ITMI20110799A1 - SPOT-ON FORMULATION BASED ON NATURAL COMPOUNDS WITH ADULTICIDAL ACTIVITY - Google Patents

Description

"SPOT-ON FORMULATION BASED ON NATURAL COMPOUNDS WITH ADULTICIDE ACTIVITIES"

DESCRIPTION

[0001] It is known that numerous insects and pests (mosquitoes, flies, fleas, cockroaches, ringworms, moths, sand flies, mites and lice) represent not only a nuisance but also a danger for animals. In fact, they are often carriers of even serious and lethal diseases such as leishmaniasis, Lyme borreliosis or ehrlichiosis.

[0002] The problem is even more acute in the case of pets, especially dogs and cats; in these cases, in fact, the transmission of pathologies is certainly facilitated by the close proximity to man.

[0003] Precisely in order to preserve the health of the animal, preparations with repellent or adulticide activity have already existed for some time. The former have the ability to make the host unpleasant to the parasite through a substantially olfactory mechanism. This, therefore, does not stick to the hair of the animal to which a similar product has been applied. The â € œ-cideâ € preparations, on the other hand, eliminate the parasite causing its death.

[0004] The compounds that are used for this purpose are harmful to ectoparasites, but at the same time they are sufficiently selective not to be toxic to animals or humans at the doses of application.

[0005] Preferably, these compounds remain active for a fairly long time, so as to exert their protective activity for a long period.

[0006] It must be taken into account that the preparation must be tolerable for the animal, which otherwise would refuse its application or would tend to eliminate it by rubbing, for example, on the grass or trying to lick its hair.

[0007] Depending on the target, the compounds are generally classified as larvicides, if they act purely on the larval development stage, or adulticides, if they are active against a fully developed parasite.

[0008] Among the adulticidal compositions already on the market, some contain compounds known as pyrethroids (allethrin, bioallethrin, tetramethrin, resmethrin, bioresmethrin and the more recent cypermethrin, deltamethrin and permethrin).

[0009] These are characterized by a chemical structure similar to that of pyrethrin, a natural compound obtained from Tanacetum cinerariifolium, but modified in order to enhance its activity and improve its stability.

[0010] The mechanism of action of these compounds, in particular, is based on the affinity for sodium channels, which determines the blocking of membrane repolarization.

[0011] Other authors believe that the GABA-ergic system is also partially involved.

[0012] In any case, the activity of the compound, with which the parasite comes into contact by inhalation / ingestion, causes paralysis, death and the consequent detachment of the ectoparasite itself from the host.

[0013] The use of pyrethrodes, however, is not free from problems linked to environmental toxicity, which prevents their massive use.

[0014] In humans these compounds have shown some contact toxicity, while in the domestic animal toxicity has been found due to accumulation mainly in the kidneys and liver.

Furthermore, the release of cyanide groups following the decomposition of these compounds has been ascertained.

[0016] There is therefore a need for effective and safe preparations, which can be applied to the skin of the animal for the control of infestations.

OBJECT OF THE INVENTION

[0017] According to a first object, the present invention describes a preparation with adulticidal, protective and repellent activity which comprises compounds of natural origin derived from Quassia amara.

[0018] In accordance with a particular aspect, the described preparation may further comprise other extracts of natural origin obtained from rosemary, lemongrass and geranium.

[0019] Preparations comprising traditional adulticidal compounds in admixture with the formulations of the invention are likewise contemplated.

[0020] The present invention also describes a process for the preparation of a stable composition based on Quassia extracts.

[0021] The use of this extract in adulticidal treatments in animals represents a further aspect of the invention, as well as its use for the control of infestations, in particular, in pets.

DETAILED DESCRIPTION OF THE INVENTION

[0022] According to a first aspect, the invention describes a pharmaceutical preparation for veterinary use having adulticidal activity which comprises active ingredients obtained from Quassia.

[0023] Quassia L. (or Quassia amara) belongs to the Simaroubaceae family and the so-called quassins are obtained from its bark, including: neoquassin, 18-hydroxyquassin and simalikalactone-D.

OCH3OCH3OOC

O O

CH3H3C CH3H3C

H3CO H3CO

H H H H O O

H H

H H

CH CH

3 3

quassina neoquassina

OH

H O <CH> 3

O CH

OH3

CH3O O

HH

OR CH3

OR

I HAVE

H.

CH3

Simalikalactone-D

[0024] Other compounds in smaller quantities such as isoquassin, paraine, quassimarin, quassinol and quassol are also present.

For the purposes of the present invention, the preparation comprises a fluid extract of quassia (E.D. 1: 1) titrated at 30% in quassin, neoquassin and 18-hydroquassin.

[0026] In particular, this extract preferably has a quassin titer of 10%, so that 100 ml of a fluid extract contain 10 g of quassin (and, respectively, 10 ml contain 1 g of quassin).

[0027] Typically, the Quassia fluid extract can be included in the formulations in percentages (v / 100 ml of final formulation) of 5-70%, preferably 20-60%.

[0028] In addition to the active ingredients of Quassia (in addition to the fluid extract of Quassia), the preparations of the invention may include compounds of natural origin obtained from Rosmarinus officinalis L.

[0029] In particular, a fluid extract of rosemary (title F.U. 1: 1 E / D) can be used.

[0030] Even more particularly, 10 ml of said extract contain about 1 g of borneol, saponins, glycosides and choline.

[0031] According to a further aspect of the present invention, the adulticidal formulations described include, in addition to the Quassia extract and any rosemary extract, compounds of a terpenic nature.

[0032] In particular, these are essential oils obtained by squeezing or extracting, for example by steam or by supercritical carbon dioxide, from vegetable drugs.

[0033] For example, some of the essential oils are those with insect-repellent activity derived from Java Citronella (of the genus Cymbopogon), from geranium (of the genus Pelargonium) or from rosemary (Rosmarinus officinalis).

[0034] As regards the essential oil of citronella, for the purposes of the present invention an oil titrated at 32% in citronellal and 85% in geraniol is used.

Therefore, 1 g of this citronella essential oil contains about 0.3 g of geraniol and citronellal.

CH3

<CH> 3 CH3

H3C

H3 C <CH> 3

citronellal geraniol

[0035] The geranium essential oil used, on the other hand, is preferably titrated to 25-35% in geraniol esters and 1 g of this essential oil contains approximately 0.3 g of geraniol.

[0036] As described above, in addition to the fluid extract of rosemary, the essential oil of rosemary may be used in the preparation of the formulations of the invention.

[0037] In particular, this is preferably titrated in about 30% borneol; therefore 1 g of essential oil contains about 0.3 g of borneol.

[0038] The formulations of the invention may also contain additives and excipients such as solvents, diluents, bulking agents, rheological modifiers, stabilizers, preservatives, pH modifiers, antioxidants, buffering agents, chelating agents, emulsifiers, dyes and perfumes, pharmaceutically acceptable in order to adapt the compositions to specific needs.

[0039] For example, to prolong the activity of essential oils over time, preservatives such as butylhydroxytoluene (BHT) or butylhydroxyanisole (BHA) or other suitable preservatives and antioxidants, possibly mixed together, may be included.

[0040] Suitable quantities of such preservatives are preferably comprised between about 0.01-0.04% (v / 100 ml of final composition).

[0041] In this way, advantageously, the preparations of the invention are very stable and maintain their repellent and organoleptic properties, such as color and fragrance, for a long time.

[0042] In order to obtain a homogeneous preparation, a suitable solubilizer is used, preferably chosen from: lamacitâ „¢ ER, solubilisant LRIâ„ ¢, hydrogenated castor oil and polysorbates, for example polysorbate 20 or polysorbate 80, or their mixtures .

[0043] In particular, the polysorbate has been shown to convey quassin in an optimal way while at the same time solubilizing the essential oils.

For the purposes of the present invention, the solubilizer or mixture of solubilizers is present in concentrations of about 5-25% (v / 100 ml of final composition), preferably about 8-12%.

[0045] In particular, in order to obtain a homogeneous solubilization of essential oils, a quantity of polysorbate 80 comprised between about 3.5 and 1 is used, preferably between 2.7 and 1.3 times the volume of oils essential (in ml).

[0046] The formulations of the invention are essentially hydroalcoholic solutions.

[0047] For their preparation, therefore, water is used, preferably distilled (therefore without ions and degassed) or a specific distilled water obtained from plants, so as to provide active ingredients characterized by particular properties.

[0048] For example, the distilled water of Hamamelis virginiana can be used, which is rich in gallic acid and other tannin compounds, having an astringent action.

[0049] Alternatively, distilled waters can be chosen obtained, for example, from bearberry or Camelia sinesis, lavender or chamomile, known for their soothing properties.

As regards the alcoholic portion, preferably ethyl alcohol, in particular 96 ° ethyl alcohol, will be used.

[0051] Within the scope of the present invention, adulticidal preparations are also described comprising traditional compounds with adulticidal activity in admixture with one of the formulations comprising active ingredients deriving from Quassia as detailed above.

[0052] By â € œtraditionalâ € compounds we mean molecules, pure or in combination with each other, already known in the art for their ability to control the proliferation of parasites.

[0053] For example, such molecules include pyrethrum as well as its pyrethrode derivatives (pyrethrin, allethrin, tetramethrin, cadethrin, resmetrin, phenothrin, permethrin, cypermethrin, phenpropantrin, deltamethrin, cypothrin, phenvalerate and fluvalinate), organochlorinated compounds ( DDT and analogues, cyclodienes, etc.), organophosphorus (parathion, dichlorvos, dazinon, trichlorfan, etc) and carbamates (carbaril, carbofuran, phenoxycarb, etc.).

[0054] In this way, it is advantageously possible to obtain formulations characterized by an equivalent adulticidal efficacy but by less toxicity.

[0055] In accordance with a further aspect, a process for the preparation of the formulations of the present invention is described below.

[0056] More in detail, this process comprises a first phase a) in which the essential oils (lemongrass and / or geranium and / or rosemary) are solubilized in an appropriate quantity of solubilizer.

[0057] Separately, (step b)) ethyl alcohol is mixed with preservatives, such as BHA and / or BHT, by slightly heating the mixture, if necessary, to facilitate complete solubilization.

[0058] Next, (step c)) the alcoholic mixture is added to the essential oil mixture.

[0059] In a last phase (phase e)), a previously prepared mixture (in phase d)) comprising distilled water and the fluid extract of Quassia, and possibly also the fluid extract of rosemary, is added very slowly to the mixture obtained from step c), until a clear and homogeneous solution is obtained.

[0060] According to a preferred aspect of the invention, in step a) the essential oils are solubilized in a suitable quantity of polysorbate 80.

[0061] More particularly, the volume ratio between polysorbate 80 and essential oils is comprised between about 3.5: 1 and 1: 1 and, preferably, between about 2.7: 1 and 1.3: 1.

[0062] As regards step c), in order to maintain an optimal mixing of essential oils, alcohol is added in quantities (in ml) between 7 and 1, preferably between about 6 and 2, 5 and even more preferably about 3.3 times the volume of essential oils (in ml).

[0063] According to the further aspect of the present invention, the preparations obtained with the process described above can be mixed in an additional step f) with one or more â € œtraditionalâ € adulticidal compounds selected from pyrethroids, organochlorinated compounds, organophosphoric compounds and carbamates.

[0064] The formulations obtained in accordance with the present invention are finally presented as clear solutions, of a brown / brown color, have a reduced viscosity and a characteristic perfume pleasant for man.

According to a further aspect of the present invention, the preparations described above can be used for the control of ectoparasite infestations.

[0066] As already mentioned here, this use finds particular application for the treatment of domestic animals, especially dogs and cats.

[0067] However, other animals such as, for example, the ferret and the rabbit are not to be excluded.

[0068] The amount of formulation to be used essentially depends on the size (understood as weight) of the animal.

[0069] The following table shows examples of volume in ml of formulation to be used in relation to the weight of the animal and the corresponding mg of active principle (quassin) contained therein and, therefore, administered.

Weight (kg) ml of quassin mg formulation

5-10 (dog) 1,2 66

> 5 (cat) 1.2 66

10-20 2.4 132

20-40 4 220

> 40 6 330

[0070] The application of the formulation is preferably carried out by means of a suitable applicator / dispenser, such as a pipette, on some points located between the base of the neck and the shoulder blades, especially in the interscapular space.

[0071] The application must be carried out directly on the skin, avoiding as much as possible that part of the product remains on the hair.

[0072] Preferably, the treatment should be started in spring and continued until autumn in order to protect the animal throughout the period of possible exposure to parasites, repeating the application every 20-30 days approximately.

[0073] The formulations of the invention, in fact, have been shown to be active for a period of 3-4 weeks.

[0074] If the animal is housed in communities such as kennels or catteries, it may be preferable to increase the frequency of applications, so that no more than about 15-20 days pass between one application and the next. This is because generally they are rather spacious environments and subject to massive infestations by ectoparasites.

[0075] In any case, after each application it is advisable that the animal is not washed for the next 48 hours in order to ensure the greatest effectiveness of the product.

[0076] To facilitate the use of the formulations of the present invention, ready-to-use single-dose forms can be provided which differ according to the size of the animal; this solution is very practical especially from the hygienic point of view.

[0077] The invention will be better described with reference to particular exemplary formulations, which are not to be understood in any way as limiting the scope of protection defined by the appended claims.

EXAMPLE 1

SUBSTANCE% (v / v)

QUASSIUM FLUID EXTRACT (title E: D 1: 1) 5

ROSEMARY FLUID EXTRACT (title E: D 1: 1) 5

CITRONELLA ESSENTIAL OIL 3.94

GERANIUM ESSENTIAL OIL 3.94

POLYYSORBATE 80 8

BUTYL HYDROXYANISOLE (BHA) 0.0195

BUTYL HYDROXYTOLUENE (BHT) 0.0105

ETHANOL 96 ° 74.09

DISTILLED WATER

EXAMPLE 2

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 10 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 3 GERANIUM ESSENTIAL OIL 3 POLYYSORBATE 80 12 BUTYL HYDROXYANISOLE (BHA) 0, 0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 7.9 DISTILLED WATER 44.07

EXAMPLE 3

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 20 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 3 GERANIUM ESSENTIAL OIL 3 POLYYSORBATE 80 20 BUTYL HYDROXYANISOLE (BHA) 0, 0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 7.9 DISTILLED WATER 36.07

EXAMPLE 4

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 20 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 3 GERANIUM ESSENTIAL OIL 3 POLYYSORBATE 80 15 BUTYL HYDROXYANISOLE (BHA) 0, 0

195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 9 DISTILLED WATER 39.97

EXAMPLE 5

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 20 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 3 GERANIUM ESSENTIAL OIL 3 POLYYSORBATE 80 12 BUTYL HYDROXYANISOLE (BHA) 0, 0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 15 DISTILLED WATER OF Hamamelis virginiana 36.97

EXAMPLE 6

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 20 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 2 GERANIUM ESSENTIAL OIL 2 ROSEMARY ESSENTIAL OIL 2 POLYYSORBATE 80 8 BUTYLHYDY BHA) 0.0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 20 DISTILLED WATER OF Hamamelis virginiana 35.97

EXAMPLE 7

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 40 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 2 GERANIUM ESSENTIAL OIL 2 ROSEMARY ESSENTIAL OIL 2 POLYYSORBATE 80 8 BUTYLHYLID BHA) 0.0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 20 DISTILLED WATER OF Hamamelis virginiana 15.97

EXAMPLE 8

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 40 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 2 GERANIUM ESSENTIAL OIL 2 ROSEMARY ESSENTIAL OIL 2 POLYYSORBATE 80 10 BUTYLHYDY BHA) 0.0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 20 DISTILLED WATER OF Hamamelis virginiana 13.97

EXAMPLE 9

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 45 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 1 GERANIUM ESSENTIAL OIL 1 ROSEMARY ESSENTIAL OIL 1 POLYYSORBATE 80 8 BUTYLHYDY BHA) 0.0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 20 DISTILLED WATER OF Hamamelis virginiana 13.97

EXAMPLE 10

SUBSTANCE% (v / v) QUASSIUM FLUID EXTRACT (title E: D 1: 1) 55 ROSEMARY FLUID EXTRACT (title E: D 1: 1) 10 CITRONELLA ESSENTIAL OIL 1 GERANIUM ESSENTIAL OIL 1 ROSEMARY ESSENTIAL OIL 1 POLYYSORBATE 80 8 BUTYLHYDY BHA) 0.0195 BUTYL HYDROXYTOLUENE (BHT) 0.0105 ETHANOL 96 ° 10 DISTILLED WATER OF Hamamelis virginiana 13.97

EXAMPLE 11

Preparation of the composition of Example 10 [0078] To obtain the formulation of Example 10, the following steps were separately prepared:

Quassia fluid extract 55% *

PHASE A: 10% rosemary fluid extract

distilled water of Hamamelis 13.97% citronella O.E. 1%

geranium O.E. 1%

PHASE B:

rosemary O.E. 1%

polysorbate-80 8%

BHA 0.0195%

PHASE C: BHT 0.0105%

ethanol 96 ° 10%

% expressed as v / 100 ml of final formulation Subsequently, phase C was added to phase B until complete solubilization.

Phase A was added to the mixture thus obtained very slowly until a clear and homogeneous solution was obtained.

[0079] From what has been reported above, the numerous advantages offered by the formulations of the invention are evident.

[0080] First of all, such compositions have proved to be equally effective with respect to formulations comprising known molecules with adulticidal activity.

[0081] Thanks to the use of less toxic active ingredients for animals and humans, their use is nevertheless safer.

[0082] Furthermore, their production and use have a lower environmental impact.

This feature is very advantageous from an industrial point of view, because the costs for the disposal of potentially dangerous products are significantly reduced.

[0083] The formulations described have been shown to maintain their activity for a long period: up to 20/30 days.

They are therefore ideal in the preparation of formulations called â € œspot-onâ €, which do not require frequent application.

[0084] Moreover, thanks to their particular composition, the formulations described have a pleasant fragrance, such as not to be bothersome for man.

[0085] From the above description of the adulticidal formulations comprising active ingredients derived from Quassia amara according to the invention, the skilled person, in order to meet specific contingent needs, can make numerous modifications, additions or replacements of elements with other functionally equivalent ones, without however departing from the scope of the attached claims. Each of the features described as belonging to a possible embodiment can be realized independently of the other described embodiments.

Claims (17)

CLAIMS 1. An adulticidal phytotherapeutic formulation comprising a fluid extract obtained from Quassia L. 2. The adulticidal phytotherapeutic formulation according to claim 1, wherein said fluid extract obtained from Quassia L. comprises quassia, neoquassin, simalikalactone-D and 18-hydroxyquassin. 3. The adulticidal phytotherapeutic formulation according to claim 1 or 2, in which said fluid extract of Quassia L. is titrated to 30% in quassin, neoquassin and 18-hydroquassin. The adulticidal phytotherapeutic formulation according to any one of claims 1 to 3, further comprising a fluid extract obtained from rosemary. 5. The adulticidal phytotherapeutic formulation according to any one of claims 1 to 4, further comprising one or more essential oils selected from citronella, geranium or rosemary essential oil. The adulticidal phytotherapeutic formulation according to any one of claims 1 to 5, comprising one or more pharmaceutically acceptable additives and excipients selected from solvents, diluents, bulking agents, rheological modifiers, stabilizers, preservatives, pH modifiers, antioxidants, buffering agents , chelating agents, emulsifiers, dyes and perfumes. 7. The adulticidal phytotherapeutic formulation according to any one of claims 1 to 6 comprising polysorbate in an amount of about 5-25%, preferably about 8-12% (v / 100 ml of final formulation). The adulticidal phytotherapeutic formulation according to any one of claims 1 to 7 comprising distilled water or distilled water obtained from plants. 9. The adulticidal phytotherapeutic formulation according to claim 8, in which the distilled water is obtained from Hamamelis virginiana. 10. The adulticidal phytotherapeutic formulation according to any one of the preceding claims further comprising one or more traditional compounds with adulticidal activity selected from the group which includes pyrethrodes, organochlorinated compounds, organophosphorus compounds and carbamates. 11. A process for the preparation of one of the adulticidal phytotherapeutic formulations according to claims 1 to 10, comprising the following operations: a) solubilize one or more of the essential oils in an appropriate quantity of solubilizer; b) preparing an alcoholic phase comprising one or more suitable preservatives; c) add the alcoholic phase to the phase obtained from operation a) until complete solubilization, heating slightly if necessary; d) prepare an aqueous phase comprising the fluid extract of Quassia and any fluid extract of rosemary in an appropriate quantity of distilled water; e) slowly add to the mixture obtained from step c) the aqueous phase of step d) until a clear and homogeneous solution is obtained; and, possibly, f) add one or more compounds with adulticidal action selected from the group which includes pyrethrodes, organochlorinated compounds, organophosphorus compounds and carbamates. 12. Process according to claim 11, wherein in step a) the solubilizer used is selected from among the acidity ER, solubilisant LRIâ „¢, hydrogenated castor oil and polysorbate. 13. Process according to claim 11 or 12, wherein in step a) the volume ratio between polysorbate and essential oils is comprised between about 3.5 and 1 and, preferably, between about 2.7 and 1.3 the volume of essential oils (in ml). 14. Process according to any one of claims 11 to 13, in which in step c) the alcohol is added in a quantity (by volume) comprised between about 7 and 1, preferably between about 6 and 2.5 and even more preferably about 3.3 times the volume of essential oils. 15. Fluid extract obtained from Quassia L. and comprising quassia, neoquassin, simalikalactone-D and 18-hydroxyquassin for use in an adulticide treatment in animals. 16. Fluid extract obtained from Quassia L. and comprising quassia, neoquassin, simalikalactone-D and 18-hydroxyquassin for use in an adulticide treatment in animals, in which this fluid extract is applied to the skin of the animal. 17. Fluid extract according to claim 15 or 16, wherein said animal is selected from the dog, cat, rabbit or ferret.