NON-STAINING CURCUMINOID COMPOSITION

Abstract

The invention describes a non-staining composition comprising high content of curcuminoids in granular form, which is substantially free of excipients and is comprised of at least about 94% of curcuminoids. The non-staining composition may be comprised of 0 to 5% by weight of excipients, which are used as processing aids. The non-staining curcuminoid composition does not cause staining and dusting of the equipment and the contact surfaces, while formulating into finished dosage forms. The invention also relates to solvent-free process for preparation of non-staining granular composition; wherein the curcuminoids may be subjected to granulation process at specific temperature conditions. The granular composition is free flowing and retains original yellowish orange colour of the curcuminoids along with its crystalline nature. The solvent-free process for non-staining granular curcuminoid composition is simple, economical and environment friendly, thus making it industrially useful and applicable for formulating finished dosage forms.

Claims

1. A non-staining composition comprising high content of curcuminoids in granular form; wherein the composition is substantially free of excipients.

2. The non-staining composition of claim 1, wherein curcuminoid granules do not cause staining and dusting of equipment and contact surfaces while formulating into finished dosage forms.

3. The non-staining composition of claim 1, which may be comprised of at least about 94% of curcuminoids and about 0 to 5% by weight of excipients, which are used as processing aid in nutraceutical, food and cosmetics industry.

4. The non-staining composition of claim 3, wherein the processing aid may be selected from the class of lipids, fats, fatty alcohol, fatty acid esters, waxes, oils, their derivatives and the combination thereof.

5. The non-staining composition of claim 4, wherein the processing aid is selected from carnauba wax, beeswax, stearic acid, cetyl alcohol, pegylated fatty acids, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, pegylated vegetable oils, partially hydrogenated oils of soy, cottonseed, palm, sunflower, castor oil, sorbitan esters, polyoxyethylene sorbitan esters, propylene glycol mono- or diesters, phospholipids, glycolipids, glycerolipid, sphingolipid, phosphatides, phosphatic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol, glycerophospholipids, cerebrosides, gangliosides, cephalins, sulfatides, sugar esters, sugar ethers, sucrose esters, sterols, polyglycerol esters, ceramide, sterol, fat-soluble vitamins, prenol, saccharolipid, polyketides, their derivatives or the combination thereof.

6. The non-staining composition of claim 1, wherein the granules may vary in size from 50 to 1500 microns, preferably from 100 to 1000 microns.

7. The solvent free process for preparation of non-staining composition with high content of curcuminoids, which is comprised of a. subjecting the curcuminoids to heat treatment using suitable granulator b. optionally mixing the granules with 0 to 5% by weight of processing aid c. processing the mixture of step b using heat treatment in suitable granulator to get the granules d. sizing the resulting granules to get non-staining composition with at least 94% curcuminoids.

8. The process of claim 7, wherein the non-staining composition can be granulated using heat treatment between the temperature ranging from 50 to 200° C., using granulator selected from rapid mixer granulator, extrusion spheronizer, hot melt extruder, roller compactor, fluid bed granulator and the like.

9. The process of claim 7, wherein the processing aid may be selected from fats, lipids, fatty acids, fatty alcohol, waxes, oils and the combination thereof.

10. The non-staining composition of claim 1, which retains original yellowish orange colour of curcuminoids and can be formulated in capsules, tablets, caplets, pills, beads, beadlets, pellets and dosage forms, without staining the equipment and contact surfaces during formulation.

Description

DETAILED DESCRIPTION

[0028] It has surprisingly been found that granular composition of the present invention comprising high content of curcuminoids, which is substantially free of excipients, exhibits non-staining property. The composition is comprised of at least about 94% of curcuminoids and retains original colour as well as crystalline pattern like that of curcuminoids. The granular curcuminoid composition prevents staining of equipment, body parts and all other surfaces in contact, while processing the granules for converting into finished dosage forms. The composition is thus useful for further processing of the granules in desired dosage forms, as the granules do not cause any dusting on equipment and formulation area which otherwise happens due to unformulated plain curcuminoids.

[0029] The present invention uses curcuminoids, purchased in the form of extract from the external vendor. The extract is obtained from Curcuma species of the Zingiberaceae (ginger) family, and contains specific percentage content of curcuminoids.

[0030] The term ‘curcuminoid extract’ is used herein to mean the extract of roots, tubers or rhizomes of the Curcuma species of the Zingiberaceae (ginger) family including but not limited to species like Curcuma longa, Curcuma amada, Curcuma angustifolra, Curcuma caesia, Curcuma zedoaria, Curcuma caulina, Curcuma aromatica, Curcuma wenyujin, Curcuma xanfhorrhiza, Curcuma phaeocaulis, Curcuma leucorrhiza and Curcuma kwangsiensis.

[0031] The term ‘curcuminoid’ is used herein to mean curcumin (diferuloylmethane), desmethoxycurcumin, or bisdesmethoxycurcumin, including their polymorphs, hydrates, solvates, derivatives, and mixtures thereof.

[0032] The terminology ‘non-staining’ as used herein, is the property exhibited by granular curcuminoid composition, as described herein, by virtue of which, the composition does not stain or colour any equipment and contact surfaces, which are used to handle granules during formulation into desired dosage forms. The composition also does not cause dusting on the formulation area and equipment, while carrying out different processes like weighing, sifting, mixing or during filling in the capsules or compression in tablet dosage forms. Non-staining composition is obtained from curcuminoids, which has characteristic yellowish orange colour. Even though this original colour as well as crystallinity is retained in non-staining granular composition, it does not significantly stain or colour any of the contact surfaces or formulation equipment, while formulating into finished dosage forms. The non-staining composition does not even significantly stain the hands while handling the granules. Thus even though the composition is prepared from curcuminoids, which have characteristic yellowish orange colour, the composition exhibits non-coloring characteristic, in its granular form.

[0033] The terminology ‘substantially free of excipients’ as used herein means the composition may contain only about 0 to 5% of the excipients by weight of the composition, which may be used as processing aid, while preparation of non-staining composition in granular form. Thus as per one embodiment, the composition may be substantially free of excipients. As per one more embodiment, the composition may contain 1 to 5% of excipients by weight of the composition, which may be selected from the group of diluent, filler, carrier, stabilizer, antioxidant, disintegrant, lubricant, antiglidant, anti-tacking agent, oil vehicle and the like, which are commonly used in pharmaceutical, nutraceutical, food and cosmetics industry. According to one important embodiment, the processing aid may be selected from the group of lipids, fats, fatty acids, fatty alcohols, fatty acid esters, waxes, oils and the combination thereof.

[0034] The processing aid may facilitate preparation of the composition in free-flowing granular form, which have non-staining property. The processing aid may be required to convert the extract comprising high content of curcuminoids in the form of granules, using process of heat treatment and granulation.

[0035] The terminology ‘high content of curcuminoids’ as used herein means the composition comprised of at least about 94% of curcuminoids, calculated as total curcuminoids. Thus these compositions may contain about 94 to 100% of curcuminoids in granular form and the composition may be substantially free of excipients. Thus the composition may be free of any excipients or may contain only about 1 to 5% by weight of processing aids, thus resulting into very high content of curcuminoids in the non-staining granular composition. The granules having non-staining property can be used by formulators for converting into desired dosage forms as per the requirement of active content.

[0036] The terminology ‘yellowish orange’ as used herein refers to wide colour range of curcuminoids obtained from turmeric extract, wherein the colour may vary from different shades of yellow to red to orange. The colour shade of curcuminoids may vary depending upon source, processing conditions, storage conditions, but the spectrum of color shade may vary from bright yellow, dull yellow, yellowish orange to light orange or reddish orange or dark orange, and the possible shades of curcuminoids lying between this colour range. The granular non-staining composition as described herein retains the original color shade of plain unformulated curcuminoids; but it exhibits the property in the granular composition as described herein, wherein it does not significantly stain the equipment and contact surfaces, while processing into final formulations.

[0037] The terminology ‘solvent-free process’ as used herein refers to the process for preparation of non-staining granular composition of the invention, which is comprised of high content of curcuminoids. The process does not make use of any organic solvents while preparing the granules, thus rendering the process simple, cost and time effective as well as environment friendly. The process makes use of granulation process using heat treatment and suitable granulator equipped for application of heat. Solvent-free process, as used herein also provides the advantage of getting non-staining granular product, which is free from traces of any residual organic solvent, thus making the product safe for consumption for various application in nutraceutical, food and cosmetic industry.

[0038] According to one embodiment of the present invention, the composition uses a curcuminoid extract containing at least about 94% by weight of one or more curcuminoids.

[0039] As per one more embodiment of the invention, the non-staining composition may be comprised of high content of curcuminoids, wherein the granules may contain about 94% to 100% of curcuminoids, calculated as total curcuminoids.

[0040] According to one more embodiment of the invention, the composition is free flowing and granular in nature and the granule size may range from 50 to 1500 microns. More preferably the size of granules may range from 100 to 1000 microns, most preferably it may range from 200 to 800 microns.

[0041] According to another embodiment of the invention, the granular composition may be comprised of curcuminoids which are substantially crystalline in nature. The granular composition retains the original crystallinity of curcuminoids even after converting in the granular composition.

[0042] Curcuminoids have their characteristic yellowish orange colour, which is mainly due to its polyphenol content. The composition as described herein, retains its characteristic yellowish orange colour after processing into the granules. The composition exhibits non-staining property, because of which it does not stain the equipment, contact surfaces and even the formulation area while converting into finished dosage forms.

[0043] As per one important embodiment of the invention, the composition is in the form of non-staining granules, which may prevent dusting of curcuminoids while handling and processing it during weighing, mixing, granulation, compression, filling and so on, for converting in finished dosage forms like tablets, capsules and the like.

[0044] As per one more embodiment of the current invention, the composition may be substantially free of excipients. The composition may contain about 0 to 5% by weight of processing aids, which may facilitate process for preparation of the composition in its granular form.

[0045] According to another embodiment, the composition may be comprised of 100% by weight of curcuminoids, and thus do not contain any processing aid in the granules.

[0046] As per one more embodiment, the composition may be comprised of 1 to 5% by weight of processing aids, thus the composition may be comprised of very high content of curcuminoids, ranging from 95 to 100% in the granular composition.

[0047] According to one important embodiment of the invention, the processing aid may be selected from the group of lipids, fats, fatty acids, fatty alcohols, fatty acid esters, waxes, oils and the combination thereof.

[0048] As per one more embodiment, the processing aid may be selected from, but not limited to, saturated fatty acids having 12 to 28 carbons, such as stearic acid, fatty alcohols having from 16 to 44 carbons, cetyl alcohol, pegylated fatty acids, glycerol fatty acid esters, monoglycerides, diglycerides, triglycerides, derivatives of mono-diglycerides, glyceryl behenate, glyceryl monostearate, glyceryl palmitostearate, pegylated vegetable oils, partially hydrogenated oils of soy, cottonseed, palm, sunflower, castor oil, sorbitan esters, polyoxyethylene sorbitan esters, propylene glycol mono- or diesters, phospholipids, phosphatides, cerebrosides, gangliosides, cephalins, lipids, glycolipids, sulfatides, sugar esters, sugar ethers, sucrose esters, sterols, polyglycerol esters, glycerolipid, phosphatic acid, phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, phosphatidylinositol or other glycerophospholipids, ceramide, sphingolipid, sterol, fat-soluble vitamin, prenol, saccharolipid, polyketide, their salts and esters and the combination thereof.

[0049] Processing aid may also be selected from, but not limited to, beeswax, candelilla wax, carnauba wax, spermaceti, paraffin wax, synthetic waxes and the combination thereof.

[0050] According to one embodiment of the invention, the compositions may be prepared by solvent-free process using suitable granulation process, selected from dry granulation, melt granulation, extrusion, coacervation, congealing, steam granulation, freeze granulation, foam granulation and the like.

[0051] According to one embodiment of the invention, the granular composition may be prepared by single step or multi-step granulation, using various suitable granulation equipment such as rapid mixer granulator, extrusion spheronizer, hot melt extruder, roller compactor, fluid bed granulator, generally used in food, nutraceutical or pharmaceutical industry.

[0052] According to another embodiment, the composition may be prepared by one step continuous granulation process by processing the active in twin screw processor. Curcuminoid extract may be subjected to continuous granulation process, wherein the input material is continuously fed into the granulator, while the output (granular non-staining composition) is taken out in one-step process.

[0053] As per one embodiment, the solvent-free process as described herein may be comprised of granulating curcuminoids by heat treatment to get granular mass. The mass may be optionally mixed with about 1 to 5% by weight of processing aids and granulated again using heat treatment in suitable granulating apparatus. The granules obtained are non-staining, free flowing and retain original colour and crystallinity of curcuminoids. Thus these are suitable granular and non-staining compositions for formulating in variety of dosage forms of curcuminoids

[0054] The granules may be formed by varying the heat treatment in the range of 50 to 200° C., using suitable granulation process such as hot melt granulation or hot melt extrusion. The resulting granular composition is significantly non-staining to equipment and contact surfaces and it is suitable for converting into finished dosage forms such as tablets, capsules, caplets, beads, beadlets and the like.

[0055] The composition as described herein may overcome process difficulties such as bulk handling of active unformulated curcuminoids due to the colour explosion and dusting characteristics. The routine problem of staining due to curcuminoids, makes the production process troublesome, expensive and time consuming because of complete change over cleaning required using organic solvents after processing the batches manufacturing. The composition as described herein helps to overcome these difficulties. The composition as described herein provides high content of non-staining curcuminoids in granular form, which is convenient to process in finished dosage form, thus providing clean and cost-effective alternative to handling regular staining curcuminoids in powder form.

[0056] The composition as described herein is prepared by solvent-free process and it is in the form of granules, which exhibit non-staining property. Curcuminoid granules prepared by this process overcome the tedious problems of staining of the equipment and other contact surfaces and therefore are useful for formulation into finished dosage forms. Non-staining curcuminoid granules as described herein prevent problem of dusting of curcuminoids in and around formulation area.

[0057] The non-staining granular compositions as described herein have various advantages with respect to industrial processing. The composition is comprised of high content of curcuminoids by weight of granules as the composition is substantially free of the excipients. Curcuminoid granules is a non-staining composition and can be formulated into tablets, capsules and other dosage forms by using suitable processes and equipment employed in nutraceutical, pharmaceutical or food industry. The granules do not stain the equipment used in the processing, thus making the formulation process convenient and industrially useful.

[0058] According to one more embodiment, curcuminoid granules may be converted in tablet dosage forms by adding excipients selected from the group of, but not restricted to diluents, fillers, carriers, stabilizers, antioxidants, anti-tacking agents, glidants, disintegrants, lubricants, oil vehicles and the like. The composition, being non-staining in nature, will not stain the equipment involved in formulation processes, thus making the process non-tedious, convenient and industrially useful.

[0059] The non-staining curcuminoid composition, as described herein is granular in nature, retains original yellowish orange colour and crystalline form of unformulated curcuminoids. The composition is substantially free of any excipients and thus may be comprised of very high content of active, at least about 94% curcuminoids in the form of free-flowing granules. The invention also relates to process for preparation of non-staining curcuminoid granules, without use of any excipient. The process described herein is solvent free, wherein the active may be subjected to one step continuous granulation method. Although the process results in maintaining yellowish orange natural colour of curcuminoids, these granules do not cause staining and dusting of curcuminoids during formulating into finished dosage forms. The non-staining curcuminoid compositions are thus industrially useful and suitable for various formulation related operations, without any colour explosion.

[0060] The granular composition of curcuminoids can be evaluated through characterization of the granules for properties like non-staining property, assay content, crystallinity along with formulation stability.

EXAMPLES

Example 1: Non-Staining Curcuminoid Composition Comprising 0 to 5% Wax

[0061]

TABLE-US-00001 TABLE 1 A. Composition of Formula 1 to 6 (with and without processing aid) Formula Formula Formula Formula Formula Formula Ingredients 1 2 3 4 5 6 Curcuminoids 95% 100.0% 99.0% 98.0% 97.0% 96.0% 95.0% Carnauba wax 0.0 1.0% 2.0% 3.0% 4.0% 5.0% Total 100.0% 100.0% 100.0% 100.0% 100.0% 100.0%

Process for Preparation of Formula 1

[0062] Weighed quantity of extract comprising curcuminoids is melt granulated in Hot Melt Extruder operating with the heating range of 150-180° C. in various compartments. The resultant granules are sized to get the granules in the range of 150 to 800 microns.

Process for Preparation of Formula 2 to Formula 6

[0063] Weighed quantity of curcuminoids are melt granulated in Hot Melt Extruder operating with the heating range of 150-180° C. in various compartments. The resultant granules are mixed with corresponding quantity of carnauba wax and again melt granulated in Hot Melt Extruder operating with the heating range of 50-80° C. in various compartments. The re-granulated non-staining composition is sized to have granules varying in size from 200 to 600 microns.

[0064] B. Determination of Curcuminoids Content

[0065] Non-staining composition is analyzed for its total curcuminoids content by using HPLC (High Performance Liquid Chromatography). Weighed sample equivalent to 50 mg of Curcuminoids is powdered and transferred into 200 mL dry volumetric flask, to which methanol is added and subjected to centrifugation. 2 mL of the supernatant solution was transferred to 100 mL volumetric flask and the volume is made-up with mobile phase (Tetrahydrofuran: Buffer (40:60). The solution is filtered through 0.45 μm PVDF filter. The detection is done by using C18 column at 420 nm, using flow rate as 1.0 mL/min and 100 μL Injection Volume. Total curcuminoids content is calculated using the area of test solutions and standard solution

TABLE-US-00002 TABLE 2 Determination of curcuminoid content of Formula 1 to 6 Formula Formula Formula Formula Formula Formula Assay Active 1 2 3 4 5 6 Total 103.2% 100.0% 100.4% 98.9% 98.8% 97.9% 98.0% curcuminoids The active content of the compositions is observed to be in the range of 97 to 100.5%.

[0066] C. Evaluation of Non-Staining Properties of the Composition

[0067] Curcuminoids granular composition is analyzed for non-staining property by the following method: [0068] a) 500 mg of sample is weighed on butter paper and it is transferred and spread on 10×10 cm.sup.2 stainless steel plate. The plate is then tilted so that powder falls on butter paper. The plate is observed carefully to check whether the sample sticks to the plate. [0069] b) The plate is rinsed using 10 ml of 90% methanol in water and the rinsate is collected in 25 ml glass beaker. This procedure is repeated for 3 times and each time the rinsate is collected in separate glass beaker and absorbance is checked at 420 nm against standard solution; which is prepared by weighing 50 mg of Curcuminoid working standard and dissolved in 90% methanol in water.

TABLE-US-00003 TABLE 3 Evaluation of non-staining property of Formula 1 to 6 Assay Formula Formula Formula Formula Formula Formula (mg) Active 1 2 3 4 5 6 Rinse 0.32 0.28 0.25 0.09 0.05 0.05 0.04 solution 1 Rinse 0.26 0.003 0.003 0.005 0.002 0.003 0.001 solution 2

[0070] It can be seen from Table 3 that the compositions comprising 3 to 5% excipient (Formula 4, 5 and 6) did not produce significant staining on the stainless steel plate after first rinsing.

[0071] After second rinsing, the composition without excipients (i.e., 0% excipients—Formula 1) did not show any stain on the stainless-steel plate and addition of excipients, at the level of 1-5% as processing aid, did not change the property of non-staining produced by melt granulation process.

[0072] If plain active (curcuminoids) is used for preparing final formulations, about 3-4 times cleaning of machine and equipment will be required; whereas the above non-staining compositions will require only 1-2 times cleaning of the equipment, thus saving the time and cost of the processing.

[0073] D. Evaluation of Crystallinity of Non-Staining Composition

[0074] Non-staining composition of Formula 1 was subjected to XRD analysis and the diffractogram was compared with that of plain curcuminoid to check crystallinity pattern of both the test samples.

[0075] It was found that the diffractogram of curcuminoids and the non-staining composition was substantially same, suggesting that the crystallinity pattern of curcuminoids was retained in non-staining composition.

[0076] E. Evaluation of Stability of Non-Staining Composition

[0077] Composition of Formula 3 was subjected to stability study at different storage conditions as shown in Table 4 and the active content was analyzed over a period of 3 months.

TABLE-US-00004 TABLE 4 Stability Data of non-staining curcuminoid composition Stability Incubation Composition Condition Period Assay Formula 3 Before stability Initial 99.3% 40° C./75% RH 1 month 100.5 2 month 100.3 3 month 100.2 30° C./75% RH 3 month 99.2 25° C./60% RH 3 month 100.5

[0078] The composition was found to be stable over a period of 3 months at all three different storage conditions.

Example 2: Non-Staining Curcuminoid Composition Comprising 1 to 5% Cetyl Alcohol

[0079]

TABLE-US-00005 TABLE 5 Composition and active content of non-staining granules (Formula 7 to 11) Formula Formula Formula Formula Formula Ingredients 7 8 9 10 11 Curcuminoids 99.0% 98.0% 97.0% 96.0% 95.0% 95% Cetyl alcohol 1.0% 2.0% 3.0% 4.0% 5.0% Total 100.0% 100.0% 100.0% 100.0% 100.0% Assay Total 101.8% 101.3% 99.9% 99.8% 98.0% curcuminoids

[0080] Process: Weighed quantity of curcuminoids are melt granulated in Hot Melt Extruder operating with the heating range of 150-180° C. in various compartments. The resultant granules are mixed with corresponding quantity of cetyl alcohol and again melt granulated in Hot Melt Extruder operating with the heating range of 50-80° C. in various compartments. The re-granulated non-staining composition is sized to have granules varying in size from 200 to 600 microns.

[0081] The composition is evaluated for active content and non-staining property.

TABLE-US-00006 TABLE 6 Evaluation of Non-staining properties of the composition Assay Formula Formula Formula Formula Formula (mg) Active 7 8 9 10 11 Rinse 0.32 0.24 0.25 0.14 0.19 0.15 solution 1 Rinse 0.26 0.005 0.004 0.0004 0.0009 0.0003 solution 2 Rinse 0.03 0.0007 0.0001 0.0001 0.0006 0.0001 solution 3

[0082] The formulations contain excipient at the levels of 1 to 5% did not produce stain on the stainless-steel plate, even after second rinsing.

[0083] If the unformulated active is used in the formulation, there will be need of 3-4 times cleaning of machine and equipment whereas the above said non-staining compositions will require 1-2 times cleaning, thus resulting into saving of time and cost in formulating the finished dosage forms using non-staining granular curcuminoid compositions.

Example 3: Non-Staining Curcuminoid Composition Comprising 1 to 3% Glyceryl Behenate

[0084]

TABLE-US-00007 TABLE 7 Composition and active content of non-staining granules (Formula 12 to 14) Ingredients Formula 12 Formula 13 Formula 14 Curcuminoids 95% 99.0% 98.0% 97.0% Glyceryl Behenate 1.0% 2.0% 3.0% Total 100.0% 100.0% 100.0% Assay Total curcuminoids 100.7% 99.9% 99.8%

[0085] Process: Weighed quantity of extract comprising curcuminoids is melt granulated in Hot Melt Extruder operating with the heating range of 150-180° C. in various compartments. The resultant granules are mixed with corresponding quantity of glyceryl behenate and again melt granulated in Hot Melt Extruder operating with the heating range of 50-80° C. in various compartments. The re-granulated non-staining composition is sized to have granules varying in size from 200 to 600 microns. The composition is evaluated for active content and non-staining property.

TABLE-US-00008 TABLE 8 Evaluation of non-staining properties of Formula 12 to 14 With 1% With 2% With 3% Assay (mg) Active excipients excipients excipients Rinse solution 1 0.32 0.27 0.25 0.20 Rinse solution 2 0.26 0.001 0.002 0.004

[0086] The compositions comprising excipient at levels of 1 to 3% did not produce stain on the stainless-steel plate after second rinsing, indicating non-staining property of curcuminoid granular compositions on equipment or contact surfaces.