A water-soluble micellar formulation comprising curcumin and piperine and preparation method thereof

Abstract

Disclosed is a micellar formulation of curcumin and piperine includes a mixture of non-ionic surfactant and cosurfactant wherein the surfactant is water soluble surfactant. Also provided is method of manufacturing the formulation.

Description

[0001] “A WATER-SOLUBLE MICELLAR FORMULATION COMPRISING CURCUMIN

[0002] AND PIPERINE AND PREPARATION METHOD THEREOF”

[0003] FIELD OF INVENTION:

[0004] The present invention is related to a water-soluble micellar formulation comprising curcumin and piperine that would enhance solubility and bioavailability of curcumin. The invention further describes the method for preparation of water-soluble micellar formulation comprising curcumin and piperine.

[0005] BACKGROUND ART:

[0006] Curcumin is a yellow orange coloured crystalline compound that is extracted from Curcuma longa, Zingiberaceae. Chemically, curcumin is known as diferuloylmethane (C21H20O6) with a molecular mass of 368.37 g / mol. It is a polyphenol compound and has melting point of 183°C. The IUPAC name of curcumin is 1,7-bis (4-hydroxy-3- methoxy phenyl)- 1,6- heptadiene-3, 5-dione (1E-6E). The two aryl rings in curcumin contain orthomethoxy phenolic groups are symmetrically linked to a p-diketone moiety. Curcumin exhibits a pH dependent keto-enol tautomerism, where in an acidic or neutral solution, the keto form of curcumin is predominant while in an alkaline medium the enol form of curcumin becomes predominant. The colour of curcumin also changes at different pH levels forming a bright yellow coloured solution at pH range 2.5 to 7.0 with the colour changing to dark red when the pH is increased above 7.

[0007] Curcumin is a natural compound found in turmeric, a popular spice with a long history of use in traditional medicine. It is known for its various pharmacological properties, and research has shown that it may have a range of potential health benefits. Few pharmacological properties of curcumin include;

[0008] Anti-Inflammatory: Curcumin has potent anti-inflammatory properties and can help reduce inflammation in the body. It works by inhibiting various inflammatory molecules and pathways.

[0009] • Antioxidant: Curcumin is an antioxidant, which means it can neutralize harmful free radicals in the body, reducing oxidative stress and protecting cells from damage.

[0010] • Anti-Cancer: Some studies suggest that curcumin may have anticancer properties. It can inhibit the growth of cancer cells, promote apoptosis (cell death), and interfere with the development of blood vessels that feed tumors.

[0011] • Pain Relief: Curcumin may have analgesic (pain-relieving) properties due to its anti- inflammatory and antioxidant effects. It is sometimes used to manage conditions associated with chronic pain.

[0012] • Antimicrobial: Curcumin has demonstrated antimicrobial properties, which means it can help fight against various bacteria, viruses, and fungi.

[0013] • Cardiovascular Benefits: Curcumin may support heart health by improving the function of the endothelium (the lining of blood vessels), reducing the risk of blood clot formation, and lowering blood pressure.

[0014] • Neuroprotective: Some studies suggest that curcumin may have neuroprotective properties and could potentially help in the management of neurodegenerative diseases like Alzheimer's and Parkinson's.

[0015] • Anti-Depressant: Curcumin may have mild anti-depressant effects and could be used as an adjunct therapy for depression. It may influence brain chemicals like serotonin and dopamine.

[0016] • Anti-Arthritic: Curcumin's anti-inflammatory properties make it a potential natural remedy for conditions like osteoarthritis and rheumatoid arthritis.

[0017] • Wound Healing: Some research indicates that curcumin can help in the wound healing process, potentially by reducing inflammation and promoting tissue repair.

[0018] While curcumin has demonstrated a range of potential health benefits and pharmacological properties, it also has some limitations and challenges when considered as a drug or therapeutic agent. Some of the problems associated with curcumin are as follows:

[0019] Curcumin has a relatively large and complex molecular structure, and is highly hydrophobic (repels water), which makes it poorly soluble in water. This low solubility contributes to its limited absorption in the gastrointestinal tract. One of the major challenges with curcumin is its low bioavailability, which means that the body absorbs and utilizes only a small fraction of the curcumin consumed when it is taken orally. This limitation can reduce its effectiveness in achieving therapeutic outcomes. Curcumin is rapidly metabolized and excreted from the body, further limiting its bioavailability and duration of action.

[0020] To overcome the solubility issue of curcumin and improve its bioavailability, several strategies can be employed. These methods aim to make curcumin more soluble in water and enhance its absorption in the body. The common approaches are as follows.

[0021] Nano-formulations involve reducing the particle size of curcumin to nanoparticles, which are much smaller than regular curcumin particles. These nanoparticles have improved solubility and absorption properties. Nano-curcumin products are commercially available and can provide better bioavailability.

[0022] Curcumin can be encapsulated in liposomes, which are tiny lipid vesicles. Liposomal curcumin protects the compound from degradation and improves its solubility in water. Liposomal formulations are designed to enhance absorption in the gastrointestinal tract.

[0023] Phytosomes are complexes of curcumin with phospholipids. This improves the solubility of curcumin and makes it more readily absorbed in the body. Phytosomal curcumin products are available as supplements.

[0024] Microemulsions are mixtures of oil, water, and surfactants that can improve the solubility of curcumin. These formulations help disperse curcumin more effectively in water, enhancing its bioavailability.

[0025] Cyclodextrins are a type of molecule that can form inclusion complexes with curcumin. This complexation increases the water solubility of curcumin. Cyclodextrin-complexed curcumin is available in some supplements.

[0026] Curcumin can be prepared as nanosuspensions, which are stable colloidal dispersions of nanosized curcumin particles in water. This approach increases the surface area and solubility of curcumin, improving its bioavailability.

[0027] Curcumin can be dissolved in oil, which increases its solubility. This approach is often used in traditional cooking with turmeric, where turmeric is cooked in oil before being added to dishes.

[0028] Most of the above techniques have following limitations for the use in preparing formulation for curcumin.

[0029] 1. Preparation of nanoparticles or liposomes involves sophisticated techniques which is not economic and easy to scale up. 2. Drug loading in such formulation is also limited therefore conversion in a suitable dosage form is difficult.

[0030] 3. Stability of these system is also not predictable therefore special storage conditions may be required.

[0031] 4. Oral absorption of curcumin from such formulations is incomplete and unpredictable, due to dilution and effects of physiological conditions.

[0032] Another approach is micellar system or self-assembling micellar system (SAMS) which is formed by mixing the active with amphiphilic molecules (molecules with both hydrophilic and hydrophobic regions) . These micelles can enhance the solubility of the active and improve its absorption. The other advantages of the micellar system are reduction of surface tension, fast Release, taste-Masking, versatility, reduction of toxicity and improve stability.

[0033] “Bioavailable curcumin” in the form of micellar system was developed by one of the present inventors along with other co-researcher in past by adding curcumin (3.00-6.06%) with a non-ionic water insoluble surfactant (5.56-6.67%) accompanied by other non-ionic surfactant (72.73-83.33%) and cosurfactant (3.33-15.15%) which is water soluble or miscible in nature. However, this research is related to single active curcumin only not the curcumin and piperine. Also, achieving of a micellar formulation containing an active and excipients cannot be compared with micellar formulation containing the same drug, another drug for instance piperine and excipients because of behavior of each component with respect to other in a given condition. Moreover, stability of curcumin and piperine in the miceller formulation is not taught in this disclosure.

[0034] Piperine ( l-[5-[ l,3-benzodioxol-5-yl]-l-oxo-2,4-pentadienyl]piperidine) is a nitrogen-containing alkaloid molecule, first isolated in the form of yellow crystalline solid (MW 285.33 g.mol- 1 , mp = 128-130 °C) from the dried fruit extract of pepper. Piperine is obtained from Piper nigrum and Piper longum species, chemically, piperine molecules consist of conjugated aliphatic chains, which act as a connecting structure between piperidine and 5-(3, 4-methylenedioxyphenyl) moiety. Piperine occurs naturally in black, green, and white pepper. Piperine is a type of amide alkaloid that exhibits pleiotropic properties like antioxidant, anticancer, antiinfammatory, antihypertensive, hepatoprotective, neuroprotective and enhancing bioavailability and fertility-related activities. Piperine has the ability to alter gastrointestinal disorders, drug-metabolizing enzymes, and bioavailability of several drugs including curcumin. However, it is not known as to how piperine and curcumin is combined in order to achieve the desired effect.

[0035] A review article entitled, ‘Curcumin Formulations for Better Bioavailability: What We Learned from Clinical Trials Thus Far?’ by Mangala Hegde, SosmithaGirisa, BandariBharathwajChetty, RavichandranVishwa, and Ajaikumar B. Kunnumakkara in March, 2023 discloses curcumin having wide spectrum of pharmacological properties for the prevention and treatment of several chronic diseases. However, due to its weak solubility and bioavailability, it has limited potential as an oral medication. Numerous factors including low water solubility, poor intestinal permeability, instability at alkaline pH, and fast metabolism contribute to curcumin’s limited oral bioavailability. In order to improve its oral bioavailability, different formulation techniques such as coadministration with piperine, incorporation into micelles, micro / nanoemulsions, nanoparticles, liposomes, solid dispersions, spray drying, and noncovalent complex formation with galactomannosides have been investigated with in vitro cell culture models, in vivo animal models, and humans. Mangala Hegde et al, 2023 is failed to suggest stable miceller form of curcumin-piperine.

[0036] A research article entitled, ‘Formulation Development of Curcumin-piperine solid dispersion via hot-melt extrusion’ by Abdulmajeed A. Althobaiti, Eman A. Ashour, Mashan Almutairi and Ahmed Almotairy in Journal of Drug Delivery Science and Technology August, 2022 discloses the study that improve the release profile of curcumin utilizing the hot -melt extrusion technique (HME) to prepare curcumin-piperine solid dispersion in which component curcumin and piperine (in a ratio of 3: 1) was added to a solid ethoxylated solubilizer Soluplus®. The physical mixtures were blended using V-shell blender for 10 minutes and the resulting physical mixtures were extruded using the co -rotating twin-screw extruder. Two different extrusion temperatures were applied for each formulation (130°C and 140 °C), with a screw speed of 75 rpm. Abdulmajeed A. Althobaitiw et al 2022 is failed to suggest stable micellar form of curcumin-piperine.

[0037] An article entitled, ‘Recent developments in formulation design for improving oral bioavailability of curcumin: a review’ by Zhenqi Liu, John D Smart, Ananth S Pannala discloses novel formulations of curcumin for oral delivery that were developed in recent years were reviewed and discussed. The prior art is failed to suggest stable micellar form of curcumin-piperine.

[0038] Therefore, there is still a need to provide a water-soluble stable micellar formulation of curcumin and piperine.

[0039] OBJECT OF THE INVENTION:

[0040] It is primary object of the invention is to provide a water-soluble micellar formulation of curcumin and piperine. It is another object of the invention is to provide a water-soluble micellar formulation of curcumin and piperine with improved solubility and permeability.

[0041] It is yet another object of the invention is to provide a stable micellar formulation of curcumin and piperine.

[0042] It is yet another object of the invention is to provide a micellar formulation upon which faster release of curcumin can be achieved.

[0043] It is further object of the invention is to provide a process for preparing the formulation.

[0044] SUMMARY OF THE INVENTION:

[0045] According one aspect of the invention, there is provided a micellar formulation of curcumin and piperine, said formulation comprises a) curcumin; b) piperine; c) non-ionic surfactant; d) cosurfactant.

[0046] In an embodiment, the surfactant is water soluble surfactant.

[0047] In an embodiment, the ratio of curcumin and piperine is 20: 1 to 50 : 1 by weight.

[0048] In an embodiment, amount of the surfactant is 77-82%.

[0049] In an embodiment, the amount of cosurfactant is 0.1-50%.

[0050] In an embodiment, a micellar formulation of curcumin and piperine comprises i) curcumin in an amount of 2-8% w / w; ii) piperine in an amount of 0.04-0. 16%w / w; iii) non-ionic water-soluble surfactant in an amount of 5-95 % w / w; iv) cosurfactant in an amount of 0.1 -50% w / w.

[0051] According to another aspect of the invention, there is provided a process for preparing the aforesaid formulation, said process comprising the steps of subjecting non-ionic surfactant for melting in order to obtain a molten surfactant; dispersing curcumin and piperine in cosurfactant; adding the product as obtained in step (ii) into the molten surfactant; subjecting the product as obtained in step (iii) for homogenization in order to get a homogenous product.

[0052] In an embodiment, the wherein the process further comprising a filling step upon which the said homogenized product is filled in a capsule casing.

[0053] Hereinafter, exemplary embodiments of the present invention will be described in detail with reference to the accompanying description.

[0054] BRIEF DESCRIPTION OF ACCOMPANYING DRAWINGS:

[0055] Figure 1 illustrates IR spectra of i) curcumin; ii) piperine; iii) curcumin + piperine (50: 1) in accordance with the present invention;

[0056] Figure 2 illustrates comparative permeation of curcumin in accordance with the present invention;

[0057] Figure 3 illustrates percentage release of curcumin in accordance with the present invention; Figure 4 illustrates dissolution data up to 6 months of the micellar formulation in accordance with the present invention.

[0058] Other objects, features and advantages of the inventions will be apparent from the following detailed description in conjunction with the accompanying drawings of the inventions.

[0059] DETAILED DESCRIPTION OF THE INVENTION:

[0060] While the present invention is described herein by way of example, using various embodiments and illustrative drawings, those skilled in the art will recognize that the invention is not intended to be limited to the embodiment as exemplified in example of the instant disclosure. Further, some components that may form a part of the invention may not be illustrated with specific example, for ease of illustration, and such omissions do not limit the embodiment outlined in any way. The examples, drawings and detailed description of it are not intended to restrict the invention to the form disclosed, but on the contrary, the invention covers all modification / s, equivalents, and alternatives falling within the spirit and scope of the present invention as defined by the appended claims. The headings are used for organizational purposes only and are not meant to limit the scope of the description or the claims.

[0061] Further, the words "an" or "a" mean and "at least one” means one or more unless otherwise mentioned. Furthermore, the terminology and phraseology used herein is solely used for descriptive purposes and should not be construed as limiting in scope. Language such as "including," "comprising," "having," "containing," or "involving," and variations thereof, is intended to be broad and encompass the subject matter listed thereafter, equivalents and any additional subject matter not recited, and is not supposed to exclude any other additives, components, integers, or steps. Likewise, the term "comprising" is considered synonymous with the terms "including" or "containing" for applicable legal purposes. Any discussion of documents acts, materials, devices, articles, and the like are included in the specification solely to provide a context for the present invention.

[0062] In this disclosure, whenever an element or a group of elements is preceded with the transitional phrase "comprising", it is also understood that it contemplates the same element or group of elements with transitional phrases "consisting essentially of, "consisting", "selected from the group comprising”, "including", or "is" preceding the recitation of the element or group of elements and vice versa.

[0063] Before explaining at least one embodiment of the invention in detail, it is to be understood that the present invention is not limited in its application to the details outlined in the following description or exemplified by the examples. The invention is capable of other embodiments or of being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for description and should not be regarded as limiting.

[0064] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Besides, the descriptions, materials, methods, and examples are illustrative only and not intended to be limiting. Methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention.

[0065] The present invention provides a stable micellar formulation of curcumin and piperine, said formulation includes i) curcumin; ii) piperine; iii) non-ionic surfactant; & iv) cosurfactant

[0066] In an embodiment of the invention, the present invention is distinct from the existing art in view of type of surfactant. In order to achieve the desired effect, the surfactant herein is water soluble surfactant.

[0067] The present invention is also distinct in view of the ratio of curcumin and piperine. In an embodiment, the ratio of curcumin and piperine is 20: 1 to 50 : 1 by weight, in preferred embodiment, the ratio is 30: 1 to 50: 1, in most preferred embodiment, the ratio is 40: 1 to 50: 1, in utmost preferred embodiment the ratio is 50: 1. The desired effect would not attained if the ratio is beyond the aforesaid ratio.

[0068] In an embodiment of the invention, the amount of surfactant is 77-82%. The desired effect would not attain if the ratio is beyond the aforesaid ratio.

[0069] In an embodiment of the invention, the amount of cosurfactant is 13-18%. The desired effect would not attain if the ratio is beyond the aforesaid ratio.

[0070] In an embodiment of the invention, the surfactant is selected from a known group which is not limited to polyoxyethylene sorbitan monooleate (Tween 80), Polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyl-32 stearate (type I) NF (Gelucire® 48 / 16), Poloxamer, polyethylene glycol monododecyl ether (Laureth-23) and polyethylene glycol hexadecyl ether (brij 58), Labrasol®, PEG esters, Polyethylene glycol 400 (PEG400), Polyethylene glycol 600 (PEG600), Kolliphor® EL (Polyoxyethylene castor oil), Kolliphor® RH40 (Polyoxyl 40 hydrogenated castor oil), Pluronic F68 (Polyethylene glycol-polypropylene glycol block copolymer) , Kolliphor® TPGS (D-a- tocopheryl polyethylene glycol succinate), Kolliphor® HS 15 (Polyethylene glycol 660 12-hydoxystearate), Soluplus® (Polyvinyl caprolactam -polyvinyl acetate-polyethylene glycol graft co-polyme), Gelucire® 50 / 13 (PEG-32 glycerides), Gelucire® 44 / 14 (Lauroyl PEG-32 glyceride), Labrafil® M 1944 CS (Oleoyl polyoxyl-6 glycerides), Labrafil® M2125 CS (Linoleoyl polyoxyl- 6 glycerides), Labrafil® M2 130 CS (Lauroyl polyoxyl-6 glycerides), Cetomacrogol™ 1000 pharma (Polyoxyl 20 Cetostearyl Ether), Ariatone™ TV pharma (PEG 40 Sorbitan Peroleate), Super Refined™ CCMG 400 (Caprylocaproyl polyoxylglycerides), Super Refined™ P35 Castor Oil (Polyoxyl 35 Castor Oil), Cithrol™ DPHS pharma (PEG-30 Dipolyhydroxystearate), Arlacel™ 170 (Glyceryl Stearate and PEG 100 Stearate) or a combination thereof.

[0071] In an embodiment of the invention, the cosurfactant is selected from a known group which is not limited to ethanol, isopropyl alcohol, dimethylsulfoxide, diethylene glycol monoethyl ether (Transcutol®), tetrahydro furfuryldiethylene glycol ether, propylene glycol, polyethylene glycol, lecithin, sorbitan, polysorbates, Labrasol® (Caprylocaproyl Polyoxyl-8 glycerides), Lauroglycol® 90 (Propylene glycol monolaurate) or a combination thereof.

[0072] In an embodiment of the invention, the formulation is administered through a route selected from oral, sublingual, transdermal, naso -gastric, rectal, parenteral, topical or inhalation. In preferred embodiment, the route is oral route.

[0073] In an embodiment of the invention, the formulation is in the form of tablet, capsule, pellet, lozenge, film, powder, liquid, cream, ointment, gel injection, spray, suppository, soap, lotion, drop or any cosmetic preparation. In preferred embodiment, the form is capsule. In most preferred embodiment, the form is hard gelatin capsule or HPMC (hydroxypropylmethyl cellulose) capsule.

[0074] In an embodiment of the invention, the micellar formulation of curcumin and piperine comprises i) curcumin in an amount of 2-8% w / w; ii) piperine in an amount of 0.04-0. 16%w / w; iii) non-ionic water-soluble surfactant in an amount of 77-82% w / w; iv) cosurfactant in an amount of 13- 18% w / w.

[0075] In an embodiment of the invention the present invention provides a process for preparing the aforesaid micellar formulation, said process comprising the steps of:- i) subjecting non-ionic surfactant for melting in order to obtain a molten surfactant; ii) dispersing curcumin and piperine in cosurfactant; iii) adding the product as obtained in step (ii) into the molten surfactant; iv) subjecting the product as obtained in step (iii) for homogenization in order to get a homogenous product.

[0076] In an embodiment of the invention, the process further comprising a filling step upon which the said homogenized product is filled in a capsule casing made up of gelatin.

[0077] In an embodiment of the invention, the melting step (step i) is carried out at 70°C.

[0078] In an embodiment of the invention, the homogenization is carried out at 55°C for 1 hour.

[0079] In an embodiment of the invention, the ratio of curcumin and piperine is 20: 1 to 50 : 1 by weight.

[0080] In an embodiment of the invention, the surfactant is selected from a known group which is not limited to polyoxyethylene sorbitan monooleate (Tween 80), Polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyl-32 stearate (type I) NF (Gelucire® 48 / 16), Poloxamer, polyethylene glycol monododecyl ether (Laureth-23) and polyethylene glycol hexadecyl ether (brij 58), Labrasol®, PEG esters, Polyethylene glycol 400 (PEG400), Polyethylene glycol 600 (PEG600), Kolliphor® EL (Polyoxyethylene castor oil), Kolliphor® RH40 (Polyoxyl 40 hydrogenated castor oil), Pluronic F68 (Polyethylene glycol-polypropylene glycol block copolymer) , Kolliphor® TPGS (D-a- tocopheryl polyethylene glycol succinate), Kolliphor® HS 15 (Polyethylene glycol 660 12-hydoxystearate), Soluplus® (Polyvinyl caprolactam -polyvinyl acetate-polyethylene glycol graft co-polyme), Gelucire® 50 / 13 (PEG-32 glycerides), Gelucire® 44 / 14 (Lauroyl PEG-32 glyceride), Labrafil® M 1944 CS (Oleoyl polyoxyl-6 glycerides), Labrafil® M2125 CS (Linoleoyl polyoxyl- 6 glycerides), Labrafil® M2 130 CS (Lauroyl polyoxyl-6 glycerides), Cetomacrogol™ 1000 pharma (Polyoxyl 20 Cetostearyl Ether), Ariatone™ TV pharma (PEG 40 Sorbitan Peroleate), Super Refined™ CCMG 400 (Caprylocaproyl polyoxylglycerides), Super Refined™ P35 Castor Oil (Polyoxyl 35 Castor Oil), Cithrol™ DPHS pharma (PEG-30 Dipolyhydroxystearate), Arlacel™ 170 (Glyceryl Stearate (and) PEG 100 Stearate) or a combination thereof.

[0081] In an embodiment of the invention, the cosurfactant is selected from a known group which is not limited to ethanol, isopropyl alcohol, dimethylsulfoxide, diethylene glycol monoethyl ether (Transcutol®), tetrahydro furfuryldiethylene glycol ether, propylene glycol, polyethylene glycol, lecithin, sorbitan, polysorbates, Labrasol® (Caprylocaproyl Polyoxyl-8 glycerides), Lauroglycol® 90 (Propylene glycol monolaurate) or a combination thereof.

[0082] This invention is now illustrated by non-limiting examples:

[0083] EXAMPLE:

[0084] Materials: Curcumin powder (Batch No. CPE-024 / 2207 / S-27) and Piperine powder (Batch No. PIP-005 / 2309 / S- 11) were obtained from Arjuna Natural Private Limited, Kerala. All other chemicals were procured from the local market. The chemicals / solvents as used was LR / AR grade Compatibility of the mixture of curcumin and piperine was observed by using FT-IR spectrum (Spectrum 2, Perkin Elmer USA) and the result was found as follows:

[0085] Table 1 : IR results

[0086] As shown in Fig l(a-c), the peaks of each drug (curcumin and piperine) were retained in the physical mixture and no new significant peak was observed in the physical mixture. Hence, both these drugs were found compatible with each other for further processing. EXAMPLE 1:

[0087] Product formula (curcumin and piperine 20: 1): i) Curcumin : 3.99% ii) Piperine : 0.20% iii) Gelucire®48 / 16 : : 79.84% iv) Transcutol® HP : 10.65% V) PEG 400 5.32%

[0088] Method of manufacturing the product:

[0089] The Gelucire® 48 / 16 pellets were melted at 70°C in order to obtain molten Gelucire® 48 / 16. The above quantified curcumin and the piperine was dispersed in the mixture of Transcutol® HP and PEG 400. The dispersion thus obtained was added to the molten Gelucire 48 / 16. The product as obtained was then subjected for homogenization at 55°C for 1 hour. The product thus obtained was filled into a capsule casing made of gelatin or HPMC.

[0090] EXAMPLE 2:

[0091] Product formula (curcumin and piperine 30: 1): i) Curcumin : 3.99% ii) Piperine : 0.13% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0092] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1.

[0093] EXAMPLE 3:

[0094] Product formula (curcumin and piperine 40: 1): i) Curcumin : 3.99% ii) Piperine : 0.10% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0095] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1.

[0096] EXAMPLE 4: Product formula (curcumin and piperine 50: 1): i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0097] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1.

[0098] COMPARATIVE EXAMPLE 1:

[0099] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.07% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0100] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of curcumin and piperine. In this embodiment, the ratio was 60: 1.

[0101] COMPARATIVE EXAMPLE 2:

[0102] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.06% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0103] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of curcumin and piperine. In this embodiment, the ratio was 70: 1.

[0104] COMPARATIVE EXAMPLE 3:

[0105] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.05% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0106] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of curcumin and piperine. In this embodiment, the ratio was 80: 1.

[0107] COMPARATIVE EXAMPLE 4:

[0108] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.04% iii) Gelucire® 48 / 16: : 79.84% iv) Transcutol® HP : 10.65% v) PEG 400 5.32%

[0109] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of curcumin and piperine. In this embodiment, the ratio was 90: 1.

[0110] COMPARATIVE EXAMPLE 5:

[0111] Product formula: i) Curcumin : 3.99% ii) Gelucire® 48 / 16: : 79.84% iii) Transcutol® HP : 10.85% iv) PEG 400 : 5.32%

[0112] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 without incorporating Piperine.

[0113] COMPARATIVE EXAMPLE 6:

[0114] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Gelucire® 48 / 16: : 59.84% iv) Transcutol® HP : 30.65% v) PEG 400 5.32%

[0115] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of surfactant and cosurfactant.

[0116] COMPARATIVE EXAMPLE 7:

[0117] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Gelucire® 48 / 16: : 69.84% iv) Transcutol® HP : 20.65% v) PEG 400 5.32%

[0118] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of surfactant and cosurfactant.

[0119] COMPARATIVE EXAMPLE 8:

[0120] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Gelucire® 48 / 16: : 69.84% iv) Transcutol® HP : 20.65% v) PEG 400 5.32%

[0121] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 except the ratio of surfactant and cosurfactant. COMPARATIVE EXAMPLE 9:

[0122] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Gelucire® 48 / 16: : 90.49% iv) PEG 400 : 5.32%

[0123] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 without involving Transcutol® HP.

[0124] COMPARATIVE EXAMPLE 10:

[0125] Product formula: i) Curcumin : 3.99% ii) Piperine : 0.08% iii) Transcutol® HP: : 90.49% iv) PEG 400 : 5.32%

[0126] Method of manufacturing the product: In this embodiment, the product was prepared as per the process described in Example 1 without involving the surfactant (Gelucire® 48 / 16).

[0127] Table 2: Finished Product description (Example 4)

[0128] PERMEATION STUDY BY EX-VIVO GUT SAC MODEL: The formulation of Example 1-9 was evaluated for gut-sac permeability as herein below:

[0129] Permeation study protocol: i. Ex-vivo permeation apparatus: Beaker ii. Sample substrate: Rat small intestine iii. Permeation media: USP Phosphate buffer [pH 6.8] iv. Temperature: 37± 0.2°C v. Speed: Aeration vi. Volume of media: 100ml vii. Duration of study: 24 hours viii. Dose: Formulations equivalent to lmg of Curcumin ix. Sample preparation: Formulation equivalent to 1 mg of curcumin dispersed in 0.5ml of media and instilled in the rat small intestine and tied from both the ends. x. Sampling time points: 15 min, 30 min, 45 min, 1 h, 1.5h, 2h, 3h, 4h, 6h, 8h and 24h xi. Sampling: Sampling was done by removing 1ml media and replacing with the fresh media of same volume. xii. Analysis:

[0130] Samples were analyzed using UV-visible spectrophotometer at XMax 428 nm.

[0131] As shown in Fig. 2, the piperine has positive impact on permeation of curcumin when the ratio of curcumin and piperine was 20: 1 to 50: 1 (i.e. Example 1-4) and provides the similar permeation pattern up to 8 hr. The maximumpermeation was observed when the ratio is 50: 1 (Example 4). The permeation starts decreasing as the ratio further increased from 60: 1 to 90: 1 (Comparative Example 1-5) which is not desired. Piperine doesn’t show any improvement in permeation of curcumin above the ratio of 80: 1 (Comparative Example 3 & 4) and its as good as without piperine (Comparative Example 5) . It was also observed that the formulation containing curcumin and piperine (10: 1) provides appreciable permeability, however, it results saturation of the system and due to which the product doesn’t show long-term stability on storage. On the other hand, it was also found that the higher concentration of piperine (i.e. more than 1.0 by weight) also destabilises the formulation.

[0132] DISSOLUTION STUDY:

[0133] The formulation of Example 1-4 was subjected for dissolution studies as follows in order to observe the release pattern of curcumin.

[0134] Dissolution Study Protocol: i. Dissolution apparatus: USP type 1 (Basket). ii. Dissolution media: 0.1N HCl pH 1.2 iii. Temperature: 37 ± 0.2 °C iv. Rotation Speed: 50 rpm v. Volume of dissolution media: 900 ml vi. Dose: Curcumin 30 mg vii. Sampling time points: 10, 15, 20, 30, 45, 60, 90, 120 minutes viii. Sampling: 5 ml of sample were withdrawn using a syringe, followed by filtration and replenishing the vessel with the fresh media of the same volume. ix. Samples were analysed using UV-visible spectrophotometry at XMax 428 nm after suitable dilution if required. x. Standard preparation: The calibration curve of curcumin was done in 0.1N HC1 pH 1.2.

[0135] Table 3: % release of curcumin

[0136] As shown in Table 3 and Fig. 3, it was observed that the formulation (Example

[0137] 4) results the release of curcumin more than 70% in 5 mins confirming faster release of the drug.

[0138] STABILITY OF CURCUMIN-PIPERINE IN THE FORMULATION:

[0139] The developed formulation (Example 4, Comparative Example 7-10) was studied for stability of curcumin and piperine in that formulation by observing homogeneous dispersion or precipitation after 24 hours. If the precipitation occurs in any formulation after 24 hours, then curcumin-piperine is not considered as stable.

[0140] Table 3: Stability of curcumin-piperine

[0141] CE: Comparative Example; IE: Inventive Example

[0142] The particle size of the above formulations studied by adding approximately one drop of formulation in 5 mL of Millipore water and mixed by vortex mixer. Required sample of the above dispersions was taken for particle size analysis by Zetasizer (Malvern).

[0143] The precipitation was observed in the formulation of Comparative Example 7- 10 after 24 hours at room temperature whereas no precipitation was seen in the inventive example (Example 4) after 24 hours and the formulation (IE4) when dispersed in water instantly arranged itself in the micellar structure with particle size below 12 nm (i.e. homogeneous dispersion) thereby ensures the stability of curcumin and piperine in the formulation. The said finding recites that in micellar formulation, the combination of curcumin and piperine would not be stable without the water-soluble surfactant or without cosurfactant or other than the ratio of surfactant (77-82%) and cosurfactant (13-18%).

[0144] STABILITY DATA:

[0145] The stability study of formulation (IE4) was carried out at 40°C and 75% RH for 6 months. The dissolution study was carried out in 900 ml phosphate buffer pH 6.8 using Type 1 (basket) USP dissolution apparatus at 100 rpm and 37°C for 2 hours. The samples were analyzed using validated UV spectroscopic method. As shown in Fig. 4 the formulation was found stable and there was no significant change observed in the dissolution profile compare to the initial dissolution confirming that the formulation has good stability over 6 months. Although the foregoing description of the present invention has been shown and described with reference to particular embodiments and applications thereof, it has been presented for purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the particular embodiments and applications disclosed. It will be apparent to those having ordinary skill in the art that a number of changes, modifications, variations, or alterations to the invention as described herein may be made, none of which depart from the spirit or scope of the present invention. The particular embodiments and applications were chosen and described to provide the best illustration of the principles of the invention and its practical application to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such changes, modifications, variations, and alterations should therefore be seen as being within the scope of the present invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally, and equitably entitled.

Claims

CLAIMS:

1. A micellar formulation of curcumin and piperine includes non-ionic surfactant and cosurfactant wherein the surfactant is water soluble surfactant.

2. The formulation as claimed in claim 1, wherein the ratio of curcumin and piperine is 20: 1 to 50 : 1 by weight.

3. The formulation as claimed in claim 1, wherein the amount of surfactant is 77-82%.

4. The formulation as claimed in claim 1, wherein the amount of cosurfactant is 13- 18%.

5. The formulation as claimed in claim 1, wherein the surfactant is selected from a group consisting of polyoxyethylene sorbitan monooleate, Polyoxyethylene sorbitan monolaurate, polyoxyl-32 stearate (type I) NF, Poloxamer, polyethylene glycol monododecyl ether, polyethylene glycol hexadecyl ether, Labrasol, PEG esters, Polyethylene glycol 400 (PEG400), Polyethylene glycol 600 (PEG600), Polyoxyethylene castor oil, Polyoxyl 40 hydrogenated castor oil, Polyethylene glycol -polypropylene glycol block copolymer, (D-u-tocopheryl polyethylene glycol succinate, Polyethylene glycol 660 12-hydoxystearate, Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co- polyme, PEG-32 glycerides, Lauroyl PEG-32 glyceride, Oleoyl polyoxyl-6 glycerides, Linoleoyl polyoxyl-6 glycerides, Lauroyl polyoxyl-6 glycerides, Polyoxyl 20 Cetostearyl Ether, PEG 40 Sorbitan Peroleate, Caprylocaproyl polyoxylglycerides, Polyoxyl 35 Castor Oil, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate & PEG 100 Stearate or a combination thereof.

6. The formulation as claimed in claim 1, wherein the cosurfactant is selected from a group consisting of ethanol, isopropyl alcohol, dimethylsulfoxide, diethylene glycol monoethyl ether, tetrahydrofurfuiyldiethylene glycol ether, propylene glycol, polyethylene glycol, lecithin, sorbitan, polysorbates,Caprylocaproyl Polyoxyl-8 glycerides, I monolaurate or a combination thereof.

7. The formulation as claimed in claim 1 is administered through a route selected from oral, sublingual, transdermal, naso- gastric, rectal, parenteral, topical or inhalation.

8. The formulation as claimed in claim 1 is administered preferably through oral route.

9. The formulation as claimed in claim 1 is in the form of tablet, capsule, pellet, lozenge, film, powder, liquid, cream, ointment, gel injection, spray, suppository, lotion, drop, soap or cosmetic preparation.

10. The formulation as claimed in claim 1 is preferably in the form of capsule.

11. A micellar formulation of curcumin and piperine comprises i) curcumin in an amount of 2-8% w / w; ii) piperine in an amount of 0.04-0. 16%w / w; iii) non-ionic water-soluble surfactant in an amount of 77-82% w / w; iv) cosurfactant in an amount of 13- 18% w / w.

12. A process for preparing micellar formulation of curcumin and piperine comprising the steps of:- i) subjecting non-ionic surfactant for melting in order to obtain a molten surfactant; ii) dispersing curcumin and piperine in cosurfactant; iii) adding the product as obtained in step (ii) into the molten surfactant; iv) subjecting the product as obtained in step (iii) for homogenization in order to get a homogenous product; wherein the surfactant is water soluble surfactant.

13. The process as claimed in claim 12, wherein the process further comprising a filling step upon which the said homogenized product is filled in a capsule casing.

14. The process as claimed in claim 12, wherein th( i) is carried out at 70°C.

15. The process as claimed in claim 12, wherein the homogenization is carried out at 55°C for 1 hour.

16. The process as claimed in claim 12, wherein the ratio of curcumin and piperine is 20: 1 to 50 : 1 by weight.

17. The process as claimed in claim 1, wherein the surfactant is selected from a group consisting of polyoxyethylene sorbitan monooleate, Polyoxyethylene sorbitan monolaurate, polyoxyl-32 stearate (type I) NF, Poloxamer, polyethylene glycol monododecyl ether, polyethylene glycol hexadecyl ether, Labrasol, PEG esters, Polyethylene glycol 400 (PEG400), Polyethylene glycol 600 (PEG600), Polyoxyethylene castor oil, Polyoxyl 40 hydrogenated castor oil, Polyethylene glycol -polypropylene glycol block copolymer, (D-u-tocopheryl polyethylene glycol succinate, Polyethylene glycol 660 12-hydoxystearate, Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft co- polyme, PEG-32 glycerides, Lauroyl PEG-32 glyceride, Oleoyl polyoxyl-6 glycerides, Linoleoyl polyoxyl-6 glycerides, Lauroyl polyoxyl-6 glycerides, Polyoxyl 20 Cetostearyl Ether, PEG 40 Sorbitan Peroleate, Caprylocaproyl polyoxylglycerides, Polyoxyl 35 Castor Oil, PEG-30 Dipolyhydroxystearate, Glyceryl Stearate & PEG 100 Stearate or a combination thereof.

18. The process as claimed in claim 12, wherein the cosurfactant is selected from a group consisting of ethanol, isopropyl alcohol, dimethylsulfoxide, diethylene glycol monoethyl ether, tetrahydrofurfuiyldiethylene glycol ether, propylene glycol, polyethylene glycol, lecithin, sorbitan, polysorbates, Caprylocaproyl Polyoxyl -8 glycerides, Propylene glycol monolaurate or a combination thereof.

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