Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
  • A61K36/18—Magnoliophyta (angiosperms)
  • A61K36/88—Liliopsida (monocotyledons)
  • A61K36/906—Zingiberaceae (Ginger family)
  • A61K36/9066—Curcuma, e.g. common turmeric, East Indian arrowroot or mango ginger

Definitions

• the disclosure relates to a sustained release pharmaceutical composition, which includes bioavailable curcumin formulation as medicament and release rate controlling excipients such as ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose etc either alone or in combination.
• the formulation is a powder.
• the formulation is in the form of granules.
• the disclosure also relates to a process for the manufacturing of sustained release formulations including bioavailable curcumin formulation and rate controlling excipients such as ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose etc either alone or in combination.
• bioavailable curcumin formulation and rate controlling excipients such as ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose etc either alone or in combination.
• the disclosure also relates to a process of development of sustained release formulation and further representation into a suitable dosage form which may include but not limited to powder, granules, pellets, tablets, capsules etc.
• the disclosure relates to a sustained release curcuminoid formulation which enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 36 hours and in tissues for more than 24 hours after a single dose of sustained release formulation.
• the disclosure also relates to a sustained release curcuminoid formulation having a bioavailable curcumin composition. Administering a single dose of the sustained release curcuminoid formulation results in detection of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for about 24 to about 36 hours.
• the disclosure relates to a sustained release curcuminoid formulation in which the half-life (tl /2) and area under the curve (AUC) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased after a single dose of sustained release formulation.
• Curcumin [l ,7-bis(4-hydroxy-3-methoxyphenyl)- I ,6-heptadiene-3,5-dione] is the major yellow pigment of turmeric, a commonly used spice, derived from the rhizome of the herb Curcuma longa Linn. In the Indian subcontinent and Southeast Asia, turmeric has traditionally been used as a treatment for inflammation, skin wounds, and tumors. In preclinical animal models, curcumin has shown cancer chemo preventive, antineoplastic and anti-inflammatory properties ( elloff, G. I., et al, J. Cell Biochem., 1996, 265:54-71 ).
• Curcumin suppresses a number of key elements in cellular signal induction pathways pertinent to growth, differentiation and malignant transformations.
• signaling events inhibited by curcumin are protein kinases (Liu, J. V. et al, Carcinogenesis, 1993, 14:857-61 ), c-Jun/AP- l activation (Huang, T. S. et al, Proc. Natl Acad. ScL, 1991 ,88:5292-96), prostaglandin biosynthesis (Huang, M- T. et al, In L. W.
• curcumin demonstrates poor systemic bioavailabil ity (lreson, C. R. et al, Cancer Res., 2001 , 41 -.1058-64) which may be related to its inadequate absorption and fast metabolism . Curcumin bioavai lability may also be poor in humans as seen from the results of a pi lot study of a standardized turmeric extract in colorectal cancer patients (Sharma, R. A. et al, Clin. Cancer Res., 2001 , 7: 1 834- 1900).
• Bioavailable curcumin formulation is a composition containing curcuminoid mixture and an added essential oil of turmeric, wherein the essential oil is present in an amount sufficient to cause an enhancement of bioavailability of the curcumin.
• the essential oil of turmeric contains turmerones principal ly ct- turmerone . and ar-turmerone. In earlier clinical trial Bioavailable curcuminformulation has shown higher bioavai labil ity when compared with turmeric extract containing 95% total curcuminoids.
• curcumin was detected upto 8 hours in the blood of subjects administered with Bioavai lable curcuminformulation as compared to only 4.5 hours in the subjects admistered with turmeric extract containing 95% curcuminoids (Antony et al., Indian J Pharrn Sci. 2008; 70:445-449).
• Yue et al. the effects of turmerones on curcumin transport were evaluated in human intestinal epithelial Caco-2 cells. The roles of turmerones on P-glycoprotein activities and mRNA expression were also evaluated. The authors concluded that the transport of curcumin in Caco-2 cell monolayers could be enhanced in the presence of turmerones. This study further validated our findings with Bioavailable curcuminformulation (Yue, G. L. et al, J Med Food, 2012, 1 5:242-252).
• Controlled drug delivery systems deliver drug to the body so as to establish therapeutically effective blood levels of the active ingredient and once these blood levels are achieved they continue to maintain constant blood levels for long durations by delivering the drug to the body at the same rate as the body eliminates the drug.
• controlled drug delivery systems lower the incidence of adverse effects or side effects.
• Very importantly controlled drug delivery systems reduce the frequency of dosing leading to convenience to the patient in terms of dosing and compliance to specified dosage regimens.
• the rate at which an oral controlled drug delivery system delivers the drug into the blood is not the same as the rate at which it releases the drug into a test aqueous fluid because the gastrointestinal fluid's pH, composition and agitation intensity change with the specific location of the drug delivery system in the gastrointestinal tract i.e. from the stomach to the colon, fasted versus fed state, type and amount of food ingested, and also vary from individual to individual.
• the drug may not be absorbed in the same manner and propensity as we move from the stomach to the colon.
• Some drugs have an "absorption window" i.e. they are absorbed only from the upper parts of the gastrointestinal tract, whereas there are others whose absorption from the • colon is not uniform or complete.
• Ethylcellulose has become a polymer widely used in pharmaceutical film coating, especially when it is necessary to produce a modified-release dosage form.
• Ethylcellulose is a cellulose ether made by the reaction of ethyl chloride with alkali cellulose, as expressed by the reaction: ONa + C 2 H 5 CI ⁇ ROC 2 H5 + NaCI, where R represents the cellulose radical.
• R represents the cellulose radical.
• the structure that is most widely accepted for the cellulose molecule is a chain of ⁇ anhydroglucose units joined together by acetal linkages. These long, oxygen-linked anhydroglucose-unit chains have great strength, which is passed on to cellulose derivatives such as nitrocellulose, cellulose acetate, and ethylcellulose. The properties of flexibility and toughness in these derivatives are directly attributable to this long-chain structure.
• Ethylcellulose is practically colorless, and retains this condition under a wide range of uses.
• Ethylcellulose is compatible with an unusually wide range of resins and plasticizers, including oils and waxes. It is soluble in a wide variety of solvents, thus making it easy to formulate this versatile material for any purpose where solvent application is desirable.
• Useful solvents among them are the esters, aromatic hydrocarbons, alcohols, ketones, and chlorinated solvents.
• Shellac is a well-known commercial resin which originates as a secretion of an insect, Laccifer lacca or Tachardia lacca, found in Eastern countries, such as India, Pakistan and Sri Lanka. Principal components of shellac include aleuritic acid, shellolic acid and jalaric acid. Under some conditions, shellac can polymerize. However, shellac is not generally considered to be a polymer.
• Shellac has been used as a coating on some foods and medications in order to improve their appearance.
• foods on which shellac has been applied include apples and confections.
• Forms of medications on which shellac has been employed as a coating include pills and tablets.
• shellac coatings are enteric and non-toxic, shellac exhibits physical properties which make formation of such coatings problematic.
• shellac is not water-soluble and has a melting point in the range of between about 75 - 80°C. Therefore, in order to minimize damage to surfaces to which it is applied, shellac typically must be dissolved in a medium before it is applied to a surface. The solvent can then be evaporated to leave a shellac coating.
• Others have provided technologies for coating of tablets, pills, pellets etc using various polymers to protect the active drug in the stomach environment and to release the medicament in the intestine.
• An object of the disclosure is to provide a solid dosage form in the form of powder, granules, pellets, capsules, tablets or any other dosage form capable of delivering curcuminoids incorporated therein over an extended period of time.
• Another object of the disclosure is to use ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or any other similar polymer either alone or as a mixture of them and curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone to make the sustained release formu lation.
• HPMC hydroxy propyl methyl cellulose
• Another object of the disclosure is to provide slow release of active principles (curcuminoids) from the delivery systems for extended period of time, thus allowing the gastro-intestinal mucosa to absorb the drug for long duration so that significant blood level of the curcuminoids can be maintained for long duration of time.
• active principles curcuminoids
• Another object of the disclosure is to provide a sustained release curcuminoid formulation which enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 36 hours and in tissues for more than 24 hours after a single dose of sustained release formulation.
• Yet another object of the disclosure is to provide a sustained release curcuminoid formulation in which curcumin, demethoxycurcumin and bisdemethoxycurcumin are detected in the blood for about 24 to about 36 hours after a single dose of sustained release formulation.
• Another object of the disclosure is to provide a sustained release curcuminoid formulation in which the half-life (tl /2) and area under the curve (AUC) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased after a single dose of sustained release formulation.
• the disclosure provides a sustained release drug delivery system for oral administration in the form of powder, granules, pellets, capsules, tablets or any other dosage form which provides sustained release of curcuminoids for extended period of time.
• the disclosure also provides a composition of sustained drug delivery system which includes ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or any other similar polymer either alone or as a mixture of them.
• a composition of sustained drug delivery system which includes ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or any other similar polymer either alone or as a mixture of them.
• the disclosure provides the ratio of active principles, i.e. Bioavailable curcumin formulation to release rate controlling polymer (for example, ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose, hydroxy propyl cellulose or any other similar polymer either alone or in combination with each other) in the range of about 3: 1 to about 50: 1 .
• the disclosure also provides the ratio of active principles, i.e.
• Bioavailable curcuminformulation or Regular turmeric extract obtained from turmeric rhizomes by extraction with ethyl acetate) to polymer (for example, ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose, hydroxy propyl cellulose or any other similar polymer either alone or in combination with each other) ranges from about 10: 1 to 20: 1.
• the disclosure also provides a process for the making of sustained release drug delivery system which provides slow release of active constituents from the delivery system for a long time duration.
• the disclosure provides a sustained release curcuminoid formulation which enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 36 hours and in tissues for more than 24 hours after single dose of sustained release bioavailable curcumin formulation.
• the disclosure provides a sustained release curcuminoid formulation in which curcumin, demethoxycurcumin and bisdemethoxycurcumin are detected in the blood for about 24 to about 36 hours after a single dose of sustained release bioavailable curcumin formulation.
• the disclosure provide a sustained release curcuminoid formulation in which the half-life (tl /2) and area under the curve (AUC) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased after a single dose of sustained release bioavailable curcumin formulation.
• Fig. 1 provides a graph showing Mean blood concentration of curcumin (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio.
• Fig. 2 provides a graph showing Mean blood concentration of demethoxy curcumin (DMC) (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio.
• DMC demethoxy curcumin
• Fig. 3 provides a graph showing Mean blood concentration of bisdemethoxy curcumin (BDMC) (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio.
• BDMC bisdemethoxy curcumin
• Fig. 4 provides a graph showing Mean blood concentration of curcumin (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 500:25 ratio.
• Fig. 5 provides a graph showing Mean blood concentration of demethoxy curcumin (DMC) (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 500:25 ratio.
• DMC demethoxy curcumin
• Fig. 6 provides a graph showing Mean blood concentration of bisdemethoxy curcumin (BDMC) (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with ethyl cellulose in 500:25 ratio.
• BDMC bisdemethoxy curcumin
• Fig. 7 provides a graph showing mean blood concentration of curcumin (ng/gm) Vs Time in human subjects after administering sustained release curcuminoid formulation coated with shellac in 10: 1 ratio.
• Fig. 8 provides a graph showing mean blood concentration in human subjects of demethoxy curcumin (DMC) (ng/gm) versus time after administering sustained release curcuminoid formulation coated with shellac in 10: 1 ratio.
• DMC demethoxy curcumin
• Fig. 9 provides a graph showing in human subjects the mean blood concentration of bisdemethoxy curcumin (BDMC) (ng/gm) versus time after administering sustained curcuminoid release formulation coated with shellac in 10: 1 ratio of bioavailable eurcumin composition to shellac.
• BDMC bisdemethoxy curcumin
• Fig. 10 provides a graph showing in human subjects the mean blood concentration of curcumin (ng/gm) Vs Time after administering sustained release curcuminoid formulation coated with shellac in 14: 1 ratio.
• Fig. 1 1 provides a graph showing in human subjects, the mean blood concentration of demethoxy curcumin (DMC) (ng/gm) Vs Time after administering sustained release curcuminoid formulation coated with shellac in 14: 1 ratio.
• DMC demethoxy curcumin
• Fig. 12 provides a graph showing in human subjects the mean blood concentration of bisdemethoxy curcumin (BDMC) (ng/gm) Vs Time after administering sustained release curcuminoid formulation coated with shellac in 14: 1 ratio.
• BDMC bisdemethoxy curcumin
• Fig. 13 provides a graph showing in human subjects mean blood concentration of curcumin (ng/gm) Vs Time after administering a bioavailable curcumin formulation and shellac coated sustained release curcuminoid formulation and ethyl cellulose coated sustained release curcuminoid formulation in different ratios.
• Fig. 14 provides a graph showing in human subjects the mean blood concentration of demethoxy curcumin (DMC) (ng/gm) Vs Time after administering a formulation contain bioavailable curcumin formulation and shellac coated sustained curcuminoid release formulation and ethyl cellulose coated sustained release curcuminoid formulation in different ratios.
• DMC demethoxy curcumin
• Fig. 15 provides a graph showing in human subjects, the mean blood concentration of bis demethoxy curcumin (BDMC) (ng/gm) Vs Time after administering a formulation containing a bioavailable curcumin formulation and shellac coated sustained release curcuminoid formulation and ethyl cellulose coated sustained release curcuminoid formulation in different ratios.
• BDMC bis demethoxy curcumin
• Fig 16 provides a graph showing Mean blood concentration of curcumin (ng/gm) Vs Time after administering in human subjects a sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio(examp!e 26 Table 23 a).
• Fig 17 provides a graph showing Mean blood concentration of DMC (ng/gm) Vs Time after administering in human subjects sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio(example 26 Table 23 a).
• Fig 18 provides a graph showing Mean blood concentration of BDMC (ng/gm) Vs Time after administering human subjects a sustained release curcuminoid formulation coated with ethyl cellulose in 10: 1 ratio(example 26 Table 23 a).
• Fig 19 provides a graph showing Mean blood concentration of curcumin (ng/gm) Vs Time after administering human subjects a sustained release curcuminoid formulation coated with shellac in 10: 1 ratio(example 26 Table 23 b).
• Fig 20 provides a graph showing Mean blood concentration of DMC (ng/gm) Vs Time after administering human subjects a sustained release curcuminoid formulation coated with shellac in 10: 1 ratio(examp(e 26 Table 23 b).
• Fig 21 provides a graph showing Mean blood concentration of BDMC (ng/gm) Vs Time after administering human subjects a sustained release formulation of bioavailable curcumin coated with shellac in 10: 1 ratio(example 26 Table 23 b).
• Fig 22 provides a graph showing T half (Hours) of Sustained release groups, regular turmeric extract and curcuminoids blended with essential oil of turmeric in 10: 1 and 12: 1 ratios as per example 27.
• Fig 23 provides a graph showing AUC (ng/gm) of Sustained release groups, regular turmeric extract and curcuminoids blended with essential oil of turmeric in 10: 1 and 12: 1 ratios as per example 27.
• Fig 24 provides a graph showing T half (Hours) of Sustained release groups, regular turmeric extract and curcuminoids blended with essential oil of turmeric in 10: 1 and 12: 1 ratios as per example 26. ,
• Fig 25 provides a graph showing AUC (ng/gm) of Sustained release groups, regular turmeric extract and curcuminoids blended with essential oil of turmeric in 10: 1 and 12: 1 ratios as per example 26.
• Fig 26 provides Table 20(a) showing Mean blood concentration of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 27 provides Table 20(b) showing Mean blood concentration of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 28 provides Table 21 (a) showing Mean blood concentration of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 29 provides Table 21 (b) showing Mean blood concentration of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 30 provides Table22 showing Cross over pattern of subjects treated with study drug.
• Fig 3 1 provides Table 23(a) showing Mean blood concentration, half life (ti /2 ), and AUC of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 32 provides Table 23(b) showing Mean blood concentration, half life (ti /2 ), and AUC of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• Fig 33 provides Table 24 showing Mean blood concentration, half life (ti /2 ), and AUC of curcumin, demethoxy curcumin and bisdemethoxy curcumin in healthy human subjects.
• the disclosure provides coating on a bioavailable curcumin formulation to obtain sustained release of curcumin, demethoxyeurcumin and bisdemethoxycurcum in.
• a dosage form of the sustained release composition allowing absorption of curcuminoids for a long duration of time throughout the entire gastro-intestinal tract is provided.
• the physiological condition in the gastro intestinal tract (GIT) varies from stomach to large intestine.
• the absorption of an ingested compound varies with the release of compound from the formulation at various parts of the GIT. If drugs can be delivered to the different absorptive sites in the GIT at different time points, the absorption as well as bioavailability of actives can be increased.
• the pH of GIT is different at different parts ranging from 1 .2 to 2 in stomach to 6-7.2 in intestine. If the release of compounds in GIT can be modified to bring the compounds in direct contact with the absorptive site at substantially longer time points during the transit will lead to enhanced bioavailability.
• the bioavailable curcumin formulation was coated with different formulations of ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, and combinations thereof to modify the release of the active compounds in the GIT. ⁇
• sustained release curcuminoid composition administering a single dosage of the composition enhances bioavailability of curcumin, demethoxyeurcumin and bisdemethoxycurcumin in the body tissues even after 24 hours post drug.
• bioavailable curcumin formulation showed detection of low levels of curcumin only in the body tissues after 24 hours.
• Bioavailable curcumin formulation is a blend of curcuminoids and essential oil of turmeric.
• Curcuminoid is a mixture of curcumin, demethoxyeurcumin and bisdemethoxycurcumin.
• "Essential oil” or "essential oil of turmeric” is also referred to as “volatile oil” or “volatile oil of turmeric.”
• Ar-turmerone is the main constituent of essential oil. Ar-turmerone constitutes about 40-50% of the essential oil of turmeric. In some embodiments, ar-turmerone constitutes about 45% of the essential oil of turmeric. In some embodiments, the weight ratio of the curcuminoid mixture to the essential oil of turmeric having 45% Ar-turmerone ranges from about 1 :3 to about 99: 1.
• the weight ratio of curcuminoid mixture to the essential oil of turmeric having 45% Ar-turmerone is about 10: 1. In some embodiments, the weight ratio of curcuminoid mixture to the essential oil of turmeric having 45% Ar-turmerone is about 12: 1 .
• the disclosure also provides a process for the making of sustained release drug delivery system which provides slow release of active constituents from the delivery system for a long time duration, which includes dissolving the bioavailable curcumin formulation in ethyl acetate or any other suitable organic solvent in which the Bioavailable curcumin formulation is soluble to form a solution of bioavailable curcumin formulation (Solution A).
• the polymers for example, ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or any other similar polymer either in combination or alone
• the organic solvent taken in this step should be miscible with the solvent taken in previous step to prepare solution of bioavailable curcuminformulation or solution of Regular turmeric extact (both are referred to as Solution ⁇ ').
• Solution of bioavailable curcuminformulation or a solution of Regular turmeric extact (Solution A) with solution of polymer (Solution B) are mixed.
• the mixture is stirred for about 30 min to 1 hr using a mechanical or magnetic stirrer.
• the solvent is evaporated under reduced pressure to obtain the sustained release product.
• the active principle selected to make sustained release delivery system for extended period of time is Bioavailable curcumin formulation.
• the excipients/polymers may be but not limited to ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or any other similar polymer either alone or in combination with each other.
• the solvents selected to dissolve active principles may be ethyl acetate, alcohols, acetone, dichloromethane, dichloroethane, chloroform, diethyl ether or any other suitable solvent either alone or as a mixture of two or more solvents.
• the disclosure provides a sustained release curcuminoid composition having a bioavailable curcumin composition and a release rate controlling excipient.
• the bioavailable composition of curcumin includes a curcuminoid mixture and an added essential oil of turmeric.
• the curcuminoid mixture includes curcumin, demethoxycurcumin and bisdemethoxycurcumin.
• the added essential oil of turmeric includes about 40 % to about 50% of ar-turmerone. In some embodiments of the sustained release curcuminoid composition, the added essential oil of turmeric includes about 45% ar-turmerone.
• a weight ratio of the curcuminoid mixture to the added essential oil of turmeric ranges from about 1 :3 to about 99: 1. In some embodiments of the sustained release curcuminoid composition, the weight ratio of the curcuminoid mixture to the essential oil of turmeric is about 10: 1 . In some embodiments of the sustained release curcuminoid composition, the weight ratio of the curcuminoid mixture to the essential oil of turmeric is about 12: 1.
• the release rate controlling excipient is ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose or combinations thereof.
• a weight ratio of the bioavaiiable curcumin composition to the release rate controlling excipient ranges from about 3: 1 to about 50: 1. In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavaiiable curcumin composition to the release rate controlling excipient ranges from about 10: 1 to about 20: 1. In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavaiiable curcumin composition to the release rate controlling excipient is about 10: 1 . In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavaiiable curcumin composition to the release rate controlling excipient is about 14: 1 . in some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavaiiable curcumin composition to the release rate controlling excipient is about 20: 1.
• the release rate controlling excipient is shellac.
• shellac forms a coating on the bioavaiiable curcumin composition.
• a weight ratio of the bioavaiiable curcumin composition to the shellac ranges from about 3: 1 to about 50: 1 .
• a weight ratio of the bioavaiiable curcumin composition to the shellac ranges from about 10: 1 to about 14: 1.
• a weight ratio of the bioavaiiable curcumin composition to the shellac is about 10: 1 . In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavaiiable curcumin composition to the shellac is about 14: 1. In some embodiments of the sustained release curcuminoid composition, the release rate controlling excipient is ethyl cellulose. In some embodiments of the sustained release curcuminoid composition, ethyl cellulose forms a coating on the bioavailable curcumin composition.
• a weight ratio of the bioavailable curcumin composition to the ethyl cellulose ranges from about 3: 1 to about 50: 1 . In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavailable curcumin composition to the ethyl cellulose ranges from about 10: 1 to about 20: 1 . In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 10:1. In some embodiments of the sustained release curcuminoid composition, a weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 20: 1.
• a weight ratio of the bioavailable curcumin composition to the copolymer of ethyl acrylate and methyl methacrylate ranges from about 3: 1 to about 50: 1 . In some embodiments of the sustained release curcuminoid composition, the weight ratio of the bioavailable curcumin composition to the copolymer of ethyl acrylate and methyl methacrylate ranges from about 10: 1 to about 20: 1 . In some embodiments, the sustained release curcuminoid composition is orally administration. In some embodiments, a dosage form of the sustained release curcuminoid composition for oral administration is provided.
• the dosage form of the sustained release curcuminoid composition can be a powder, pellets, granules, tablets or capsules.
• curcumin, demethoxycurcumin and bisdemethoxycurcumin are detected in the blood for about 24 to about 36 hours.
• a single dosage of the composition provides curcumin, demethoxycurcumin and bisdemethoxycurcumin in the body for 24 hours.
• a single dosage of the composition provides curcumin, demethoxycurcumin and bisdemethoxycurcumin in the body for 36 hours.
• the disclosure provides a sustained release curcuminoid composition, wherein administering a single dosage of the sustained release curcuminoid composition enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 24 hours, whereas a single dosage administration of the bioavailable curcumin composition alone did not provide bioavailability of curcum in, demethoxycurcumin and bis demethoxy curcumin in the blood for 24 hours.
• administering a single dosage of the sustained release curcuminoid composition provided bioavailable curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 36 hours when compared to a single dosage administration of the bioavailable curcumin composition alone (without the rate controlling excipients).
• administering a single dosage of the sustained release curcuminoid composition enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in a body tissue for more than 24 hours when compared to administration of the bioavailable curcumin composition alone.
• /2 ) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased when compared to the half life (ti/ 2 ) of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood following a single dose administration of the bioavailable curcumin composition alone.
• the half life (tl /2) of curcumin is. 1 1 .8 and 1 1.4 hours respectively.
• the half life of curcumin is 4.5 and 4.7 respectively.
• Administering a single dose administration of sustained release curcuminoid formulation prepared as per Example 21 resulted in a half life (tl /2) of demethoxycurcumin and bisdemethoxycurcumin is 10.4 and 10.2 hours respectively. But after administering bioavailable curcumin formulation demethoxycurcumin and bisdemethoxycurcumin is not detected in blood.
• Administering the sustained release curcuminoid formulation prepared as per Example 22 the half life (t l /2) of demethoxycurcumin . and bisdemethoxycurcumin is about 9.9 and about 9.2 hours respectively.
• Administering regular turmeric extract resulted in a half life (tl /2) of curcumin of about 1.07 hours. Demethoxycurcumin and bisdemethoxycurcumin is not detected in blood after administration of the regular turmeric extract.
• Half life means the period of time required for the concentration or amount of drug in the body to be reduced to exactly one-half of a given concentration or amount.
• a drug's blood half life depends on how quickly the drug is eliminated from the blood. Higher 1 ⁇ 2 indicates the longer stay of the drug in the body.
• the area under the curve (AUCo-t) of the curcumin, demethoxy curcumin and bisdemethoxy curcumin in. the blood is increased after a single dosage of sustained release curcuminoid formulation.
• the AUC (ng/gm) of curcumin in blood is about 4002.5 and about 3752.8 respectively.
• the AUC of curcumin in blood is about 321 .9 and about 414.9 ng/gm respectively.
• the AUC of demethoxycurcumin and bisdemethoxycurcumin in blood is about 3226. 1 and about 1056.8 ng/gm respectively. But after administering a single dose of bioavailable curcumin formulation demethoxycurcumin and bisdemethoxycurcumin is not detected in blood.
• the AUC of demethoxycurcumin and bisdemethoxycurcumin is about 2939.7 and about 957. 1 ng/gm respectively.
• Administering regular turmeric extract resulted in an AUC (ng/gm) of curcumin of about 23.9. Demethoxycurcumin and bisdemethoxycurcumin is not detected in blood after administration of the regular turmeric extract.
• the area under the blood drug concentration-time curve reflects the actual body exposure to drug after administration of a dose of the drug. This area under the curve is dependent on the rate of elimination of the drug from the body and the dose administered. AUC gives a measure of how much and how long a drug stays in a body.
• the total amount of drug eliminated by the body may be assessed by adding up or integrating the amounts eliminated in each time interval, from time zero (time of the administration of the drug) to a definite time (AUC(O-t)) or infinite time(AUC (0-co)). This total amount corresponds to the fraction of the dose administered that reaches the systemic circulation.
• Bioavailability is usually assessed by determining the area under the blood concentration-time curve. Bioavailability is proportional to the total area under the blood concentration- time curve (AUC).
• the area under the curve (AUC) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased when compared to the AUC of curcumin, demethoxycurcumin and bisdemethoxycurcumin upon administration of the bioavailable curcumin composition alone (without the rate controlling excipients).
• the disclosure provides a method of preparing a sustained release curcuminoid composition.
• the method includes suspending a curcuminoid mixture in water to form a suspension. Then adding essential oil of turmeric to the suspension to form a second mixture. Then homogenizing the second mixture to obtain a slurry. Then drying the slurry under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition. Next dissolving the bioavailable curcumin composition in ethyl acetate to obtain a solution of the bioavailable curcumin composition. Mixing the solution of the bioavailable curcumin composition with an ethyl cellulose solution to obtain a mixture.
• the ethyl cellulose solution is made by dissolving the ethyl cellulose in ethanol. Evaporating the mixture of the bioavailable curcumin composition and ethyl cellulose at 50°C under reduced pressure to obtain the sustained release curcuminoid composition.
• the disclosure provides a method of preparing a sustained release curcuminoid composition.
• the method includes suspending a curcuminoid mixture in water to form a suspension. Then adding essential oil of turmeric to the suspension to form a second mixture. Then homogenizing the second mixture to obtain a slurry. Then drying the slurry under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition. Next dissolving the bioavailable curcumin composition in ethyl acetate to obtain a solution of the bioavailable curcumin composition. Mixing the solution of the bioavailable curcumin composition with a solution having a copolymer of ethyl acrylate and methyl methacrylate to obtain a mixture.
• the solution having a copolymer of ethyl acrylate and methyl methacrylate is made by dissolving the copolymer of ethyl acrylate and methyl methacrylate in 1 : I ratio of methanol : ethyl acetate. Evaporating the mixture of the bioavailable curcumin composition and the copolymer of ethyl acrylate and methyl methacrylate at 50 °C under reduced pressure to obtain the sustained release curcuminoid composition.
• the disclosure provides a method of preparing a sustained release curcuminoid composition.
• the method includes suspending a curcuminoid mixture in water to form a suspension. Then adding essential oil of turmeric to the suspension to form a second mixture. Then homogenizing the second mixture to obtain a slurry. Then drying the slurry under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition. " Next dissolving the bioavailable curcumin composition in ethyl acetate to obtain a solution of the bioavailable curcumin composition.
• the solution having a shellac, a copolymer of ethyl acrylate and methyl methacrylate, an ethyl cellulose and a hydroxyl propyl methyl cellulose is made by dissolving shellac, copolymer of ethyl acrylate and methyl methacrylate, ethyl cellulose and hydroxyl propyl methyl cellulose in 1 : 1 ratio of methanol : ethyl acetate.
• the disclosure provides a method of preparing a sustained release curcuminoid composition.
• the method includes suspending a curcuminoid mixture in water to form a suspension.
• essential oil of turmeric is added to the suspension to form a second mixture.
• the second mixture is homogenized to obtain a slurry.
• the slurry is dried under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition.
• the bioavailable curcumin composition is dissolved in ethyl acetate to obtain a solution of the bioavailable curcumin composition.
• the solution of the bioavailable curcumin composition is mixed with shellac solution to obtain a mixture.
• the shellac solution is prepared by dissolving shellac in ethanol.
• the mixture of the bioavailable curcumin composition and shellac is evaporated at 50 ° C under reduced pressure to obtain the sustained release curcuminoid composition.
• Some embodiments are related to a method of treatment by administering the sustained release composition to a subject.
• the disclosure provides a sustained release curcuminoid composition having first component and a second component.
• the first component includes a bioavailable curcumin composition.
• the bioavailable curcumin composition includes a curcuminoid mixture and an added essential oil of turmeric.
• the curcuminoid mixture includes curcumin, demethoxycurcumin and bisdemethoxycurcumin.
• the ar-turmerone constitutes about 40% to about 50% of the added essential oil of turmeric.
• the added essential oil of turmeric includes about 45% ar- turmerone.
• the first component has a weight ratio of the curcuminoid mixture to the added essential oil of turmeric ranging from about 1 :3 to about 99: 1 .
• the first component has a weight ratio of the curcuminoid mixture to the added essential oil of turmeric of about 10: 1 . In some embodiments, the first component includes a weight ratio of the curcuminoid mixture to the added essential oil of turmeric of about 12: 1.
• the second component includes the bioavailable curcumin composition and a release rate controlling excipient.
• the release rate controlling excipient can be ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, or combinations thereof.
• the second component includes a weight ratio of the bioavailable curcumin composition to the release rate controlling excipient ranging from about 3: 1 to about 50: 1. In some embodiments, the second component includes a weight ratio of the bioavailable curcumin composition to the release rate controlling excipient ranging from about 10: 1 to about 20: 1 . In some embodiments of the sustained release curcuminoid composition, the first component ranges from about 5% to about 30%; and, the second component ranges from about 30 to about 80%, and the weight ratio of the bioavailable curcumin composition to the release rate controlling excipient is about 10: 1.
• the disclosure provides a sustained release curcuminoid composition having first component, a second component and a third component.
• the first component includes a bioavailable curcumin composition.
• the bioavailable curcumin composition includes a curcuminoid mixture and an added essential oil of turmeric.
• the curcuminoid mixture includes curcumin, demethoxycurcumin and bisdemethoxycurcumin.
• the ar- turmerone constitutes about 40% to about 50% of the added essential oil of turmeric.
• the added essential oil of turmeric includes about 45% ar-turmerone.
• the first component has a weight ratio of the curcuminoid mixture to the added essential oil of turmeric ranging from about 1 :3 to about 99: 1 .
• the first component has a weight ratio of the curcuminoid mixture to the added essential oil of turmeric of about 10: 1. In some embodiments, the first component includes a weight ratio of the curcuminoid mixture to the added essential oil of turmeric of about 12: 1.
• the second component includes the bioavailable curcumin composition and a release rate controlling excipient.
• the release rate controlling excipient can be ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, or combinations thereof.
• the second component includes a weight ratio of the bioavailable curcumin composition to the release rate controlling excipient ranging from about 3: 1 to about 50: 1. In some embodiments, the second component, includes a weight ratio of the bioavailable curcumin composition to the release rate controlling excipient ranging from about 10: 1 to about 20: 1 . In some embodiments of the sustained release curcuminoid composition, the first component ranges from about 5% to about 30%; and, the second component ranges from about 30 to about 80%), and the weight ratio of the bioavailable curcumin composition to the release rate controlling excipient is about 10: 1.
• the third component includes the bioavailable curcumin composition and the release rate controlling excipient. In some embodiments, the third component includes a weight ratio of the bioavailable curcumin to the release rate controlling excipient ranges from about 3: 1 to about 50: 1 .
• the disclosure provides a sustained release curcuminoid composition having about 5% to about 30% of the first component; about 30 to about 80% of the second component, and about 15% to about 40% of a third component.
• the second component includes the bioavailable curcumin composition and shellac, and the weight ratio of the bioavailable curcumin composition to the shellac is about 10: 1 .
• the third component includes the bioavailable curcumin composition and shellac, and the weight ratio of the bioavailable curcumin composition to the shellac is about 14: 1.
• Some embodiments of the sustained release curcuminoid composition include about 10% of the first component, about 60% of the second component, and about 30% of the third component.
• the second component includes the bioavailable curcumin composition and shellac. In the second component, the weight ratio of shellac to the bioavailable curcumin composition is about 10: 1 .
• the third component includes the bioavailable curcumin composition and shellac. In the third component, the weight ratio of the bioavailable curcumin composition to the shellac is about 14: 1.
• Some embodiments of the sustained release curcuminoid composition include about 5% to about 30% of the first component, about 30 to about 80% of the second component, and, about 15% to about 40% of a third component.
• the second component includes the bioavailable curcumin composition and the ethyl cellulose, and the weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 10: 1.
• the third component includes the bioavailable curcumin composition and the ethyl cellulose, and the weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 20: 1.
• Some embodiments of the sustained release curcuminoid composition includes about 10% of the first component, about 60% of the second component, and, about 30% of a third component.
• the second component includes the bioavailable curcumin composition and the ethyl cellulose, and the weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 10: 1 .
• the third component includes the bioavailable curcumin composition and ethyl cellulose. The weight ratio of the bioavailable curcumin composition to the ethyl cellulose in the third component is about 20: 1 .
• Some embodiments provide a sustained release curcuminoid composition having a first component, a second component and a third component.
• the first component includes a bioavailable curcumin composition.
• the second component includes a first weight ratio of the bioavailable curcumin composition to a release rate controlling excipient.
• the third component includes a second weight ratio of the bioavailable curcumin composition to the release rate controlling excipient.
• the bioavailable curcumin composition is a blend of a curcuminoid mixture and an added essential oil of turmeric.
• the curcuminoid mixture includes curcumin, demethoxycurcumin and bisdemethoxycurcumin.
• the added essential oil of turmeric includes about 40% to about 50% of ar- turmerone.
• the first weight ratio in the second component ranges from about 3: 1 to about 50: 1 . In some embodiments of the sustained release composition, the first weight ratio in the second component ranges from about 10: 1 to about 20: 1 .
• the third component includes a second weight ratio of the bioavailable curcumin composition to the release rate limiting excipient ranging from about 3: 1 to about 50: 1.
• the release rate controlling excipient is ethyl cellulose, shellac, copolymer of ethyl acrylate and methyl methacrylate, acrylic acid copolymers, hydroxy propyl methyl cellulose (HPMC), hydroxy propyl cellulose, or combinations thereof.
• the sustained release composition includes about 5% to about 30% of the first component, about 30 to about 80% of the second component, and about 15% to about 40% of the third component.
• the weight ratio of the bioavailable curcumin composition to the release rate controlling excipient is about 10: 1 .
• the weight ratio of the bioavailable curcumin to the release rate controlling excipient ranges from about 3: 1 to about 50: 1.
• the sustained release curcuminoid composition includes about 5% to about 30% of the first component, about 30 to about 80% of the second component, and about 15% to about 40% of a third component.
• the second component includes the bioavailable curcumin composition and shellac, in a weight ratio of bioavailable curcumin composition to shellac of about 10: 1.
• the third component includes the bioavailable curcumin composition and shellac, and the weight ratio of the bioavailable curcumin composition to shellac is about 14: 1 .
• the sustained release curcuminoid composition includes about 10% of the first component, about 60% of the second component, and about 30% of a third component.
• the second component includes bioavailable curcumin composition and shellac in the weight ratio of the bioavailable curcumin composition to shellac of about 10: 1 .
• the third component includes bioavailable curcumin composition and shellac, and the weight ratio of the bioavailable curcumin composition to shellac is about 14: 1 .
• the sustained release curcuminoid composition includes about 5% to about 30% of the first component, about 30 to about 80% of the second component, and, about 15% to about 40% of a third component.
• the second component includes the bioavailable curcumin composition and the ethyl cellulose, and the weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 10: 1.
• the third component includes the bioavailable curcumin composition and the ethyl cellulose, and the weight ratio of the bioavailable curcumin composition to the ethyl cellulose is about 20: 1 .
• the sustained release curcuminoid composition includes about 10% of the first component, about 60% of the second component, and, about 30% of a third component.
• the second component includes the bioavailable curcumin composition and ethyl cellulose, and in a weight ratio of the bioavailable curcumin composition to the ethyl cellulose of about 10: 1 .
• the third component includes the bioavailable curcumin composition and ethyl cellulose, and in a weight ratio of the bioavailable curcumin composition to the ethyl cellulose of about 20: 1.
• the sustained release curcuminoid composition having the first component, the second component and the third component is administered orally.
• a dosage form of the sustained release curcuminoid composition is disclosed for oral administration.
• the dosage forms include powder, pellets, granules, tablets or capsules.
• curcumin, demethoxycurcumin and bisdemethoxycurcumin are detected in the blood for about 24 to about 36 hours.
• administering a single dosage of the sustained release curcuminoid composition provides curcumin, demethoxycurcumin and bisdemethoxycurcumin in the body for 24 hours.
• administering a single dosage of the sustained release curcuminoid composition provides curcumin, demethoxycurcumin and bisdemethoxycurcumin in the body for 36 hours. In some embodiments, administering a single dosage of the sustained release curcuminoid composition provides bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 24 hours when compared to administration of the bioavailable curcumin composition alone. In some embodiments, administering a single dosage of the sustained release curcuminoid composition enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 24 hours when compared to administration of the bioavailable curcumin composition alone.
• administering a single dosage of the sustained release curcuminoid composition enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood for 36 hours when compared to administration of the bioavailable curcumin composition alone. In some embodiments, administering a single dosage of the sustained release curcuminoid composition enhances bioavailability of curcumin, demethoxycurcumin and bisdemethoxycurcumin in body tissues for more than 24 hours when compared to administration of the bioavailable curcumin composition alone.
• the half-life (ti/ 2 ) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased when compared to the half-life (ti/ 2 ) of curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood upon administration of the bioavailable curcumin composition alone.
• the area under the curve (AUC) of the curcumin, demethoxycurcumin and bisdemethoxycurcumin in the blood is increased when compared to the AUC of curcumin, demethoxycurcumin and bisdemethoxycurcumin upon administration of the bioavailable curcumin composition.
• a method of preparing a sustained release curcuminoid composition includes suspending the curcuminoid mixture in water to form a suspension. Then essential oil of turmeric is added to the suspension to form a second mixture. Then the second mixture is homogenized to obtain a slurry. Next the slurry is dried under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition. Then the bioavailable curcumin composition is dissolved in ethyl acetate to obtain a • solution of the bioavailable curcumin composition.
• the solution of the bioavailable curcumin composition is mixed with a solution of ethyl cellulose dissolved in ethanol to obtain a mixture having the first weight ratio of the bioavailable curcumin composition to the ethyl cellulose.
• the mixture is evaporated at 50 ° C under reduced pressure to obtain the second component
• the dried uniform blend of the bioavailable curcumin composition is sprayed with a solution of ethyl cellulose dissolved in ethanol to obtain ethyl cellulose coated bioavailable curcumin composition.
• the ethyl cellulose coated bioavailable curcumin composition has the second weight ratio of the bioavailable curcumin composition to the ethyl cellulose.
• a 5% solution of ethyl cellulose dissolved in ethanol is sprayed on a powder of bioavailable curcumin composition to obtain an ethyl cellulose coated sustained release curcuminoid composition having the second weight ratio of the bioavailable curcumin composition to the ethyl cellulose.
• the ethyl cellulose coated sustained release curcuminoid product is dried at 50°C for 2 hours under reduced pressure to obtain the third component.
• the bioavailable curcumin composition, the second component and the third component are mixed to obtain another sustained release composition.
• the sustained release curcuminoid product can be stored at room temperature.
• Some embodiments provide a method of preparing the sustained release curcuminoid composition.
• the method includes suspending the curcuminoid mixture in water to form a suspension.
• essential oil of turmeric is added to the suspension to form a second mixture.
• the second mixture is homogenized to obtain a slurry.
• the slurry is dried under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition.
• the bioavailable curcumin composition is dissolved in ethyl acetate to obtain a solution of the bioavailable curcumin composition.
• the solution of the bioavailable curcumin composition is mixed with a solution having a copolymer of ethyl acrylate and methyl methacrylate to obtain a mixture.
• the mixture is evaporated at 50 °C under reduced pressure to obtain the sustained release curcuminoid composition.
• the solution having the copolymer of ethyl acrylate and methyl methacrylate is prepared by dissolving the copolymer of ethyl acrylate and methyl methacrylate in a solution having a 1 : 1 ratio of methanol: ethyl acetate. 1
• Some embodiments provide a method of preparing the sustained release curcuminoid composition.
• the method includes suspending the curcuminoid mixture in water to form a suspension.
• essential oil of turmeric is added to the suspension to form a second mixture.
• the second mixture is homogenized to obtain a slurry.
• the slurry is dried under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition.
• the bioavailable curcumin composition is dissolved in ethyl acetate to obtain a solution of the bioavailable curcumin composition.
• the solution of the bioavailable curcumin composition is mixed with a solution having a release rate controlling excipient to form a mixture.
• the mixture is evaporated at 50°C under reduced pressure to obtain the sustained release curcuminoid composition.
• the solution having the release rate controlling excipient is prepared by dissolving shellac, a copolymer of ethyl acetate and methyl methacrylate, ethyl cellulose and hydroxyl propyl methyl cellulose in a solution having a 1 : 1 ratio of methanol to ethyl acetate.
• Some embodiments provide a method of preparing the sustained release curcuminoid composition.
• the method includes suspending the curcuminoid mixture in water to form a suspension.
• essential oil of turmeric is added to the suspension to form a second mixture.
• the second mixture is homogenized to obtain a slurry.
• the slurry is dried under heat and vacuum to obtain a uniform blend of the bioavailable curcumin composition.
• the bioavailable curcumin composition is dissolved in ethyl acetate to obtain a solution of the bioavailable curcumin composition.
• the solution of the bioavailable curcumin composition is mixed with a shellac solution to obtain a mixture having the first weight ratio of the bioavailable curcumin composition to the shellac.
• the shellac solution is prepared by dissolving shellac in ethanol. The mixture is evaporated at 50°C under reduced pressure to obtain the second component.
• the solution of the bioavailable curcumin composition is mixed with a shellac solution to obtain a mixture having the second weight ratio of the bioavailable curcumin composition to the shellac.
• the solution is evaporated at 50 °C under reduced pressure to obtain the third component.
• the bioavailable curcumin composition, the second component and the third component are mixed to obtain the sustained release composition.
• the rhizomes of turmeric (500Kg) were dried.
• the dried turmeric rhizomes were powdered to form powdered turmeric.
• Ethyl acetate extraction of the powdered turmeric was performed.
• ethyl acetate (1 500 L) was added to the powdered turmeric at 78°C temperature and extracted for 1 hr.
• a solution and a residue 1 were obtained.
• the residue 1 was separated from the solution and 1500 liters of ethyl acetate was again added to the residue 1 for extraction at 78°C temperature for 1 hr.
• the resultant residue was similarly extracted with ethyl acetate for three more times.
• the solution from each of the ethyl acetate extraction steps was combined and filtered.
• the solvent from the filtered solution was stripped to form an extract.
• the extract was cooled to about 4°C to obtain crystals of curcuminoid (20 g) and a liquid.
• the crystals of curcuminoid were isolated from the liquid by filtration.
• the crystal of curcuminoid included mixture of curcumin (78.16%), demethoxycurcumin ( 13.79%) and bisdemethoxycurcumin (2.87%).
• the crystals of curcuminoids are referred to as regular turmeric extract.
• the rhizomes of turmeric (500 g) were dried.
• the dried turmeric rhizomes were powdered to form powdered turmeric.
• Ethyl acetate extraction of the powdered turmeric was performed.
• ethyl acetate (1 500 L) was added to the powdered turmeric at 78°C temperature and extracted for 1 hr.
• a solution and a residue 1 were obtained.
• the residue 1 was separated from the solution and 1500 liters of ethyl acetate was again added to the residue 1 for extraction at 78°C temperature for 1 hr.
• the resultant residue was similarly extracted with ethyl acetate for three more times.
• the solution from each of the ethyl acetate extraction steps was combined and filtered.
• the solvent from the filtered solution was stripped to form an extract.
• the extract was cooled to about 4°C to obtain crystals of curcuminoid and a liquid.
• the crystals of curcuminoid were isolated from the liquid by filtration.
• the crystal of curcuminoid included mixture of curcumin, demethoxycurcumin and bisdemethoxycurcumin.
• the crystals of curcuminoid are referred to as regular turmeric extract.
• the liquid included essential oil of turmeric, flavouring compounds,, any impurities that remained in solution, and, curcuminoids that did not crystallize.
• the liquid was then steam distilled to isolate essential oil of turmeric having 10- 1 5% Ar-turmerone (25 g) and a residue 2.
• the essential oil having 10- 15% Ar- turmerone was fractionated to obtain three fractions.
• Essential oil of turmeric having 2-3% Ar-turmerone (9.3 Kg) was obtained at 1 10°C and designated as fraction 1 .
• Essential oil of turmeric having 4-5 % Ar-turmerone (8.3Kg) was obtained at 125°C and designated as fraction 2.
• Essential oil of turmeric having 45% Ar-turmerone (7.5Kg) was obtained at 140°C and designated as fraction 3.
• Example 5 3.5 Kg of turmeric extract (From Example 1 ) was suspended in water ( 15 L) to form a suspension. From Example 2, the fraction of essential oil (fraction 3) having 45 % Ar- turmerone (0.29Kg) was added to the suspension in a 12: 1 ratio of turmeric extract: essential oil of turmeric to obtain a mixture of turmeric extract and essential oil of turmeric. The mixture of turmeric extract blended with essential oil of turmeric was pulverized in a colloidal mill to form fine slurry. Water was stripped from the slurry under heat and vacuum to form a uniform blend (3.8Kg) containing curcuminoids and essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio. This blend contains 70.0% curcumin, 17. 1 % demethoxy curcumin, 3.3% bisdemethoxy curcumin and 7.3 % essential oil of turmeric having 45% Ar-turmerone.
• Example 5 Example 5
• the curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio was combined with ethyl cellulose in a 10: 1 weight/weight ratio as shown in Table 1 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 68% Curcumin, 12% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 6% Essential oil of turmeric having 45% Ar-turmerone and 9% Ethyl cellulose.
• the curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio was combined with ethyl cellulose in a 10: 1 weight/weight ratio as shown in Table 2 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 68.5% Curcumin, 12.5% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 5% Essential oil of turmeric having 45% Ar-turmerone and 9% Ethyl cellulose.
• the regular turmeric extract (from Example 1 ) was combined with ethyl cellulose in a 10: 1 weight/weight ratio as shown in Table 3 below to form a curcumin sustained-release composition.
• the sustained release composition had 72% Curcumin, 12% Demethoxy curcumin, 3% Bisdemethoxy curcumin and 9% Ethyl cellulose.
• the curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio was combined with ethyl cellulose in a 50: 2.5 weight/weight ratio as shown in Table 4 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 69% Curcumin, 13% Demethoxy curcumin, 3% Bisdemethoxy curcumin, 6% Essential oil of turmeric having 45% Ar-turmerone and 5% Ethyl cellulose.
• ethyl cellulose was dissolved in 500 ml of ethanol by stirring and heating at 50°C to get 5% solution of ethyl cellulose in ethanol. The solution was filtered and kept for spraying (5% solution of ethyl cellulose was referred as Solution A). Curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (from Example 3) was taken as a fine powder and passed through a sieve of 60 mesh. The sieved material was used to make sustained release formulation. The ethyl cellulose solution (Solution A) was sprayed on the sieved material using a sprayer. The obtained sustained release product was dried at 50°C for 2 hours and stored at room temperature.
• the curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio was combined with ethyl cellulose in a 50:2.5 weight/weight ratio as shown in Table 5 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 69.5% Curcumin, 13.5% Demethoxy curcumin, 3% Bisdemethoxy curcumin, 5% Essential oil of turmeric having 45% Ar-turmerone and 5% Ethyl cellulose.
• the regular turmeric extract (from Example 1 ) was combined with ethyl cellulose in a 50:2.5 weight/weight ratio as shown in Table 6 below to form a curcumin sustained-release composition.
• the sustained release composition had 74% Curcumin, 14% Demethoxy curcumin, 3% Bisdemethoxy curcumin and 5% ethyl cellulose.
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 10: 1 ratio was combined with copolymer of ethyl acrylate and methyl methacrylate in a 10: 1 weight/weight ratio as shown in Table 7 below to form a bioavailabie curcumin sustained-release composition.
• the sustained release composition had 68% Curcumin, 12% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 6% essential oil of turmeric having 45% Ar- turmerone and 9% Copolymer of ethyl acrylate and methyl methacrylate.
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 12: 1 ratio was combined with copolymer of ethyl acrylate and methyl methacrylate in a 10: 1 weight/weight ratio as shown in Table 8 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 68.5% curcumin, 12.5% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 5% essential oil of turmeric having 45% Ar- turmerone and 9% Copolymer of ethyl acrylate and methyl methacrylate.
• the regular turmeric extract (from Example 1 ) was combined with copolymer of ethyl acrylate and methyl methacrylate in a 10: 1 weight/weight ratio as shown in Table 9 below to form a curcumin sustained-release composition.
• the sustained release composition had 72% curcumin, 12% Demethoxy curcumin, 3% Bisdemethoxy curcumin and 9% Copolymer of ethyl acrylate and methyl methacrylate.
• curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 10: 1 ratio prepared was combined with Shellac, Copolymer of ethyl acrylate and methyl methacrylate, Ethyl cellulose, and Hydroxy propyl methyl cellulose as shown in Table 10 below to form a bioavailable curcumin sustained release composition.
• the sustained release composition had 68% Curcumin, 12% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 6% essential oil of turmeric having 45% Ar-turmerone, 2.5% shellac, 1.5% Copolymer of ethyl acrylate and methyl methacrylate , 4% ethyl cellulose and 1 % Hydroxy propyl methyl cellulose.
• Example 15 The curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 10:1 ratio (from Example 3) was combined with shellac in a 14: 1 weight/weight ratio as shown in Table 1 1 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 67.9% Curcumin, 14.2% Demethoxy curcumin, 2.9% Bisdemethoxy curcumin, 8.5 % Essential oil of turmeric having 45% Ar-turmerone and 6.5% shellac.
• Solution A was mixed with Solution B and the mixture was stirred at 500 rpm for 30 min using a mechanical stirrer.
• the resultant solution was kept in a round bottom flask and solvent was evaporated completely at 50°C under reduced pressure to get the curcumin sustained-release product in 14: 1 ratio.
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 12:1 ratio was combined with shellac in a 14: 1 weight/weight ratio as shown in Table 12 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 68.7% Curcumin, 14.6% Demethoxy curcumin, 3% Bisdemethoxy curcumin, 7.2% Essential oil of turmeric having 45% Ar-turmerone and 6.5% shellac.
• Solution A was mixed with Solution B and the mixture was stirred at 500 rpm for 30 min using a mechanical stirrer.
• the resultant solution was kept in a round bottom flask and solvent was evaporated completely at 50°C under reduced pressure to get the curcumin sustained-release product in 14: 1 ratio.
• Example 17 The curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 10: 1 ratio (from Example 3) was combined with shellac in a 10: 1 weight/weight ratio as shown in Table 13 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 66.7% Curcumin, 13.6% Demethoxy curcumin, 2.7% Bisdemethoxy curcumin, 8.3% Essential oil of turmeric having 45% Ar-turmerone and 8.7% shellac.
• Solution A was mixed with Solution B and the mixture was stirred at 500 rpm for 30 min using a mechanical stirrer.
• the resultant solution was kept in a round bottom flask and solvent was evaporated completely at 50°C under reduced pressure to get the curcumin sustained-release product in 10: 1 ratio.
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 12: 1 ratio was combined with shellac in a 10: 1 weight/weight ratio as shown in Table 14 below to form a bioavailable curcumin sustained-release composition.
• the sustained release composition had 67.6% Curcumin, 13.9% Demethoxy curcumin, 2.8% Bisdemethoxy curcumin, 7% Essential oil of turmeric having 45% Ar-turmerone and 8.7% shellac.
• the regular turmeric extract (from Example 1 ) was combined with shellac in a 14: 1 weight/weight ratio as shown in Table 15 below to form a curcumin sustained-release composition.
• the sustained release composition had 72.1 % Curcumin, 17.9% Demethoxy curcumin, 3.5% Bisdemethoxy curcum in and 6.5% Shellac.
• the regular turmeric extract (from Example 1) was combined with shellac in a 10: 1 weight/weight ratio as shown in Table 16 below to form a curcumin sustained-release composition.
• the sustained release composition had 70.7% Curcumin, 17.3% Demethoxy curcumin, 3.3% Bisdemethoxy curcumin and 8.7% Shellac. Table 16
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 12: 1 ratio prepared (from Example 4) was blended with 1 : 1 ratio of bioavailable curcumin sustained-release composition coated with shellac (from example 16) and 10: 1 ratio of bioavailable curcumin sustained-release composition coated with shellac (from example 18) as shown in Table 1 7 below to form a bioavailable curcumin sustained release composition.
• the sustained release composition had 68.37% Curcumin, 14.45% Demethoxy curcumin, 2.91 % Bisdemethoxy curcumin, 7. 1 % essential oil of turmeric having 45% Ar- turmerone, 7. 17% shellac.
• the curcuminoids blended with essential oil of turmeric having 45% Ar- turmerone in 12: 1 ratio prepared (from Example 4) was blended with 500:25 (20: 1 ) ratio of bioavailabie curcumin sustained-release composition coated with ethyl cellulose (from example 9) and 10: 1 ratio of bioavailabie curcumin sustained-release composition coated with ethyl cellulose (from example 6) as shown in Table 18 below to form a bioavailabie curcumin sustained release composition.
• the sustained release composition had 69.27% Curcumin, 15. 1 % Demethoxy curcumin, 3.5% Bisdemethoxy curcumin, 5.23% essential oil of turmeric having 45% Ar-turmerone, 6.9 % ethyl cellulose.
• bioavailabie curcumin sustained-release composition coated with ethyl cellulose in 20: 1 ratio Example 9
• bioavailabie curcumin sustained-release composition coated with ethyl cellulose in 10: 1 ratio from example 6 were dissolved in 50 ml of ethanol and filtered to form solution of bioavailabie curcumin sustained-release composition coated with ethyl cellulose in 20: 1 ratio and bioavailabie curcumin sustained- release composition coated with ethyl cellulose in 10: 1 ratioand referred as Solution B.
• Solution A was mixed with Solution B and the mixture was stirred at 500 rpm for 30 min using a mechanical stirrer.
• the resultant solution was kept in a round bottom flask and solvent was evaporated completely at 50°C under reduced pressure to get the sustained release product.
• Dissolution study is a standard method for measuring the rate of drug release from dosage form.
• the release pattern was tested in simulated gastric fluid upto 2 hours (pH 1 .2) and simulated intestinal fluid from 2 to 24 hours (pH 6.8) by in vitro USP dissolution apparatus.
• the dissolution medium (simulated gastric fluid without enzyme. pH 1 .2), free from dissolved air, was filled into the vessel of the dissolution apparatus.
• Apparatus was assembled and dissolution medium was heated to 36.5° to 37.5°.
• the capsule containing sustained release formulation was sunk to the bottom of the vessel prior to the rotation of the paddle.
• a suitable device such as a wire of glass helix was used to keep horizontal at the bottom of the vessel capsules that would otherwise float.
• the ethyl acetate extract was analyzed by HPLC on a C I 8 ODS Phenomenox column (250x4.6mm, 5 ⁇ particle size) using 40% tetrahydrofuran (THF), 60% water containing 1 % citric acid (pH adjusted to 3 with concentrated OH solution) as solvent system and UV detection at 420 nm.
• the eluent flow rate was I ml/min. Table 19 shows the percentage of curcuminoid dissolved.
• Example 1 The absorption of curcumin after oral administration of sustained release formulations prepared in Example (1 , 3, 4, 5, 6, 7, 8, 9 and 10) was studied in healthy human volunteers. Thirty six healthy male volunteers were enrolled for the study. The subjects were fasted overnight before administration of the formulation. Standard meals were provided at 4 hours and 8 hours after dosing and at appropriate times thereafter taking care that the food does not contain turmeric. The subjects were divided into nine groups having four subjects in each group. Subjects of Group 1 received a single dose (2 gm) of regular turmeric extract (Examplel ). Subjects of Group 2 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (Example 3).
• Subjects of Group 3 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (Example 4).
• Subjects of Group 4 received a single dose (2gm) of sustained release formulation of regular turmeric extract (Example 7).
• Group 5 and 6 received a single dose (2 gm) of sustained release formulation coated with ethyl cellulose in 10: 1 ratio (Example 5) (curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio) and sustained release formulation coated with ethyl cellulose in 10: 1 ratio (Example 6) (curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio) respectively.
• Subjects of Group 7 received a single dose (2gm) of sustained release formulation of regular turmeric extract coated with ethyl cellulose in 500: 25 (20: 1 ) ratio (Example 10).
• Group 8 and 9 received a single dose (2 gm) of sustained release formulation coated with ethyl cellulose in 500:25 ratio (Example 8) (curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ) and sustained release formulation coated with ethyl cellulose in 500:25 ratio (Example 9) (curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio) respectively with 250 ml of water at ambient temperature after the overnight fast.
• results show that curcumin was detected in subjects of all the groups.
• the curcumin was detected only up to 6 hr in the subjects treated with Regular turmeric extract (Example 1 ).
• the Cmax was 14.5 ng/gm in the group fed only Regular turmeric extract (Group 1).
• Sustained release formulations developed with regular turmeric extract did not show any significant increase in blood concentration of curcumin, and, curcumin was detected only up to 6 hr.
• Example 5 and Example 8 The subjects treated with sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio coated with ethyl cellulose (Example 5 and Example 8) showed high curcumin level in the blood. Cmax was 133.4 and 138.1 ng/gm respectively for subjects treated with formulation prepared in Example 5 and Example 8 respectively. Curcumin was also detected up to 30 hr in the blood.
• BDMC Bisdemethoxy curcumin
• Blending essential oil of turmeric with regular turmeric extract increased the blood concentration of curcumin to significant levels. For example, at 4 hours following administration of the formulations, 10.2 ng/g curcumin was detected in the blood when regular turmeric extract was administered. 80.3 ng/g of curcumin was detected when administered with curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (Example 3). 102. 1 ng/g of curcumin was detected when administered with curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (Example 4).
• Sustained release formulations prepared with curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 or 12: 1 ratio provided higher blood concentration of curcumin, demethoxy curcumin and bisdemethoxy curcumin.
• Sustained release curcuminoid formulations also provided significant concentration of curcumin, DMC and BDMC up to more than 24 hour. Thus a single dose of sustained release curcuminoid formulation a day was sufficient to obtain higher levels curcumin, DMC and BDMC in the blood.
• Example 1 The absorption of curcumin after oral administration of sustained release formulations prepared in Example (1 , 3, 4, 15, 16, 17, 18, 19 and 20) was studied in healthy human volunteers. Thirty six healthy male volunteers were enrolled for the study. The subjects were fasted overnight before administration of the formulation. Standard meals were provided at 4 hours and 8 hours after dosing and at appropriate times thereafter taking care that the food does not contain turmeric. The subjects were divided into nine groups having four subjects in each group. Subjects of Group 1 received a single dose (2 gm) of regular turmeric extract (Example 1). Subjects of Group 2 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (Example 3).
• Subjects of Group 3 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (Example 4).
• Subjects of Group 4 received a single dose (2gm) of sustained release formulation of regular turmeric extract coated with shellac in 14: 1 ratio (Example 19).
• Subjects of Group 5 and 6 received a single dose (2gm) of sustained release formulation coated with shellac in 14: 1 ratio prepared as per Example 15 (curcuminoid blended with essential oil of turmeric having 45% Ar- turmerone in 10:1 ratio) and sustained release formulation coated with shellac prepared in 14: 1 ratio prepared as per Example 16 (curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio).
• Group 7 and 8 received a single dose (2 gm) of sustained release formulation coated with shellac in 10: 1 ratio prepared as per Example 1 7 (curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio) and sustained release formulation coated with shellac in 10: 1 ratio prepared as per Example 18 (curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio) respectively.
• Subjects of Group 9 received a single dose (2gm) of sustained release formulation of regular turmeric extract coated with shellac in 10: 1 ratio (Example 20) with 250 ml of water at ambient temperature after the overnight fast.
• Blood was collected at different time intervals at baseline, 1 , 2, 4, 6, 8, 12, 24, 27 and 30 hours post drug.
• the whole blood was extracted exhaustively with ethyl acetate to recover curcumin.
• the ethyl acetate extract was analyzed by HPLC on a P-C 18 column (250 x 4.5 mm) using tetrahydrofuran (THF) as solvent and UV detection at 420 nm.
• the eluant flow rate was 1 ml/min.
• the blood level concentration of curcumin, DMC (Demethoxy curcumin) and BDMC (Bis- Demethoxy curcumin) was determined by HPLC against working standards for samples collected at different time points and averaged over the four volunteers.
• Sustained release formulations developed with regular turmeric extract did not show any significant increase in blood concentration of curcumin, and, curcumin was detected only up to 4 hr.
• the subjects treated with shellac coated sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio showed high curcumin level in the blood.
• Cmax was 142.1 and 132.4 ng/gm respectively for subjects treated with formulation prepared in Example 1 7 and Example 15 respectively.
• Curcumin was also detected up to 30 hr in the blood.
• Example 16 and Example 1 8 also showed high curcumin level in the blood.
• Cmax was 169.8 and 159.4 ng/gm respectively for subjects treated with formulation prepared in Example 1 8 and Example 16 respectively.
• Curcumin was also detected up to 30 hr in the blood.
• sustained release curcuminoid formulation provides curcumin, demethoxy curcumin and bisdemethoxy curcumin for at least up to 30 hr, and, at significant levels required to produce pharmacological effects.
• Demethoxy curcumin (D C) was not detected in the subjects treated with formulations prepared in Example 1 , 19 and 20. It was detected in the subjects treated with formulations prepared in Example 15, 16, 17 and 18. DMC was detected upto 27 hr in the subjects treated with shellac coated sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (Example 15 and Example 1 7). DMC was detected upto 30 hr in the subjects treated with shellac coated sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (Example 1 6 and Example 1 8). This further indicates the superiority of sustained release formulations.
• BDMC Bisdemethoxy curcumin
• Subjects of Group 3 received a single dose (2gm) of ethyl cellulose coated sustained release formulation of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio( EC coated SR formulation) (study drug III prepared as per Example 6).
• Subjects of Group 4 (R 1 13 to 1 16) received a single dose (2 gm) of shellac coated sustained release formulation of regular turmeric extract(S coated RTE) (study drug IV prepared as per Example20).
• Subjects of Group 5 received a single dose (2gm) of shellac coated sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio( S coated SR formulation) (study drug V prepared as per Example 1 8).
• Subjects of Group 6 received a single dose (2gm) of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (C+EOT with 45% Ar-t in 10: 1 ratio) (study drug
• results show that half life (t
• sustained release curcuminoid formulation prepared as per example 6 following the administration of the composition results a half life of 7.5, 6.9 and 5.97hours for curcumin, demethoxy curcumin and bis-Demethoxy curcumin respectively.
• curcuminoids blended with essential oil of turmeric with 45% Ar- turmerone in 10: 1 and 12: 1 ratios results a half life of curcumin 4.6 and 4.9 hours respectively.
• sustained release curcuminoid formulation prepared as per example 18 following the administration of the composition results a half life of 8.2, 7.4 and 5.89 hours for curcumin, demethoxy curcumin and bis-Demethoxy curcumin respectively.
• tw 2 indicates the longer stay of the curcuminoids in the formulation in the body.
• Area under the curve (AUCO-t) of curcumin, demethoxy curcumin and bisdemethoxy curcumin in sustained release groups were calculated from the respective graphs, which showed that the AUC was increased.
• sustained release curcuminoid formulation prepared as per example 6 following the administration of the composition results an AUC of 2508.2, 1 5 1 7.9 and 322.6 ng/gm for curcumin, demethoxy curcumin and bis-Demethoxy curcumin respectively.
• curcuminoids blended with essential oil of turmeric with 45% Ar-turmerone in 10: 1 and 12: 1 ratios results a AUC of curcumin 333.3 and 421.1 ng/gm respectively.
• sustained release curcuminoid formulation prepared as per example 18 following the administration of the composition results a AUC of 2653.4, 1560.7 and 330.8 ng/gm for curcumin, demethoxy curcumin and bis-Demethoxy curcumin respectively.
• Example 21 and 22 The absorption of curcumin after oral administration of sustained release formulations prepared in Example 21 and 22 was studied in healthy human volunteers. Twenty five healthy male volunteers were enrolled for the study. The subjects were fasted overnight before administration of the formulation. Standard meals were provided at 4 hours and 8 hours after dosing and at appropriate times thereafter taking care that the food does not contain turmeric. The subjects were divided into five groups having five subjects in each group. Subjects of Group 1 received a single dose (2 gm) of regular turmeric extract (RTE) (Example 1 ). Subjects of Group 2 received a single dose (2gm) of sustained release formulation ( S coated SR formulation) prepared as per Example 21 and subjects of Group 3 received a single dose (2gm) of sustained release formulation (EC coated SR formulation) prepared as per Example 22.
• RTE regular turmeric extract
• Subjects of Group 4 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric in 10: 1 ratio (C+EOT with 45% Ar-t in 10: 1 ratio) prepared as per Example 3 and subjects of Group 5 received a single dose (2gm) of curcuminoids blended with essential oil of turmeric in 12: 1 ratio (C+EOT with 45% Ar-t in 12: 1 ratio) prepared as per Example 4 with 250 ml of water at ambient temperature after the overnight fast.
• Blood was collected at different time intervals at baseline, 0.5,1 , 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32 and 36 hours post drug.
• the whole blood was extracted exhaustively with ethyl acetate to recover curcumin.
• the ethyl acetate extract was analyzed by HPLC on a RP-C 18 column (250 x 4.5 mm) using tetrahydrofuran (THF) as solvent and UV detection at 420 nm.
• THF tetrahydrofuran
• the eluant flow rate was I ml/min.
• the blood level concentration of curcumin, DMC (Demethoxy curcumin) and BDMC (Bis-Demethoxy curcumin) was determined by HPLC against working standards for samples collected at different time points and averaged over the five volunteers.
• the subjects treated with sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone prepared as per example 21 showed high curcumin level in the blood. Cmax was 186.4 for subjects treated with formulation prepared in Example 21 . Curcumin was also detected up to 36 hr in the blood.
• the subjects treated with sustained release formulation of curcuminoid blended with essential oil of turmeric having 45% Ar-turmerone prepared as per example 22 showed a Cmax of 169.6 for subjects treated with formulation prepared in Example 22. Curcumin was also detected up to 36 hr in the blood.
• Demethoxy curcumin was not detected in the subjects treated with Regular turmeric extract. It was detected in the subjects treated with sustained release formulation prepared as per Example 21 and 22. DMC was detected upto 36 hr in the subjects treated with sustained release formulation prepared as per Example 21 and 22. This further indicates the superiority of sustained release formulation.
• BDMC Bisdemethoxy curcumin
• results indicate that half life (ti /2 ) of sustained release formulations prepared as in example 2 l and 22-was increased.
• the half life (tl /2) of curcumin was 1 1.8 and 1 1.4 hours respectively.
• the half life of curcumin was 4.5 and 4.7 respectively.
• Administering a single dose administration of sustained release curcuminoid formulation prepared as per Example 21 resulted in a half life (tl/2) of demethoxycurcumin and bisdemethoxycurcumin was 10.4 and 10.2 hours respectively. But after administering bioavailable curcumin formulation demethoxycurcumin and bisdemethoxycurcumin was not detected in blood.
• Administering the sustained release curcuminoid formulation prepared as per Example 22 the half life (tl/2) of demethoxycurcumin and bisdemethoxycurcumin was about 9.9 and about 9.2 hours respectively.
• Administering regular turmeric extract resulted in a half life (tl /2) of curcumin of about 1 .07 hours. Demethoxycurcumin and bisdemethoxycurcumin was not detected in blood after administration of the regular turmeric extract.
• AUC Area under the curve (AUCO-t) of curcumin, demethoxy curcumin and bisdemethoxy curcumin in sustained release groups were calculated from the respective graphs, which showed found that AUC was increased.
• the AUC (ng/gm) of curcumin in blood was about 4002.5 and about 3752.8 respectively.
• the AUC of curcumin in blood was about 321.9 and about 414.9 ng/gm respectively.
• the AUC of demethoxycurcumin and bisdemethoxycurcumin in blood was about 3226. 1 and about 1056.8 ng/gm respectively. But after administering a single dose of bioavailable curcumin formulation demethoxycurcumin and bisdemethoxycurcumin was not detected in blood.
• the AUC of demethoxycurcumin and bisdemethoxycurcumin was about 2939.7 and about 957.1 ng/gm respectively.
• Administering regular turmeric extract resulted in an AUC (ng/gm) of curcumin of about 23.9. Demethoxycurcumin and bisdemethoxycurcumin was not detected in blood after administration of the regular turmeric extract.
• Rabbits weighing 2-2.5 Kg were used for the study. Animals were divided into 10 groups and 4 animals were used for each group. The dosage administered was 60 mg curcuminoids /Kg body weight of the rabbit.
• Group 1 animal were given vehicle, Tween 80.
• Group 2 animals were given Regular turmeric extract prepared as per example 1 haying 95% curcuminoids of which curcumin (78.16%), demethoxycurcumin (13.79%) and bisdemethoxycurcumin (2.87%) solubilized in Tween 80.
• ethyl cellulose coated sustained release formulation (Prepared as per example 5) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (68% Curcumin, 12% Demethoxy curcumin, 2.5% Bisdemethoxy curcumin, 6% Essential oil of turmeric having 45% Ar-turmerone and 9% Ethyl cellulose) solubilized in Tween 80 and fed.
• ethyl cellulose coated Sustained release formulation (Prepared as per example 6) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12:1 ratio (Curcumin 68.5%, Demethoxy curcumin 12.5%, Bisdemethoxy curcumin 2.5%, Essential oil of turmeric having 45% Ar-turmerone 5% and Ethyl cellulose 9%) solubilized in Tween 80 and fed.
• Group 5 animals were given Regular turmeric extract sustained release formulation (Prepared as per example 7) having Curcumin 72%, Demethoxy curcumin 12%, Bisdemethoxy curcumin 3% and Ethyl cellulose 9% solubilized in Tween 80.
• Shellac coated Sustained release formulation of curcuminoids (Prepared as per example 17) blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio (66.7% Curcumin, 13.6% Demethoxy curcumin, 2.7% Bisdemethoxy curcumin, 8.3% Essential oil of turmeric having 45% Ar-turmerone and 8.7% shellac.) solubilized in Tween 80 and fed.
• Shellac coated Sustained release formulation (Prepared as per example 18) of curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (67.6% Curcumin, 13.9% Demethoxy curcumin, 2.8% Bisdemethoxy curcumin, 7% Essential oil of turmeric having 45% Ar- turmerone and 8.7% shellac) solubilized in Tween 80 and fed.
• Group 8 animals were given shellac coated Regular turmeric extract sustained release formulation (Prepared as per example 20) of which 70.7% Curcumin, 1 7.3% Demethoxy curcumin, 3.3% Bisdemethoxy curcumin and 8.7% Shellac solubilized in Tween 80.
• curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 10: 1 ratio Prepared as per example 3) with curcumin 69.8%, demethoxy curcumin 17.0%, bisdemethoxy curcumin 3.2% and essential oil of turmeric having 45% Ar-turmerone 8.8% solubilized in Tween 80 and fed.
• curcuminoids blended with essential oil of turmeric having 45% Ar-turmerone in 12: 1 ratio (Prepared as per example 4) with 70.0% curcumin, 17. 1 % demethoxy curcumin, 3.3% bisdemethoxy curcumin and 7.3 % essential oil of turmeric having 45% Ar-turmerone solubilized in Tween 80 and fed.
• the study drugs were given by oral route. Twenty four hours post drug rabbits were sacrificed by cervical dislocation and dissected to obtain various tissues (Heart, Kidney, Brain, Liver, Pancreas, Lungs, and Skin). Each tissue was weighed and stored at -80°C until analysis. Tissues were homogenized and extracted with chloroform- methanol (2: 1 ). The homogenate was filtered through a Whatman filter paper and the filtrate collected and mixed thoroughly with 0.2 vol of 0.9% NaCI solution and centrifuged. The upper layer was siphoned off. The lower layer was evaporated to dryness under a stream of nitrogen at 40-45°C in a "Turbo Vap" Concentration Work Station (Caliper Life Sciences, USA).

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