EP2563351A1

EP2563351A1 - Adhesive slow-release formulations for the local administration of curcumin

Info

Publication number: EP2563351A1
Application number: EP11717608A
Authority: EP
Inventors: Andreas Obwaller
Original assignee: Orphanidis Pharma Research GmbH
Current assignee: Orphanidis Pharma Research GmbH
Priority date: 2010-04-30
Filing date: 2011-04-29
Publication date: 2013-03-06
Also published as: US20130052145A1; MX2012012476A; EA201201480A1; AU2011247569A1; IL222616A0; JP2013525412A; AT509777A1; CA2797779A1; AT509777B1; ZA201209038B; WO2011135073A1

Abstract

As a result of the combined use of solvents and polyacrylic acids, curcumin formulations can be produced that are stable in liquid form, exhibit both mucoadhesive and slow-releasing properties, and assure solubility of the active ingredient of up to 15% (m/v).

Description

Adhesive sustained-release formulations for local administration of

curcumin

Curcumin is an intense orange-yellow compound that occurs naturally in the goldenseal, also known as Curcuma longa. Recent studies have shown that curcumin has an anti-inflammatory and antimicrobial effect when applied topically. It is necessary to keep the active substance as long as possible on the tissue to be treated.

Achieving this goal poses a major pharmaceutical and technological challenge and a problem that until now could not be solved in terms of formulation. The reason for this lies above all in the fact that in liquid and semi-solid preparations, on the one hand, the adhesion of the active substance to the mucous membrane, such as the oral, vaginal or rectal mucosa or on the skin, must be prolonged and, on the other hand, the active ingredient must be released in a delayed manner. to achieve the desired effect. For the achievement of the largest possible areas with the active ingredient, however, solid administration forms are not considered, in which properties such as adhesion and retardation are already state-of-the-art. Add to that

Problem that curcumin itself has no charge, which would allow a retardation of the drug with charged carrier polymers due to ionic interactions effects. Another problem is that carrier systems which have adhesive properties on mucous membranes lose these mucoadhesive properties when at the same time an active substance is bound to them, which, however, is essential for retardation. In addition, curcumin is very slightly soluble in an aqueous environment.

WO 2006/027248 A2 describes the use of a multiplicity of different plant extracts, i.a. also from the order Zingiberales for the inhibition of dextran sucrase. A process for the preparation of a turmeric plant extract and a

Composition for cosmetic applications containing an extract

Curcuma plants is described in EP 2 057 995 A2, WO2010 / 070664 A1 describes the use of curcuminoids such as curcumin for the treatment of ocular diseases.

WO2010 / 1 15852 A1 describes the use of curcuminoids in combination with docetaxel for the treatment of cancers, wherein the

Administration of curcumin preferably takes place orally

The object of the invention is therefore to provide a formulation in which curcumin is stable in solution and which preferably has mucoadhesive and retarding properties.

The object of the invention is achieved by a composition containing curcumin, polyacrylic acid, a solvent and optionally other auxiliaries. In the invention disclosed herein, surprisingly, a way could be found to combine both properties - adhesion and retardation - in a liquid formulation and to keep curcumin in solution even at high concentrations. It turned out that polyacrylic acid, as an adhesive and, above all

mukoadhesive polymer is known (Grabovac V, Guggi D, Bernkop-Schnürch A. Comparison of the mucoadhesive properties of various polymers. Adv Drug Deliv Rev. 2005 Nov 3; 57 (11): 1713-23) in combination with a solvent in is able to provide even in liquid preparations for a sustained release drug without losing attachment. According to a particular embodiment of the invention, curcumin in the

Composition in a concentration of 0, 1 to 15%, preferably from 1 to 10%.

The solvent may in particular be selected from the group consisting of dimethylacetamides, polyoxyethylated oleic acid glycerides (Labrafil), pyrrolidones, / V-ethyl-2-pyrrolidones, / V-methyl-2-pyrrolidones, polyethylene glycols or polyoxamers such as methyl oxirane (Pluronic L44). , Preferably, polyethylene glycol can be used which has a molecular weight of 106 to 10,000 Da, preferably from 300 to 6000 Da. In particular, polyacrylic acid has a molecular weight of 1 to 10,000 kDa and may optionally be crosslinked.

The composition may contain other adjuvants such as, but not limited to, water, neutralizers, viscosity enhancers,

Flavoring agents, colorants, preservatives and stabilizers.

According to the present invention, the composition may be in any form which is applicable to the use of the curcumin, preferably it is a liquid or gel formulation such as a cream or ointment or rinse. Alternatively, the inventive

Formulation as a solid formulation, for example as a suppository, preferably as vaginal suppositories. Curcumin, for example, as a liquid

Formulated slow release formulation.

Preferably, the composition according to the invention results in at least 10%, preferably at least 20% retardation of curcumin in the liquid form of the formulation within 30 minutes. The invention also encompasses a pharmaceutical preparation containing the formulation according to the invention and its therapeutic application. Furthermore, the invention also encompasses the use of the composition in combination with an analgesic.

Characters:

Figure 1: Release of curcumin from a PEG 300 solution with various concentrations of cross-linked polyacrylic acid (Carbopol 974P NF) (gray: 0% polyacrylic acid; black: 0.05% polyacrylic acid, gray dashed line: 0.1% polyacrylic acid, black dashed lines: 0.5% polyacrylic acid). The values shown correspond to the average of at least three experiments (± standard deviation).

Figure 2: graphical representation of the mucoadhesive properties of pure crosslinked polyacrylic acid (Carbopol 974P NF) and this with 2% curcumin. The values shown correspond to the average of at least three experiments (± standard deviation).

Figure 3: the HPLC spectrum before (top) and after (bottom) one month storage. FIG. 4: Ointment No. 1 prepared from 2% curcumin, 12.5% PEG 6000, 19% PEG 600 and 66.5% PEG 300 was stable when stored for 4 weeks at 40 ° C./75% relative atmospheric humidity. The values shown correspond to the average of at least three experiments (± standard deviation).

The invention comprises a composition comprising curcumin, polyacrylic acid and a solvent in which curcumin is soluble, which composition advantageously has a sustained-release of drug. The term "curcumin" according to the present invention includes curcumin and metabolites or analogs of curcumin, provided that the

Metabolites or analogs have an anti-inflammatory or antimicrobial effect. Examples of metabolites are dihydroferulic acid, ferulic acid, glycosides of tetrahydrocurcumin or hydroxyhydrocurcumin.

Curcumin may be an isolate from the natural source Curcuma longa L. or chemically synthesized. Curcumin also includes isomers of curcumin, pharmaceutically acceptable salts thereof, precursors of curcumin or polymorphs or tautomers thereof. Curcumin may also be formulated as a metal chelate, for example as

Copper chelate.

Delayed drug release could be based on the formation of hydrogen bonds between the phenolic moieties of curcumin with the carboxylic acid moieties of the polyacrylic acid, which are stabilized by the presence of a solvent such as polyethylene glycol (PEG).

Surprisingly, it has been shown that although solvents such as PEGs are normally incompatible with phenolic compounds in higher concentrations, this effect is seen in the combined use of

Polyacrylic acid with solvents such as PEG even at higher

Concentration does not occur.

Despite the binding of curcumin to polyacrylic acid, it has surprisingly been found that the polymer does not lose its adhesive properties. The The formulation according to the invention therefore also has adhesive properties on body surfaces or skin surfaces, preferably mucoadhesive properties, for example in the oral, vaginal or rectal mucosa. These adhesive properties are also particularly advantageous for the retarding of the active ingredient on the surface to which the formulation is applied. As a result, the active ingredient can adhere to the skin surface over an extended period of time, be released through the skin surface and unfold its effectiveness over a longer period of time. The formulation according to the invention preferably also has a high storage stability. Curcumin, which is normally very unstable in liquid preparations because of its sensitivity to oxidation, surprisingly has a high storage stability in the formulations according to the invention. The content of curcumin may be selected according to the therapeutic requirements of the composition. According to a particular embodiment of the invention, curcumin may also be stably contained in the composition in higher concentrations, for example in a concentration of up to 2.5% (m / v).

Curcumin is preferably present in a concentration of 0.1 to 15%, preferably of 1 to 10%.

According to the present invention, any solvent in which curcumin can be dissolved and in which curcumin has a sufficiently high storage stability can be selected.

As a "solvent" is understood according to the present invention, any mixture or chemical compound, the solubility of curcumin below

improved physiological conditions. By physiological conditions is meant a pH range of 4-8 and a temperature of 30-42 ° C.

At least 0.5% solubility, preferably at least 1% solubility, is preferred. The solubility of curcumin can be tested by the skilled person in a simple manner by means of known methods for solubility determination. Preferably, the solvent is selected from the group consisting of

Dimethylacetamide, polyoxyethylated oleic acid glycerides (Labrafil), pyrrolidone, / V-ethyl-2-pyrrolidone, / V-methyl-2-pyrrolidone, polyethylene glycol, a polyethylene glycol derivative and polyoxamers such as methyl oxirane (Pluronic L44) or a mixture thereof. Preferably, polyethylene glycol having a molecular weight of 106 to 10,000 Da, preferably from 300 to 6000 D is used.

The polyacrylic acid used in the composition of the invention has in particular a molecular weight of 1 to 10,000 kDa. The polyacrylic acid may be linear or crosslinked.

As a specific embodiment, the composition according to the invention comprises curcumin, a solvent, polyacrylic acid and, optionally, further auxiliaries, where the polyacrylic acid has a molecular mass of 1 to 10,000 kDa and is optionally crosslinked.

The composition may contain other adjuvants known for pharmaceutical or cosmetic composition. These may be, for example, water, neutralizing agents such as NaOH, KOH, tromethamol, triethanolamine or diisopropanolamine, viscosity enhancers such as poloxamers, cellulose derivatives or

Alginates, flavoring agents such as essential oils or sweeteners, dyes such as food colors, preservatives such as sorbic acid, benzoic acid, chlorhexidine, benzalkonium chloride or parabens and stabilizers. According to the present invention, the composition may be in any form which is applicable to the inventive formulation.

Preference is given to liquid or gel-form or semisolid formulations such as, for example, gels, creams or ointments for dermal or mucosal administration or solid formulations such as suppositories. Alternatively, the inventive formulation may also be in the form of suppositories, preferably as vaginal or rectal suppositories.

According to a further embodiment, the composition according to the invention may also be present as a combined preparation with an analgesic. there Painkillers may be used as known in the art. For example, they may be opioid analgesics such as morphine, fentanyl or methadone or nonopoid analgesics such as nicotinergic analgesics or acidic antiphlogistic and antipyretic analgesics such as salicylic acid derivatives such as acetylsalicylic acid, phenylacetic acid derivatives such as diclofenac, 2-phenylpropionic acid derivatives such as ibuprofen and naproxen; Oxicams such as meloxicam or piroxicam, non-acid analgesics such as 4-aminophenol derivatives such as paracetamol, pyrazolones such as metamizole or phenazone or other non-opioid analgesics such as flupirtine.

Furthermore, the invention also includes the use of the composition in

Combination with an analgesic

For the solid formulations, liquid PEGs or other solvents, for example, are replaced by room-temperature semi-solid or solid PEGs or other solvents.

When using PEG, the molecular weight is in the range of 106 to 10,000 Da and more particularly between 300 and 6000 Da. Since the application of higher molecular weight PEGs by the warming to body temperature and / or the access of aqueous medium to liquefaction of these, the invention disclosed here is to apply this mutatis mutandis.

Liquid formulations may be rinses which may be used orally, nasally, vaginally or rectally. Mouthwashes are a special embodiment. The formulation according to the invention can also be used as nasal rinse or nasal spray.

The formulation of the invention has a sustained release of curcumin. Preferably, the composition according to the invention results in at least 10%, preferably at least 20%, retardation of

Curcumin in the liquid form of the formulation within 30 minutes.

In particular, the composition according to the invention is a liquid

Sustained-release formulation. The invention also encompasses a pharmaceutical preparation containing the formulation according to the invention and its therapeutic application.

The composition can be used for the manufacture of a medicament for the prevention or treatment of microbial infections, inflammatory diseases or for the treatment of cancer, or by cancer therapies

caused secondary diseases and clinical pictures such as

Mucosal inflammations and infections of the mucous membranes in the mouth and

Throat area and the digestive tract.

Examples:

The following examples are merely exemplary and are intended to better illustrate the invention disclosed herein. Changes and variations of the following examples within the scope of the present claims may be made.

EXAMPLE 1

Solubility studies with curcumin

For intraoral solutions, curcumin must be dissolved. The solvents listed in Table 1 were tested. For each solvent is the maximum

Concentration of curcumin, which could be solved, listed. When curcumin was soluble, water was added to the solvents and the solubility in this mixture was also determined.

Table 1: Solubility of curcumin in organic solvents

Organic solvents% solubility

No solvent

+ Water mixtures (m / v)

1 dimethylacetamide 4

2 Labrafil 3

3 A / ethyl-2-pyrrolidone 6 + 4 4

4 A / ethyl 2-pyrrolidone 7 + 3 5

6 A / ethyl 2-pyrrolidone 30

7 A / -methyl-2-pyrrolidone 6 + 4 4

8 A / -methyl-2-pyrrolidone 7 + 3 4

10 A / methyl 2-pyrrolidone 30

1 1 PEG 300 2.5

12 PEG 300 9 + 1 2.5

13 PEG 300 8 + 2 2.5

14 Pluronic L44 3 Organic solvents% solubility

No solvent

+ Water mixtures (m / v)

15 pyrrolidone 1 + 9 1

16 pyrrolidone 5 + 5 2.5

17 pyrrolidone 6 + 4 3

18 pyrrolidone 7 + 3 5

19 pyrrolidone 9 + 1 5

20 pyrrolidone 20

21 Capmul 0

22 Refined corn oil 0

23 Cremophore 0

24 glycerol 0

25 Kollidon 12 5 + 5 0

26 Kollidon 12 4 + 6 0

27 Kollidon 17 5 + 5 0

28 Kollidon 17 4 + 6 0

29 Labrasol 0

30 hydrogenated peanut oil 0

31 Pluronic F-68 3 + 7 0

32 propylene glycol 0

33 PVA 0

34 PVP 3 + 7 0

EXAMPLE 2

Preparation of liquid curcumin formulations

0, 1 to 2 g of curcumin and 0.01 to 1 g of Carbopol 974 NF are dissolved or suspended in 100 ml of PEG 300. As an option, 1 -20% of the PEG 300 portion can be replaced by water. In addition, polyacrylic acid can be partially or completely neutralized by the addition of alkalis such as NaOH, KOH or tromethamol. The solutions are dark yellow to brown and have a fine-spicy smell. They taste slightly bitter and there is no irritation of the oral mucosa or gums. Mouthwashes with a comparatively higher Carbopol content taste slightly sour. There is generally no staining of the teeth, however, the tongue is intensely discolored yellow, but disappears after a few hours or eating again. Because of the pleasant taste of the mouthwashes can be dispensed with other auxiliaries that affect the taste. EXAMPLE 3

Storage stability studies with liquid curcumin formulations

Storage stability studies of the anhydrous solutions described in Example 2 under accelerated conditions (40 ° C., relative humidity 75%) showed no oxidation or degradation of curcumin even after one month. FIG. 3 shows the HPLC spectrum before (above) and after (below) one month of storage.

EXAMPLE 4

Preparation of semi-solid curcumin formulations

Curcumin ointments were made based on PEG. For this purpose, polyethylene glycols in various concentrations and combinations together with

Polyacrylic acid (Carbopol 974NF) used. A detailed listing of the ointments produced is shown in Table 2 and Table 3. Table 2: Curcumin ointments made with different concentrations of PEG 6000, PEG 600 and PEG 300 as well as polyacrylic acid

Table 3: Curcumin ointments made with different concentrations of PEG 4000, PEG 1000 and PEG 400 as well as polyacrylic acid

All ointments were red-brown and had a fine-spicy smell. When used, the skin was intensely yellowed but not irritated. The stain could be washed away easily with soap and water. Ointment No. 1 made from 2% curcumin, 12.5% PEG 6000, 19% PEG 600 and 66.5% PEG 300 was stable when stored for 4 weeks at 40 ° C / 75% relative humidity as shown in FIG. The values shown correspond to the average of at least three Experiments (± standard deviation). In addition, the ointments were stable even after sterilization by autoclaving for 15 minutes.

EXAMPLE 5

Preparation of solid curcumin formulations

Curcumin suppositories for vaginal or rectal use were prepared based on PEG and polyacrylic acid. To prevent too rapid liquefaction of the suppositories at body temperature, Poloxamer 408 (= Pluronic F-127) was added. The exact formulation is listed in Table 4.

Table 4: Formulation for curcumin suppositories

The suppositories did not deform at room temperature. They were orange-brown. Curcumin suppositories were stable at room temperature for a period of three weeks.

EXAMPLE 6

Retarding effect of polyacrylic acid

10 ml of curcumin solution consisting of 2% (m / v) curcumin dissolved in PEG 300 and various concentrations of Carbopol 974 NF were placed in a dialysis tube and sealed with clamps. A beaker was filled with 500 ml of the same solvent used for the curcumin solution and the filled dialysis tube placed in the beaker. The solvent in the beaker was stirred gently and gently. Samples were taken at 0, 5, 10, 15, 20 and 30 minutes and the absorbance at 400 nm was measured with a "FLUOStar OPTIMA microplate reader." The results of this study are shown in Figure 1 (gray: 0% Carbopol; : 0.05% Carbopol, gray dashed: 0, 1% Carbopol;

black dashed: 0.5% Carbopol). It turned out that the more polyacrylic acid the liquid formulation is added, the slower the active ingredient from the

Formulation is released.

This phenomenon is likely to be based on the formation of hydrogen bonds between the phenolic substructures of curcumin with the carboxylic acid substructures of polyacrylic acid, which are sufficiently stabilized by PEG. Although it is known that PEGs are incompatible with phenolic compounds in higher concentrations, this effect could not be detected in the combined use of polyacrylic acid with PEG. Despite the binding of curcumin to polyacrylic acid, it has surprisingly been found that the polymer does not lose its (muco) adhesive properties.

EXAMPLE 7

Mucoadhesive properties of curcumin formulations

The influence of curcumin on the mucoadhesive properties of polyacrylic acid was tested by a rotating cylinder method (Grabovac V, Guggi D, Bernkop- Schnürch A. Comparison of the mucoadhesive properties of various polymers. Adv. Drug Deliv Rev. 2005 Nov 3; 57 (1 1): 1713-23). The mucoadhesive properties of pure Carbopol 71 G NF were compared with those of Carbopol 71 G NF containing 2% curcumin. To this end, at constant pressure, 30 mg Carbopol with and without 2% curcumin were compressed into test discs of 5.0 mm diameter.

The test discs were placed on fresh bovine buccal mucosa. The mucosa had previously been adhered to a stainless steel cylinder (diameter: 4.4 cm, height 5, 1 cm) using cyanoacrylate adhesive.

The cylinder was placed at 37 ° C ± 1 ° C in the dissolution tester (Erweka DT600) containing 0.1 M saline phosphate buffer pH 7.2. The fully submerged cylinder was stirred at 125 rpm. The adhesion of the test discs was checked after 15, 30, 45, 60, 90, 120, 150 and 180 minutes and after 4, 6, 8, 23 and 24 hours.

The adhesion results are shown graphically in FIG. It was found that the addition of curcumin even improved the adhesion.

Furthermore, it has been found that curcumin, which is very unstable in liquid preparations due to its sensitivity to oxidation, has a comparatively high storage stability in PEG formulations.

Claims

claims

1 . A composition containing curcumin, a solvent, polyacrylic acid and optionally other auxiliaries.

2. Composition according to claim 1, characterized in that curcumin is present in a concentration of 0, 1 to 15%, preferably from 1 to 10%.

3. Composition according to one of claims 1 or 2, characterized

in that the solvent is selected from the group consisting of dimethylacetamide, labrafil, pyrrolidone, / V-ethyl-2-pyrrolidone, / V-methyl-2-pyrrolidone, polyethylene glycol, polyoxamers, Pluronic L44.

4. Composition according to one of claims 1 to 3, characterized

characterized in that polyethylene glycol has a molecular weight of 106 to 10,000 Da, preferably from 300 to 6000 Da.

5. Composition according to one of claims 1 to 4, characterized

characterized in that polyacrylic acid has a molecular weight of 1 to 10,000 kDa and may optionally be present crosslinked.

6. Composition according to one of claims 1 to 5, characterized

in that the further auxiliaries are selected from the group consisting of water, neutralizing agent, viscosity enhancer,

Flavoring agents, colorants, preservatives and stabilizers.

7. Composition according to one of claims 1 to 6, characterized

characterized in that it is a liquid or semi-solid formulation.

8. Composition according to one of claims 1 to 7, characterized

characterized in that it is a mouthwash.

9. Composition according to one of claims 1 to 7, characterized

characterized in that it is a gel or ointment.

Composition according to any one of Claims 1 to 6, characterized in that it is a solid formulation.

1 1 .Zusammensetzung according to any one of claims 1 to 6 or 10, characterized in that it is a suppository, preferably a vaginal suppository.

A composition according to any one of claims 1 to 7, characterized

characterized in that it is a liquid sustained-release formulation.

13. A composition according to any one of claims 1 to 12 as

Combination preparation with at least one analgesic

14. Use of a composition according to any one of claims 1 to 13 for the preparation of a pharmaceutical or cosmetic preparation.

Use of a composition according to any one of claims 1 to 13 for the manufacture of a medicament for the prevention or treatment of microbial infections, inflammatory diseases or of cancer and by

Cancer treatments secondary diseases and symptoms.