Pharmaceutical composition based on curcuminoids

Abstract

The invention relates to a pharmaceutical composition based on curcuminoids, selected from among the group consisting of curcumin, demetoxicurcumin, bismetoxicurcumin, and the derivatives thereof, containing excipients such as surfactants, vegetable oils, lipophilic vitamins, antioxidants and / or polyphenols, among other lipophilic excipients. The invention likewise presents a composition distinctly characterized in that it presents improved solubility. This advance is a significant achievement in the field, making it possible to make more efficient and versatile curcuminoid formulations, enhancing use thereof in various therapeutic and pharmaceutical applications.

Description

PHARMACEUTICAL COMPOSITION BASED ON CURCUMINOIDS TECHNICAL FIELD

[0001] The present invention relates to a pharmaceutical composition based on compounds of plant origin, in particular, the invention based on curcuminoids with a significant increase in solubility. This advance represents a significant achievement in the pharmaceutical field, allowing the development of more efficient and versatile formulations containing curcuminoids, enhancing their application in various areas of use. STATE OF THE TECHNIQUE

[0002] The powdered rhizome of Curcuma longa L. (Zingiberaceae) has been used extensively in Indian and Asian cuisine and is used as a coloring and flavoring agent. Turmeric powder or its extract is found in numerous commercially available supplements. In Ayurvedic medicine, turmeric has been traditionally used to treat inflammation, skin wounds, and tumors (Ammon and Wahl, 1991, Planta Med., 57:1-7). Turmeric extracts are known to have therapeutic activities, including antimicrobial, anti-inflammatory, antioxidant, and anticancer agents (Kelloff et al., 1996, J. Cell. Biochem. Supplement 26:54-71).

[0003] Curcuminoids have phenolic, hydroxyl and methyl groups, which are related to the biological actions of these substances and some highly relevant aspects must be considered to ensure the appropriate use of these compounds.

[0004] A relevant aspect, described in the state of the art, to be considered to ensure the appropriate use of curcuminoids, lies in the fact that they have low aqueous solubility in media with acidic pH and degrade rapidly in media with alkaline pH.

[0005] The low aqueous solubility of curcuminoids hinders the effective administration of the substance, which makes it difficult to develop drugs / supplements to be administered orally, which are easy to absorption and potential improvement of bioavailability. Therefore, it is one of the main objectives of the present invention to develop a composition capable of employing curcuminoids in preparations that present therapeutically adequate concentrations.

[0006] It is of equal importance for the present invention to ensure the adequate release of curcuminoids from liquid, solid, and / or semi-solid pharmaceutical forms, in order to guarantee the bioavailability of the substance of interest.

[0007] Document WO2016065442A1 refers to soluble, stable, anti-inflammatory, proliferative, protective and mucoadhesive pharmaceutical compositions based on curcumin.

[0008] The state of the art document PI0801401-9 discloses the use of Curcuma Longa compounds in hydrogels for human and veterinary consumption.

[0009] Document PI0508750-3 describes a phytocomposition, a pharmaceutical composition and its use, containing curcuma longa.

[0010] However, some of the documents found in the state of the art have significant disadvantages compared to the product claimed here. Among these limitations we can mention solubility / bioavailability.

[0011] Therefore, the present invention aims to overcome the disadvantages presented in the state of the art to provide a composition suitable and compatible with the objectives that are desired to be achieved here. SUMMARY OF THE INVENTION

[0012] Curcuminoids are widely used as a natural antioxidant, seasoning / condiment and for medicinal purposes, presenting robust evidence for their use as anti-inflammatory, antioxidant, antimicrobial, antidiarrheal, antispasmodic, antiemetic, antidepressant, diuretic, neuroprotective, in addition to acting in the prevention of cardiovascular diseases. reducers of acetaldehyde in the bloodstream, among other commercially foreseen uses.

[0013] The production of curcuminoid-based compositions has been widely explored, with the achievement of better solubilization for improved use of curcuminoids being the most relevant search currently. However, the physicochemical particularities of such compounds pose challenges to be overcome for their application in the processing industry.

[0014] The objective of the present invention is to obtain a pharmaceutical composition based on curcuminoids solubilized in an anhydrous base in a concentration between 5 and 20% m / v in relation to the content of the unitary pharmaceutical form, in which the composition presents a bioavailability profile in an acidic medium greater than or equal to 40% of the curcuminoids content, in a period of up to 180 minutes. The curcuminoids, which can be selected from the group consisting of curcumin, demethoxycurcumin, bismethoxycurcumin, among others, including their derivatives or mixtures thereof, and the anhydrous base is composed of low molecular weight polyols and / or high molecular weight polyols, with the low molecular weight polyol having between 200 and 900 Daltons, and the high molecular weight polyol between 1000 and 9000 Daltons.

[0015] Another objective of the present invention is a pharmaceutical composition where the high molecular weight polyol is present in a concentration of up to 95% and containing excipients such as surfactants, vegetable oils, lipophilic vitamins, antioxidants and / or polyphenols, among other lipophilic excipients, in a hydrophilic lipophilic balance (HLB) of 10 to 20, in a concentration of up to 80%.

[0016] Lipophilic excipients can also be vegetable oils, lipophilic vitamins, antioxidants, polyphenols, fatty acids, triglycerides, and their derivatives, among others. Vegetable oils can be corn oil, soybean oil, cottonseed oil, sunflower oil, grape seed oil, among others. Lipophilic vitamins can be vitamins A, D, E, among others. Antioxidants can be flavonoids and anthocyanins, among others.

[0017] The pharmaceutical composition here may be presented in liquid, solid and semi-solid form and be transported in pharmaceutical forms such as gelatin capsules, syrups, vials, solutions, suspensions, gels, creams, ointments, tablets, gelatin capsules, sachets and / or fractionable presentations. BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1 shows the comparison of the release profiles of curcuminoids in acidic medium, from 3 prototypes of the present invention compared to two commercially available products on the market.

[0019] Figure 2 shows the release profiles of the products commercially available on the market and of the prototype of the present invention with the worst release performance. DETAILED DESCRIPTION OF THE INVENTION

[0020] The relevant problem, which lacks an adequate solution in the state of the art, is the viability of a pharmaceutical composition for effective oral administration, with easy absorption and potential improvement in bioavailability. The origin of this problem lies in the fact that curcuminoids have reduced aqueous solubility, which makes the development of drugs / supplements difficult.

[0021] Therefore, it is relevant, and constitutes one of the main objects of the present invention, to develop a pharmaceutical composition based on curcuminoids that present therapeutically adequate concentrations. Similarly, it is important to ensure the adequate release of this substance from liquid, solid and semi-solid pharmaceutical forms, favoring the bioavailability of the substances of interest.

[0022] Due to the complex composition of plant extracts and the special solubility characteristics of curcuminoids, the combination of these agents in compositions requires technological development, which constitutes one of the main aspects of the present invention.

[0023] Therefore, the present invention describes a pharmaceutical composition based on curcuminoids, selected from the group consisting of curcumin, demethoxycurcumin, bismethoxycurcumin, or a mixture thereof, and their derivatives, containing excipients such as surfactants, vegetable oils, lipophilic vitamins, antioxidants and / or polyphenols, among other excipients.

[0024] The composition obtained here can act as an excellent reducer of acetaldehyde in the blood after drinking alcohol, and also as an anti-inflammatory, antioxidant, antimicrobial, antidiarrheal, antispasmodic, antiemetic, antidepressant, diuretic, neuroprotector, in addition to acting in the prevention of cardiovascular diseases.

[0025] In view of the above, it is worth highlighting that the different compositions obtained here, in liquid, semi-solid and solid forms, present dispersions of curcuminoids in their respective matrices / vehicles, allowing a significant increase in release in relation to the products currently available on the market.

[0026] It is worth noting that most commercial products are presented in solid form, which limits the use of the substance of interest, given that curcuminoids belong to Class 2 in the biopharmaceutical classification, indicating low solubility and high permeability. Therefore, the compositions requested here offer the possibility of administering the aforementioned substances through their prior solubilization in their respective matrices / vehicles. EXPERIMENTAL DATA

[0027] The development described below includes the individual evaluation of different excipients, in addition to the exploration of interactions between excipients and their synergistic effect that results in the modulation of response variables, such as intrinsic solubility, viscosity and release profile.

[0028] Among the main parameters evaluated are: a. the proportion of excipients, b. temperature change, c. choice of surfactant system, d. methodology for preparing formulations.

[0029] Thus, solubility tests were conducted with different excipients (solvents, surfactants and oils) in order to select substances that allowed maximum solubility of curcuminoids. In this way, a quantity of curcuminoids greater than their intrinsic solubility was placed in contact with these different study excipients under constant agitation, for a time ranging from 24 to 72 hours, until their solubility equilibrium was reached.

[0030] After equilibrium, an aliquot was removed and subjected to a dosage test using a validated method in high-performance liquid chromatography. The concentrations obtained in the different excipients were compared regarding the soluble mass in each substance evaluated. Among the best results, the low and high molecular weight polyols presented the best results, with solubility values ​​of 140 to 190 mg of curcuminoids per gram of anhydrous base.

[0031] Other important factors that had a positive impact on the solubility tests were the increase in temperature, the modulation of viscosity by the association of two molecular masses of polyols and the definition of the surfactant system. These factors were also evaluated in relation to different methods of preparation of the formulations.

[0032] Thus, the experimental plan led to results that demonstrate a significant increase in the solubility of curcuminoids, almost double, when compared to the performance of the best vehicle alone at room temperature.

[0033] The modulation of the viscosity of the formulation was not mediated by conventional thickening agents, but by the variation of the proportions of polyols of different molecular weights. This modulation was evaluated in relation to the response variables indicated above. As an example, Blends of 95% low molecular weight polyol with 5% high molecular weight polyol obtained a viscosity of 1000 cps. Other proportions evaluated, such as 90:10, 85:15 and 80:20, presented viscosity values ​​of 2300, 4100 and 8500 cps respectively.

[0034] It is worth highlighting that the know-how developed allows the use of viscosity modulation as a planning tool for a range of formulations ranging from liquid to solid state.

[0035] The development generated several prototypes, and those that presented the best performance from the point of view of solubility and physical-chemical stability were sent for evaluation of the release profile in an acidic medium.

[0036] The prototypes were compared with two commercial formulations regarding the release profile in acidic medium. Product A (capsules with an average weight of 0.383 g, containing 50 mg of curcuminoids) and product B (tablet with an average weight of 0.964 g, containing 80 mg of curcuminoids and 14 mg of vitamin C) represent the commercial products.

[0037] Figure 1 shows a comparison of the release profiles of curcuminoids in acidic medium obtained from these two products as well as from three of the prototypes developed. In turn, these prototypes have an average weight of 0.720 g per pharmacotechnical unit containing 50 mg of curcuminoids. The release profiles were performed in a dissolution apparatus, using high-performance liquid chromatography for the quantification of curcuminoids.

[0038] An experimental design was developed with a view to selecting excipients and defining a production method for formulations containing curcuminoids. The different formulations were compared regarding solubility efficiency, curcuminoid release profile in acidic medium and physicochemical stability, hereinafter referred to as response variables.

[0039] Figure 2 presents a better visualization of the profiles of release obtained for prototype II and for products A and B, which correspond to the worst performances. It is worth noting that product B has 60% more curcuminoids compared to all the formulations evaluated.

[0040] The invention is described herein with reference being made to its preferred embodiments. It must, however, be clear that the invention is not limited to these embodiments, and those skilled in the art will immediately realize that changes and substitutions can be adopted without departing from the inventive concept described herein.

Claims

CLAIMS 1. Pharmaceutical composition based on curcuminoids, characterized by comprising curcuminoids solubilized in an anhydrous base in a concentration between 5 and 20% m / v in relation to the content of the unitary pharmaceutical form, in which the composition presents a bioavailability profile in an acidic medium greater than or equal to 40% of the curcuminoid content, in a period of time of up to 180 minutes.

2. Pharmaceutical composition, according to claim 1, characterized in that the curcuminoids are selected from the group consisting of curcumin, demethoxycurcumin, bismethoxycurcumin, among others, including their derivatives.

3. Pharmaceutical composition, according to claim 1, characterized in that the anhydrous base is composed of low molecular weight polyols and / or high molecular weight polyols.

4. Pharmaceutical composition, according to claim 3, characterized in that the low molecular weight polyol has between 200 and 900 Daltons.

5. Pharmaceutical composition, according to claim 3, characterized in that the high molecular weight polyol has between 1000 and 9000 Daltons.

6. Pharmaceutical composition, according to claim 3, characterized in that the high molecular weight polyol may be present in a concentration of up to 95%.

7. Pharmaceutical composition, according to claim 1, characterized by containing excipients such as surfactants, vegetable oils, lipophilic vitamins, antioxidants and / or polyphenols, among other lipophilic excipients.

8. Pharmaceutical composition, according to claim 7, characterized in that the surfactants present a hydrophilic lipophilic balance (HLB) of 10 to 20.

9. Pharmaceutical composition according to claims 7 or 8, characterized in that the surfactants are present in the composition in concentration of up to 80%.

10. Pharmaceutical composition, according to claim 7, characterized in that said excipients are vegetable oils, lipophilic vitamins, antioxidants and / or polyphenols, among other lipophilic excipients.

11. Pharmaceutical composition, according to claim 8, characterized in that the vegetable oils may be corn oil, soybean oil, cottonseed oil, sunflower oil, grape seed oil, among others.

12. Pharmaceutical composition, according to claim 8, characterized in that the lipophilic vitamins may be vitamins A, D, E, among others.

13. Pharmaceutical composition, according to claim 8, characterized in that the antioxidants may be flavonoids and anthocyanins, among others.

14. Pharmaceutical composition, according to claim 8, characterized in that the lipophilic excipients may be fatty acids, triglycerides, and their derivatives.

15. Pharmaceutical composition, according to any of the previous claims, characterized by being presented in liquid, solid and semi-solid form.

16. Pharmaceutical composition, according to any of the preceding claims, characterized by being conveyed in pharmaceutical forms such as gelatin capsules, syrups, vials, solutions, suspensions, gels, creams, ointments, tablets, gelatin capsules, sachets and / or divisible presentations.

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