopol polymers, cellulose derivatives, phosphate buffer, xanthum gum, polyethylene glycol, or combinations thereof. [0054] In an embodiment, the formulation prevents hepatic and intestinal metabolism of the active components. Natural bio-enhancer compounds such as curcumin can significantly suppress the drug-metabolising enzyme cytochrome P450 3A, hepatic glucuronidation and intestinal glucuronidation and thereby increase the bioavailability of a drug. Curcumin also reverses multidrug resistance by modulating ATP-binding cassette transporter proteins such as P-gp, MDRP1, MDRP2 and BCRP. This natural bio-enhancer also exhibits a wide spectrum of pharmacological activities including anti-diabetic activity.
[0055] In an embodiment, the formulation has anti-diabetic effect. In an embodiment, the formulation demonstrates synergistic anti-diabetic effect by the active components in the formulation.
[0056] In an embodiment, the formulation has improved solubility and dissolution rate. In an embodiment, the formulation improves the bioavailability of the active components in the physiological environment. In an embodiment, the formulation comprising of curcumin synergistically improves the bioavailability of

Nateglinide in the physiological environment. The higher bioavailability decreases
the dosage and frequency of formulation required.
[0057] In an embodiment, the formulation demonstrates synergism. In an
embodiment, the formulation is stable at room temperature.
[0058] The formulation comprising of the solid lipid nanoparticles may be
prepared by methods well-known in the art, such as homogenization or
microemulsion.
[0059] In an embodiment, the present disclosure provides a process of preparing a
pharmaceutical formulation comprising the steps of:
(a) weighing Nateglinide, pharmaceutically active salts or hydrates thereof, bio-enhancer curcumin, a lipid matrix, and a surfactant;
(b) heating the lipid matrix above melting temperature and mixing with the Nateglinide and curcumin by magnetic stirring to give a pre-emulsion;
(c) preparing an aqueous solution of the surfactant in water;
(d) homogenizing the pre-emulsion with the aqueous solution of the
surfactant by a high speed homogenizer at about 2500 rpm for about 60
minutes to give a coarse oil-in-water mixture;
(e) ultrasonicating using probe sonicator followed by centrifuging in a high speed centrifugator at about 10000 rpm to give the solid lipid nanoparticles; and
(f) separating and lyophilizing the solid lipid nanoparticles to give the formulation.
[0060] In an embodiment, the present disclosure provides a method of treatment, amelioration or prevention of diabetes mellitus in a subject by administering to the subject a therapeutically effective amount of the pharmaceutical formulation. [0061] In still another embodiment, the present disclosure a medicament for diabetes mellitus comprising the pharmaceutical formulation. [0062] In still another embodiment, the present disclosure relates to use of the formulation for treatment, amelioration or prevention of diabetes mellitus and associated disorders in a subject.

[0063] While the foregoing describes various embodiments of the disclosure, other and further embodiments of the disclosure may be devised without departing from the basic scope thereof. The scope of the invention is determined by the claims that follow. The invention is not limited to the described embodiments, versions or examples, which are included to enable a person having ordinary skill in the art to make and use the invention when combined with information and knowledge available to the person having ordinary skill in the art.
ADVANTAGES OF THE PRESENT INVENTION
[0064] The present disclosure provides a pharmaceutical formulation for
increasing the solubility and dissolution rate of Nateglinide.
[0065] The present disclosure provides a pharmaceutical formulation for
increasing the bioavailability of Nateglinide.
[0066] The present disclosure provides a pharmaceutical formulation with
synergistic therapeutic activity of Nateglinide and curcumin.

We Claim:

1. A pharmaceutical formulation comprising of solid lipid nanoparticles
comprising of:
a core consisting of Nateglinide, pharmaceutically active salts or hydrates thereof; bio-enhancer curcumin; and a lipid matrix; and a coating consisting of a surfactant; wherein the coating covers the core of the nanoparticles.
2. The formulation as claimed in claim 1, wherein the lipid matrix comprises of glyceryl behenate, glyceryl monostearate, stearic acid, beeswax, cholesterol or combinations thereof.
3. The formulation as claimed in claim 1, wherein the surfactant is selected from polysorbate, poloxamer, or combinations thereof.
4. The formulation as claimed in claim 1, wherein the formulation consists of Nateglinide in a weight percentage range of 40% to 45% of the formulation.
5. The formulation as claimed in claim 1, wherein the formulation consists of curcumin in a weight percentage range of 0.1% to 5% of the formulation.
6. The formulation as claimed in claim 1, wherein the formulation consists of the lipid matrix in a weight percentage range of 40% to 45% of the formulation.
7. The formulation as claimed in claim 1, wherein the formulation consists of the surfactant in a weight percentage range of 2% to 5% of the formulation.
8. The formulation as claimed in claim 1, wherein the formulation is administered in a solid dosage form including powder, tablet, capsule, sachet, granules, lozenges, beads, patch, or suppositories.
9. A process of preparing a pharmaceutical formulation comprising the steps of:

(a) weighing Nateglinide, pharmaceutically active salts or hydrates thereof, bio-enhancer curcumin, a lipid matrix, and a surfactant;
(b) heating the lipid matrix above melting temperature and mixing with the Nateglinide and curcumin by magnetic stirring to give a pre-emulsion;
(c) preparing an aqueous solution of the surfactant in water;

(d) homogenizing the pre-emulsion with the aqueous solution of the
surfactant by a high speed homogenizer at about 2500 rpm for about 60
minutes to give a coarse oil-in-water mixture;
(e) ultrasonicating using probe sonicator followed by centrifuging in a high speed centrifugator at about 10000 rpm to give the solid lipid nanoparticles; and
(f) separating and lyophilizing the solid lipid nanoparticles to give the formulation.