EP0836478A1

EP0836478A1 - Terpene-based pharmaceutical product

Info

Publication number: EP0836478A1
Application number: EP96922041A
Authority: EP
Inventors: Matteo Bevilacqua; Carlo Alberto Zaccagna
Original assignee: Bevilacqua Maria
Current assignee: Bevilacqua Maria
Priority date: 1995-07-03
Filing date: 1996-06-27
Publication date: 1998-04-22
Also published as: WO1997002040A1; AU6305896A

Abstract

A pharmaceutical product that is the combination of one or more terpene-containing substances with propolis, preferably consisting in the combination of natural olibanum or its derivatives with propolis.

Description

TERPENE-BASED PHARMACEUTICAL PRODUCT Technical field

The present invention relates to a terpene-based pharmaceutical product. Background Art

Olibanum is a substance commonly known as incense and available in nature in several varieties. It is a hardened gum-resin that flows out from cuts in the bark of various species of plants that are present in the regions between the equator and the tropics, particularly of India, Somalia, Eritrea, Saudi Arabia, and Guinea. They are mainly small plants, usually shrubs, or fruticeε, which grow sparsely in the savanna on dry gypseous calcareous soils and belong to the Burseraceae family and the Boswellia species; they produce a gummy oleoresin that is collected in small receptacles inside the plant which are supplied by the schizogenous ducts.

Olibanum is known for its balsamic and anti- fermentative properties and has been used since antiquity in the treatment of colitides, parasitoseε, and eye diseases. In popular medicine, olibanum is used for treating disorders of the respiratory system.

Patents are also directed to an active principle of olibanum, namely boswellic acid, and relate to usual forms of administration, such as ampoules, tablets, suppositories, ointments, and aerosols.

The composition of olibanum varies according to the species of the plants that produce it; chemical research has shown the presence of cyclic monoterpenes, bicyclic terpenes, and sesquiterpenes, triterpenes (the only ones to which anti-inflammatory therapeutic properties have been attributed) .

The main feature of incense obtained from plants of the genus Boswellia has been the presence of tetracyclic and pentacyclic triterpenes, the parent substances whereof are boswellic acid and alpha-amyrin, having a distinctly anti-inflammatory action.

Alcoholic extracts of Boswellia plants contain both active principles with their derivatives and have an evident anti-inflammatory activity; it is therefore implicit to admit that there is a synergy in their combined action.

The same remark holds for diterpenes and sesquiterpenes, which are present in a plant growing mostly in central western Africa and belonging to the Burseraceae family, the Dacryoides genus, and the Klaineana species, and called "Tghurai" by the local population.

The height of these trees can exceed twenty meters and they are scattered individually or in small groups and have a very abundant foliage. The resinous substance that is produced is substantially different from the ordinary Boswellia incense and it has a series of interesting pharmacological properties that are unknown to the local population: — it has a considerable anti-inflammatory power; — it has a considerable antimycotic power; — it has a considerable anti-cryptogenic activity;

— it has an insect-repellent activity, especially against Anopheles mosquitoes, and an insecticidal power.

It is therefore reasonable to assume, εo far, that the association of various incenses extends the therapeutic powers and increases the anti-inflammatory effects. Disclosure of the Invention

A principal aim of the present invention is to provide a pharmaceutical product based on olibanum that increases its therapeutic effects.

Within the scope of this aim, an important object is to provide a pharmaceutical product composed of natural substances, particularly substances of vegetable origin, and therapeutically particularly effective. Another important aim is to provide a pharmaceutical product use whereof iε εubstantially harmless.

Another aim is to provide a very inexpensive pharmaceutical product.

With these aims and other objects in view, which will become apparent hereinafter, there is provided a pharmaceutical product characterized in that it is the combination of one or more terpene-containing substances and of propolis.

Advantageously, the pharmaceutical product consists of the combination of natural olibanum or derivatives thereof and propolis.

Propolis is a mixture of resinous, gummy, and balsamic substances collected by bees on the buds of various trees to reinforce their honeycombs, line the entry walls, and close the openings of the hive.

Its composition varies according to the local flora and the flowers that are present, the climate, the availability of resins on the buds, the gathering period, and the inclusion of contaminants such as wax.

Since antiquity, several peoples were aware of the anti-infective and anti-inflammatory properties of these products, particularly for diseaεes affecting the skin, the mouth, and the intestine. Research shows that propolis generally produces a bacteriostatic effect and, at high concentrations, alεo a bactericidal effect.

The antibiotic action is equal to that of sulfonamides and is one third or one quarter of the antibiotic action of streptomycin.

The antibacterial activity of propolis is attributed to acids and aromatic esterε, with a predominantly bactericidal action, and to flavonoidε, with a predominantly bacterioεtatic action. Propoliε also has an antiviral, antifungal, antiparasitic, and anticancer activity.

Propolis is considered to be a very different substance with respect to incense, the difference being supported most of all by the difference of the plants from which these substances are extracted by man or by bees.

Tests have instead proved that this difference is only apparent, since the source and composition of the two substances are highly similar.

The same tests have proved the synergy existing between the two substances, the active principles whereof, when paired, have led to an enhancement of the therapeutic effects that are already present in each individual substance.

In particular, an enhancement of the antibacterial and anticancer properties, which are more conspicuous in propolis, and of the anti-inflammatory propertieε, which are more evident in incenεe, has been observed.

Furthermore, as regards central western Africa incense, which does not contain monoterpenes and triterpenes but is particularly rich in bicyclic terpenes and sesquiterpenes, the association with propolis has led to an enhancement of antimicrobial activity.

At this point the possibility should also be pointed out of combining various types of incense (the synergy whereof among the various components already in itself enhances the various therapeutic activities) with propolis to obtain a natural product that is particularly effective and harmless in use.

The product can be provided in the form of tablets, pastilles, capsules, solutions, emulsions, ointments, creams, preparationε for inhalations, aerosolε, suppositories, and pessaries.

A preferred pharmaceutical product uses a powder of diluted natural propolis and olibanum and said compound is applied in the form of a cataplasm, preferably at the sick organ or on its nearest skin projection.

As regards the preparation, olibanum and propolis are used as whole productε (resins, oils, terpenes, gums), reduced to powder or microgranules beforehand and stored away from light and possibly in vacuum or in any case not in contact with the air.

At the time of use, the product is combined with a water-alcohol solvent or with an alcohol derivative or an ether. Conveniently, the powder of olibanum and propolis is spread on a lap of cotton and is then wet with a 35-40% water-alcohol solution.

Said cataplasm is then applied at the sick organ or on its nearest skin projection by means of adhesive patches or inert self-adhesive systems.

The retention period of the product thus applied may vary from a few days to a few weeks.

As an alternative, it is possible to prepare an oily solution by heating to around 100°, in a bain-marie, the powdered olibanum together with the propolis in olive oil or sesame oil, in a proportion, by way of example, of

1:1.5.

The oily solution is kept in place with inert liquid- tight and self-adhesive material. The oily solution can also be obtained by using particular fractions of oils, particularly omega-3 polyunsaturated fatty acids, in view of the synergy that increases the anti-inflammatory action of the resins and of said acids. As an alternative to preparation at the time of use, the product can be packaged as dry powder on a medium to be wet, or it can be a pre-packaged product that is kept in vacuum until it is applied.

Transdermal application can be performed in all skin regions, particularly the paranasal sinuseε, the entire spine, articular regions, chest and back regions, and abdominal regions.

Percutaneous absorption of the cataplasm in an oily solution is good, in view of the solubility of the components of olibanum and of propolis in fatε, and therefore alεo in the lipids constituting the sebaceous secretion layer that covers the horny skin layer and the cell membranes, and in view of the presence of terpenes.

The cataplasm, activated by the solvent, causes its active principles, absorbed transdermally, to arrive directly in the sick organ at maximum concentration without being metabolized first.

The possibilities of use of the product are all those in which disorders occur that have an inflammatory, bacterial, and dystrophic aεpect, of varying etiology, both post-traumatic and not; as a main or secondary event, acute, chronic, in remission, or with effusion, even those that are resistant to ordinary steroid therapy and to FANS, both for human diseaεes and for veterinary diseases. The product can therefore be used in the field of affections: a) of the respiratory system:

— rhinitides, sinusitides, tonsillitides, pharyngitides, laryngitides; — acute, chronic, and recurring, specific or nonspecific pulmonary diseases, in particular on the basis of altered reactivity, such as asthma, asth oid bronchitis, chronic obstructive pulmonary disease; b) of the muscles, the skeleton, and the connective tissue, the pathogenesis whereof is predominantly: -- inflammatory (rheumatoid arthritis, goneitis, epicondylitis);

— degenerative (arthrosis);

— post-traumatic; d) of the teeth and mouth (periodontitides, carieε, gingivitides, herpetic manifestations, pharyngitis caused by beta-hemolytic streptococcus, by coagulase-positive staphylococcus, and by Candida albicans); e) of the gastrointestinal system (oesophagitideε, gastritides, peptic ulcer, affections of the intestinal bacterial flora, regional enteritis, ulcerative colitis, hae orrhoides); f) of the liver and the biliary tract (chronic hepatitis, cholecystitides); g) of the genitourinary tract (vulvovaginitides, salpingitises, inflammations of the kidney and of the urinary tract, Coli and Proteus infections, phlogosis of the male genital tract); h) of the eye and ear (blepharitis, conjunctivitides, inflammation of the lachrymal gland, otitides); i) of the skin (pruritus, erythema, seborrhoeic dermatitis, bacterial infections, chromophytosis, infant intertrigo, cradle cap, rhagades, acne, eczema, burns, bedsores, traumatic and surgical wounds with particular regard for episioto y, pεoriasis, hyperkeratoεis, to facilitate εeparation of the epidermiε);

1) of the vascular system (phlebitides, endangiitis obliterans, arteritides) .

Furthermore, as regardε the cataplasm preparation, gastrointeεtinal and hepatic firεt-pass metabolism before reaching the target organ has been eliminated, and the releaεe rate has been kept conεtant, avoiding discontinuous treatments, with elimination of the peak and minimum of the underlying-tissue and plasma concentrations.

With the cataplasm, a prolonged action duration is furthermore provided with low administration frequency and a low daily total dose of the drug, with high terpene absorption. It should alεσ be noted that the preparation iε well- accepted, inexpensive, and easily uεable even by the patient.

Another terpene-baεed pharmaceutical product according to the invention iε the combination of myrrh with at least one other resin.

Myrrh is a fragrant resinouε εubstance produced by most of the specieε of Commiphora (Balεamodendron) , such as C. mukul, C. incisa, C. myrrha, C. molmol, C. africana, gileadensis, erkeri, which are preεent mainly in northwestern Africa and constitute the εo-called "myrrh family" .

In practice, theεe are bushes, rarely small trees, of two to seven meters, typical of rocky, calcareous or gypseous soils, more rarely on alluvial soil or consolidated dunes, usually without leaves, flowers, and fruits, which appear only as a consequence of rain.

The gum-resin known as myrrh exudes from the tree spontaneouεly or through cuts in the bark, hardens in air into drops or lumps, softens without melting at approximately 100° Celsius, and melts at approximately 120° Celsius.

Myrrh has a remarkable antimicrobial, disinfectant, insect-repellent, and insecticidal power.

Myrrh also has a considerable analgesic, antispasmodic, and sedative activity with respect to the central and vegetative nervous system, probably to be ascribed to sesquiterpenes, some whereof have recently been isolated (furaneudesma-1,3-diene and curzarene), the analgesic action whereof has been attributed to a mechanism of interaction with brain opioids.

The use of whole myrrh is preferable to use of its individual components, due to synergy with enhancement and to the wide range of therapeutic properties that are harmoniously blended and make it a product that has been known since antiquity both for its therapeutic properties and for its harmlessnesε.

According to the invention, myrrh is combined, in an original way, with another resin, which can be the mentioned Dacryoides Klaineana resin, propolis, or common incenses.

Said Dacryoides Klaineana resin has shown affinity in composition and pharmacological action with respect to myrrh since it contains terpenes (it has a particular content of sesquiterpenes, approximately 51.8%), so that its combination with myrrh has shown a considerable enhancement of effects and extension of activities, which include analgesic activities and the neuroendocrine syεtem.

The Dacryoideε reεin is furthermore characterized in that it has a low rubber content (23%), softens without melting at approximately 80° Celsius, melts around 90° Celsius, and is only slightly aromatic.

Propolis, too, has shown affinity in composition and pharmacological action with respect to myrrh and its combination with myrrh has shown an enhanced effect and an extended activity range.

This combination with myrrh can be conveniently extended to common incenseε.

The product obtained from the combination of myrrh with Dacryoides Klaineana resin and/or with propolis and/or common incenses can be provided in the form of tablets, pills, capsules, solutions, emulsions, ointments, creams, preparations for inhalationε, aeroεols, suppoεitorieε, and peεsaries. Among the methods of use, vaporization or sublimation by constant ( thermoεtat-controlled ) heating to temperatures between 90° and 120° Celsius is particularly interesting.

In particular, if the product is the combination of myrrh with Dacryoides Klaineana resin, the optimum temperature iε between 90° and 120° Celsius; for myrrh combined with Boswellia incense, between 100° and 120° Celsius; for propolis combined with myrrh, between 90° and 120° Celsiuε. The poεεibilitieε of use of the product are all those in which it is necessary to provide an anti-inflammatory, antimycotic, antimicrobial, and particularly antifungal, antibacterial, insect-repellent, insecticide, anti- cryptogenic, analgesic, anti-anxiety, antidepresεant action. From the above description it is evident that the intended aim and obj ects of the present invention have been achieved .

Claims

1. Pharmaceutical product, characterized in that it is a combination of one or more terpene-containing substanceε with propolis.

2. Pharmaceutical product according to claim 1, characterized in that it is the combination of natural olibanum or derivatives thereof with propolis.

3. Pharmaceutical product according to claim 2, characterized in that it is the combination of natural olibanum of the central western region of Africa or derivatives thereof with propolis.

4. Pharmaceutical product according to one or more of the preceding claims, characterized in that it is provided in the form of tablets, pills, capsules, solutionε, emulεions, ointments, creams, preparations for inhalations, aerosols, suppoεitories, pessaries.

5. Preparation of a pharmaceutical product based on olibanum and propolis according to claim 2, characterized in that powder or microgranules of natural olibanum and propolis powder are used and are diluted at the time of use in a solvent, the compound thus obtained being then applied transdermally, preferably at the sick organ or on the nearest εkin projection.

6. Preparation of a pharmaceutical product according to claim 5, characterized in that the olibanum powder, together with the propoliε powder, is combined with a water-alcohol solvent or alcohol derivative or ether or ether derivative.

7. Preparation of a pharmaceutical product according to claim 5 , characterized in that the olibanum powder , together with the propolis powder , is combined with an oily solvent .

8. Preparation of a product according to claim 5, characterized in that as an alternative to preparation with an alcoholic εolvent it iε possible to perform preparation with olibanum powder associated with propolis powder, dissolved in an oily solvent, by heating in a bain-marie to a temperature around 100°C.

9. Preparation of a product according to claim 7, characterized in that the oily solution can also be obtained by resorting to particular fractions of oils, particularly omega-3 polyunsaturated fatty acids.

10. Preparation of a pharmaceutical product according to claim 5, characterized in that as an alternative to the preparation of a water-alcohol solution, preparations of oily solutions or solutions with an alcohol derivative, or with ether, or with an ether derivative are used, kept in opaque vacuum-filled liquid-tight containers.

11. Preparation of a pharmaceutical product according to claim 2, characterized in that as an alternative to preparation performed at the time of use, it is possible to perform a preparation with olibanum powder associated with propolis powder, dissolved in a water-alcohol solution on an absorbent medium that is kept in an opaque vacuum-filled liquid-tight container.

12. Use of a pharmaceutical product according to claim 2, characterized in that finely pulverized olibanum and propolis are spread on an absorbent medium, such as a lap of cotton that is wet with the water-alcohol solution and is applied to the region to be treated, fixing it with adhesive means.

13. Use of a pharmaceutical product according to claim 12, characterized in that the application is maintained for a period of 5-10 days.

14. Use of a pharmaceutical product according to the preceding claimε, characterized in that uεe is for the treatment of predominantly inflammatory diεorderε of varying etiology, both poεt-traumatic and not; aε a main or secondary event, acute, chronic, or in remission, with or without effusion, even if resistant to common steroid therapy or to FANS.

15. Use of a pharmaceutical product according to one or more of claims 1 to 13, characterized in that use is for the treatment of inflammatory disorderε of the εkin, respiratory system, and vascular system; of the muscles and skeleton and of connective tisεue; of the eye and ear, of the teeth and mouth, of the gastrointestinal tract, of the liver and of the biliary and genitourinary tracts.

16. Pharmaceutical product baεed on terpeneε, characterized in that it iε the combination of myrrh with at least one other resin.

17. Pharmaceutical product according to claim 16, characterized in that it is the combination of myrrh with Dacryoideε Klaineana reεin.

18. Pharmaceutical product according to claim 16, characterized in that it iε the combination of myrrh with propolis.

19. Pharmaceutical product according to claim 16, characterized in that it iε the combination of myrrh with common incenses.

20. Pharmaceutical product according to claim 16, characterized in that it is the combination of myrrh with Dacryoides Klaineana resin and propolis.

21. Pharmaceutical product according to claim 16, characterized in that it is the combination of myrrh with Dacryoides Klaineana resin and common incenses.

22. Pharmaceutical product according to claim 16, characterized in that it is the combination of myrrh with propolis and common incenses.

23. Pharmaceutical product according to claim 16, characterized in that it is the combination of myrrh, Dacryoideε Klaineana reεin, propoliε, and common incenseε.

24. Pharmaceutical product according to one or more of claims 16 to 23, characterized in that it is provided in the form of tablets, pills, capsules, solutions, emulsions, ointments, creams, eye drops, preparations for inhalations, aerosols, suppositories, pessaries, cataplasms, transdermal patches.

25. Use of a pharmaceutical product according to one or more of claims 16 to 24, characterized in that εaid uεe iε for anti-inflammatory, antimycotic, antimicrobial, antifungal, antibacterial, inεect-repellent, insecticidal, anti-cryptogenic, analgesic, anti-anxiety, antidepreεεant, antiviral, anticancer, anaeεthetic action.

26. Uεe of a pharmaceutical product according to one or more of claims 16 to 24, characterized in that it provides for vaporization or sublimation by constant thermostat-controlled heating to temperatures chosen between 90° and 120° Celsius according to the components.