Patent Description:
<CIT>, discloses a methods for drug delivery, tumor imaging, and oxidative dehydrogenation using hierarchical ZSM-<NUM> complex. The invention is directed to hierarchical aluminosilicates that contain both micro- and meso-pores to methods for loading and delivering poorly soluble antioxidants such as CoQ10 and curcumin to subjects, and to a top-down method for producing hierarchical aluminosilicates. A composition comprising curcumin and a hierarchical aluminosilicate having an SiO<NUM>/Al<NUM>O<NUM> ratio ranging from <NUM> to <NUM>, and an external surface area of <NUM> to <NUM><NUM>/g, a mesopore volume of from <NUM> to <NUM> cc/g, and a bimodal mesopore diameter distribution with a first pore diameter at <NUM> and a second pore diameter at <NUM>. The curcumin is adsorbed onto the hierarchical aluminosilicate in an amorphous form, wherein the hierarchical aluminosilicate has a curcumin adsorption of about <NUM>%, and composition comprises at least <NUM> wt. % of the curcumin based on the total weight of the composition.

Hierarchical zeolites are materials which are characterised by possessing, in addition to micropores with a size of <<NUM> according to IUPAC classification (primary porosity), secondary porosity, which results in the presence of at least one, additional system of pores, mainly in the mesopores range (pores size from <NUM> to <NUM> according to IUPAC classification). These materials demonstrate a range of uses, e.g. in catalysis [<NPL>], adsorption [<NPL>] or in medicine [<NPL>]. These materials may be used as carriers for active substances, enabling therefore their prolonged release and transport to specific tissues and organs [Therapeutic and prophylactic compositions including catalytic biomimetic solids and methods to prepare and use them, <CIT>].

The requirement for prolonged release carriers of active substances is for them to be effective and safe. Moreover in such carriers the dependency between dose and therapeutic effect of the active substance must be well established. Additionally, the effect obtained by its administration should be at least comparable with the effect obtained by using a conventional form of the medicine/supplement, while simultaneously reducing the adverse effects [<NPL>. Therefore, an important element of therapy is delivering the active substance to a specific location in the organism and releasing it for a desired duration. For this purpose, the necessary drug carriers are used, which may be carbon, polymer or porous materials [A. Pérez-Pariente, M. Vallet-Regí, J. Sol-Gel Sci. , <NUM>, <NUM>, <NUM>-<NUM>; <NPL>].

The main advantage of using zeolites as matrices for the application of medicinal substances, with the possibility of their release in a permanent manner result from their unique properties [<NPL>]. These materials are characterised by high biocompatibility and non-toxicity for various types of cells and tissues [<NPL>. <NPL>] and are successfully used as the carriers of various therapeutic substances [<NPL>].

Turmeric is a substance isolated from the root of Indian saffron Curcuma longa, a natural substance in the group of polyphenols. Due to its ability to regulate many important transcription factors, cytokines, protein kinases and adhesive properties of particles, turmeric has found use as anti-inflammatory, anti-oxidant, anti-proliferative, anti-angiogenic and anti-cancer agent. Due to these properties it is currently used in the treatment of various diseases, such as cardiovascular diseases, diabetes, asthma and bronchitis, neurodegenerative diseases, rheumatoid arthritis, psoriasis, AIDS, but is mainly used in the treatment of cancers [<NPL>; <NPL>; <NPL>; <NPL>].

Synergistic activity of zeolites and curcumin extract was described in [Food supplements, drug or medicine product contains a portion of zeolite for tissue detoxification and/pollutant excretion, where the food supplement contains a portion of curcumin extract, <CIT>]. Zeolite (clinoptilolite) due to its porosity demonstrates the ability of ion exchange and of binding toxins. Additionally, the use of zeolite slows down ageing processes, protects against free radicals and helps in reduce inflammation.

Metal-organic frameworks (MOF) type ZIF-<NUM> (topologically isomorphic with zeolites) encapsulated with turmeric have demonstrated activity in cervical cancer [<NPL>].

In the group of Shoba et al. it was indicated that piperine, which is a hepatic and intestinal glucuronidation inhibitor, impacts the bioavailability of turmeric in healthy persons. After administration of <NUM> of turmeric with <NUM> of piperine a positive effect was observed, that is piperine has increased the bioavailability of turmeric by as many as <NUM>%. Based on obtained studies it was demonstrated that piperine increases the serum concentration, absorption and bioavailability of turmeric in humans, without adverse effects [<NPL>].

Moreover, turmeric is also a potential active substance used in photodynamic therapies. The American National Institutes of Health (NIH) agency defines photodynamic therapies as one of the methods used in the treatment of cancer, through the use of active substances, called "photosensitizers" and of radiation with precisely determined energy. This method is an alternative to traditional cancer treatment methods, that is, radio-, chemo- and hormone therapy. It may be also used as complementary therapy [http://www. gov/cancertopics/factsheet/Therapy/photodynamic - downloaded on <NUM>. Therefore, the idea of the invention is to create a photodynamic method of prolonged release of turmeric with anti-cancer properties from hierarchical zeolites.

The goal of the invention is to create a method of applying turmeric on hierarchical zeolites characterised by secondary porosity with size in the range of <NUM>-<NUM>, which were synthesised on the basis of faujasite and ionic (e.g. hexadecyltrimethylammonium bromide) and non-ionic structure-forming agents (e.g. polyethylene glycol octadecyl ether or Pluronic F127), which enables obtaining hierarchical zeolite with an additional system of pores with applied turmeric for photodynamic, delayed release from the hierarchic zeolite caused by visible light. This invention concerns pharmaceutical pre-formulation (medicinal product) appropriate for the creation of solid galenic forms, e.g. for tabletting.

The essence of the invention is a method of applying turmeric on hierarchical zeolites possessing secondary porosity, pores in the range <NUM>-<NUM>, synthesised on the basis of faujasite and either non-ionic structure forming agents selected from the group of polyethylene glycol octadecyl ether or Pluronic F127 or the ionic structure-forming agent hexadecyltrimethylammonium bromide in the presence or absence of piperine, the following is added:.

The material obtained in this manner is subjected to photodynamic release of turmeric.

A method according to the invention is a method of photodynamic release of turmeric from hierarchical zeolite, consisting of:.

It is advantageous when the penetration promoter is glycerine or ethyl alcohol or Tween <NUM>.

The method according to the invention demonstrates a number of advantages, in particular, turmeric may be processed up to a high degree of loading. The method according to the invention uses materials synthesised in a simpler manner than the MOF material. An undesirable effect of caking of the carrier is not observed, and thus using the method according to the invention enables simple manufacturing of tablets for therapeutic (pharmaceutical) purposes. The method according to the invention ensures a higher degree of release of active substance in conditions of expected working temperatures, and the release process is caused by visible light. Due to the low temperature at which the process is conducted, the impact on temperature on the activity of the active substance is very low in case of the method according to the invention.

Unexpectedly, it turned out that turmeric may be in a simple manner applied to a solid carrier with a uniform distribution of pores with the use of created method of application. It turned out that the hierarchical zeolite on the basis of faujasite and either non-ionic structure-forming agents or ionic structure-forming agents may be obtained using a known practical chemistry of material [<NPL>; <NPL>, patent application: A. Feliczak-Guzik, I. Musielak P. <NUM> [WIPO ST <NUM>/C PL433556]. According to the invention to a mixture containing hierarchical zeolite characterised by secondary porosity with pore size in the range of <NUM>-<NUM>, obtained on the basis of commercial faujasite type zeolite and ionic structure-forming agent e.g. hexadecyltrimethylammonium bromide or non-ionic structure forming agent e.g. polyethylene glycol octadecyl ether or Pluronic F127 a solvent is added in an amount of <NUM>-<NUM>% w/w in relation to hierarchical zeolite, <NUM>-<NUM>% w/w of turmeric in relation to hierarchical zeolite and <NUM>-<NUM>% w/w of piperine in relation to hierarchical zeolite at a temperature of <NUM>-<NUM>. The entire mixture is transferred to a magnetic stirrer and stirred for <NUM>-<NUM> in a temperature of <NUM>-<NUM>, and then the product is separated from the mixture in a known manner. This pharmaceutical pre-formulation may be conveniently galenically processed, in particular by tabletting them into solid pharmaceutical preparations (medicinal products). In the method according to the invention ethyl alcohol, acetone, n-butanol and a mixture of acetone with the aforementioned solvents were used as a solvent.

Additionally it turned out that the hierarchical zeolite with the applied active substance (turmeric) may be subjected to photodynamic release of the active substance. According to the invention, a phosphate buffer is added to a mixture containing hierarchical zeolite characterised by secondary porosity with pore sizes in the range of <NUM> to <NUM>, obtained on the basis of commercial faujasite type zeolite and ionic structure-forming agent, e.g. hexadecyltrimethylammonium bromide along with applied turmeric (from <NUM> to <NUM>% w/w in relation to hierarchical zeolite), with the amount of buffer being <NUM>:<NUM>; <NUM>:<NUM> and <NUM>:<NUM> in weight by weight relation to hierarchical zeolite with applied turmeric, advantageously <NUM>:<NUM> with a pH ranging from <NUM> to <NUM>, from <NUM> to <NUM>% w/w in relation to glycerine at a temperature from <NUM> to <NUM>. The entire mixture is transferred to a magnetic stirrer and stirred for <NUM>-<NUM> in a temperature of <NUM>-<NUM> with the use of UV-VIS radiation and without access of light.

The product obtained using the method according to the invention is characterised by a high turmeric load, which was presented in Table <NUM> and a high degree of release of turmeric, which was presented in Table <NUM>.

The invention is illustrated by the examples below:.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (hexadecyltrimethylammonium bromide) a <NUM>% w/w of turmeric was added and <NUM>% w/w of acetone was added in relation to hierarchical zeolite. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

Procedure was the same as in example <NUM>, changing the stirring temperature to <NUM>.

Procedure was the same as in example <NUM>, changing the stirring time to <NUM>.

Procedure was the same as in example <NUM>, changing the amount of acetone to <NUM>% w/w in relation to hierarchical zeolite.

Procedure was the same as in example <NUM>, changing the type of solvent to ethyl alcohol, <NUM>% w/w in relation to hierarchical zeolite.

Procedure was the same as in example <NUM>, changing type of solvent to n-butanol <NUM>% w/w in relation to hierarchical zeolite.

Procedure was the same as in example <NUM>, changing the type of solvent to n-butanol <NUM>% w/w in relation to hierarchical zeolite.

Procedure was the same as in example <NUM>, changing the amount of turmeric to <NUM>% w/w in relation to hierarchical zeolite.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of non-ionic structure-forming agent (polyethylene glycol octadecyl ether) a <NUM>% w/w in relation to hierarchical zeolite of turmeric was added and <NUM>% w/w in relation to hierarchical zeolite of acetone was added. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of non-ionic structure-forming agent (Pluronic F127) a <NUM>% w/w in relation to hierarchical zeolite of turmeric was added and <NUM>% w/w in relation to hierarchical zeolite of acetone was added. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (hexadecyltrimethylammonium bromide) a <NUM>% w/w in relation to hierarchical zeolite of turmeric and <NUM>% w/w in relation to hierarchical zeolite of piperine was added and <NUM>% w/w in relation to hierarchical zeolite of acetone was added. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

Procedure was the same as in example <NUM>, changing the amount of piperine to <NUM>% w/w in relation to hierarchical zeolite.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of non-ionic structure-forming agent (polyethylene glycol octadecyl ether) a <NUM>% w/w in relation to hierarchical zeolite of turmeric and <NUM>% w/w in relation to hierarchical zeolite of piperine was added and <NUM>% w/w in relation to hierarchical zeolite of acetone was added. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of non-ionic structure-forming agent (Pluronic F127) a <NUM>% w/w in relation to hierarchical zeolite of turmeric and <NUM>% w/w in relation to hierarchical zeolite of piperine was added and <NUM>% w/w in relation to hierarchical zeolite of acetone was added. The entire mixture was stirred for <NUM> in a temperature of <NUM> in a magnetic stirrer. The obtained product was filtered and washed three times with a water-ethanol mixture in a <NUM>:<NUM> relationship by volume and air dried for <NUM>. The degree of turmeric loading was calculated using the formula: <MAT>.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (e.g. hexadecyltrimethylammonium bromide) with applied turmeric in an amount of <NUM>% w/w in relation to hierarchical zeolite a phosphate buffer with a pH of <NUM> was added in an amount of <NUM>:<NUM> by weight in relation to hierarchical zeolite with the applied turmeric. The turmeric release process was conducted for <NUM> at a temperature of <NUM> on a magnetic stirrer with the use of visible light (radiation wavelength range of <NUM>-<NUM>).

The degree of turmeric release was established with the use of UV-Vis spectrophotometer, by measuring the adsorption of turmeric in the buffer mixture. It was calculated on the basis of the following formula: <MAT>.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (e.g. hexadecyltrimethylammonium bromide) with applied turmeric in an amount of <NUM>% w/w in relation to hierarchical zeolite a phosphate buffer with a pH of <NUM> was added in an amount of <NUM>:<NUM> by weight in relation to hierarchical zeolite with the applied turmeric and <NUM>% w/w in relation to phosphate buffer of penetration promoter - glycerine was added. The turmeric release process was conducted for <NUM> at a temperature of <NUM> on a magnetic stirrer with the use of visible light (radiation wavelength range of <NUM>-<NUM>).

The degree of turmeric release was established with the use of UV-Vis spectrophotometer, by measuring the adsorption of turmeric in the buffer mixture with the penetration promoter. It was calculated on the basis of the following formula: <MAT>.

Procedure was the same as in example <NUM>, adding phosphate buffer with a pH of <NUM> in an amount of <NUM>:<NUM> by weight in relation to hierarchical zeolite with the applied turmeric.

Procedure was the same as in example <NUM>, adding glycerine <NUM>% w/w in relation to phosphate buffer.

Procedure was the same as in example <NUM>, changing the type of penetration promoter to ethyl alcohol, <NUM>% w/w in relation to phosphate buffer.

Procedure was the same as in example <NUM>, adding ethyl alcohol <NUM>% w/w in relation to phosphate buffer.

Procedure was the same as in example <NUM>, changing the type of penetration promoter to Tween <NUM>, <NUM>% w/w in relation to phosphate buffer.

Procedure was the same as in example <NUM>, adding Tween <NUM><NUM>% w/w in relation to phosphate buffer.

Procedure was the same as in example <NUM>, changing the turmeric release process time to <NUM>.

Procedure was the same as in example <NUM>, changing the turmeric release process temperature to <NUM>.

Procedure was the same as in example <NUM>, changing the wavelength range of radiation to <NUM> to <NUM>.

Procedure was the same as in example <NUM>, conducting turmeric release process without access of light.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (e.g. hexadecyltrimethylammonium bromide) with applied turmeric in an amount of <NUM>% w/w in relation to hierarchical zeolite a phosphate buffer with a pH of <NUM> was added in an amount of <NUM>:<NUM> by weight in relation to hierarchical zeolite with the applied turmeric. The turmeric release process was conducted for <NUM> at a temperature of <NUM> on a magnetic stirrer with the use of visible light (radiation wavelength range of <NUM>-<NUM>). The degree of turmeric release was established with the use of UV-Vis spectrophotometer, by measuring the adsorption of turmeric in the buffer mixture.

To hierarchical zeolite characterised by secondary porosity with the pore sizes in the range of <NUM>-<NUM>, obtained on the basis of ionic structure-forming agent (e.g. hexadecyltrimethylammonium bromide) with applied turmeric in an amount of <NUM>% w/w in relation to hierarchical zeolite a phosphate buffer with a pH of <NUM> was added in an amount of <NUM>:<NUM> by weight in relation to hierarchical zeolite with the applied turmeric and <NUM>% w/w in relation to phosphate buffer of penetration promoter - glycerine was added. The turmeric release process was conducted for <NUM> at a temperature of <NUM> on a magnetic stirrer with the use of visible light (radiation wavelength range of <NUM>-<NUM>). The degree of turmeric release was established with the use of UV-Vis spectrophotometer, by measuring the adsorption of turmeric in the buffer mixture with the penetration promoter.

Procedure was the same as in example <NUM>, conducting the turmeric release process without access of light.

According to the examples <NUM>-<NUM> a high degree of turmeric loading was obtained, as demonstrated in table <NUM>.

According to the examples <NUM>-<NUM> a high degree of turmeric release was obtained, as demonstrated in table <NUM>.

Claim 1:
A method of applying turmeric on hierarchical zeolites, characterized in that to hierarchical zeolite possessing secondary porosity, pores in the range <NUM>-<NUM>, synthesised on the basis of faujasite and either non-ionic structure forming agents selected from the group of polyethylene glycol octadecyl ether or Pluronic F127 or the ionic structure-forming agent hexadecyltrimethylammonium bromide in the presence or absence of piperine, the following is added:
- a solvent, advantageously acetone in an amount of <NUM>-<NUM>% w/w, advantageously <NUM>% w/w in relation to hierarchical zeolite,
- <NUM>-<NUM>% w/w of turmeric, advantageously <NUM>% w/w of turmeric in relation to hierarchical zeolite, and
- <NUM>-<NUM>% w/w of piperine, advantageously <NUM>% w/w of piperine in relation to hierarchical zeolite,
whereas the entire process of mixing is conducted for <NUM>-<NUM> advantageously <NUM> in a temperature of <NUM>-<NUM> advantageously in <NUM>, and
- washing the obtained product with a water-ethanol solution in a volumetric ration of <NUM>:<NUM> and
- drying afterwards.