Compositions for the treatment of infections caused by mite Demodex spp

Abstract

The invention relates to compositions and kits for treating infections caused by the mite Demodex Spp, said compositions comprising essential oils selected from the group consisting of Eruca sativa oil, Zingiber officinale oil, and Alpinia officinarum oil and mixtures thereof incorporated into solvents and vehicles, and presented in a kit in the form of a solution, a suspension, an emulsion or a dispersion. The compositions are topically applied for the treatment of infections and disorders caused by Demodex Spp in humans.

Claims

1. An acaricidal composition for the treatment of infections and diseases caused by a mite that is a species of Demodex, which comprises a mixture of essential oils, wherein the oils are Eruca sativa mill oil, Zingiber officinale oil and Alpinia officinarum oil.

2. The composition according to claim 1, wherein the essential oils are incorporated in an acceptable solvent.

3. The composition according to claim 2, wherein the acceptable solvent is selected from the group consisting of: mineral oils, olive oil, decyl oleate, isopropyl myristate, polyoxyethylene glyceryl monococoate, alcohols and mixtures thereof.

4. The composition according to claim 1, further comprising a pharmaceutically acceptable carrier.

5. The composition according to claim 3, wherein the composition is a solution, suspension, emulsion or dispersion.

6. A method of treating a disease in a human caused by a species of Demodex, said method comprising applying topically on the human a therapeutically effective amount of the composition of claim 1.

7. A Kit for the treatment of illnesses in humans that are caused by a mite that is a species of Demodex comprising: (A) the composition of claim 1, wherein the essential oils are incorporated into an acceptable solvent; and wherein the composition is a pharmaceutical solid, semisolid or liquid; (B) an insert specifying applying said composition to the affected area and the frequency of application; and (C) an appropriate container for the dosage forms.

8. The composition of claim 1, wherein the composition is formulated for topical application.

Description

BRIEF DESCRIPTION OF THE FIGURES

(1) To further clarify the invention and its advantages compared to the prior art, the invention is described below with the help of the attached FIGURES, and includes possible ways of illustrating nonlimiting embodiments of the principles and application of the invention.

(2) FIG. 1 shows a microscopic 4 photographic sequence observation of the mites in the sample of an in vitro tab from the start of the acaricidal activity assay of the composition of the present invention to after 5 minutes.

SUMMARY OF THE INVENTION

(3) The invention provides an acaricidal a composition for the treatment of infections and diseases caused by Demodex Spp mite, which comprises essential oils selected from the group consisting of Eruca sativa mili oil, Zingiber officinale and Alpinia officinarum oil and mixtures thereof.

(4) The invention also provides a kit for the treatment of illnesses in humans by the mite Demodex Spp comprising: (A) a composition comprising essential oils selected from the group consisting of Eruca sativa oil mili oil, Zingiber officinale oil and Alpinia officinarum oil and mixtures thereof wherein the essential oils are incorporated in an acceptable solvent; forming a pharmaceutical solid, semisolid or liquid; (B) an insert specifying the use of said composition to the affected area and the frequency of application; and (C) an appropriate container for application of the dosage forms.

DESCRIPTION OF THE INVENTION

(5) The present invention comprises a composition having acaricidal activity (especially anti-mite activity) based on the combination of essential oils obtained from the plants Eruca sativa mili, Alpinia officinarum and Zingiber officinale for topical application that destroys mite eggs and their lipolytic effect which solubilizes the lipid membranes of the anatomical structure of the animal. The individual oils are also usable by themselves.

(6) The present invention resides in the long term need in the art of a composition which relative to the form of administration includes easy therapeutic application without causing toxicity, it has rapid acaricide action and effective action not only against the mite itself but the eggs deposited, resulting in greater activity in the clinical treatment setting.

(7) For this long term need purpose, based on the background art for the present invention the acaricidal effect of various types of plant oils, including the prior reference essential oil or tea tree of Maleleuca was evaluated.

(8) For the present invention, a comparative study and analysis was conducted which studied the acaricidal activity and characteristics of essential oils used in pure and undiluted form, from plants such as Eruca sativa mili, the Alpinia officinarum, Zingiber officinale, the Tea Tree, galanga and Black Pepper whose results are evident and reported in the comparison table 1 below.

(9) TABLE-US-00001 TABLE NO. 1 Results of the acaricidal activity of the pure essential oils. Descriptive Statistics Average life time in Standard Essential pure Oil minutes of Acaro (mites) deviation N Galanga 10.22 1.26458 10 Zingiber officinale 11.45 1.17059 10 Tea tree 3.6327 0.43713 11 Black Pepper 30.049 8.85451 10 Eruca saliva mili seeds 9.794 1.18796 10 Alpinia officinarum 4.853 1.11517 10 N: number of mites tested in the oils.

(10) As evidenced and described in Table 1, it is seen that the pepper and Galanga had lower acaricide activity. The Maleleuca or tea tree was the product that was taken as a reference based on the prior art, where it was found to have acaricidal effect at certain concentrations but having adverse effects, causing severe effects in humans ranging from burns to tissue necrosis as evidenced in some patients according to the studies reported by Gao.

(11) Therefore, for the composition of the present invention, the essential oils of Eruca sativa mili, Alpinia officinarum and Zingiber officinale were selected for the novel compositions of the invention.

(12) For its part, the Eruca sativa mili includes names such as Arugula, Arugula or Jazamango and belongs to the family of Brassicaceaes and gender of Eruca. This plant is native to the Mediterranean and western Asia and the uses of this plant are mostly for consumption of leaves and young stems, which are eaten raw in salads and Mediterranean diets. It is also considered as a medicinal plant and can be used in biological pest control.

(13) Next, the plant Zingiber officinale, belongs to the family of Zingiberaceaes and gender of Alpinia. The Zingiber officinale is a plant that is distributed in the Himalayan region and South Western Ghats region in India. It is a plant used in cooking as food, especially Thai and Indonesian cuisine. It is one of the four plants known as galangal and differs from the others in being the largest. It is also used in diets for poor appetite, hypersecretory dyspepsia, flatulence, asthenia and convalescence. Popularly, it is also used in dysmenorrhea, prevention of vomiting and dizziness and chewed to help relieve toothaches. It is also used as digestive aids, anti-spasmodic, anti-inflammatory, carminative, anti-emetic and general well being.

(14) Finally, the Alpinia officinarum is a plant of the family of gingers, Alpinia gender. The Alpinia officinarum comes from Asian countries, especially China, and is commonly known as lesser Chinese galanga, Alpinia officinarum whose underground stem is a horizontal rhizome prized for its aroma and spicy flavor. The plant grows to have 90 cm in length, with 20 cm long leaves.

(15) For the present invention, an experimental design for acaricidal evaluation of essential oils of the plants Zingiber officinale, Eruca sativa and Alpinia officinarum mili was chosen. An experimental evaluation scheme was used to evaluate the acaricidal effect of each of the oils both individually and in combinations thereof using field microscopy. The experiments were carried out on mites individually and in between one and the others. The experiments were repeated more than 50 times and the clustering of mite was evaluated by field microscopy and always in fields that showed a number of mites greater than 5 per microscopic field. According to the results obtained, the present invention comprises a mixture represented by the concentrations of the three oils mentioned above as being most effective in their acaricidal action to demonstrate their effect on the Demodex Spp.

(16) For the purpose of the invention, the evaluation of the acaricidal activity of the mixture was done on more than 30 microscopic fields, showing the acaricidal effect, as evidenced in the tables defined below and accompanied by the descriptive statistics on each one. These studies were carried out by the inventors in the Laboratory of Immunology and Molecular Biology of the University of the North in Barranquilla, Colombia.

(17) According to studies of the compositions of the present invention, assays were performed in real time about the total number of mites that were present under the same observation field. The minimum number of mites per field was five and the average number of mites was always equal to or greater than five.

(18) Before evaluating the miticide effect of each of the oils, miscibility and safety thereof on mites was studied. Tables 2 and 3 show the results of those tests.

(19) TABLE-US-00002 TABLE NO. 2 Evaluation of the solvent action on the survival of mites Average life time of Acaro (mites) in Standard Solvents the solvents (Hours) Deviation N Isopropyl Myristate 3.37 1.0294767 10 Cetiol V 8 0 10 Cetiol HE 0.08938 0.0126723 5 Mineral Oil 0.66412 0.3298975 5 Absolute Ethanol 0.03434 0.0092846 5 N: Number of mites in test

(20) To prepare compositions, decyl oleate solvent (Cetiol V) was selected due to its excellent wetting properties on the skin. The Cetiol V is used in the preparation of water in oil emulsions or oil in water emulsions as the oil and is a good solvent of liposoluble active ingredients. Also, it has good flow properties, good penetrating power, and it facilitates entry through the epidermis.

(21) TABLE-US-00003 TABLE NO. 3 Miscibility of oils in solvents Parts by Isopropy volume v/v Myristate Cetiol V Cetiol HE Galanga 1/2 YES YES YES 1/10 YES YES YES 1/100 YES YES YES 1/1000 YES YES YES Zingiber officinale 1/2 YES YES NO 1/10 YES YES NO 1/100 YES YES NO 1/1000 YES YES NO Tree Tea 1/2 YES YES YES 1/10 YES YES YES 1/100 YES YES YES 1/1000 YES YES YES Black Pepper 1/2 YES YES NO 1/10 YES YES NO 1/100 YES YES NO 1/1000 YES YES NO Alpinia officinarum 1/2 YES YES NO 1/10 YES YES NO 1/100 YES YES NO 1/1000 YES YES NO Eruca sativa mili 1/2 ND ND ND 1/10 ND YES ND 1/100 ND YES ND 1/1000 ND YES ND ND: no determinado YES: Miscibilidad completa < 1 min NO: Miscibilidad incompleta > 1 min

(22) In Table 4 there is shown results of another the study of the present invention, using concentrations of 100%, 90%, 50% 25%, 12.5%, 1%, 0.5% and 0.25% dilution of Cetiol V for Alpinia officinarum oil and its acaricidal effect.

(23) TABLE-US-00004 TABLE NO. 4 Evaluation acaricidal oil from Alpinia officinarum on Demodex Spp at different dilutions with Cetiol V Number of Average Minimum time Maximum time mites lifetime of Standard of death of of death of Dilution evaluated the mite Median Trend Deviation Variance the mite the mite Alpinia .sup.100% 10 3.95 4.02 4 0.27183 0.074 3.45 4.2 officinarum 90.00% 11 4.0136 4 4 0.17043 0.029 3.75 4.35 50.00% 10 4.17 4.2 4.3 0.14181 0.02 3.9 4.3 25.00% 10 7.855 7.65 7.3 1.09429 1.197 6.3 9.45 12.50% 13 8.7962 9 10 1.8691 3.494 6 13 1% 17 13.3529 14 14 0.93148 0.868 12 15 0.50% 18 17.3333 17 16 2.0292 4.118 14 21 0.25% 41 20.6544 21 28 6.5245 42.569 9.38 29

(24) Table 5 below shows dilution of Eruca sativa mili essential oil with the diluent Cetiol V in various ranges of 100%, 90%, 50% 25%, 12.5%, 1%, 0.5% and 0.25% and the acaricidal effect.

(25) TABLE-US-00005 TABLE NO. 5 Evaluation of Dilution of Eruca sativa mili essential oil with Cetiol V Number of Average Minimum time Maximum time mites lifetime of Standard of death of of death of Dilution evaluated the mite Median Trend Deviation Variance the mite. the mite Eruca 100% 10 11.45 11.5 11 1.31581 1.731 9 13 sativa 90.00% 10 11.2600 11.0000 11 .96056 .923 10.00 13.00 mili 50.00% 10 9.2170 9.5100 8.3 1.36074 1.852 7.10 11.00 25.00% 10 11.5810 11.3700 11.2 1.08005 1.166 10.00 14.25 12.5% 10 11.0990 11.0000 10.2 .99169 .983 10.20 13.20 1% 17 14.3041 15 15 0.92787 0.861 13 15.5 0.50% 43 18.5116 18 17 2.17532 4.732 15 24 0.25% 19 23.3363 24 24 1.37057 1.878 20 25

(26) According to table 6 below, there is shown dilution of Zingiber officinale oil with the diluent Cetiol V in various ranges of 100%, 90%, 50% 25%, 12.5%, 1%, 0.5% and 0.25% and the acaricidal effect.

(27) TABLE-US-00006 TABLE 6 Results acaricide activity of essential oils Zingiber officinale at different dilutions Number of Average Minimum time Maximum time mites lifetime of Standard of death of of death of Dilution evaluated the mite Median Trend Deviation Variance the mite. the mite Zingiber 100% ND ND ND ND ND ND ND ND officinale 90.00% ND ND ND ND ND ND ND ND 50.00% ND ND ND ND ND ND ND ND 25.00% ND ND ND ND ND ND ND ND 12.5% ND ND ND ND ND ND ND ND* 1% 20 18.8 19 17 1.50787 2.274 17 22 0.50% 21 39.8229 40.28 42 4.54292 20.638 30 53 0.25% 17 57.0588 57 56 1.74895 3.059 53 59 *Not determined because defined by the prior oils.

(28) From the studies described in the tables above, it is clearly established that the percentage of effective dilution according to the present invention comprises between 50% and 0.25% for each essential oil.

(29) Having established a working range for the effective amounts, the studies based herein show the most suitable percentages for each of the essential oils derived from each plant and their effect as an acaricide.

(30) For the purpose of the invention, Table 7 describes several experimental evaluations of the acaricidal effect of the essential oils (death within minutes from the application to the mites) as defined by several fields of observation at different concentrations for each essential oil obtained from each plant. The concentration refers to the dilution of the oil from a 100% pure amount (pure essential oil obtained by reference). The dilution that was made, under the preferred embodiment according to the present invention was validated by studying the acaricidal effect in vivo through a clinical trial on the diluent. The Decyl Oleate (Cetiol V) diluent did not have acaricidal activity within 8 hours.

(31) TABLE-US-00007 TABLE NO. 7 Results acaricidal activity of the three diluted essential oils Number Number Average Minimum time Maximum time of sets of mites lifetime of Standard of death of of death of Dilution analyzed evaluated the mite Median Trend Deviation Variance the mite. the mite Eruca 12.5% 5 10 11.0990 11.0000 10.2 0.99169 0.983 10.20 13.20 saliva mili 1% 5 17 14.3600 14.33 13.83 0.53122 0.28200 13.83 15.11 0.25% 5 19 23.4000 23.64 21.75 1.11020 1.23 21.75 24.66 Alpinia 12.5% 5 13 8.7962 9 10 1.86910 3.494 6.00 13.00 officinarum 1% 5 17 13.4160 13.33 14 .57143 0.57 12.75 14.00 0.25% 8 41 20.7863 21.77 9.61 6.73591 45 9.61 27.68 Zingiber 1% 5 20 18.7360 18.6 17.33 .95694 0.916 17.33 19.75 officinale 0.50% 5 21 39.9040 40.6000 37.27 1.75961 3.096 37.27 41.66 0.25% 5 17 56.9840 57.6 54.33 1.50267 2.28 54.33 58.00

(32) The study described above established the effective concentration levels for each plant oil and based on those results, we proceeded to study and evaluate the acaricidal action of a combination preparation of essential oil blends of Alpinia officinarum, Eruca sativa mili and Zingiber officinale according to the present invention. To make the combined blend preparations, as reported above, decyl oleate (Cetiol V) solvent was used, because of its excellent wetting properties on the skin. It is also excellent for making oil in water and water in oil emulsions. Cetiol V is a good solvent for liposoluble active principles, it has good fluidity and penetrating power, and it also facilitates entry through the epidermis.

(33) Other diluents also suggested for the composition of the present invention include PEG-7 Glycerol Cocoate (Cetiol HE), isopropyl myristate, isopropyl alcohol and absolute ethanol or combinations thereof.

(34) According to the present invention, Cetiol V is especially suitable for combination with the essential oils of Alpinia officinarum, Eruca sativa mili and Zingiber officinale due to its compatibility for use on the skin and is fully compatible with skin fats without causing any irritation. According to the present invention, Cetiol V is incorporated into the fat phase of emulsions.

(35) So, according to another object of the present invention, we proceeded to establish a combination of essential oils of these plants at different required concentrations based on the results of acaricidal action of each separately based on the tables above. This is evident in Table 8 below with Eruca sativa milli combined concentrations of between 12.5% and 0.25%; Alpinia officinarum between 12.5% and 0.25% and Zingiber officinale between 1% and 0.25%.

(36) TABLE-US-00008 TABLE NO. 8 Cetiol V is incorporated into the emulsions in the oil phase Initial final Time to Concentration Vol. (ul) volume (ul) death (min) Eruca sativa mili 12.5%-0.25% 5 1000 19 Alpinia officinarum 12.5%-0.5% 2.5 18 Zingiber officinale 1%-0.25% 10 19

(37) For the above proposed combinations according to the present invention, efficacy in acaricidal action was found given the effective concentrations. The time of death of mites per field of observation (CO) is shown in Table 9 and in the last row the average of each field is defined for CO.

(38) TABLE-US-00009 TABLE NO. 9 DMX Mixture (min) CO1 CO2 CO3 CO4 CO5 CO6 CO7 CO8 CO9 CO10 CO11 CO12 CO13 CO14 CO15 26 20 28 17 28 27 17 22 21 23 28 26 31 23 18 27 24 28 19 28 26 17 23 22 24 28 22 25 24 19 21 30 29 20 29 28 18 22 16 25 28 23 26 24 20 22 22 30 21 23 32 21 23 34 23 28 22 27 23 17 18 24 32 17 24 33 18 22 33 24 33 24 27 18 17 22 23 22.8 24 29 18.66 26.4 29.2 18 22.33 25.2 23.8 29 22.4 27.25 23.5 17.5

(39) In conclusion and based on the studies discussed above, according to the present invention, an effective miticidal composition comprising a combination of essential oils of Eruca sativa mili at a dilution up to 99% is provided, preferably in an amount of 50% to 0.25% and more preferably between 12.5% and 0.25% Eruca sativa mili essential oil. The Alpinia officinarum is present in the composition, diluted in a proportion up to 99% and preferably up to 25% and more preferably between 12.5% and 0.25% of the Alpinia officinarum oil. The oil Zingiber officinale, is diluted in a ratio up to 99%, preferably up to 25% and more preferably between 1% and 0.25%. This combination of essential oils, then comprises the effective active blend having acaricidal action.

(40) As illustrated in the photographic sequence of FIG. 1, the composition once it is delivered to the patient, their acaricidal activity starts with dehydration of the mite eggs by lipolytic effect that solubilizes the lipid membranes of the anatomical structure of the animal and therefore the consequent total elimination of the mite, forty minutes elapsed applied.

(41) Meanwhile, then the acceptable for dilution of the essential oil solvent is selected from the group consisting of mineral oil, olive oil, Cetiol V, isopropyl myristate, Cetiol HE, alcohols and mixtures thereof. Also, as above, the preferred solvent for such dilution is decyl oleate.

(42) Among the selected alcohols, they may be chosen from the group consisting of PEG-7, Glycerol Cocoate, (Cetiol HE), isopropyl myristate, isopropyl alcohol and absolute ethanol or combinations thereof.

(43) Having determined as shown above the effective dilution for each essential oil, acaricides whose characteristics are the most effective, we also provide compositions for topical use.

(44) One embodiment of the embodiments of the invention are compositions which comprise aqueous liquid solutions for ophthalmological use including extracts of essential oils of high quality in a precise relationship between them, said acaricidal compositions being 100% affective against Demodex ssp infestation. The pharmaceutical preparations or liquid forms according to the present invention comprises dosage forms such as solutions, emulsions and suspensions, among others.

(45) Other therapeutic suitable delivery means according to the present invention without limiting the scope of the invention include powders, granules, capsules and tableting among others. Similarly, preparations or semisolid drug forms, for the present invention include ointments, creams and gels, among others.

(46) Extracts of the essential oils of the invention are incorporated either in a liquid matrix compatible for use on the skin and eyes.

(47) According to the present invention, particularly the composition comprises a proportion of Eruca sativa milli essential oil from 12.5 and 0.25%; a proportion of essential oil of Alpinia officinarum between 12.5 and 0.25%; a proportion of essential oil of Zingiber officinale between 1 and 0.25%; in combination with an pharmaceutically acceptable carrier.

(48) Examples of delivery methods and physical forms include solutions, suspensions, aerosols, lotions, gels, pastes, impregnated wipes, impregnated tissue, impregnated non-woven substrates, medicinal balsams, cleaning products (including shampoos and soaps), creams or ointments, or a phytocosmetics composition in an preferred embodiment.

(49) The composition of the present invention comprises in combination the essential oils of Eruca sativa mili, Genjibre and Zingiber officinale, water and at least pharmaceutically acceptable carrier; and at least one stabilizing agent and at least one excipient. It may also include consistency agents that impart texture and body to the final gel, and other optional components such as antioxidants, defoamers and flavoring.

(50) So, under the preferred combination, the composition of the present invention provides an effective acaricide for eliminating 100% of the Demodex spp mite and their eggs, which causes Demodicosis and some forms of related diseases and rosacea.

(51) According to the discussion above, in the prior art ophthalmic compositions are disclosed comprising natural oils such as tea tree oil and oils of the plants of the genus Rhamnaceae. However, in the disclosed prior art, the compositions of the invention including the oil (Eruca sativa), essential oil of Alpinia officinarum (Alpinia officinarum) or essential oil Zingiber officinale Alpinia galanga) are silent. The prior art does not specifically mention the inclusion of these three essential oils individually or in combination in a composition, which compositions facilitate comprehensive and efficient control of infection by Demodex and which in turn does not cause eye irritation.

(52) So, the present invention comprises an acaricidal composition for the treatment of infections and diseases caused by the mite Demodex Spp, including essential oils selected from the group consisting of oil Eruca sativa mili oil, Zingiber officinale oil and Alpinia officinarum oil which essential oils are diluted in an acceptable solvent to form a composition as a solution, suspension, emulsion or dispersion.

(53) The present invention comprises the use of a composition for the treatment of infections and diseases in humans caused by Demodex Spp, and the method of treatment of diseases in humans comprising solid forms, semisolid and liquid as liquid solutions emulsion, ointment, solution, lotion, shampoo, soap, foam and powder compact among others.

(54) The present invention also relates to a kit for the treatment of diseases caused by the human Demodex Spp mite consists of:

(55) (A) a composition comprising essential oils selected from the group consisting of Eruca sativa oil mili oil, Zingiber officinale and Alpinia officinarum oil; where essential oils are incorporated in an acceptable solvent; forming a solid or liquid dosage form, semisolid;

(56) (B) an insert specifying the use of said composition to the affected area and the frequency of application; Y, and

(57) (C) an appropriate container for application of the dosage forms described.

(58) The composition of the present invention, while comprising the combination of essential oils, whose therapeutic properties have been extensively studied over other microorganisms other than Demodex spp, necessarily incorporates these three oils into a single formulation, which is not specifically disclosed in the prior art. The composition of the present invention achieves greater efficiency and improved action of each of the three essential oils and they are incorporated at specific concentrations and in defined proportions, which is not specifically disclosed in the prior art. Additionally, the composition of the present invention is highly specific and of proven efficacy against mites.

(59) The contents of all references cited in the instant specification and all cited references in each of those references are incorporated in their entirety by reference herein as if each of those references were individually denoted in the text.

(60) Although the foregoing description (Angres) contains many specifics, these should not be construed as limiting the scope of the present invention, but merely as providing illustrations of some of the presently preferred embodiments. Similarly, other embodiments may be devised without departing from the spirit or scope of the present invention. Features from different embodiments may be employed in combination. The scope of the invention is, therefore, indicated and limited only by the appended claims and their legal equivalents rather than by the foregoing description. All additions, deletions and modifications to the invention as disclosed herein which fall within the meaning and scope of the claims are to be embraced thereby.