ITFE20060032A1 - PROCEDURE FOR THE PREPARATION OF OZONIZED TERPENES, TERPENOIDS AND ESSENTIAL OILS AND APPLICATION OF THESE PRODUCTS WITH PHARMACOLOGICAL AND COSMETIC PURPOSES - Google Patents

Description

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DESCRIPTION of the industrial invention entitled:

<*> Process for the preparation of terpenes, terpenes / cf / and essential oils 3 ozonated and application of these products with pharmacological and cosmetic purposes

filed on -6 NOV2006 at the Provincial Office of Industry, Commerce and Crafts of Ferrara under the application number

on behalf of ISTITUTO F ITOFARMACE UTICO EUGANEO S R L.

TORRESfN Flavio

VALERI Gualtiero

designated inventors: TORRESIN Flavio

VALERI Gualtiero

The present invention relates to a preparation process

of terpenes, terpenoids and ozonated essential oils and application of these

products with pharmacological and cosmetic purposes.

Ozone is an allotropic form of oxygen, formed by molecules

triatomic rather than diatomic like ordinary oxygen.

Particularly important reaction with organic substances is

that of addition to double bonds, with the formation of cylic groups - molozonides and ozonides (also defined in the literature as trioxolans).

In the literature there is also mention of the formation of hydroperoxide groups

and diperoxide.

Ozonides break down to form two aldehydes, as is known from chemistry

organic analytics, if subjected to the action of water and a reducing agent; or they can break apart to form an aldehyde and a carboxylic acid. It is as well

-VX it can be understood how the decomposition kinetics of ozonated derivatives is accelerated by the presence of water.

Although several studies have been done on the medical application of free ozone and on the pharmacological applications of ozonated vegetable oils,

never before have the following two electrochemical, or, if you like, biophysical aspects been observed:

1. Ozonated compounds are characterized by electrochemical potentials

high half-rows when they come into contact with the tissues, resulting in logically non-negligible potentials and currents

at the cellular level.

2. The theory of asepsis must be reinterpreted, at least partially, according to more modern chemical-physical schemes <'> each type of microorganism has <its own field of life which. reported on a Cartesian diagram

four-axis, they become the electrochemical potential, the activity of

hydrogen ions, osmotic voltage, temperature, Each microorganism has its own precise vital domain in this four-dimensional space, outside of which it enters into a state of stasis or dies. Yup

recalls how Luis Pasteur had already observed the importance of

pH factor for fermentations, and temperature factor for anthrax development in hens. There are also known studies on the growth of coionias of marine organisms (eg Molgula) on the basis of salt concentration and temperature. Always Pasteur already, he had

noted the differences in the development of yeast and gold colonies

metabolism in an aerobic or anaerobic environment, indirectly. ^

S.

that is, based on the electrochemical potential. 3⁄4 S <■> 3⁄4 ·

'N From these considerations we <1> could extend the particular case of the

role of electrochemical potentials in the organism to a general model fi¬

based on the theory of chemical potential, which would open a third

branch of physiology: after the physical and mechanical study of phenomena and the physiological one, a study based on a physioenergetic approach. where there is not

we limit ourselves to considering the biochemical reactions involved, but we consider them

the termod aspect in friend.

These premises lead us to formulate a more general interpretation of the pharmacological action of ozone derivatives, that is the electrochemical / thermochemical interpretation, that is, in terms of chemical potentials rather than considering vertically the chemical-organic aspects.

On this interpretative basis, it is deduced that the ozonides act by restoring the ionic electric potential of the membrane of the cells of the altered tissues,

The ozonides also tend to decompose, forming free radicals. They

they are able to recombine with the free radicals generated by! f metabolic activity eliminating you "This may appear Unusual, as an etymological faction

of the roots; free is often associated with reducing agents such as ascorbic acid;

however sometimes oxidizing species can act as reducing agents towards oxidants

stronger (depends on the respective redox potentials: a species can

therefore being a reductant to a stronger oxidant, but an oxidant

towards a more energetic reducing agent), so we have the case that hydrogen peroxide (hydrogen peroxide) is used as a reducing agent in certain reactions

of analytical chemistry.

These considerations give a more complete interpretation of the breadth of the pharmacological action spectrum of these compounds.

the peroxide number gives us a measure of the electrochemical potential

that the obtained compound is capable of generating, while its molecular weight

and affinity with the tissues gives us a measure of its diffusion speed through the tissues themselves, therefore the ability to reach, by diffusion ap

point. more or less deep area

Terpenes are unsaturated hydrocarbons (considered multiples of the isoprenoid unit.

lipid class), which, as such, have the ability to add ozone to the double bond by stopping the corresponding ozonide. it was found that such

compounds, under normal environmental conditions, in an anhydrous and reducing agent-free environment, are reasonably stable to survive for long periods. Such # X ozonides have the ability to behave as liposoluble oxidants and to develop

free oxygen. Terpenoids are compounds in which a hydrogen atom of

terpenes is substituted with a functional group, and for deirozonation purposes

they have a behavior similar to that of terpenes. For deirozonation purposes

5 mcnoterpenes are most interesting due to their low molecular weight and therefore to their greater diffusion capacity in the tissues: but,

next to these, they fall into the class of terpenes sesquiterpenes, diterpenes,

triterpenes, tetraterpenes, polyterpenes. We can still consider interesting

for the purposes of! ozonation of sesquiterpenes and diterpenes, by molecular weight

content.

Terpenes and te <r> penoids are often contained in significant quantities in oils

essential, which besides these, also contain other compostilo grade

form ozonides following ozonation

Ss also assumes that the time stability of these ozonides is correlated

to the length of the aliphatic chain of which the original double bond made

3 part, even if the oxidizing power gradually becomes less intense.

The pharmacological activity of various orga-P substances has been known for several years

nare ozonized.

Agi; - the following applications in various therapeutic fields of terpenes and ozonated essential oils are known

The first known experiment is that of William D. Meel in 1902, a patent issued in 1909, which ozonates the terpenes and specifically the essential eucalyptus oil, and the evolving peroxide fumes are used for therapeutic inhalations (US 925 590).

The second note is the ozonation of terpenes, in particular if pine "and kinamic phaldehyde, by William John Knox in 1911, a patent issued in 1913 again to produce terpene peroxide vapors for therapeutic purposes; Knox recognizes the highly germicidal ration of the compound formed by ozonation of pinene as well as its ability to destroy toxic substances in the blood once absorbed by inhalation (US 1.081617),

The third note is the ozonation of various compounds / containing double bonds discìOti in different substances by Austin G. Habib in 1959, patent issued in 1963, to obtain the respective ozonides (but not for therapeutic purposes), the conditions operating at a temperature between t -50 * C and i ÷ 40 <i> C and a pressure between 1 Atm and 15 Atm (US 3.083.209).

The fourth note is the Pòzonization of liquid hydrocarbons dissolved in solvents by Joseph T. Horeczy and Robert H. Perry in 1961, patent issued in 1964, for obtaining ozonolysis products (not yet for therapeutic purposes); here too the production of a peroxide mist is observed; the operating conditions are a concentration of the olefin to be ozonated between Γ1 and 40%, a concentration of ozone in the gas between Γ1 and 10%. in a temperature range between -100 <C> C and 30 ° C (US 3 145,217).

The fifth note is the ozonation of terpenes by <'> Stephen Herman in 1989, patent reissued in 1991; t products are used to treat viral infections and immune disorders, administering them for various

routes (prepared for intravenous, intramuscular, intraperitoneal, or

Inhalations, or for ophthalmic use, or rectally, or vaginally, or by way,

oral). (US 4,983 637).

The sixth note is the ozonation of non-terpenid unsaturated hydrocarbons in

apofaric solvents again by Stephen Herman in February 1994, patent issued oe; November 1394, with the aim of obtaining the respective ozonides and dipeross of; the operating conditions are a concentration of the product to be treated comprised between 0.01 and 1 M and a variable temperature between

-150 ° C and 35 <e> G; the preparations obtained starting from these compounds are administered by various routes (intravenous, intramuscular, intra perito neai,

or rectally, or vaginally or topically, or sublingually),

for the purpose of treating various infections by bacteria, protozoan viruses, fungi), herpes simplex, herpes genitalis. chickenpox, vaginal infections, fungal infections

of the skin and nails, athlete's foot, onieomycosis, warts, moles

condoms both to hinder the spread of venereal diseases and as

spermicide, for the treatment of sunburn burns, dermatitis, psoriasis,

seborrheic dermatitis. punctures of inserted tumors, rheumatoid arthritis, osteoarthritis,

polyarthritis, chronic fatigue syndrome, lupus erythematosus, acne, pharyngitis, hemorrhoids fUS 5.364 879).

It is also known (ozonation of essential oils in aqueous emulsion

to obtain the so-called activated or peroxidated essential oils, the cut absorption

percutaneous is described as much greater than essential oils as they are. Yes Λ.

notes, in this regard, that rather than sticking to ozonides or peroxides, there is the decomposition and oxidation of unsaturated compounds with the formation of carboxylic acids, so there is reason to doubt the efficacy of this process for the purpose of obtaining substances pharmacologically active.

You know. furthermore, that in nature there are essential oils with a prevalent content of peroxides (ascaridol in Chenopodium).

THE! proceeding from no? proposed consists in treating essential terpenes, terpenoldi, or gn ofr essential to aito content of these in mixture with fixed oils, petroleum jelly or polar solvents with a current of ozone, in the form of a mixture of ozone / oxygen , or ozone / air, or ozone / oxygen or / nitrogen, or again ozone diluted in one or more inert gases. An essential characteristic is that the solvents used do not react, or react moderately, with the ozone, It is also essential that these solvents 3⁄4-are compatible with the use for which the ozonation product is intended,

By way of non-limiting example, vaseline oil, vegetable oils extracted from plants or seeds (which can be olive oil, or essential oils Jojoba or any other liquid oil at room temperature or close to it: ', l <'> oleic acid,

IB: terpenes, terpenoids or essential oils were not so diluted, would the aeration be excessively violent and in any case so? mixtures have proved to be excellent for conveying the ozonides obtained in the uses for which they are intended,

Practically ss is found to be convenient for the purposes of ozonation a solution of! terpene, terpenoid or essential oil up to 20% in a fixed oil, in vaseline oil or in oleic acid,

and this concentration is also shown to be suitable for subsequent use;

pharmacological and cosmetic of the product obtained.

VX

Ozonating essential oils with a high content of terpenes (for example

the essential oil of rudder, the essential oil of sweet orange, the essence of turpentine) dissolved in vaseline oil, the precipitation of a substance similar to an oleoresin of yellow-gold color, insoluble in water and solu .sN-bile in carbon tetrachloride, and the exact chemical nature of which has not yet been determined. \ r

In addition, in the pozonation of terpenes or essential oils at high

content In terpenes it was noted the development of the characteristic white fumes

dense already observed by William John Knox in the 1911 patent, and,

later and in more detail, by Joseph T. Horeczy and Robert H.

Perry in the 1961 brief, identified as peroxides of terpenes.

In the case of the use of neirozonization of a mixture between a terpene,

a terpenoid or an essential oil and - for example - oleic acid or oil of

olive, there is a simultaneous ozonation of the terpenes present and of the double bonds of the unsaturated fatty acids present, and these compounds show in the ap ^

therapeutic application a synergistic action, having molecular weights and solubilitsC ^^? different from each other, for which different rates of absorption by the tissues,

for example in topical use.

In previous patents, and exactly those cited filed by Stephen Herman, the medium in which the terpenes are dispersed is not given much importance.

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Neither importance nor precise relevance is given to the alkene of which the respective ozonide is to be obtained for a therapeutic use. It has been said of the relief that the mixture has initiated for ozonation in order to obtain a mixture of ozonides and f> Zi ficative therapeutically. But the aspect of deriving the ozonides is also relevant

N 'from substances of biological origin, since, although the ozonides that are formed are not ordinarily present in nature, the products that are formed as a result of their action on the organism are aldehydes and acids that are organic or ordinarily present in biological systems , or structurally analogous to them, so it is reasonably possible to think that they are -S <'> which can be processed by human or animal organisms in general. It is therefore important to use terpenes or essential oils for the purpose of ozonation, and as solvents

_Q for them liquid oils or waxes of vegetable or animal origin, or substances obtained from these always liquid at room temperature or close to this, as in the case of oleic acid. Given the ordinary presence in vegetable or animal organisms, specifically combined with fats, of hydrocarbons, also melted of pharmaceutical-type mineral oils (for example vaseline folio), it can be considered in line with what is specified above.

The two most important advantages of terpenes, terpenoids or ozonated essential oils compared to ozonated vegetable or animal oils are the following:

- a molecular weight generally equal to approximately one fifth or one sixth, therefore greater ease of diffusion through the tissues:

- higher specific content of active oxygen, or higher ratio of active oxygen / moles of substance.

Furthermore, by treating terpenes, terpenoids or essential oils in the anhydrous anhydrous state, the ozonides formed remain stable due to the impossibility of

hydrolyze by the action of water.

The action of ozone on the solution of terpenes, terpenoids or essential oils can last for a shorter or longer time, and the degree of ozonation obtained can be evaluated on the basis of known parameters, including, particularly useful, on the level of industrial production, is the density

On the operational level, a stream of ozonated gas (for example a mixture of ozone / oxygen or ozone / anaì with the solution of terpenes, terpenoids or essential oils was put into contact, using a suitable contact device (by way of example and not limiting a gorgogf lator of the type of a DrescheL bottle a column with plates or a column with bodies J = 5 of filling) and keeping! at a temperature around 2CTC (and in any case 3⁄4: not more than 30 <*> 0 ), since the reaction is exothermic. At higher temperatures, in fact, the ozone decomposes to form nascent oxygen, which favors the formation of epoxides (potentially toxic and irritating, the concentration of which in the product, therefore, must be limited to Furthermore, at high temperatures, the decomposition itself of the ozonides of the above compounds is favored! a the viscosity of the solution, especially if in oils, and the contact between gas and liquid becomes less effective; a temperature of! 0 ÷ f5 <"> C where the viscosity of the solvent used permits it can still be usefully used, and this reduces the losses of the terpene component due to volatility. The degree of ozonation was detected by checking the density, since this increases

with the degree of ozonation, stopping the reaction once the desired density is reached,

It is thus possible to reach the desired degree of ozonation of the terpenic compounds, also to their complete transformation into the corresponding ozonides.

Regarding the terpenes and terpenoids and which can be used, limonene, Ρα-pinene, β-pinene, terpinene are mentioned as an example and not a limitation. myrcene, geraniaie, neral, terpineol.

Regarding the essential oils that can be used, the essential oil of lemon, the essential oil of \ 3⁄4: orange, the essence of turpentine, the essential oil of hyssop are cited as an example and not limiting , the essential oil of nutmeg, the essential oil of rosemary, the essential oil of frankincense.

Regarding the solvents for terpenes and essential oils that can be used, we cite as an example and not a limitation, Vaseline polio, oleic acid, Jojoba polio, olive polio.

Note that essential oils still contain compounds such as, ad; for example, eugenol, anethole or cinammic aldehyde which ozonated develop- / V / no pharmacological activities similar to that of terpenes or terpenoids

you.

The products obtained can be used as they are, or formulated in the form of ointments and ointments, or lotions, which in any case exclude water in their composition.

It has been noted that it is also possible to improve the pharmacological effects of the products obtained by mixing them, in the appropriate ways, with extracts of medicinal plants, essential oils or other active ingredients not likely to be

data from the ozonides formed or to decompose them.

On the basis of the theoretical and practical studies carried out, ì terpenes Λ ozonated and conveyed as mentioned, are indicated as having a pharmacological activity

in the following cases, in addition to those already known from the state of the art exposed:

1, Rheumatic affections

2. Osteoarthritis

3. Painkiller

4. Swelling from slowed veno-lymphatic circulation

5, Treatment of mite diseases

6. Vasodilator

Even in cases of pathologies already mentioned in the state of the art described above, the ozonation products obtained as mentioned show a more complete, prompt and effective action.

Another application in the cosmetic field of these products is in the formulation of personal deodorants, which do not require the presence of aluminum flavors or antiperspirant products; The bactericidal faction of the ozonated terpenes, in fact, inhibits bacterial growth which leads to the formation of unpleasant odors, and also the chemical species characterized by unpleasant odors tend to be oxidized and destroyed by the ozonated terpenes and terpenes.

In practical application, both for preparatory and therapeutic purposes, solutions of terpenes, terpenoids or essential oils to the extent of a maximum of 20% in natural fixed oils (for example olive oil), liquid natural waxes (for example Jojoba oil for example), or liquid substances deriving from them at room temperature or close to it (for example oleic acid), show ease of handling and excellent therapeutic efficacy. In this way, in the ozonation operation it is not necessary to go down to particularly low temperatures to conduct the reaction so as to have a stable and <"> therapeutically effective product, nor is v <r> the danger that the temperature saiga in ma¬

uncontrollable, and, should the temperature rise excessively due to too rapid ozone supply or insufficient cooling, the reagent mixture remains perfectly stable.

For purely illustrative and non-limiting purposes, some cases of greatest interest of patients treated with \ 3⁄4 solutions of essential oils in oleic acid, ozonated and formulated in oils, ointments are reported below. ointments or oleogels.

Example Ί

The case concerns a 92-year-old patient, suffering from deforming arthritis of the wrists for ten years, after a few days of treatment the pain disappeared.

Example 2 VJ The case in question concerned a 54-year-old patient, suffering from lumbar arthrosis, who had been in pain for twenty days, after two days of application the pain disappeared.

Example 3

the case in question concerned a 62-year-old patient, suffering from arthrosis of the shoulder, with pains that have persisted for 2 years, since the first applications, is

a decrease was noted and, with the continuation of the applications,

disappearance of pain.

Example 4

34-year-old female patient, with symptoms of initial cervical arthrosis, with intermittent pain, since the first applications she has noticed the disappearance of the pain.

Example 5

A 76-year-old female patient, with a traumatic event in her right knee with very evident swelling, noted an attenuation and disappearance of pain after application of the product.

Example 6

48-year-old male patient with severe ankle sprain, from the very first applications, noted an evident relief from pain, and, afterwards. / po a week of application, while maintaining normal walking - ^? / '<'> ne. the pain disappeared completely to the extent that the normal continuation of the work activity was allowed.

Example 7

53-year-old female patient with L5S1 disc herniation in the acute phase, after ten days of treatment the pain gradually disappeared.

Example 8

74-year-old female patient suffering from arthritis in the hands and feet, intense pain in the knees and shoulders, the patient applied the

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produced with a light massage on the affected parts; after three days of application she was able to start moving her hands again

previously blocked by arthritis, after six weeks of application

he could again write and manipulate delicate or heavy objects, while pain in the shoulders, feet, knees was almost gone.

Claims (1)

REVIEWS 1. Process for the preparation of terpenes, terpenoids and essential oils ozonated by dissolution of these in a suitable non-polar solvent / inert or less reactive than Utozono, subsequent ozonation and application of this product for pharmacological and cosmetic purposes. VK 2. Process according to claim 1, for applying the product to the external treatment of rheumatic diseases. 3. Process according to claim 1, for applying the product to the treatment of arthrosis externally. 4. Method according to claim 1: for the application of product Cz as an external pain reliever, 5. Process according to claim 1, for the application of the product to the external treatment of swelling caused by slowed veno-Ijnfatico circulation 6. Process according to claim 1, for applying the product to the external treatment of mite diseases. 7. Process according to claim 1, for applying the product as an external vasodilator. S. Process according to claim 1, for applying the product / as a personal deodorant. S, Process according to claim 1, obtaining the terpenes, terpenoids and ozonated essential oils by contact between these dissolved in a suitable non-polar solvent inert or less reactive with respect to ozone with a mixture of ozone / oxygen, at a temperature between 10 ° C and 2G <C> C and co however not higher than 3Q <Q> C. 10. Process according to claim 1, obtaining the terpenes, terpenoids and ozonated essential oils by contact between these dissolved in an op -% ^ a non-polar solvent inert or less reactive than ozone with a ozone / air mixture, at a temperature between 10 ° C and 2G ° C and in any case not higher than 30 <e> C. 1 1. Process according to claim 1, obtaining the terpenes, terpenoids and essential oils ozonated by contact between them dissolved in a suitable non-polar solvent inert or less reactive with respect to ozone with a ozone / Inert gas mixture, at a temperature between 10 ° C and 2Q <C> C and in any case not higher than 3Q ° C. 12. Process according to claim 1, obtaining the terpenes, terpenoids and ozonated essential oils by contact between these discioites in a suitable non-polar solvent inert or less reactive with respect to ozone with a ozone / oxygen / nitrogen mixture, at a temperature between 10 ° C and 20 ° C N and in any case not higher than 30 ° C. 13. Process according to claim 1, obtaining the terpenes, terpenoids and ozonated essential oils by contact between these discioites in an oil fixed vegetable with a gaseous mixture containing ozone, at a temperature between 10 ° C and 2Q ° C and in any case not higher than 30 <'2> C, 14. Process according to claim 1. obtaining the terpenes, terpenoids and ozonated essential oils by contact between these dissolves in an oil animal with a gaseous mixture containing ozone, at a temperature between 10 ° C and 20 <*> C and in any case not higher than 30 <C> C. 15. Process according to claim 1, obtaining the terpenes, terpenoids and essential oils ozonated by contact between these discioites in vaseline oil with a gaseous mixture containing ozone, at a temperature between 1G ° C and 20 ° C and in any case not higher than 30 ° C. 16. Process according to claim 1, obtaining the terpenes, terpenoids and essential oils ozonated by contact between these discioites in oleic acid with a gaseous mixture containing ozone, at a temperature between 10 ° C and 20 ° C and in any case not above 30 ° C. 17. Process according to claim 1, obtaining the terpenes, terpenoids and essential oils ozonated by contact between these discioites in a liquid wax with a gaseous mixture containing ozone, at a temperature between 10 ° C and 20 ° C and in any case not higher than 30 ° C. 18. Process according to claim 1, obtaining the terpenes, terpenoids and ozonated essential oils by contact between these dissolved in Jojoba oil with a gaseous mixture containing ozone, at a temperature between 10 <G> C and 20 ° C and in any case not higher than 30 ° C. 19. Process according to claim 1, obtaining the terpenes, terpenoids and essential oils ozonated by contact between these discioites in olive oil with a gaseous mixture containing ozone, at a temperature between 1G <e> G and ì 20 <Q > C and in any case not higher than 30 ° C. for the Euganeo S.r Fiiofarmaceutico Institute, L the legal representative