WO2010010431A1

WO2010010431A1 - Self-nano-emulsifying curcuminoids composition with enhanced bioavailability

Info

Publication number: WO2010010431A1
Application number: PCT/IB2009/005154
Authority: WO
Inventors: Arvind Kumar Bansal; Bhushan Munjal; Sarsvat Babulal Patel
Original assignee: National Institute Of Pharmaceutical Education And Research
Priority date: 2008-07-24
Filing date: 2009-04-02
Publication date: 2010-01-28

Abstract

The present invention relates to a pharmaceutical composition of curcuminiods with higher drug loading ability, improved bioavailability having adequate physical and chemical stability as a self nanoemulsifying composition.

Description

SELF-NANO-EMULSIFYING CURCUMINOIDS COMPOSITION WITH ENHANCED BIOAVAILABILITY

Field of the Invention

The present invention is in the field of composition of curcuminoids.

Background and Prior Art

Turmeric is known to have a number of pharmacological activities. Its uses are well known and widely reported in the ancient Indian, Chinese and Japanese literature. In the US, curcumin is used as a colouring agent in cheese, spices, yoghurt, mustard, cereals, pickles, potato flakes, soups and ice creams. The active ingredient of turmeric is curcumin, and after its identification two decades ago, a number of pharmacological activities of curcumin have been explored by various researchers across the globe (Hatcher, et al.).

Evidences are accruing on the multiple therapeutic property of curcumin from being an anti-proliferative, anti-invasive, anti carcinogenic to being a therapeutic agent for various disease conditions such as Parkinson's disease (Cole, et al.), cardiovascular disease, pulmonary disease, and arthritis (Goel, et al., Sharma, et al., Maheshwari, et al., Shishodia, et al.).

Curcuminoids are the main active ingredients of Curcuma longa (Turmeric, fam: zingiber aceae). There are several curcuminoids and curcumin I (diferuyl methane) is the most potent of all. The other curcuminoids are curcumin II (demethoxycurcumin), curcumin III (didemethoxycurcumin) and cyclocurcumin (Goel, et al.). The chemical structure of curcumin is given in Formula 1. Curcumin is an orange-yellow, highly staining compound. It is a polyphenols compound with antioxidant properties. Its molecular weight is 368.37 and it is having a molecular formula of C₂iH₂o0₆. It is a crystalline compound with a melting point of 183°C. It is poorly soluble in water at pH less than 7. The commercially available curcumin is a mixture of curcuminoids wherein -95% is curcumin I. It is having 3 Pk_as (Sharma, et al.).

Formula 1 The poor bioavailability has been the major limitation of it not being approved as a therapeutic agent, in spite of its efficacy and safety. It has been reported that more than 75% of curcumin administered orally is excreted unchanged via faeces. The major reasons responsible for its poor absorption and bioavailability via oral route are very poor aqueous solubility, poor chemical stability in the alkaline pH of the gastro-intestinal tract and susceptibility to enzymatic degradation in the gastrointestinal tract. It has a short biological half life due to poor absorption, rapid metabolism and high clearance rate from the serum and body.

Curcumin is very hydrophobic with a log P of 2.92 and it is not dissolved in aqueous system of pH less than 7.0 when delivered as a powdered extract as in common nutraceuticals. Most curcumin activities require 100-2000 nanomolar concentration levels in vitro, but current supplements result in negligible levels.

Several groups have come up with theoretical ideas for improving absorption of curcumin and most were entirely in vitro studies, due to the difficulty in measuring curcumin and its metabolites concentration in body fluids or tissues.

Bisht et al. reported the synthesis, physicochemical characterization and cancer related application of a polymer based nanoparticle of curcumin namely "nanocurcumin" with less than 100 nm size. They have found it to have similar in vitro activity as that of free curcumin in pancreatic cell lines. However, the authors neither determined the in vivo effect of nanocurcumin in any animal model nor its biodistribution and bioavailability to show any potential increase in efficacy of nanocurcumin over free curcumin in vivo.

Li et al. developed and investigated the in vitro and in vivo antitumor activity of liposomal curcumin against pancreatic carcinoma cells. However, they did not evaluate the enhancement in the bioavailability of curcumin in the liposomal form over that of free curcumin as the objective was to test the efficacy of liposomal curcumin in the inhibition of pancreatic carcinoma.

WO2005/020958 discloses the concept of administration of curcumin in the form of aerosol delivery. However, no data with respect to the bio-distribution and bioavailability of curcumin was reported which would actually show to what extent the approach can be useful. Moreover, aerosol delivery is quite less popular in terms of patient compliance compared to the oral dosage forms and is expensive. Some of the possible ways that have been tried to overcome the problems to develop a curcumin formulation for oral administration are described below.

Piperine, a known inhibitor of hepatic and intestinal glucoronidation was combined with curcumin to increase its oral bioavailability (Shoba et al). Concomitant administration of piperine with curcumin resulted in 154% and 2000% increase in the oral bioavailability of curcumin in rats and human respectively (Shoba, et al.). Glucoronidation is protective against many toxins as it is involved in the metabolism of commonly used drugs. Inhibition of glucoronidation will affect the metabolism of drugs, and may have implications in multiple drug users, mostly elderly patients where it results in unsafe levels of drugs.

WO 2007103435 discloses the use of antioxidant (ascorbic acid, lipodated vitamin C, N- acetylcysteine, reduced glutathione and tetrahydrocurcumin) for the enhancement of bioavailability of curcumin when incorporated in a pharmaceutically acceptable carrier. The carriers that they have stated are solid lipid nanoparticles and lipid micelles. In both of these formulations, drug loading remains limited.

WO 2006022012 discloses a solid dispersion of curcumin with polyvinyl pyrrolidone. They have stated that the said embodiment would have enhanced bioavailability, on the basis of in vitro solubility studies. However, whether improved solubility enhanced bioavailability has not been reported.

The formulation of any of the lipidic systems requires suitable screening of the various excipients used so as to fulfil the criteria of drug loading, self emulsification or microemulsification on dilution, precipitation of the drug upon dilution and an overall enhancement in the bioavailability. This varies from drug to drug, depending upon the physicochemical and physiological behaviour of the drug molecule.

In view of the above stated it is desirable to develop a stable formulation with higher drug loading capacity and solubility of curcumin (or curcuminoids) capable of improving its oral bioavailability, and which the present invention discloses. Object of the invention

The object of the present invention is to provide a pharmaceutical composition of curcumin or curcuminiods with improved bioavailability and higher drug loading ability, having adequate physical and chemical stability as a self nanoemulsifying formulation.

Description of the figure

Figure 1 is a graphical representation of plasma concentration-time profiles after oral administration of 250 mg/kg curcumin in the form of (i) self emulsifying composition (ii) aqueous suspension suspended with sodium carboxymethyl cellulose, (iii) aqueous micronised suspension and (iv) curcumin with piperine (20mg/kg).

Detailed description of invention

Accordingly, the present invention provides a novel curcuminoid composition comprising curcumin or curcuminoids, a lipidic carrier system with an HLB between 3 and 14, and a pH buffer, which forms a self nanoemulsion dilution with water, gastric fluid, or intestinal fluid of globule size of less than 200 nm.

The amount of curcumin or curcuminoids is about 0.001% and 30%, preferably between 0.1 % and 10%, most preferably between 0.1% and 6% (w/w) of the final composition.

The lipidic carrier system in the composition is selected from one or more mono-, and di-, esters of - saturated or unsaturated long chain fatty acids having C6 to C24 carbon chain length with low and medium molecular weight polyoxyethylene glycerol ethers or combinations.

The fatty acid in the composition is selected from a group consisting of mono-, di-, and tricapric acid, mono-, di-, and tricaprylic acid, mono-, di-, and trioleic acid, mono-, di- and trilinoleic acid, mono-, di-, and trilauric acid, mono-, di-, and tripalmitic, stearic acid, myristic acid, behenic acid, elaidic acid, arachidic acid or palmitoleic acid.

The polyoxyethylene glycerol ethers in the composition is selected from PEG of molecular weights ranging from 200 to 1600, more preferably PEG 200- 600 and most preferably PEG 1500. The lipidic carrier system is also selected from a group consisting of PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-8 glyceryl caprylate/caprate, PEG-6 glyceryl linoleate, PEG-6 glyceryl oleate, PEG-4 glyceryl caprylate/caprate and mixtures thereof.

The hydrophilic-lipophilic balance of lipidic carrier system in the composition is preferably between 5 and 14 and more preferably between 10 and 14.

The pH buffer in the composition is selected from the group consisting of citric acid, benzoic acid, stearic acid, formic acid, lactic acid, fumaric acid, hydrochloric acid, acetic acid, butyric acid, phosphoric acid, orthophosphoric acid, malic acid, sorbic acid, oxalic acid and oleic acid and mixtures thereof.

The composition further comprises a polymeric molecular aggregation inhibitor, a surface active agent and a co-solvent.

The molecular aggregation inhibitor in the composition is selected from a group consisting of hydroxymethyl propyl cellulose, carboxymethyl cellulose, hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol or derivatives and combinations thereof.

The surface acting agent in the composition is selected from a group consisting of non ionic surfactants Vitamin E TPGS (tocopheryl polyethylene glycol succinate) and polysorbates.

The concentration of the surface acting agent in the composition ranges from 0.001 to 20%, more preferably 0.01 to 10% and most preferably 0.1 to 5% w/w with a hydrophilic lipophilic balance higher than 10.

The co-solvent in the composition is selected from ethanol, propylene glycol, glycerol, polyethylene glycols, solutol and mixture thereof.

The composition additionally contains a bioenhancer selected from glucoronidation inhibitor or Cytochrome P 450 or P-glycoprotein inhibitor) inhibitor, alkaloids (e.g., piperine, piperine derivatives, piperidine derivatives), glycosides (e.g., quercetin, flavones derivatives), tannins and mixture thereof. The invention also provides a process of preparing a self nanoemulsifying composition comprising step of adding the curcuminoids and/ or curcumin to the acidified lipidic carrier system, wherein the lipophilic-hydrohilic balance of the lipid phase is in the range of 3-14. Dissolving or preparation of a suspension by one of the following- vortexing, shaking, vibrating, sonicating or heating.

The composition so prepared is provided as a liquid or semisolid formulation in a pharmaceutically acceptable dosage form containing pharmaceutically acceptable excipients selected from sweeteners, antioxidants, preservatives, stabilizers, flavouring agents, solid adsorbents, colorants and thickeners.

The said composition is administered orally as such or may be administered in the form of a liquid oily preparation.

The said composition may be encapsulated in a soft or hard gelatin capsule

The following examples are for the purpose of illustration of the invention and are not intended in any way to limit the scope of the invention.

EXAMPLES

General Procedure for Preparing the Compositions of the Present Invention. The lipidic carrier mixture is placed in a container and the cap is tightened. The container is put in a water bath at a temperature above the melting point of the components and shaken gently until all of the solid materials are molten. Next, the pH buffer is added and allowed to dissolve or suspend. After the mixture is acidified the curcuminoid therapeutic agent is added and the mixture shaken at 50⁰C until a clear solution is formed. The container is usually left at ambient conditions for future use.

Example 1

Curcumin liquid or semi-solid self-emulsifying formulations (3 component systems) were prepared having components as shown in table 1 : Table 1. Curcumin 3 component self-emulsifying (SE) formulations

Compostion (w/w)

FORMULATION SE l SE 2 SE 3 SE 4 SE 5 SE 6

Curcumin 35 60 40 30 30 35

Gelucire 44/14 600 - - 300 300 -

Gelucire 50/13 - - 600 - - -

Labrasol - 600 - 300 - 300

Vitamin E TPGS - - - - 300 300

Citric acid 5 5 5 5 5 5

Gelucire®44/14 is the trade name of PEG-32 glyceryl laurate manufactured by Gattefosse, Gelucire®50/13 is the trade name of PEG-32 glyceryl palmitostearate manufactured by Gattefosse, Labrasol is the trade name of PEG-8 glyceryl caprylate/ caprate manufactured by Gattefosse, Vitamin E TPGS is a water-soluble form of natural-source vitamin E prepared by esterifying d-α-tocopheryl acid succinate with polyethylene glycol 1000 manufactured by Eastman.

Example 2

Curcumin semi-solid self microemulsifying formulations (3-5 component systems) were prepared having components as shown in table

Table 2. Curcumin semi solid self-emulsifying formulations

Compostion (w/w)

FORMULATION SE 7 SE 8 SE 9 SE lO SE Il SE 12

Curcumin 40 40 40 40 40 40

Gelucire 44/14 200 225 - 225 -

Gelucire 50/13 - - 225 200 - 225

Labrasol 200 225 225 200 225 225

Vitamin E TPGS 200 150 150 200 150 150

Citric acid 5 5 5 5 10 10 Example 3

Stable Self-Emulsifying Formulations of curcumin with Lower Levels of Solvents and Using molecular aggregation inhibitors to Prevent Crystal Growth without. Curcumin semi-solid self microemulsifying formulations with delayed precipitation tendency after self emulsification (3-6 component systems) were prepared having components as shown in table 3. These formulations also contain a polymeric molecular aggregation inhibitor.

Table 3. Stable Self-Emulsifying Formulations of curcumin with molecular aggregation inhibitors

Compostion (w/w)

FORMULATION SE 13 SE 14 SE 15 SE 16 SE 17 SE 18

Curcumin 40 40 40 40 40 40

Gelucire 44/14 225 225 225 225 225 225

Labrasol 225 225 225 225 225 225

Vitamin E TPGS 150 150 150 150 150 150

Citric acid 5 5 5 5 10 20

HPMC 50 25 10 5 5 5

HPMC is hydroxypropyl methyl cellulose

Example 4

Curcumin liquid self microemulsifying formulations (3-6 component systems) containing a co solvent as well as shown in table 4.

Table 4. Liquid self microemulsifying formulations of curcumin with co solvents

Compostion (w/w)

FORMULATION SE 19 SE 20 SE 21 SE 22 SE 23 SE 24

Curcumin 40 40 40 40 40 40

Gelucire 44/14 225 225 225 225 225 225

Labrasol 225 225 225 225 225 225

Vitamin E TPGS 150 150 150 150 150 150

Citric acid 5 5 5 5 10 20

Ethanol 100 100 100 100 100 100 Example 5

Curcumin self microemulsifying formulations, liquid at temperature more than or equal to 25⁰C (3-6 component systems) and delayed precipitation tendency as shown in table 5.

Table 5. Liquid self microemulsifying formulations of curcumin with co solvents and molecular aggregation inhibitors

Compostion (w/w)

FORMULATION SE 25 SE 26 SE 27 SE 28 SE 29 SE 30

Curcumin 40 40 40 40 40 40

Gelucire 44/14 225 225 225 225 225 225

Labrasol 225 225 225 225 225 225

Vitamin E TPGS 150 150 150 150 150 150

Citric acid 5 5 5 5 10 20

HPMC 50 25 10 5 5 5

Ethanol 100 100 100 100 100 100

Example 6

Curcumin self microemulsifying liquid formulations (3-6 component systems) containing a co solvent as well as a polymeric aggregation inhibitor and a bioenhancer, thus capable o giving additional bioavailability advantage as shown in table 6.

Table 6. Self microemulsifying formulations of curcumin with bioenhancer piperine

Composition (w/w)

FORMULATION SE 31 SE 32 SE 33 SE 34 SE 35 SE 36

Curcumin 40 40 40 40 40 40

Gelucire 44/14 225 225 225 225 225 225

Labrasol 225 225 225 225 225 225

Vitamin E TPGS 150 150 150 150 150 150

Citric acid 5 5 5 5 10 20

HPMC 50 25 10 5 5 5

Ethanol 100 100 100 100

Piperine 5 2 10 4 8 6 Example 7

In Vivo Activity of Self-Emulsifying Formulation

Tests were carried out to compare bioavailability of curcumin after oral administration of the self emulsifying formulation (composition given in table 7) with (i) aqueous suspension, (ii) aqueous microsuspension of curcumin and (iii) curcumin administered with the bioenhancer piperine. Male Sprague- Dawley rats (n=6) were fasted overnight and administered the respective formulation by oral gavage at dose of 250 mg/kg. Blood samples were collected at 15, 30, 60, 120, 180 and 300 minutes. Blood samples were immediately centrifuged at 6500 x g for 15 min to separate plasma. Plasma was stored at - 80⁰C until analysis. The curcumin content was quantified by a validated HPLC-UV method.

Table 7. The composition used for in vivo pharmacokinetic characterization

Ingredient Each 10 g contains

Curcumin 400 mg

Gelucire 44/14 2.97 g

Labrasol 2.97 g

Vitamin E TPGS 1.98 g

Ethanol 1.32 g

HPMC (Methocel

E5 Premium LVEP) 330 mg

Citric acid, 30 mg anhydrous

Peak plasma levels (Cmax) and area under the curve (AUC) values of curcumin obtained after administration of the self microemulsifying formulation and the aqueous suspension were determined.

The results show that the plasma concentration obtained for the self microemulsifying formulation were significantly higher than the aqueous suspension and are maintained for a longer time thus increasing the biological half life of the drug. The results are summarized in table 8 and 9 and figure 1. Table 8: Pharmacokinetic parameters calculated from the plasma profiles obtained after administration of 250mg/kg of curcumin aqueous suspension (suspended with sod. CMC) and the inventive self microemulsifying formulation to 225-250 g Sprague- Dawley rats (n=6).

Pharmacokinetic Aq. SEDDS parameter (unit) Suspension

AUC_0-Sh (ng/ml)h 23.7 514.7

^" max 26.5 174.9

T ¹ max 0.50 2.5

AUMC_0-S_h (ng/ml)h² 18.2 1452.7

Table 9: Comparative assessment of the pharmacokinetic parameters of all the formulations. % increase in the PK parameters has been shown as compared with aq. Suspension taken as 100 %.

% Increase

Parameter AUC (0- *-max AUMC (0- last) last)

Aq. Suspension 100 100 100

Micronised suspension 199 165 371

S-SEDDS 2166 660 7977

With piperine 716 319 1837

Example 8

Stability study of self emulsifying formulation

The stability study was conducted in glass vials filled under nitrogen and kept at 4O⁰C and 75% RH in the dark in stability chambers. One embodiment of the formulation was found to be stable at least for 5 weeks. The results of the stability study are shown in table 9.

Table 10. Stability study of self emulsifying formulation

Time Assay Self Appearance Colour em unification tendency

O day 100 Yes Isotropic Yellow with orange tinge

1 week 101.8 ±1.35 Yes Isotropic No change

2 week 99.0 ± 0.21 Yes Isotropic No change

3 week 99.06 ±0.45 Yes Isotropic No change

5 week 98.9 ±1.56 Yes Isotropic No change

Example 9

Self-Emulsifying Properties

To evaluate the behaviour of the self-emulsifying formulation as it becomes exposed to aqueous media, 2g of various curcumin solution formulations were prepared and known amounts of water were added to the respective formulas. The compositions of the formulations along with the outcome of the water addition are shown in Table 8.

Table 11. Effect of water addition on various liquid curcumin formulations

Composition Observation

1 Curcumin,2% in PEG 400 Curcumin precipitated out of solution and large crystal precipitates appeared

2 Curcumin, 2% in labrasol No microemulsion formed but an emulsion was formed

3 Curcumin, 2% in tween 80 Curcumin precipitated out of solution

4 Curcumin, 1% in transcutol Curcumin precipitated out of solution

5 Curcumin, 2% in PEG 200 Curcumin precipitated out of solution

6 Self emulsifying formulation Curcumin did not precipitate at least for an hour with HPMC (SE 1001)

7 Self emulsifying formulation Curcumin did not precipitate at least for half an without HPMC (SE 1002) hour

8 Self emulsifying formulation Curcumin did not precipitate at least for 15

(2 component) minutes The self-emulsifying formulations (SE 1001 and SE 1002) did not precipitate in presence of excessive amounts of water, whereas all other formulations containing various solutions of curcumin severely crashed out of solution by forming large crystalline particulates upon addition of 1 or 2 ml of water. Our self-emulsifying formulations are superior to solution formulations containing the drug and a solubilizer.

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Claims

We claim:

1. A self nanoemulsifying curcuminoids composition, said composition comprises 0.001% to 30.0% (w/w) of curcumin or curcuminoids, a lipidic carrier system wherein the hydrophilic-lipophilic balance of the lipid carrier system is in the range of 3 to 14, a pH buffer, optionally a polymeric molecular aggregation inhibitor, a surface active agent, a co-solvent and pharmaceutically acceptable excipients, the said composition is capable of spontaneously forming a nanoemulsion when added to aqueous medium with globule size below 200 nm.

2. The composition as claimed in claim 1, wherein the amount of curcumin or curcuminoids is preferably 0.005% to 20.0%, more preferably 0.01% to 20.0% and most preferably 0.1% 20.0%.

3. The composition as claimed in claim 1, wherein the lipidic carrier system is from one or more mono-, and di, esters of - saturated or unsaturated long chain fatty acids having C6 to C24 carbon chain length with low and medium molecular weight polyoxyethylene glycerol ethers or combinations thereof.

4. The composition as claimed in claim 3, wherein the fatty acid is selected from a group consisting of mono-, di-, and tricapric acid, mono-, di-, and tricaprylic acid, mono-, di-, and trioleic acid, mono-, di- and trilinoleic acid, mono-, di-, and trilauric acid, mono-, di-, and tripalmitic, stearic acid, myristic acid, behenic acid, elaidic acid, arachidic acid or palmitoleic acid.

5. The composition as claimed in claim 3, wherein the polyoxyethylene glycerol ethers is selected from PEG with molecular weights ranging from 200 to 1600, more preferably PEG 200- 600 and most preferably PEG 1500.

6. The composition as claimed in claim 3, wherein the lipidic carrier system is also selected from a group consisting of PEG-32 glyceryl laurate, PEG-32 glyceryl palmitostearate, PEG-8 glyceryl caprylate/caprate, PEG-6 glyceryl linoleate, PEG- 6 glyceryl oleate, PEG-4 glyceryl caprylate/caprate and mixtures thereof.

7. The composition as claimed in claim 1, wherein the hydrophilic-lipophilic balance of lipidic carrier system is preferably in the range of 10-14.

8. The composition as claimed in claim 1 wherein the pH buffer is selected from the group consisting of citric acid, benzoic acid, stearic acid, formic acid, lactic acid, fumaric acid, hydrochloric acid, acetic acid, butyric acid, phosphoric acid, orthophosphoric acid, malic acid, sorbic acid, oxalic acid and oleic acid and mixtures thereof.

9. The composition as claimed in claim 1, wherein the molecular aggregation inhibitor is selected from a group consisting of hydroxymethyl propyl cellulose, carboxymethyl cellulose, hydroxyl propyl cellulose, methyl cellulose, polyvinyl alcohol or derivatives and combinations thereof.

10. The composition as claimed in claim 1, wherein the surface acting agent is selected from a group consisting of non ionic surfactants Vitamin E TPGS (tocopheryl polyethylene glycol succinate) and polysorbates.

11. The composition as claimed in claim 10, wherein the concentration ranges from 0.001 to 20%, more preferably 0.01 to 10% most preferably 0.1 to 5% w/w with a hydrophilic lipophilic balance higher than 10.

12. The composition as claimed in claim 1, wherein the co-solvent is selected from ethanol, propylene glycol, glycerol, polyethylene glycols, solutol and mixture thereof.

13. The composition as claimed in claim 1, additionally contains a bioenhancer selected from glucoronidation inhibitor or Cytochrome P 450 or P-glycoprotein inhibitor) inhibitor, alkaloids (e.g., piperine, piperine derivatives, piperidine derivatives), glycosides (e.g., quercetin, flavones derivatives), tannins and mixture thereof.

14. The composition as claimed in claim 1, wherein the composition is in the form of liquid or semisolid formulation.

15. The composition as claimed in claim 1 which contains pharmaceutically acceptable excipients selected from sweeteners, antioxidants, preservatives, stabilizers, flavouring agents, solid adsorbents, colorants and thickeners.

16. The composition as claimed in claim 1 that is in a pharmaceutically acceptable dosage form and is administered orally as such or after dilution with appropriate diluents.

17. A process of preparing a self nanoemulsifying composition comprising step of adding curcuminoids and/or cucurmins to the acidified lipid phase, wherein the lipophilic-hydrophilic balance of the lipid phase is in the range of 3-14.